Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
  • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
  • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
  • C07F7/02—Silicon compounds
  • C07F7/08—Compounds having one or more C—Si linkages
  • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
  • C07F7/1804—Compounds having Si-O-C linkages

Definitions

• the present invention relates to a synthetic intermediate for a medicament and a process for the preparation thereof, and in particular to a novel synthetic intermediate for the preparation of entecavir and a process for the preparation of the intermediate.
• Entecavir is the third anti-hepatitis B virus (HBV) drug listed after lamivudine and adefovir dipivoxil, and is the most potent anti-HBV drug currently on the market.
• the anti-HBV effect of entecavir is 100 times that of lamivudine and more than 30 times that of adefovir dipivoxil; its side effects are very low, the selection index is greater than 8000, and the HBV virus resistant to lamivudine is also very Good curative effect is one of the most important drugs for the treatment of hepatitