TWI323260B - Method for the preparation of hexahydro-furo[2,3-b]furan-3-ol - Google Patents

Description

V. INSTRUCTION DESCRIPTION OF THE INVENTION (1) The present invention relates to a process for the preparation of hexahydro-indolizranium [2,3_b]n-folly-ol-ol, and a novel intermediate used in the process. More specifically, the present invention relates to a stereoselective method for the preparation of hexahydro-furo[2,3-7]furanol and an easy to accept industrial scale-up method. 5 Hexahydro-furo[2,3-7]furan-3-enol is an important pharmacological moiety present in the structure of the reverse transcriptase protease inhibitor, such as in fcfhosh, j. Med. Chem. 1996, 39(17), 3278-3290, pp. 0 715 618 'WO 99/67417 and WO 99/658*70. This publication is hereby incorporated by reference. 10 Several methods for preparing hexahydro-indolyl [2,3-7]pyran_3·alcohol (formula (7))

HO

Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperatives is known. Ghosh et al., J. Med. Chem. 1996, 39(17), 3278-3290, 15 describe the selective synthesis of palms to obtain (3R, 3aS, 6aR) and (3S, 3aR, 6aS) hexahydro-quinones. Methyl [2,3-7]furan-3-ol, optically pure, starts with 3(R)-diethyl malate and 3(S)-diethyl malate. The method comprises a number of steps 'such as a dilute propylation step using lithium diisopropylamine followed by a reduction step' and further a Swem oxidation step followed by an ozonolysis split 20 and a borohydride step, using 9 Boron-bicyclo[3.3.1]decane (9-BBN). Ghosh et al. also revealed racemic synthesis of hexahydro-furo[2,3-]furan:ol (3R,3aS,6aR) and (3S,3aR,6aS) two palmar isomers, followed by The final product is analyzed by enzyme. The synthesis described hereinafter starts with 2,3-dihydrofuran and includes the step of treating the intermediate with N-iodosuccinimide and allyl alcohol. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297). PCT 1323260 A7 B7 V. INSTRUCTIONS (2) This is followed by cyclization of the group in the presence of a catalyst, namely cobalt ruthenium. The ozonolysis is split, followed by the reduction step to provide racemic hexahydrofuran [2,3 hydrazol-3-ol. The optically active compound (m^aS^R) hexahydrofuran [2,3-7]furanol was obtained after enzyme analysis, followed by silica gel chromatography. Pezeck et al, 5 Tetrahedron Lett. 丨 986, 27, 37 丨 5_3718 also describe the use of ozonolysis to synthesize hexahydro-furo[2,3-7]furanol. Hexahydro-furo[2,3_b]furan-3-ol is also described as an intermediate in the synthesis of optically active perhydrofuran-[2,3_,fluorene]furan derivatives (Uchiyama et al., Tetrahedr〇n Lett 2〇〇1,42, 4 still 3-4656). The key step in this procedure is the 10 hydroxy selenylation of the 2,3-dihydrofuran oxy group. This procedure is suitable for use at the laboratory level and is still not easy to connect with: scale up. Although the two synthetic pathways described by Gh〇sh et al. are based on reasonable yields and high yields of excess isomers; provide (10) heart nets with (3S, 3aR, 6aS) hexahydro-furan [2, 3 seven Furan_3_alcohol, but the two are only applicable to the laboratory scale, but for many reasons, it is not easy to accept 15 cases of industrial expansion. For example, 'the shortcomings encountered by these known routes are the use of the Ministry of Economic Affairs, Smart Assets M. Bureau of Staff and Consumers Cooperatives to print mussel materials, heavy metals and rare compounds such as N_iodosuccinimide, catalyst _, Zhong Er Isopropylamine and 9_BBN. The necessary ozonolysis step has the disadvantage of producing highly reactive and explosive odorous ozonides and peroxides, making this step too dangerous to be used in industrial scales, ozonolysis and Swem gasification. ϋ is highly exothermic and must therefore be carried out at very low temperatures. In addition, the racemic pathway requires enzyme analysis in the final step of the synthesis, followed by purification of the Shiqi gum. Furthermore, the disadvantage of the racemization pathway is that the low overall mass balance is derived from the fact that it will lead to the resolution of the final pure compound in the palm of the hand-4- 1323260 A7 B7 V. Description of the invention (3) , occurs in the final step of the synthesis, and only the largest equivalent of 50% yield of the desired palm isomer can be obtained. Two techniques known in the art also produce large amounts of waste, such as solvents and salts in washing operations. Thus, such known methods are not suitable for use on an industrial scale to produce optically pure stereoisomers of hexahydro-furan 5 and [2,3-b]furan-3-ol. The main objective of the present invention is to provide an improved method for producing hexahydro-furo[2,3-b]-furan-3-ol, which is related to the art. The methods known in the comparison and their disadvantages are compared. Another item is to provide a process for the synthesis of hexahydro-furo[2,3-b]furan-3-ol which is suitable for industrial scale-up. Another object of the present invention is to provide a stereoselective method comprising the step of controlling the stereochemistry of an intermediate or final compound which permits the synthesis of hexahydro-furo[2,3-b]furan-3 a stereoisomer of an alcohol. A further further object is to provide a process which permits the manufacture of hexahydro-furo[2,3-b]furan-3-ol, 15 in a total yield equal to or higher than the above process, and having a palm The structural excess is above 50%. Another object of the present invention is to provide a process for the manufacture of hexahydro-furo[2,3-b]furan-3-ol from readily available starting materials and reagents. Another item of the present invention provides a novel intermediate compound which can be used as a precursor to the synthesis of hexahydro-furo[2,3-]furan-3-ol. The authors of the present invention have surprisingly discovered a novel and inventive method for the synthesis of stereoisomeric mixtures or stereoisomers of hexahydro-furo[2,3-b]furan-3-ol. Therefore, the method relates to the synthesis of hexahydro-furo[2,3-b]furan-3-ol, starting from the intermediate of formula (1), wherein each of P1 and P2 independently represents hydrogen and hydroxy. (CNS) A4 size (210 X 297 mm) 1323260 A7 B7 V. Description of invention (4) Protective groups, or together with a diol protecting group, such that the intermediate (OP) of the formula (1)

P1. , human / H is converted to a formula (3) nitrodecane derivative, wherein R1 represents an alkyl group, an aryl group or an aralkyl group, R2 represents hydrogen or C(=0)0R3, and R3 represents an alkyl group, an aryl group or an aralkyl group. , or R3, if present, together with R1, and the atoms to which they are attached, may form a 6 to 8-membered cyclic group, which may be optionally substituted with an alkyl, aralkyl or aryl group, OP2 R2 P10.

'COOR1 3 ~N〇2 - Next, the nitrodecane derivative is converted into a tetrahydrofuran derivative of the formula (6), wherein OR4 represents an alcoholate such as an alkoxy group, for example, by using a Nef 15 reaction,

HO

OH OR4 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 The intermediate of formula (6) is then converted to (7) hexahydro-furo[2,3-b]furan-3-ol by intramolecular cyclization.

HO ip -6 This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Description of invention (s) Another advantage of the above method is the use of readily available starting materials. For example, 〇-protected propylene glycol aldehyde. Other reagents used in this method are safe and available in large quantities. Again, the various steps of the process provide the desired compound in good yield. Further, when optically pure starting materials and reagents are used where appropriate, the various steps of the process can be carried out stereoselectively, which allows the synthesis of the pure stereoisomeric forms of the compound. Therefore, the method according to the present invention is easily accepted to be industrially scaled up. In a preferred embodiment, the invention relates to a process for the synthesis of a hexahydro-furo[2,3-b]furan-3-ol of the formula (7) which comprises the steps of: 10 a) making the formula (1) The intermediate condensation OP2 results in the formula (2) α,/5-unsaturated ester, wherein Ρ1, Ρ2, R1 and R2 are as defined above, 〇p2 R2 pi〇^A^Y〇r1 2 0 Ministry of Economics Intellectual Property Printed by the Bureau of Staff Consumer Cooperatives b) reacting the ester of formula (2) with nitrodecane to form intermediate of formula (3), 20 〇 P2 R2

COOFP hc) The intermediate of the formula (3) is subjected to the Nef reaction, resulting in the intermediates of the formulas (4) and (4'). The paper size is applicable to the Chinese national standard (210 x 297 mm). 1323260 A7 B7 V. Description of the invention ( 6)

OR4

d) converting the intermediates of formula (4) and (4) into intermediates of formula (6), and 15

HO

OR4 e) The intermediate of formula (6) is converted to the compound of formula (7) by intramolecular cyclization. In a more preferred embodiment, the invention relates to a process for the synthesis of hexahydro-furo[2,3-b]furan-3-ol of formula (7) / which comprises the steps of: a) The intermediate of formula (1) is condensed with a suitable oxycarbonylhydrazinyl reagent of the formula CHR2 R5 -(:(=0)-0111, wherein R1 and R2 are as defined above, and R5 represents hydrogen, a carboxylic acid ester, a sulphate or a phosphine Acidate, OP2P1〇_y. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on the formula (2) ^, stone-unsaturated ester, of which P1 is defined, P2, R1 and R2 are as above

b) reacting the ester of formula (2) with nitromethane, resulting in the intermediate of the formula (3). The paper size is applicable to the Chinese national standard (210x297 mm). 1323260 A7 B7 5. Invention description (7) OP2 R2 P1〇 .

c) subjecting the intermediate of formula (3) to a Nef reaction by treating it with a base, and then with a strong acid, resulting in a mixture of intermediates of formula (4) and (4,), wherein R4 is as defined above , ... -** __

OR4 d) However, if R2 is not hydrogen, the intermediates of formula (4) and (4') are decarboxylated, and thus intermediates of formula (5) and (5') are formed individually.

15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumer Cooperatives, e) using intermediates of formula (4) and (4') with appropriate reducing agents, wherein R2 is hydrogen or intermediates of formula (5) and (5') are reduced, And cause the intermediate of formula (6), and

f) The intermediate of the formula (6) is converted into the formula (7) by the intramolecular cyclization. The paper is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 1323260 A7 B7 V. Description of invention (8) Item 0 In this method, the order of the steps mentioned above may be different from the alphabetical order quoted above. For example, steps (8) and (9) of the method may be reversed, provided that an oxycarbonyl hydrazide group of the formula CHR2R8-(=0)-0111 is used, instead of one of the formulas CHR2 R5-CpCO-OR1, wherein R8 The difference from R5 is that R8 is not capable of forming Wittig or Homer-Emmons reagents such as sedative or phosphonate. ~ and -, if R2 is hydrogen, the reduction of the CPCO-OR1 moiety similar to that described in step e) can be carried out prior to the step (c) Nef reaction. An oxycarbonylmethylene reagent of the formula CHI^RS-Ceco-OR1, wherein R5 represents a carboxylic acid ester, for example, a carboxylic acid of the formula R1 0-C(=0)-CHR2 ¢: (=0)-0111 ester. An oxycarbonylmethylene reagent of the formula chWf^-cookjr1, wherein R5 represents a sedative salt, and may, for example, have the formula (R6 wherein R6 is alkyl, aryl or aralkyl. The oxygen of the formula CHI^RS-CbCO-OR1 A carbonylcarbonyl 15 hydrazyl reagent, wherein R5 represents (R70)2P(=0)-, which may, for example, have the formula (R7 0) 2 P(=0)-CHR2 -(:(=0)-0111, wherein R7 is Alkyl, aryl or aralkyl. Printed by the Intellectual Property Office of the Ministry of Economics, Employees' Consumption Cooperative. Appropriately, the present invention relates to a process in which P1 and P2 together form a diol protecting group, and in particular the diol. The protecting group is an acid labyrinth. It is still protected during the alkali treatment step of the Nef reaction. Preferably, the viridane protecting group is selected from the group consisting of an anthracene group and a diphenylarylene. Base, ethylene, 1-tert-butylethylene, 1-phenylethylene, (4-anthoxyphenyl)ethylene, 2,2,2-trisethyleneethylene Isopropyl, cyclopentylene, cyclohexylene, cycloheptylene, benzylidene, p-nonyloxybenz-10- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) PCT) 1323260 A7 _ B7 Description (9) '^ Methyl, -monomethoxybenzidine, 34 dimethoxy benzylidene and nitrobenzylidene. In the most preferred embodiment, P1 and p2- form Dialkyl imino group such as isoindolyl or 3 pentylene. Interested in this diol protecting group is not to cause another stereogenic center in the intermediates of formula (1) '(7) and (3) 5 The protecting group is suitably a Cij group, an aryl group or an aryl group, and a fluorene group, especially a fluorene group, more particularly a methyl group, an ethyl group, a propyl group, and a different group. Propyl, n-butyl, isobutyl, second yl, tert-butyl and pentyl' and preferably each independently methylethyl or 10th tri-butyl. R1 and R3 when- When it is represented by ·r1_r3·, it is preferably -cH2 or _CIVCH2·, and is optionally substituted by Cl, 6 alkyl, aryl or arylalkyl. Suitably, -6 alkyl, especially R4 is fluorenyl, ethyl, propyl, isopropyl, n-butyl 'isobutyl, second butyl, tert-butyl and 15 pentyl, and preferably R4 is decyl or ethyl In a preferred embodiment, the invention is related to Pure stereoisomer of hexahydrofuro[2,3-b]furan-3-ol, especially (3R 3aS,6aR) hexahydro-indolo[2>b]pyran-3-ol Optional method. The term "hydroxyl protecting group" as used herein by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, refers to a substituent that protects the hydroxy 20 group to prevent undesired reactions during the synthetic procedure, such as It is disclosed in Greene, the protective group of organic synthesis ('John Wiley & Sons, New York (1981)). The oxime-protecting group includes substituted decyl ethers such as decyloxy fluorenyl, benzyloxyindenyl, 2-methoxyethoxymethyl, 2-(trimethyldecyl)ethoxymethyl Base, tributyl, benzyl and tris-methyl-11 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Description of invention (1〇); Tetrahydrogen Piperanyl ethers; substituted ethyl ethers such as 2,2,2-triseoethyl; decyl ethers such as trimethyldecyl, tert-butyldimethylalkyl and Tris-butyldiphenyl fluorenyl; and esters prepared by reacting a hydroxy group with a carboxylic acid, such as acetate, propionate, acetoate, and the like. 5 The term "procarbyl protecting group" as used herein, refers to a protecting group in the form of an acetal or ketal and in the form of an orthoester. A protecting group in the form of an acetal or ketal group, and specific examples thereof include a methylene group, a dibenzylidene group, an ethylene group, a 1-tert-butylethylene group, a 1-phenylethylene group, (4-methoxyphenyl)ethylidene, 2,2,2-triethylene, isopropylidene, cyclopentylene, cyclohexylene 10, cycloheptylene, benzoquinone, pair -methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, 2-nitrophenylarylene, etc. Specific examples of the protecting group of the form include an anthracene fluorenylene group, an ethoxylated fluorenylene group, a dimethoxy fluorenylene group, a 1-decyloxyethylene group, a 1-ethoxyethylene group, and 1 , 2-dimethoxyethylidene, α-decyloxyphenylene 15 fluorenyl, fluorene (fluorene, hydrazine-dimethylamino)ethylidene, α-(Ν,Ν-dimethylamino)benzene Amidino, 2-oxocyclopentyl and the like. The term "alkyl" as used herein, as used alone or as part of a group, refers to a saturated monovalent hydrocarbon radical having a straight or branched hydrocarbon chain, or In the case where at least 3 carbon atoms are present, they are cyclic hydrocarbons or a combination thereof, and contain 20 1 to 20 carbon atoms (( ν 20 alkyl group), suitably 1 to 10 maiden atoms ((: 丨·... The alkyl group) is preferably 1 to 8 carbon atoms (Ci-8 alkyl group), more preferably 1 to 6 carbon atoms (Q-6 alkyl group), and still more preferably 1 to 4 carbon atoms ( Cn alkyl). Examples of alkyl include fluorenyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl, pentyl, isopentyl , -12- This paper scale applies to China National Standard (CNS) A4 specification (2丨Ox 297 mm) 1323260 A7 B7 V. Description of invention (11) Hexyl, cyclopropyl, cyclobutyl, cyclopentyl, ring The term "aryl" as used herein, includes an organic radical derived from an aromatic hydrocarbon by the removal of a hydrogen, and includes monocyclic and polycyclic radicals such as phenyl, hydrazine. Alkyl, naphthyl. As used herein, "aralkyl" is a group of the aryl-alkyl group of the formula 5, wherein both an alkyl group and an aryl group are as defined above. Examples of the aryl group include a benzyl group. , phenethyl, etc. - The term "alkoxy" as used herein, alone or as part of a group, refers to a radical, wherein the term "alkyl" is as defined above. Examples of the ether group include a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy 10 group, a n-butoxy group, an isobutoxy group, a second-butoxy group, and a third-butoxy group. The ''stereoselective method' and 'stereoselective step" terminology used herein is basically a method or step in which a compound of interest is of interest when an optically pure starting material is used. The pure stereoisomer form 15 is obtained at the end of the method or at the end of the step. The Department of Economic Intelligence's Intellectual Property Office employee consumption cooperative prints • • Stereochemical isomer form or “stereoisomer form” , as used herein, defines all possible isomeric and conformational forms, Consists of the same atoms, joined by the same bonding sequence, but with different three-dimensional structures, which are not exchangeable, which may be obtained by the compound 20 or intermediate obtained during the process. Unless otherwise mentioned or indicated The chemical nomenclature of a compound encompasses a mixture of all possible stereochemically isomeric forms of the compound. The mixture may contain all diastereomers, palmomeris and/or conformations of the basic molecular structure of the compound. Isomers. More specifically, the stereogenic center can have an R- or S-configuration, diastereoisomer-13 - this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. INSTRUCTIONS (12) May have an ipsilateral or contralateral configuration, a substituent on a divalent cyclic saturated base, which may have a cis- or trans-configuration, and an alkenyl group It can have an E or 厶 configuration. All stereochemically isomeric forms of the compounds, either in pure form or in intermixing with each other, are intended to be included within the scope of the invention. Intellectual Property Intelligence Officer X Consumer Consortium 5 (1) Intermediate and the pure stereoisomer form of the starting material or reagent, as indicated herein, is defined as being substantially free of the compound, starting material or The same basic molecular structure of the reagents>&isomers in the palmo-isomer or diastereomeric form. Suitably, the term "stereoisomerically pure" compound's starting material or reagent relates to an isomer having a stereoisomer of at least 5% by weight (meaning at least 75%) Up to 25% of other possible isomers), up to 100% (i.e. 100% of one isomer, without other isomers) of compounds, starting materials or reagents, preferably a compound having a stereoisomer excess of from 75% up to 100%, starting materials or reagents, more preferably having a stereoisomer of from 15% to up to 100% of the compound, starting material or The reagent, more preferably a compound or intermediate having a stereoisomeric excess of from 94% up to 1% by weight, and most preferably has a stereoisomeric excess of from 97% up to 100%. "The terminology of pure, and, and diastereomeric soils should be understood in a similar manner, but it is an individual excess of 2〇 in the discussion. An excess of the image. Although, although a method for preparing a pure compound on the stereoisomer of the formula (7) according to the present invention, a stereoisomerically pure starting material can be advantageously employed, but it is generally expected to be applied by application. The purification procedure is known to further purify the compound and the intermediate. For example, the palmo isomer can be obtained by its diastereoisomer-14-1323260 A7 B7 5. The invention (13) the selectivity of the salt and the optically active acid Separation from each other by crystallization. Alternatively, the palmomer isomer can be separated by a chromatographic technique using a palm stationary phase. Although hexahydro-furo[2,3-b]furan-3-ol has three stereo The original center, and in theory the fact that eight different stereoisomers should appear, but only four stereoisomers are considered to exist. This is due to the bicyclic ring structure in hexahydro-furan [2,3- b] caused by the rigidity of furan-3-ol, which causes its trans-fused stereo Weng is thermodynamically unfavorable. Only stereoisomers with a cis-fused configuration are thermodynamically stable, thus reducing the stereo hexahydro-furo[2,3-b]furan-3-ol The number of isomers becomes the following: 5

10 Compound Configuration Atomic 3 Configuration Atom 3a Configuration Atomic 6a Stereochemical Description Symbol 7.1 RSR (3R, 3aS, 6aR) 7.2 RRS (3R, 3aR, 6aS) 7.3 SRS (3S, 3aR, 6aS) 7.4 SSR (3S, 3aS, 6aR) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 15 The method of the present invention can be more clearly understood by referring to Figure 1, wherein P1 and P2 each independently represent hydrogen, a hydroxyl protecting group, or may form a diol protection together. R1 represents an alkyl group, an aryl group or an aralkyl group, R2 represents hydrogen or COOR3, R3 represents an alkyl group, an aryl group or an aralkyl group, or R3, if present, together with R1 and the atoms to which they are attached It can form a 6 to 8-membered cyclic group, which can be applied to the Chinese National Standard (CNS) A4 specification (210x297 mm) according to the paper scale. 1323260 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description ( μ) is substituted by an alkyl group, an aryl group or an aralkyl group; and R4 represents an alkyl group. Scheme 1 depicts a synthetic procedure for the synthesis of hexahydro-furo[2,3-b]furan-3-ol (7) starting with an intermediate of formula (1) wherein P1 and P2 each independently represent hydrogen. a hydroxy protecting group, or may together form a diol protecting group. 5 The hydroxy protecting group and the contigyl diol protecting group referred to above may be readily cleaved by methods known in the art, such as hydrolysis, reduction, etc., depending on the protecting group employed, Appropriately selected. In accordance with the preferred embodiment, the diol protecting group is an acid labile protecting group, wherein the term "acid unstable", as used herein, refers to a field that is easier to split using 10 acidic conditions. Glycol protecting group. Figure 1

_Ni_f reaction i) alkali OH ii) acid 6 OR" cyclization-16- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Invention Description (15) In the present invention Several protected propylene dialdehydes of the formula (1) are used as known compounds. The palm-selective and racemic variants for the synthesis of such protected propylene dialdehyde derivatives have been described in the literature. For example, the preparation of 2,3_0 isopropylidene-S-propanedialdehyde is described in Hubschwerlen, Synthesis, 5 1986, 962 Preparation of '2'3-0·isopropylidene-R-propanedialdehyde , described in C. R_Schmid et al., J. Org. Chem. 1"1, 56, 4〇56_4〇58, and 2,3_〇_isopropylidene-(R,S)-propane The preparation of hydroxy hair is described in Ba Yi et al., Tetrahedron Lett. 1998, 39, Η 37·144〇. The intermediate of the formula (1) is commercially available or may be prepared prior to the reaction or formed on the spot. According to a preferred embodiment, the compound is formed on the spot. In the first step of the preferred process for the preparation of a compound of formula (7), the phospho-unsaturated ester of formula (2) is subjected to a condensation reaction with a suitable oxycarbonylhydrazolyl reagent in the presence of a suitable solvent at a suitable temperature. Next, the intermediate from the formula (1). Printing by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 15 In general, any reaction procedure that introduces the =C(R2)C(=0)〇Ri group in the starting material of formula (1) can be utilized. For example, the conversion of the intermediate of formula (1) to the intermediate of formula (2) can be carried out using a reaction procedure using an oxycarbonylhydrazino moiety of formula CHR2R5_c(=0)or1, for example via Wittig reaction, using a phosphorus-burning 20-based compound of the formula (R6)3P=CR2-CPCOOR1; via a Homer-Emmons reaction, using a phosphonate of the formula (R7 〇) 2 CHR ((=0)01^1, In the presence of a base; or via a Kn〇evenagel type condensation reaction, a malonic ester derivative of the formula R1 0C(=0)-CHR2 -(:(=0)0111 is used, in the presence of a base, wherein R1, R2, R6 And R7 have the same meaning as defined above. Another alternative is to use Ref〇rmatsky -17- This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) 1323260 A7 B7 V. Invention Description (16) Reagents, such as oxycarbonyl-indenyl zinc halides. Yet another alternative involves the use of a precursor of the -C(=0)-0- moiety, such as cyanide. The reaction procedure is described in detail in the Advanced Organic Chemistry Handbook by Jerry March. 5 According to a preferred embodiment, the oxycarbonyl fluorenylene test Is selected from the group consisting of (alkoxycarbonylmethylene)phosphorane, such as (ethoxycarbonylmethylene)triphenyl-phosphane, (曱 oxycarbonylhydrazino)-triphenylphosphane, (ethoxycarbonyl) Mercapto) trimethylphosphane, (ethoxycarbonylmethylene)-triethylphosphane, (ethoxycarbonylhydrazino)tricyclohexylphosphane or (ethoxycarbonylmethylene)tributyl a phosphine; an alkyl 10 -dialkylphosphonic acid acetate and an alkyl diarylphosphonic acid acetate, such as triethyl phosphonate, ethyl dimethyl phosphonate, diethyl phosphonic acid Ethyl acetate or diphenyl-phosphonate ethyl acrylate alkyl malonate, such as dinonyl malonate, diethyl malonate, di-tert-butyl malonate and Malonic acid cyclic isopropylidene ester 15 Examples of suitable bases, including but not limited to alkylamines and aromatic amines, printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperatives such as: σ bite, tetrahydrogen σ ratio σ, hexahydrogen ratio σ set, 福福°林, N-methylmorphine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,3-diazepine Bicyclo[3.4.0]non-5-ene (DBN), 1,8-diazabicyclo[5.4 .0] +-7-ene (DBU), hydrazine, hydrazine-diethylaniline, hydrazine, hydrazine-dimethylaminopyridine, morphine, triethylamine and hydrazine, hydrazine-di-20 isopropylethylamine And sodium-, potassium- or lithium hydride; sodium-, slant 7, lithium- or cesium carbonate; sodium-, potassium-, lithium- or strontium carbonate and alkoxide bases, such as sodium, lithium or potassium Cerium oxide, ethoxylate, butoxide, third-butoxide and third-pentoxide; butyl lithium and lithium diisopropylamine. Suitable solvents for this reaction are known in the art for condensation -18- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Description of invention (17) Any hydrocarbon 'ether, halogenated hydrocarbon or aromatic solvent of the reaction. The system includes, but is not limited to, pentane 'hexane, heptane, toluene, dimethyl benzene, benzene 'trimethyl phenylene, third-butyl methyl ether, dialkyl ether (ethyl, butyl), two stupid Base, chloroform, dioxane, chloroform, tetrachloronyl, acetonitrile, gas, bi- 5, ethyl chloride, tri-ethane, cyclohexane, ethyl acetate, isopropyl acetate, tetrahydrofuran, Oxygen, methanol, ethanol and isopropanol. If a condensation of Knoevenagel is used, it is also convenient to use an acid hydrazine, such as acetic anhydride, as a dehydrating agent in this condensation reaction. The fact that water is removed from the reaction medium shifts the equilibrium of the push reaction toward <2, unsaturated two energy, and 10 causes the reaction to be complete. The acetic anhydride can be substituted with tetrahydrofuran, N-mercapto-isfosone or isopropyl acetate. Addition can increase the yield of the Knoevenagel reaction. Examples include the use of alkylamines such as triethylamine. Such a base is preferably added in a small amount. Alternatively, the Knoevenage(R) reaction can be carried out using TiCI4. 15 The appropriate temperature range for this condensation reaction is between room temperature and the temperature of the appropriate solvent stream, which is a condition readily achievable by the organic synthesis technique. It is preferred to operate the reaction at room temperature. Bu, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 20 Depending on the type of condensation reaction and the reagents used, it is possible to synthesize α(7) α, heart-unsaturated monoesters (when R2 = H) or formula (7) ^, heart is not full of vinegar (when Bu CO (10)). The α, ^ unsaturated single type vinegar of the formula (2), wherein R% Rl is different, can be obtained by stereochemistry around the double bond £ or z. The E/Z isomer ratio depends on the reaction conditions of the condensation reagent used, particularly the reaction solvent. Under the method of Ruiqi^(4)(4), the system includes the soil of the scorpion-based precursor, added to the formula (2) in the unsaturated lysate intermediate at the appropriate -19- paper scale 赖+ @ 05准(CNS ) A4 gauge; 297 mm) 1323260 A7 B7 V. Description of the invention (18) In the presence of a base, a 1,4-addition product of formula (3) is produced. This nitromethane addition step occurs in a diastereoselective manner. The newly formed stereocenter at the carbon number 3 (C-3) of the valerate skeleton is controlled by the stereochemistry at the oxidation position of the carbon number 4 (C-4).

The ipsilateral/contralateral ratio printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs is further based on the type of α,/5-unsaturated ester (2) (Ε or Ζ, mono- or di-ester), the base used. The type, and the reaction conditions, 10 are controlled, for example, by the reaction solvent and the reaction temperature. Usually mainly the ipsilateral addition product. Examples of suitable bases include, but are not limited to, DBN (1,3 = diazabicyclo[3.4.0] 壬_5_ene) and DBU (1,8-diazabicyclo[5_4.0] 十一_7 _ene), triethylamine, tetrahydrogen ratio, hexahydropyrazole, chloroform D, N-mercapto ruthenium π, 1,4-diaza 15 bicyclo[2.2.2]-octyl Alkane (DABCO), diammonium pyridine (DMAP), sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, hydrogenated slant, sodium sterol, In the sterol, sodium ethoxide, potassium ethoxide, lithium tributoxide, tris-butanol 'n, potassium tert-butoxide, tetrabutylammonium fluoride, tetrabutylammonium hydroxide. Examples of suitable solvents include, but are not limited to, pentane, hexane, heptane, indole benzene diterpenic benzene, benzene, triterpene benzene, tert-butyl-methyl ether, dialkyl ether (B Base, butyl), diphenyl ether, gas benzene, dioxane, gas imitation, carbon tetrachloride, acetonitrile, dichlorobenzene, 1,2-diethane and 1,1,1-trigas Ethane, cyclohexane, tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, dioxins (DMSO), diterpenoid-20- This paper scale applies to China National Standard (CNS) A4 specification ( 210x297 mm) 1323260 A7 B7 V. INSTRUCTIONS (19) Baseline amines (DMF), N-mercaptos. The reaction temperature is set in the range of from about 0 to about 10,000 Å, preferably in the range of from about 1 Torr to about Torr, more preferably at about room temperature. The intermediate of formula (3) may alternatively be prepared by a method comprising the following steps: first, the intermediate of formula (1) is condensed with a nitrile, thereby causing an intermediate of formula (8), and secondly, the intermediate of formula (8) is Chr2r8_c (= 〇) 〇 r1 of the appropriate oxy m-based sub-T-based test should be made, and caused by shouting (3) ten Cao. It should be understood that those skilled in the art may use other process known in the art to begin with the intermediate of formula (1) to achieve the intermediate of formula (3). 10 In the next step in the process according to the invention, starting from the intermediate of formula (3) to form an intermediate of formula (6). One way to achieve this is to convert the intermediate of formula (3) to its corresponding indolyl derivative via a Nef reaction. This step is carried out by first treating the intermediate of formula (3) with a base and then a strong acid, resulting in an intermediate of formula (4) and (4,) 15. Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

The Nef reaction is generally defined as the conversion of a primary or secondary nitro group to its corresponding carbonyl compound (N. Komblum Organic Reaction 1962, I2, 101 and H. W. ?^11^1^ Organic Reaction 1990, 38, 655). In the classical procedure, the nitro group is deprotonated with a base at the position of the nitro function, followed by the acid catalyzed hydrolysis of the intermediate "nitrogen 2 〇 oxide" salt added to the strong acid present in excess. The carbonyl derivative is obtained. Suitable bases can be selected by those skilled in the art of organic synthesis. Suitable bases include, but are not limited to, inorganic bases such as alkali metal, alkaline earth metal and ammonium hydroxides and alkoxides. Suitable bases also include but not Limited to metal amides and alkyl groups - 21 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 5. Inventive Note (20). An example of a suitable strong base is lithium diisopropyl. Base amine, sodium amine, sodium decoxide, potassium third potassium butoxide, sodium butoxide, calcium hydroxide, barium hydroxide, methyl lithium, butyl lithium, hexyl lithium, phenyl lithium and tetraalkyl hydroxide Ammonium, DBN (1,3-diazabicyclo[3_4.0]non-5-ene) and DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) 5,1, 4-diazabicyclo[2.2.2]octane (DABCO), potassium carbonate, sodium carbonate. The term "strong acid" is used herein. Means any conventional strong acid, such as strong inorganic acids, such as hydrochloric acid and 'salt: acid, and strong organic acids, such as benzenesulfonic acid and tri-acetic acid. The preferred strong acid is concentrated sulfuric acid or hydrochloric acid. The use of strong acid will cause acid instability. The deprotection of the protecting group, as a result of the formation of a diterpene intermediate, wherein the primary alcohol is condensed with the carbenyl group to form the cyclic hemiacetal of the formula

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 15 Using anhydrous conditions with an alcohol solvent such as decyl alcohol or ethanol (generally denoted as R4-OH), a thiol-based cyclic acetal acetal or B is alternatively obtained. Acetal. In addition to this classical base/acid procedure, Nef-conversion can be achieved using a wide variety of oxidation and reducing agents known in the art. According to a preferred embodiment, the appropriate alcohol solvent is selected from the group consisting of decyl alcohol, ethanol and isopropanol. 20 The Nef reaction can be carried out at a temperature ranging from about -78 ° C to about 55 ° C, preferably at a temperature between about -18 ° C and about room temperature. The reaction time can range up to about 24 hours with a suitable range between about 1 hour and about 24 hours. According to a preferred embodiment, the intermediate of the formula (3) is treated with a base, and the paper size is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1323260 A7 B7 5. Invention Description ( 21) Addition to a strong acid alcoholic solution results in the conversion of the nitromethyl group of the intermediate of formula (3) to the formazan group. At the same time, this acid treatment also catalyzes the splitting of the protecting groups P1 and P2, resulting in the formation of intramolecular acetals, resulting in intermediates of formulas (4) and (4'). The R4 substituents in the intermediates of formula (4) and (4') are derived from the alcohol R4-5 OH. The bicyclic intermediate of formula (4) is the expected reaction product from the intermediate of formula (3), which is in the same side configuration, and the intermediate of formula (4') is the expected reaction from the intermediate of formula (3). Product, in contralateral configuration. The trans configuration of the substituent 3 at the carbon atom number 3 (C-3) and the carbon number 4 (C-4) on the tetrahydrofuran ring of the intermediate of the formula (4') prevents the second lactone The ring is formed as in the case of the intermediate of formula (4).

Printed by the Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Cooperatives. 15 At this stage of the synthesis process, when R2 is COOR3, the decarboxylation step is performed. The decarboxylation step comprises removing -C(=0)-OR3 in the intermediate of formula (4) and (4). In a preferred embodiment, the decarboxylation step is via a suitable base such as sodium hydroxide or hydrogen. Potassium oxide, treating intermediates of formula (4) and (4,), is carried out under heating conditions of 20, and after acidification, the intermediates of formula (5) and (5') are separately produced. Meanwhile, in formula (4,) R1 in the intermediate is replaced by hydrogen, as found in the chemical formula of the intermediate (5,). The bicyclic lactone derivative of the formula (5) is derived from the intermediate of the formula (4). The reaction product is expected, and the formula (5 carboxylic acid derivative is from the intermediate of the formula (4') -23- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 (22) The desired reaction product. The trans configuration of the substituents at C-3 and C-4 on the tetrahydrofuran ring of the intermediate of formula (5,) prevents the formation of the second lactone ring. , as in the case of the intermediate of formula (5). At this stage of the synthesis procedure, intermediates (4) and (4') or intermediates (5) and 5 (5'), a layer known in the art can be used. The separation techniques are separated from each other. In addition to the chromatographic technique, the intermediate of formula (5.) can be extracted by acid/base and separated from the lactone of formula (5). Typically, the intermediate of formula (5') can be used as an aqueous solution. For example, a sodium bicarbonate solution is extracted from a mixture of intermediates of formula (5) and (5*) in an organic non-aqueous miscible solvent. Suitable organic non-aqueous miscible solvents are any hydrocarbon, 10 ether, halogenated hydrocarbon or Aromatic solvent, including but not limited to pentane, hexane, heptane, methyl benzene, diphenylbenzene, benzene, triterpenoid, tri-butyl decyl ether, dialkyl group (ethyl) , butyl), diphenyl ether, gas benzene, two gas combustion, gas imitation, four gasification carbon, acetonitrile, two gas benzene, 1,2-diethane, 1,1,1-three gas Ethane, ethyl acetate and isopropyl acetate. 15 To improve the extraction yield of the lipophilic compound, a water-soluble salt can be added to the mixture prior to extraction. Preferred salts include NaCl. Water-miscible salts are added. , can increase the yield of extraction. Or, you can use the intermediates (4) and (4'), or the intermediates (5) and (5) of the Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives Printing the composition without further separation, especially when it is synthesized in a stereoselective manner 20. In the following steps, an intermediate of formula (4) and/or (4') wherein R2 is hydrogen, or The intermediate of formula (5) and/or (5,) is reduced with a suitable reducing agent to form an intermediate of formula (6). This reduction step may conveniently be via a metal hydride such as borane complex-24-paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Description of invention (23), diborane, lithium borohydride, sodium borohydride-LiCl, hydrogenated diisobutyl Or lithium aluminum hydride, in a suitable anhydrous solvent, to treat the formula (4) and / or (4,), wherein R2 is hydrogen, or (5) and / or (5) intermediates. Examples of suitable anhydrous solvents include, but are not limited to, dioxane, methyl, dimethyl, stupid, pentane, hexane, heptane, light oil ether, 1,4-thiazane, diethyl ether, diisopropyl Base, tetrazo-β-propan, 1,4-dioxanthene, I,2,2-decyloxy, and, in general, readily accepted for chemical reduction using the reagents cited above Any anhydrous solvent in the process. The reduction step can be carried out at a temperature ranging between about -78 ° C and about 55 ° C, preferably at a temperature between about -18 ° C and about room temperature. The reaction time can range up to about 24 hours, and suitably varies between about 2 and about 24 hours. According to a preferred embodiment, the reduction step is carried out using lithium borohydride in tetrahydrofuran. Alternatively, the reduction can be achieved using catalytic hydrogenation. The catalytic hydrogenation can be suitably carried out using H2 and using a metal including ruthenium, Pt, Ni and carbon. 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing If R2 is hydrogen, it can be used in the preparation of the intermediate of formula (6) from the intermediate of formula (3), according to an alternative route. In either of these two alternatives, the Nef program is employed. Therefore, the intermediate of formula (3) is converted into an intermediate of formula (6), alternatively by a method comprising the steps of first reducing the intermediate of formula (3) with a suitable reducing agent, resulting in the middle of formula (9) Next, the obtained intermediate of the formula (9) is subjected to a Nef reaction in the form of a base and then a strong acid to give an intermediate of the formula (6). The final step involves the conversion of the intermediate of formula (6) to the desired compound of formula (7) by a cyclization reaction. This cyclization reaction occurs via an intramolecular acetalization exchange reaction' and can be any acid compatible organic solvent or water miscible solvent-25- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) The invention is described in the specification of (24 in combination with water) and is carried out in the presence of a strong organic or inorganic acid. The reaction is suitably carried out by treating the intermediate of the formula (6) with a catalytic amount of a strong acid. In one embodiment, the strong acid is selected from the group consisting of a ship and sulfuric acid. The cyclization step can be carried out at a temperature ranging from about _78 < t to about between pits, preferably at about -18 ° C and about room temperature. The pure stereoisomeric forms of the above compounds and intermediates can be synthesized by the above-mentioned synthetic procedures. For example, 'the starting material which is isomeric and pure to the nucleoside. According to a preferred embodiment, the above method is suitable. Preparation of (311,333 plus 11) hexahydro-indolo[2,3_15]pyran_3-alcohol of formula (71)

15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed in the first step 'reacts the intermediate of the formula (la) with the appropriate oxyl sulfhydryl reagent as described above, resulting in the formula (2a) α, heart Unsaturated brewing wherein p, P 'R1 and R2 have the same meaning as defined above. The reaction conditions are the same as those described in the context of the condensation step. The intermediate (ia) can be preheated prior to the Knoevenagel reaction. Properly pre-temperature range, covering 4〇·7〇C, preferably 5〇-65°C. The intermediate can then be allowed to cool before the reaction. The order in which the reagents are added can affect the yield of the reaction. For example, using a Knoevenagel type condensation, it is convenient to add an oxycarbonylhydrazino group to the intermediate (la) before adding the dehydrating agent. The manner in which the dehydrating reagent is added can affect the yield of the reaction. The dehydrating reagent can be added slowly, that is, by dispensing. After the addition of the dehydrating reagent, the reaction can be in the range of 20-60. Temperature range of 〇 26 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) 1323260 A7 B7 5. Invention description (汸), preferably within the range of 35-55 °C. ΏΡ2

In a second step, 'the ester of formula (h) is reacted with nitromethane in the presence of a suitable base to form an intermediate of formula (3a) and (3b) wherein R1, r2, pi and P2 are as defined above . 3a N〇2

The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print Reaction Conditions are the same as those described above for the Nitromethane Addition Step. The reaction is preferably carried out in an alcoholic solvent at room temperature in the presence of a non-nucleophilic base such as DBU or sodium hydride. Depending on the starting materials and the reaction conditions, this step can be carried out in a stereoselective manner. The next step involves the conversion of the intermediates of formula (3a) and (3b) to their corresponding indolyl derivatives via a Nef reaction. According to a preferred embodiment, the intermediate of formula 20 (3a) and (the) is treated with a base, followed by addition to a concentrated acid alcoholic solution, resulting in a nitromethylalkyl group of the intermediates of formula (3a) and (3b). The group is converted to a formazan group. At the same time, the acid treatment also catalyzes the splitting of the protecting groups P1 and P2, resulting in the formation of acetals in the molecule, which in turn leads to intermediates of the formulae (e.g.) and (4, a), wherein R1, R2 and R4 are as defined above. Examples of strong acid alcoholic solutions, including sulfuric acid 27- This paper scale applies to China National Standard (CNS) A4 specification (210x297 male dragon) 1323260 A7 B7 ----------- V. Description of invention (26) In CH3〇H. The temperature during the treatment with the strong acid alcohol solution is room temperature or lower. This temperature is preferably below, lower than listening, and the reaction is better, at less than io °c. '

The reaction conditions are the same as those described above for the Nef reaction. 10 In this stage of the synthesis procedure, when R2 is COOR3, the decarboxylation step is carried out on the intermediates of formula (4a) and (4'a). This decarboxylation step involves the removal of -C(=〇)-〇R3 in the intermediate of (4) and (4, a). In a preferred embodiment, the decarboxylation step is carried out by treating the intermediates of formula (4a) and (4'a) with a suitable base, such as sodium hydroxide or potassium hydroxide, under heating, in acidification 15 Thereafter, the individual is caused to form a decarboxylated product of (S, a). At the same time, R1 in the intermediate of formula (4,) is replaced by hydrogen, resulting in a carboxylation in the intermediate (5, a). Part of the group. Printing by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, can also be carried out using halides. Suitable reagents include phantom, Naa, Lil, LiBr and KBr, preferably hydrazine. The hydrazine is soluble in a solvent such as N-methyltetrahydropyrrolidone. ~ or 'slowing action can be carried out in a buffered aqueous solution. A suitable buffer includes a lemon acid buffer at ΡΗ = 6. Then, at a high temperature, a decarboxylation reaction is suitably carried out between 50 ° C and reflux temperature. The reaction temperature is preferably higher than 80 °C. -28- The paper size standard (CNS) A4 specification (210 x 297 mm) ' -- 1323260 % A7 B7 V. Description of invention (27) The decarboxylated mixture can be made of strong acid resin, including DOWEX-H+ ®, or mild acid resin, including AMBERJET® Neutral. The resin can also be used in the cyclization reaction. AMBERJET® mild acid resins are also suitable for neutralizing this reaction. 5

fH 广一COOH 10 In the next step, using chromatography or acid/alkali extraction, the intermediate of formula (4'a), when R2 is a hydrogen atom, or the intermediate of formula (5'a), individual and (4a) or (5a) separation of intermediates. The intermediate of formula (4fa) or (5*a) can be extracted from the reaction mixture by methods known in the art, such as by using an aqueous test solution, such as a sodium hydrogencarbonate solution, in an organic non-aqueous miscible solvent. The reaction is carried out in a step of 15 steps in the form of an isolated (e.g.) or (5a) intermediate. The intermediate (5a) can be crystallized using an organic solvent. Suitable solvents include isopropanol, ethyl acetate, ethanol, and mercaptoisobutyl ketone. An advantageous solvent is isopropanol. Printing by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives In the next step, the intermediates of formula (4a) or (5a) are reduced with appropriate reducing agents to form intermediates of formula (6a), where R4 is as defined above.

-29- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm). V. INSTRUCTIONS (28) This reduction step can be achieved using the same conditions as described above for the reduction step. According to a preferred embodiment, this step is carried out in (4) hydrogenation in tetrahydrofuran. Alternatively, the reduction can be carried out in the presence of LiCl in the presence of LiA1 or NaBH4. Catalytic hydrogenation can also be used. Catalytic nitridation can be carried out using hydrogen gas in the presence of a suitable catalyst for catalytic nitrogenation, examples of which include recording, recording and turning. Suitably, the catalyst is present on an inert surface such as charcoal. The final step involves the conversion of the intermediate of formula (6a) to the compound of formula (7.1) by a cyclization reaction. This cyclization reaction occurs via an intramolecular acetalization exchange reaction. The hydrazine reaction is preferably carried out by treating the intermediate of the formula (6a) with a catalytic amount of a strong acid. In a preferred embodiment, the strong acid is selected from the group consisting of hydrochloric acid and sulfuric acid. In a specific embodiment, the cyclic action is carried out at a low temperature. The temperature is preferably less than 15 ° C, more preferably less than 5. (: After acid treatment, use appropriate test to neutralize the mixture and separate the compound 7. ^ 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed according to the above reaction sequence, the above method is applicable to the preparation formula (7 2) (3R, 3aR, 6aS) hexahydro-bromo-[2,3-b]nonan-3-ol.

HQ 00 7.2 The reaction conditions of the condensation step and the nitromethane addition step are controlled such that the intermediate of formula (3b) is obtained in the highest possible yield by, for example, changing the type of base used, solvent and reaction. temperature. After the Nef reaction, the next step involves separating the intermediate of formula (4, a) or (5*a)' and then applying the intermediate -30 paper scale to the Chinese National Standard (CNS) A4 specification (2丨〇X 297 Public love) 1323260 A7 B7 V. Description of invention (29) Reduction of matter to obtain intermediate of formula (6b)

It is further cyclized to a compound of the formula (7.2). Similarly, (3S, 3aR, 6aS) hexahydro-furo[2,3-b]furan-3-ol of formula (7.3) can be optically derived from formula (lb) by the method according to the invention Pure intermediates are obtained. 10

In the first step, the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, in the first step, reacts the intermediate of formula (lb) with the appropriate oxycarbonyl pentylene reagent to cause α, /5- of formula (2b). A saturated ester wherein P1, Ρ2, R1 and R2 have the same meanings as defined above. OP2 R2

2b 〇 The reaction conditions are the same as those described above for the condensation step. In the second step, the ester of formula (2b) is reacted with nitrodecane in the presence of a suitable base to form an intermediate of formula (3c) and (3d) wherein R1, R2, P1 and P2 are As defined above. -31 - This paper size is applicable to China National Standard (CNS) A4 specification (2丨0 X 297 mm) 1323260 A7 B7 V. Description of invention (30)

3c ', N〇2

COOR

The reaction strips are the same as those described above for the nitromethane addition step. The reaction is preferably carried out in an alcoholic solvent in a non-nucleophilic base such as DBU 4 at room temperature.

The step comprises translating the intermediate of formula (3c) with, for example, a N-based derivative via the Nef reaction. According to a preferred embodiment, the intermediates of (3〇 and (3d) are treated with a base, followed by addition to a strong acid alcohol solution. This acid treatment also catalyzes the splitting of the protecting groups P1 and P2, resulting in internal Acetal formation, individually leading to the intermediates of (F) and (4, b), the knives and R4 are as defined above. RI 15

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. 20 The reaction conditions are the same as those described in the previous Nef response. In this stage of the synthesis procedure, when R2 is COOR3, the decarboxylation step is carried out with the (4'b) intermediate. This dislocation step includes shifting > (4 and (4, b) in the middle*. In a preferred embodiment, the decarboxylation step is via a suitable base such as sodium hydroxide or the formula (4b) and (4, b). ) Intermediates, under heating conditions, 'According to acid' 32 - This paper scale applies to China® Standard (CNS) A4 size (210 X 297 mm) 1323260 A7 B7 V. Invention description (31 after, individually caused a decarboxylation product of formula (5b) and (5*b). Meanwhile, R1 in the intermediate of formula (4'b) is replaced by hydrogen, resulting in a carboxylic acid moiety in the intermediate (5'b). group.

Printed by the Intellectual Property Office of the Ministry of Economic Affairs in the next step, the intermediate (4'b), where R2 is a hydrogen atom, or an intermediate of the formula (5'b), extracted by chromatography or acid/base , separated from the intermediate of formula (4b) or (5b). The reaction system is further carried out with an intermediate of the formula (4'b) or (5'b). In the next step, the intermediate of formula (4'b) or (5'b) is reduced with a suitable reducing agent to give an intermediate of formula (6c) wherein R4 has the same meaning as defined above. 15 The reduction step can be achieved using the same reaction conditions as described above for the reduction step. The final step involves the conversion of the intermediate of formula (6c) to the compound of formula (7.3) by a cyclization reaction. This cyclization reaction occurs via an intramolecular acetalization exchange reaction. The reaction is preferably carried out in water by treating the intermediate of formula (6c) with a catalytic amount of a strong acid. In a preferred embodiment, the strong acid is selected from the group consisting of -33-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm). 1323260 A7 B7 5. Invention Description (32) Hydrochloric acid and sulfuric acid type (7.4) (3S, 3aS, 6aR) hexahydro-furo[2,3_b]furan-3-ol can be suitably prepared by 7.4 according to the reaction sequence described above for the synthesis of the compound of formula (7.3), and The condensation step is carried out under the conditions of the nitromethane addition step such that the intermediate of the formula (3b) is obtained as the main isomer by changing, for example, the type of base used, the solvent and the reaction temperature. After the Nef reaction, the next step includes separating the (North) or (5b) intermediate, and then reducing the intermediate-intermediate to obtain the intermediate of the formula (6d).

6d 15 is further cyclized to the compound of formula (7.4). Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Another aspect of the present invention relates to novel intermediates, and methods of making the same. The present invention relates to a novel intermediate having the formula (3) wherein pi and y 2 are as defined above, 'R2 is COOR3, and R1 and R3 are as defined above, and the intermediate has the formula (3.1). -34- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public) 1323260 A7 B7 V. Invention description (33

The intermediate of the formula (3.1) can be obtained by the method of the present invention. An intermediate of the formula -(3) wherein R2 is hydrogen, the intermediate having the formula (3.2), is also considered novel, provided that when P1 and P2 are used together to form an isopropylidene group, R1 is not Methyl or ethyl.

COOR N〇2

OP2 R2 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed OP2 R2 COOR1

COOR1 3d N〇2 According to a preferred embodiment, the invention relates to an intermediate having stereochemistry (3a) 15 , (3b), (3c) and (3d), wherein P1, P2, R1, R2, R3 are Has the same meaning as defined above. 3c N〇2 According to a more preferred embodiment, the invention relates to intermediates of the formulae (3a), (3b), (3c) and (3d), wherein the P1 and P2 systems together form a a diol protecting group, R2 is COOR3, and the intermediate has the formulae (3a.l), (3b.l), (3c.l) and (3d.l) individually. Suitably, the R1 and R3 systems are each independently selected from the group consisting of Including thiol, ethyl, propyl-35 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Description of invention (34: butyl, tert-butyl, and Propyl, n-butyl, isobutyl, pentyl, more advantageously R1 and R3 are the same. ίΟ 2 C00R3 〇

C00R' 3a.l I P2 COOR3

COOR1 3b.l

OOR COOR 3

3d. l In still further preferred embodiments, the invention relates to intermediates having the formulae (3a.i_)-, (3b.l), (3c.l) and (3d.l), wherein p1 and p2 Forming a dialkyl fluorenylene group, the intermediate having the formula (3a.la), (3b.la), (3c.la) and (3d.la) 〆 suitably, R1 and R3 are each independently Selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl 'second-butyl, tert-butyl and pentyl, more advantageously R1 and R3 are the same Z In a more preferred embodiment, R1 and R3 are each independently methyl, ethyl or tert-butyl, and more advantageously R1 and R3 are the same. 15 alkyl pit alkyl alkyl

3a.la Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperation Du printed Another preferred embodiment of the present invention relates to the intermediates of formulas (3#, (3b), (3c) and (3d), wherein P1 P2 forms a diol-protecting group, and R2 is Η. The intermediate has the formulas (3a.2), (3b.2), (3c.2) and (3d.2). Suitably, the R1 system is selected. Including thiol, ethyl, propyl, isopropyl, n-butyl, isobutyl 'second-butyl, tert-butyl and pentyl. -36- This paper scale applies to Chinese national standards ( CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Description of invention (35: 3a.2 "COOR N〇2

In still another preferred embodiment, the invention relates to an intermediate having the formulae (3a.2), (3b.2), (3c.2), and (3d.2), wherein P1 and P2 are It is used to form a dialkylmethylene group which has the formulae (3a.2a), (3b.2a), (3c.2a) and (3d.2a). Suitably, R1 is selected from the group consisting of methyl 'ethyl, propyl, isopropyl, n-butyl, isobutyl, second-butyl, tert-butyl and pentyl, more advantageously R1 It is a mercapto group, an ethyl group or a tri-butyl group. Alkylalkyl 15

COOR1 炫 alkyl

COOR1 3b.2a pit base

COOR1 3c.2a \ N〇2 pit base technology base

COOR1 3d.2a Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed intermediates (3c.2a) and (3d.2a), where R1 is ethyl, has been described in Patrocinio et al., Synthesis (1994), 5, In 474-6. Suitably, in the formula (3a.la), (3b.la), (3c,la) and (3d.la) intermediates, and (3a.2a), (3b.2a), (3c.2a) and In (3d.2a), the alkyl group is a Cu alkyl group, preferably a ^4 alkyl group, and most preferably a mercapto group or an ethyl group. In general, the synthesis of the stereoisomers of formula (3a), (3b), (3c) or (3d) can be carried out individually via an optically pure intermediate of formula (la) or (lb). -37- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Inventive Note (36) Another aspect of the present invention relates to formula (4), (4,), (5) and (5f) intermediates, which are considered novel. This intermediate can be obtained by the method according to the invention. According to a preferred embodiment, the present invention relates to the intermediate 5 of the formula (Sa), (5, b), wherein R4 is selected from the group consisting of decyl, ethyl, propyl, isopropyl, n-butyl, and iso Butyl, second-butyl, tert-butyl and pentyl'. In a more preferred embodiment, R4 is a decyl or ethyl group. The synthesis of formula (5a) milk, b) intermediates, may conveniently be carried out via an optically pure intermediate of formula (10) or (lb). 10 The special use of the compound of formula (7) in the preparation of the medicament has been found. According to a preferred embodiment, the compound of the formula (7) of the present invention is used as a precursor for the preparation of an antiviral drug, particularly an anti-HIV drug, 1 especially a hiv protease inhibitor. Compounds of formula (71) and intermediates which result in the formation of such stereoisomerically pure compounds are of particular interest in the preparation of HIV protease inhibitors such as at WO 95/24385, WO 99. /65870, WOOO/47551, WO 00/76961 and US 6,127,372, WO 01/25240, EP 0 715 618 and the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives published in W0 99/674H, all of which are For reference, and in particular the following HIV-protease inhibitors. 20 [(1 S,2R)_2-hydroxy_3-[[(4·曱-oxyphenyl)sulfonyl](2-methylpropanthene*)amino]- ι-(phenyl-methyl) Propyl]-amine methyl acid (3R3aS, 6aR) hexahydrofuran [2,3b] gnach _3- ketone (HIV protease inhibitor 1);, [(lS, 2R)-3-[[( 4_Amino-phenyl)sulfonyl](2methylpropyl)amino]_2hydroxy- ι-(phenyl-indolyl)propyl]-amine methyl acid (3R, 3aS plus hexahydrofuran -38- The paper size is applicable to China's χ χ 297 297 297 297 297 297 297 297 297 297 297 297 297 4 4 4 4 4 4 4 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 -3-[(1,3-benzodioxanthene: sulfamoyl)(2methylpropyl)amino]_2-hydroxy-1_(phenylmethyl)propyl]-amine fluorenyl Acid (3R3aS, 6aR) hexahydroj-[2,3-b]furan-3-yl ester (HIV protease inhibitor 3), or any of its 5 pharmaceutically acceptable addition salts. Thus, the present invention also With regard to the HIV protease inhibitor oxime, 2, 3, or any pharmaceutically acceptable salt or prodrug thereof, in the chemical synthesis of the HIV protease inhibitor, this is obtained using a compound of formula (71) made in accordance with the present invention. a chemical synthesis system revealed in this technique For example, the following examples are intended to be illustrative of the invention, and are intended to be illustrative of the invention, and are not intended to be construed. To limit the scope of the invention. Re-examination paragraph: =! _ General procedure: Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Beizi NMR light s sauce system was recorded on the Bmker Avance DPX 400 MHz NMR spectrometer. Proton The chemical shift is reported in ppm relative to the internal tetradecyl decane (1^3, δ 0.0) (5). Analytical thin layer chromatography (TLC) is pre-coated with silica gel 6OAF254 (〇·25 mm thickness) The TLcRf value is reported. The imaging is achieved by dyeing a solution of KMn〇4 in acetone or a solution of vanillin in a 1/1 mixture of water and concentrated sulfuric acid. Analysis-Gas Chromatography (GC) The system was performed using a DB-XLB column. The analysis was performed on the palm-shaped gc system by the cyclodex-no-column column. The detection on the two columns was achieved by detecting the H by flame ionization. All solvents and reagents. All are taken from commercial suppliers and used, but not before they are used. Any treatment or purification: -39· This paper scale applies to China S Standard (CNS) A4 specification (210x297 --------- 1323260 A7 B7 V. Invention Description (38) L-5,6-0 - isopropylidene gulonic acid _14_ lactone, according to C. Hubschwerlen synthesis I986, 962.964, from L_ascorbic acid.

Example I

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1.3 Synthesis - Potassium periodate (0.25 m, 57.5 g) and potassium bicarbonate (〇25 mol, 25 g) in water (100 liters) The slurry 'cools and cools to. L-5 6_〇_ 15 isopropylidene-gulonic acid-I,4-lactone (Ι·1, 0.12 mol, 26 g) was dissolved in tetrahydrofuran (100 ml) and water (100 ml) And, within 2 minutes, added dropwise to the periodate solution (TC). After the addition, the mixture was stirred at room temperature for 4 hours and then cooled to (TC. Remove solids by filtration And washed with tetrahydrofuran (100 ml). The combined organic filtrate containing 2,3_〇_isopropylidenepropane di 20 aldehyde (L2) was used in the next step without evaporation of the solvent. Triethyl phosphonate acetate (0.114 mol, 32 g) was added to the combined filtrate of 〇° (: potassium carbonate (0.6 m, gram) dissolved in water) (6 ml) Add to the reaction mixture dropwise at 0 ° C for 1 hour. Stir the two-phase solution for 4 hours. Separate the organic phase, and apply the water phase - 40 - this paper size to the Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1323260 A7 B7 V. Inventive Note (39) "~~ Extract with ethyl acetate (3 X 1 〇〇ml). Combine the organic phase with water (2x100 ml) The solvent was evaporated to give a pale-yellow oil. The crude oil was filtered over silica gel eluting with n-hexane/ethyl acetate (1 〇/9 〇) to give compound (I.3 ' I4·3 g, yield = ^0%), which is an E/z mixture, the ratio 5 is %/4 (measured by 1H NMR). The lH NMR spectrum is consistent with the desired structure.

The synthesis of Li makes the compound (I.3, 〇·1 mol, 2 gram, E/z: 96/4) and nitro decane (〇u Moer '6.7 g) dissolved in acetonitrile (2 〇〇 ml) ) and cool to 〇. Hey. A solution of I,8-diazabicyclo-[no]undecene (〇·ΐ5 mol, 22.8 g) in acetonitrile (50 mL) was added dropwise over 5 10 min. The reaction mixture was stirred at room temperature overnight. Then, most of the solvent was removed under reduced pressure. The residue was diluted with water (200 mL) and ethyl acetate (3. The combined organic layers were washed with 5% aqueous HCl (2 mL) and then brine. Drying with MgS04 and evaporation under reduced pressure afforded intermediate (I.4''9"yield" The iH NMR spectrum is consistent with the desired structure. 1.5 Synthetic Economics Department Intellectual Property Bureau employee consumption cooperative printed compound (I·4, 〇.〇3 Mo, 7.8 g, ipsilateral/contralateral: ~25) in 20 tetrahydrofuran (1 〇〇 ml) The solution in the solution was cooled to 〇. (:. Add lithium borohydride (〇.〇45 mol, !g) in portions over 30 minutes, and stir the mixture at room temperature overnight. After cooling (〇.〇, by slowly adding saturation The solution was quenched with ammonium sulfate (100 ml), and then quenched with ethyl acetate (10×50 ml) and dried with EtOAc EtOAc EtOAc. National Standard (CNS) A4 Specification (21〇X 297 mm) ' 1323260 A7 B7 V. Description of Invention (40) ' "" ' 6. 2 g, yield = 92%), oily. The 1H NMR spectrum is consistent with the desired structure. The synthesis of the ancient oxygen suffolk jg, 3-bl furan _3-alcohol and 7.2, the compound: I.5, 0·011 mol, 24 g, ipsilateral / The contralateral mixture) 5 In a solution of isopropyl alcohol (20 ml), the third-butanol unloading (〇〇132mer' I.5g was added in portions at room temperature within 30 minutes. Transfer the test solution to the addition funnel and add dropwise to the concentrated (37%) hydrochloric acid (0.0275 mol, 2.3 ml) in isopropanol (20 ml) in 1 min. °C) intensely stirred The mixture was stirred at room temperature for 2 hours and 10 hrs. Then triethylamine (0.022 mol, 2.2 g) was added dropwise to cause precipitation of Et3N.HCl salt. The reaction mixture was taken ethyl acetate (50 ml) Diluted 'and filtered to remove the salt. Evaporate the solvent under reduced pressure. The residue was diluted with ethyl acetate (5 mL) to precipitate more Et3 N.HC1 salt. The solvent was evaporated under reduced pressure. The residual oil was filtered on a silica gel-packed column, and purified in 15 steps using ethyl acetate as a solvent to give a mixture of compounds (7.1/7.2, 1.03 g, yield = 72%). It is 78/22 (measured by 1 H NMR). The analysis sample of pure compound (u, 1 = 〇2 is used with (π Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 'Rf7.2=0.15) Obtained by silica gel chromatography using ethyl acetate as a solvent. 20 (3R, 3aS, 6aR)-hexahydro-indolo[2,3-b]nonan-3-ol (71) : 〇MHz, CDC13) 5 1.80-1.91 (1H, m), 2.28-2.34 (1H, called, 2 83 2 89 (out, m), 3.11 (1H, wide s), 3.35-3.59 (lH, m), 3.85-3.98 (3H m ) 4 38 4 45 (1H, m), 5.66. (1H, d, J = 5.2 Hz). (311> ruler, secret) - hexahydro-sniffing and [2,3-13] astringency _3_ol (7.2) :1^·^ -42- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Description of invention (41 (400 MHz, CDCI3) δ 1.68-1.75 (lH, m), 2.12-2.23 (lH,m), 2.42 (1Η> broad s)' 2.79-2.85 (1H,m),3.81-3.91 (3H, m), 3.96-4.01 (iH, m), 4.23 (lH ,m), 5.89 (1H, d, J = 4.9 Hz).

Example II

V-^^COOEt 11.1

CH3NO2 KOH

H2S〇4 Q’, /—C〇〇Et ^ \—( +

EtOH 乂 〇E 丨 II.3 , 〇Et II.3'

HQ

15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1) UBH4

2) HCI

HO

+ CQ 7.2 Synthesis of II.3 and IL3' A solution of nitro-methyl (0.011 mol, 0 67 g) in ethanol (5 liters) was cooled to 0 °C. Ethanol (5 ml) was added dropwise, 8 • diazabicyclo[5 4 〇] eleven _7-ene (0.015 mol, gram), and the reaction was stirred for 3 min. The compound (II.1, 0.01 mol, 2 g, E/z = 96/s in ethanol (5 ml) was added to the solution and added dropwise to the solution at oc. The reaction mixture was allowed to flow at room temperature. Fall overnight' then transfer to the addition funnel and add dropwise to concentrated sulfuric acid (〇.〇3mol, 〇8ml) in 30min (30°C) in ethanol (iC). After stirring at room temperature overnight, the reaction mixture was diluted with water (10 ml), extracted with dichloromethane (3 χ 5 mL), and the organic phase was washed with saturated sodium hydrogen carbonate (10 mL). Drying with _〇4, and evaporating under reduced pressure to obtain crude product-43-

1323260 A7 B7 V. INSTRUCTIONS (42) Preparation of a mixture (ΙΙ, ΜΙ·3,, I·27 g, yield = 58%), as an oil. Using 1H NMR analysis, it was confirmed that the compound II.3 was the main component in the product mixture. The crude product mixture was used as such in the next step. (7.1) and (7.2) from the narration (ΙΙ.3/ΙΙ.3'): 5 Make the crude product mixture (Π.3/ΙΙ·3·) (〇.〇〇6莫耳,1 ·27 G) was dissolved in tetra-furan (20 mL) and cooled to 〇 ° C. Lithium oxide (0.0 〇 9 mol, 200 mg) was added in portions over 5 minutes, and the mixture was allowed to stand overnight at room temperature. The solvent was evaporated under reduced pressure. Concentrated (37%) hydrochloric acid (1 mL) was added dropwise, and the mixture was stirred at room temperature for 10 hr. Then, triethylamine (5 ml) was added dropwise to cause precipitation of Et3N.HCl salt. The reaction mixture was diluted with ethyl acetate (100 mL) and filtered and evaporated. The solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (i.sub.1 mL) to afford a further Et3N. The salt was removed by filtration and the solvent was evaporated under reduced pressure. The residual oil was filtered through a silica gel packed column, and purified in 15 steps using ethyl acetate as a solvent to obtain a mixture of compounds (7.1/7.2, 0.68 g, yield 87%) in a ratio of 87/13. Measured by 1 H nmr). The iH NMR spectrum is consistent with the desired structure. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives -44 - This paper scale applies to the National Standard (CNS) A4 specification (210x297 mm). 1323260 A7 B7 V. Description of invention (43)

Example HI °Λγη mu 〇 <COOMe COOMe

COOMe COOMe III.2

Ch3no2 catalytic DBU

1) NaOMe 2) H2S04 MeOOC HQ &gt;~CO〇Me

〇 A HQ /~COOH -〇Me

〇 ‘ 〇 III.5 〇

'〇Me 1) LiBH4 2) 1N HCI

1) KOH 2) AcOH 〇/^^CO〇Me III.51 , 〇 -〇Me 111.4 〇 OMe ili.4- Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

HO 〇&gt;"&quot;〇 7.1 15 Synthesis of III.2

2,3-0-isopropylidene-propanedialdehyde (III.l, 0.1 mol, 65 g of 20% w/w III.1 in tetrahydrofuran) with dimethyl malonate (0.15 Mo The ear, 19.8 g), acetic anhydride (0.3 mol, 30.6 g) and pyridine (0.05 mol, 3_95 g) were combined and stirred at room temperature overnight. The reaction mixture was evaporated under reduced pressure. The residual oil was diluted with dioxane (200 mL), EtOAc (EtOAc) Fractional distillation gave (III.2, Boiling Point: 88-94 ° C / 〇. 〇 3 mm Hg, 14.2 g, yield = 58%, purity by GC: 83%). TLC (ethyl acetate / hexane 20/80): Rf (III.2) = 0.43 ( ΚΜ η 04 ' in acetone). 1HNMR -45 - This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Description of invention (44) (400 MHz, CDC13): δ 1.39 (3Η, s), 1.45 (3H, s), 3.71-3.75 (1H, m), 3.81 (3H, s), 3.83 (3H, s), 4.25-4.29 (1H, m), 4.90-4.95 (1H, m), 7.04 (1H, d, J = 7.1 Hz). Synthesis of (III.3): 5 In a stirred solution of (III.2, 2 mmol, 490 mg) in methanol (20 mL), first add nitromethane (2.2 Millol, 134 mg), then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mmol, 76 mg), and the reaction mixture was stirred at room temperature 3 hour. The solvent was evaporated under reduced pressure. The residual oil was diluted with a saturated ammonium chloride solution, extracted with dioxane, dehydrated and dried with 10 MgS04, and evaporated under reduced pressure to give crude (III.3) as the ipsilateral/di-side mixture. The range is from 9 (V10 to 97/3 (measured by iHNMR). TLC (ethyl acetate / hexane 20/80): Rf (III.3) = 0.29 (ΚΜη04, in acetone)·· ipsilateral/ The contra-(111,3) isomer was not shown on the TLC as the separation point. The structure of the compound ipsilateral-(III.3) was confirmed by 1 H NMR spectroscopy of the crude 15 reaction mixture: ipsilateral-(III .3) : 1 H NMR (400 MHz, CDC13) : δ 1.23 (3Η, s), 1.31 (3Η, s), 3.13 (1Η, ~五重峰, Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative Printed J = 5.5 Hz), 3.55 (1H, d, J = 5.5 Hz), 3.66-3.69 (overlap, 111, 111), 3.68 (311, s), 3.70 (3H, s), 4.05 (1H, dd, Jt = 8.8 Hz, J2 = 6.7 Hz), 4.22 (1H, ~q, J -5.9 Hz), 4.60 (1H, dd, = 14.8 Hz, J2 = 4.8 Hz), 4.67 (1H, dd, J! = 14.8 20 Hz, J2= 5.9 Hz). (III.4/III.4,) Synthesis from (III.2): Stirring in (III.2, 0.05 mol, 12.2 g) in decyl alcohol (50 ml) Inside, first add nitromethane (0.055 mol, 3_36 g), then 1,8-diazabicyclo[5.4.0]undec-7-ene (5 mmol, 760 mg)' and will -46 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1323260 Α7 Β7 5. Inventive Note (45) The mixture should be stirred at room temperature for 4 hours" to cool the reaction mixture to 〇β (: ' And add a solution of sodium methoxide in methanol (〇〇5 ml, 25 ml) dropwise over 30 minutes. Then, transfer the mixture to the addition funnel and add to the concentrate in 45 minutes. Sulfuric acid (0.125 mol, 12 g) was stirred in a vigorously stirred solution of methanol (25 5 mL) to maintain the internal temperature. During the addition, a white precipitate formed and the suspension was allowed to stand at room temperature. Stir overnight. Evaporate the reaction mixture to one and a half of the original volume, then slowly pour into a cooled saturated sodium bicarbonate solution (2 mL) maintaining the internal temperature &lt;10 ° C. Extract with vinegar (4 X 50 ml) and wash the combined solution with water (5 ml). A mixture of the crude compound was obtained (ΙΙΙ.4/ΙΙΙ.4' ' 8.3 &lt; 7 g 'yield = 78%) as a crude H. It is the main reaction product. The analysis sample of the compound (ΙΙΙ.4) was obtained by rapid-sequence chromatography on silica gel, and was obtained by dissolving acetic acid in the form of 50/50. TLC (acetate acetate 15 / hexane 50/50): π. 4 0.45 (ΚΜη04, in acetone). (UL4) : 1 H NMR (400 MHz, CDC13) : δ 3.33 (3Η, s), 3.39 (1HS dd, = 7.〇Hz, J2= 4.4 Hz), 3.58 (1H, d, J = 4.4 Hz) , 3.82 (3H, s), 3.97 (1H, dd, Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative printing = 11 Hz, J2 = 3.9 Hz), 4.10 (1H, d, J - 11 Hz), 4.95 (1H, s), 5.23 (1H, dd, 1^7.0 Hz, J2 = 3.9 Hz). 20 (ΠΙ.5) Synthesis: ... Dissolve potassium hydroxide (0.025 mol, 1.42 g) in methanol (10 ml) ) Ten with water (2 ml). A solution of crude (ΙΙΙ.4/ΙΙΙ.4,, 0.023 mol, 5.2 g) in methanol (10 ml) was added and the reaction mixture was heated under reflux for 2 to 3 hours. TLC analysis showed that all starting materials (ΠΙ·4/ΙΙΙ·4,) were completely converted, and the -47- paper scale was applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm). 1323260 A7 B7 V. Description of the invention (46) &quot; The reaction mixture is concentrated under dust reduction to the original volume. The residual solution was mixed with acetic acid (10 ml) and stirred at room temperature for 2 hr. After the absence, the reaction mixture was diluted with water (20 ml) and extracted with ethyl acetate (3 χ 2 毫升). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (2 mL), dried over EtOAc EtOAc EtOAc EtOAc EtOAc , is a solid. Compound (ms) i analysis - The sample was obtained by recrystallization from isopropanol to provide a pure compound as a colorless needle. TLC(Et〇Ac) _· Rf(In 5) = 〇49. (ιπ5) · 1H NMR (400 MHz, CDCl3): 5 2.51 (1H, dd, =18 6 Hz, J2 = 4 〇10 Hz), 2.84 (1H, dd, ίγ = 18.6 Hz, J2 = 11.3 Hz), 3.00-3.06 (1H, m), 3.33 (3H, s), 3.95 (1H, dd, = 10.9 Hz, J2 = 3.9 Hz), 4.10 (1H, d, J = l〇9 Hz), 4.88 (1H, s), 5.14 (1H, dd, Jj = 7.0 Hz, J2 = 3.9 Hz) (7.1) Synthesis from (III.5):

Ministry of Economic Affairs, Intellectual Property Office, Staff Cooperatives, M. In a solution of compound (in·5 ' 〇·〇ιι Mo, I·88 g) in tetrahydrofuran (20 ml) 15 in a cooled (0 ° c) solution, at 10 Lithium borohydride (0.0 Torr, 37 〇 mg) was added in portions over a minute. The suspension was stirred at room temperature overnight until TLC analysis showed complete conversion of starting material (111.5). Then, the reaction mixture was cooled on ice, and the reaction was quenched by water (5 ml). Evaporate the reaction mixture under reduced pressure (bath temperature = 40 〇c, p = 2 mbar), 20 until most of the tetrahydrofuran is evaporated, and the residual water is dissolved and acidified to pH Η = 0-1 . The reaction mixture was stirred at rt for EtOAc (EtOAc) (EtOAc) The combined organic layers were dried with EtOAc (EtOAc m.) (71) Structure -48- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A7 B7 V. Description of invention (π) Confirmed by 1H NMR spectroscopy. The purity of the palm isomer of the compound (7.1) was determined by GC analysis of its acetate. Therefore, the compound (7J, 〇. 5 g) was mixed with acetic anhydride (2 g) and N,N-dimethyl-glycolidine (methanol) and stirred at room temperature overnight. The reaction mixture was diluted with hexane (5 mL) and washed with EtOAc (EtOAc) The palmar enthalpy of the hexane solution (: analysis, allowing the determination of the compound (7.1) of the palmo isomer excess system &gt; 99%. -. - ^ Example IV (〇OMe Q COOMe 〇 IV.1

Η

Ch3no2 COOMe catalytic DBU COOMe IV.2

HQ 1) UBH4 2) Concentrated HC1 and COOMe I COOMe o2h IV.3 . 1) NaOMe 2) H2S04 MeOOC COOMe hq )TMCO〇Me 15

1) KOH 2) AcOH 〇-〇Me 7.1 IV.5 OMe IV.4 'OMe IV.4' Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperative (IV.2) &lt; 2,3-0- Isopropyl-propanedialdehyde (Iv.l, (6) 4 mole, 1〇75 kg 2〇% w/w (IV.l) solution in tetrahydroanion) and malonate dimethyl from ^ Equivalent, I654 Moer's training kg) mixed, and stirred for 2 hours under 2〇〇c. Pyridine (0.5 eq, 827 mol, 65.5 kg) was added and the reaction mixture was heated to 45 c. At this temperature, a solution of acetic anhydride (3 equivalents, 4% 2 moles, 506 kg) in tetrahydrofuran (5 〇 6 kg) was added over a period of 4 hours - 49. After heating at 45 C for 12 hours, most of the solvent (12 (8) kg) was removed by vacuum evaporation, and the residual oil was diluted with toluene (25 〇〇 kg). The organic solution was added to the vigorously mixed aqueous sodium bicarbonate suspension over a period of 2 hours, which was previously prepared by mixing solid carbonic acid sodium (19 〇 kg) with (1) sodium hydrogencarbonate (1760 kg). to make. After phase separation, the aqueous phase was removed and the organic phase was washed with 1N sodium bicarbonate (176 g). Then, most of the evaporation was carried out under reduced pressure until the residual amount was about "o kg. Further removal of toluene and conversion of the solvent to methanol was carried out by azeotropic distillation with methanol by repeating (twice) addition. Sterol (500 kg) and evaporate the same 10 (500 kg) under reduced pressure. Finally, add methanol (83 〇 kg) to give intermediate IV.2 (1280 kg, 23 6% solution in decyl alcohol) The intermediate ϊν.2 is used in the next step itself. (ΐν·4/ΐν·4,) from the synthesis of (IV.2) · The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, prints the intermediate ( IV.2) (5〇3 mol, wo kg, 23 w/w IV2 in 15 sterol) and nitro hydrazine &gt; (1.1 equivalent, 553 m, 62 kg, 55% w/w Mixing with thiol in decyl alcohol, and adding 1,8-diazabicyclo[5.4_〇] eleven-7 olefin (ο" equivalent, 5 under stirring in the reaction mixture. 〇, 3 m, 7.6 kg), keep the internal temperature &lt;25 °C during 3 〇 minutes. Stirring was continued for 3 hours at room temperature. The reaction mixture was cooled to 〇«&gt; 〇, 2 〇 and 2N sodium methoxide in methanol (1.1 when I, 553 Mo' 100 kg, sodium methoxide in decyl alcohol 3 〇 % w/ was added dropwise in minutes. w solution), keeping the internal temperature at 0 °C. Here. (: After the next 30 minutes, the reaction mixture was distributed to concentrated sulfuric acid (2.5 eq, 12 murole, 128 kg, 96% sulphuric acid) in decyl alcohol (2 〇〇 kg) during 1 hour. (〇.〇 Intense Stirring Solution - 50 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) B7 Description of invention (49) Inside 'Keep internal temperature&lt;10. 〇. Further cool the reaction mixture To 0〇C' and added to ethyl acetate (450 kg) and IN sodium bicarbonate (1.9 equivalents, 1905 kg) with vigorous stirring and cooling (0. in a two-phase system, maintaining internal temperature over a period of 1 hour) &lt; 15 ° C. The reaction mixture was filtered to remove most of the precipitated sodium sulfate. After phase separation, the organic phase was collected, and the aqueous phase was extracted four times with ethyl acetate (ethyl acetate: 2 is 0 kg). The collected organic phase is washed with brine (300 kg 23% w/w sodium chloride solution) and evaporated under reduced pressure to a residual amount of 75 kg (containing about 66 kg) Intermediate IV.4). The intermediate Ιν·4 was used as it is in the next step. The taste is in (IV.4) (750 kg solution, about 66 kg IV.4 in methanol) in the drop solution, add water (Μ kg) and potassium hydroxide (Μ 3 mol, egg kg 'magnesium potassium hydroxide aqueous solution), and The reaction mixture was heated to reflux for 2 hours. Quickly cooled to 35. (:, then, acetic acid (.sup.ss.sssssssssssssssssssssssssssssssssssssssssssssssssssssss , to a residual amount of about 2 〇〇 kg. After cooling to room temperature, add more acetic acid (354 kg), during the 丨 hour period. After stirring at room temperature for 2 hours, remove most of the acetic acid by vacuum evaporation. After a period of 1 hour, the residual amount is about 25 〇 kg. Add water (8 〇〇 kg), and extract the aqueous solution with ethyl acetate to the king of kilograms. The combined organic layer is m sodium bicarbonate. Wash twice (2X 586 kg). The third wash with sodium bicarbonate is carried out with pH control; sodium bicarbonate is added until the pH value is 6.8-7.2 (using about 410 kg...carbonic acid steel). Ethyl acetate to isopropanol solvent attack 'system (four) money in the lower (four) solution Residues • 51 - 1323260 A7 B7 V. Description of the invention (50) The amount is 200 kg, add isopropanol (350 kg), evaporate the organic solution under reduced pressure to a residual amount of 200 kg, and add isopropanol (350 kg) The reaction mixture was heated to 60-70 ° C, and isopropanol was further evaporated to a residual amount of about 144 kg at this temperature and reduced pressure. After filtration, 5 the reaction mixture was cooled to 0. At ° C, the intermediate (IV.5) was allowed to undergo crystallization over a period of 4-5 hours. Filtration of the crystals and drying (vacuum drying at 40 ° C) gave intermediate (IV.5) (27 kg). Intermediate IV.5 was used as such in the next step. (7.1) Synthesis: Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 10 Add boron to the intermediate (IV.5) (180 m, 30 kg) in tetrahydrofuran (160 kg) in 30 minutes. Lithium hydride (1.1 equivalents, 198 moles, 43.1 kilograms, 10% lithium borohydride in tetrahydrofuran). The reaction mixture was heated to 50 ° C over a period of 1 hour and stirred at this temperature for 2 hours. The obtained suspension was cooled to -10 ° C, and hydrochloric acid (1.2 15 equivalents, relative to LiBH 4 , 238 mol, 27.2 kg of 32% hydrochloric acid) was dispensed, and the internal temperature was maintained for -4 ° C over a period of 4 hours. . After stirring for an additional 2 hours at -1 °C, triethylamine (1.1 equivalents, 261 moles, 26.5 kg vs. HC1) was added over the period of 1 hour while maintaining the internal S degree &lt; 〇 °C. The solvent is converted to ethyl acetate by distilling the solvent under atmospheric pressure to a residual amount of about 100 20 kg, adding ethyl acetate (360 kg), and further distilling the furan/ethyl acetate solvent mixture, and continuously adding ethyl acetate to Keep a constant volume to carry it out. This procedure was continued until the ratio of tetrahydrofuran/ethyl acetate was 4:1 (confirmed by gas chromatography). The resulting mixture was cooled to 0 ° C, filtered, and the filter cake was washed with two portions of ethyl acetate (2 x 30 - 52 - paper scale applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1323260 A7 B7 V. Description of invention (51) kg). The collected filtrate was evaporated to give the compound (7.1) (18 kg). The identity of Compound 7.1 was confirmed by HPLC, NMR and palm gas chromatography using a reference sample obtained from Example III.

-Installation - Order. .

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives Printed 3 5 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

Claims (1)

1323260 公告 Announcement. 丨Α8 Β8 C8 D8 Patent Application No. 91120509 ROC Patent Appln. No. 91120509 After the amendment, please patent the broken text-Annex (3) AmpndpH ΐη (Ήίηρςρ - F.nr.l ΠϊΤ, 6. The scope of application for patents (submitted on October 28, 1998) Submitted on October 28, ί 5 1. A synthetic (7) hexahydro-puro[2,3-b]furan-3-ol The method "·----------- begins with the intermediate of formula (1), wherein P1 and P2 each independently represent hydrogen, a hydroxy protecting group, or may together form a di-Cw alkylmethylene group , OP2 pl〇^YH converts the intermediate of the formula (1) into a nitrosterane derivative of the formula (3), wherein _R1 represents a Cm alkyl group, R2 represents hydrogen or C(=0)0R3, and R3 represents CN6. Burning group, OP2 R2 P1〇v^J\^Ac〇〇R1 3, N〇2 10 Next, the nitrodecane derivative is converted into a tetrahydrofuran derivative of the formula (6), wherein OR4 represents an O-Cu alkyl group, HO OH OR* 15 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, and then converted into the formula (6) by intramolecular cyclization in the presence of a strong acid and at a temperature below 15 °C. Hexahydro-furo[2,3-b]furan-3-ol. HO ip 20 2. According to the method of claim 1 of the scope of patent application, which uses Nef anti-54 - this paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) 91409B-chasing 3 1323260 A8 B8 C8 D8 six The scope of the patent application should be such that the intermediate of formula (3) is converted into the intermediate of formula (6). 3. The method according to claim 1, wherein the method comprises the steps of: a) using a Witting reaction, a Horner-Emmons reaction, a Knoevenagel reaction or a Reformatsky reaction to condense the intermediate 5 of the formula (1) with an OP2 P1 〇々 form ( 2) α, /3-unsaturated ester, ΟΡ2 ψ 10 b) reacting the ester of formula (2) with nitromethane in the presence of a base and at a reaction temperature of from about 0 ° C to about 100 ° C. Formula (3) Intermediate, ) PZ R2 Pi〇. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Cooperatives, Printing and Clothing Co., Ltd. 15 C) The temperature is set between about -78 ° C and about 55 ° C, so that the intermediate of the formula (3) accepts the Nef reaction, resulting in the formula (4) and (4') intermediate, HO R2 COOR1 4· OR4 d) converts the intermediates of formula (4) and (4') into intermediates of formula (6), and -55 - this paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 1323260 A8 B8 C8 D8 Patent application scope HO 6〇R4 OH e) The intermediate of formula (6) is converted to the compound of formula (7) by intramolecular cyclization in the presence of a strong acid and at a temperature below 15 °C. 4. The method according to claim 1, 2 or 3, which comprises the steps of: a) condensing an intermediate of formula (1) with CHR2, wherein R5 represents hydrogen, a carboxylic acid ester, a scale salt or a phosphonate. , 10 ρι〇. Η ORt Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 15 (2) α,/5 -unsaturated ester 0Ρ2 R2 P1Q b) reacting the ester of formula (2) with nitromethane, resulting in the intermediate of formula (3) 0P2 COOR1 C) intermediate the formula (3) The Nf reaction is carried out by treating it with a base and then with a strong acid to form a mixture of intermediates of formula (4) and (4'), -56 - the paper scale applies to the Chinese National Standard (CNS) A4 Specifications (210x297 mm) 1323260 A8 B8 C8 D8 VI. Patent application scope 4 OR4 COOR1 4&lt; OR4 d) However, if R2 is not hydrogen, the intermediates of formula (4) and (4J are decarboxylated, so that intermediates of formula (5) and (5') are formed individually. 5' e) reducing the intermediate of formula (4) and (4'), or the intermediate of formula (5) and (5') with a suitable reducing agent to form an intermediate of formula (6), and 6 OR4 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 15 10 f) The intermediate of formula (6) is converted to the compound of formula (7) by intramolecular cyclization. 5. The method of claim 1, wherein the intermediate of formula (3) is prepared by a process comprising the steps of: first condensing the intermediate of formula (1) with nitromethane, resulting in The intermediate of formula (8), and secondly, the intermediate of formula (8) is reacted with CHI^RS-CtCO-OR1, wherein R8 is hydrogen or a dicarboxylic acid. -57 - This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 6. The method of claim i, 2 or 3, wherein the intermediate of formula (6) is prepared by a process comprising the steps of: first, using an appropriate reducing agent, wherein R2 is an intermediate of hydrogen Reduction, resulting in an intermediate of formula (9), and secondly, the resulting intermediate is subjected to a Nef reaction for examination and then treatment with a strong acid. C - OH 10 Ministry of Economic Affairs Intellectual Property Office Employees' Consumption Cooperatives Printed 15 20 7. According to the method of the application of the scope of the patents, item i, 2 or 3, where the ruler and R are independent of the Cl-6 yard, and R4 is burnt base. 8. The method of claim i, 2 or 3, wherein each of R1, R3 and R4 is independently methyl, ethyl, propyl, isopropyl 'n-butyl, isobutyl, second- Butyl, tert-butyl or pentyl. 9. According to the method of claim i or 2 or 3, one of them forms an acid-labile di-Cl6 alkylmethylene group with p2. 10. The method of claim i, 2 or 3, wherein pi and p2 together form a bis-(C1-6)alkylmethylene group. U. According to the method of claim 4, wherein r5 is hydrogen, r1〇_C(=〇)-, (R6)3P=, wherein "is ^^ alkyl, c6_12 aryl or aryl-C1- 6 alkyl, or (R70) 2P (=0), wherein r7 is a Cl6 top group, a C6-12 aryl group, a C6-12 aryl-C1-6 alkyl group. 12. According to the scope of the patent application No. 1, 2 or The method of 3 items, wherein the ruler 8 is 58 paper size standards (CNS) A4 specifications (2) G χ tear public love) /, the patent application scope hydrogen or 13. A method with the formula (3) Interstitial, 'COOR' N〇2 3 5 10 wherein P1 and p2 each independently represent hydrogen, a hydroxy protecting group, form a di-c, _6 silk methylene group, and Ri represents a Ci6 surface group, or a C (= 〇) 〇r3, R3 represents c丨·6, and the condition is that when R2 is hydrogen and pi is replaced with p2, when propyl is used, then R1 is not methyl or ethyl. Intermediate with formula (4) or (4,), 'R2 HO R2 4* 〇R&lt; COOR1 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperation du printing 15 where R1 denotes Cw yard base; R2 denotes hydrogen or c(= 〇)〇r3 shows the Ci_6 yard base; OR1 means 〇_(^·6 yard base. Formula (5) or (5 ') of the intermediate, Wherein OR1 represents a 〇-CU6 alkyl group. -59 - ;R3 table This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1 OR1 丄wou A8 B8 C8 16. The method of claim 1, wherein starting from the intermediate of formula (10), wherein pi is used together with p2 to form an isopropylidene group, the intermediate of formula (1.1) is condensed, resulting in the middle of formula (21) Wherein P1 and P2 are used together to form an isopropylidene group, and r2 represents _C(=0)0R3, wherein R3 is a methyl group and Ri is a fluorenyl group, 10 P〇〇Me COOMe 2.1 COOMe COOMe 15 Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, the (2.1) ester is reacted into the nitromethane derivative of formula (3.1), wherein P1 is used together with P2 to form an isopropylidene group, and R2 represents _C. (=0)0R3, wherein R3 is methyl and R1 is methyl, 3.1 using a base, and then an acid, the intermediate of formula (3.1) is converted to produce intermediates of formula (4.1) and (4'.1) And r2 represents _c(=〇)〇r3, wherein R3 is methyl, r1 is methyl, and R4 is fluorenyl, 20 COOMe -60 - This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1323260 A8 B8 C8 D8 VI. The scope of patent application decarboxylates the intermediate of formula (4.1), resulting in the intermediate of formula (5.1) R4 is methyl, its 5.1 ΟΜβ Ό Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed with appropriate reducing agents to reduce the intermediate of formula (5.1), resulting in the intermediate of formula (6.1), where R4 is methyl, 6.1 10 by intramolecular cyclization The intermediate of formula (6.1) is converted to compound 7.1. ΗΟ 7.1 7.1 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)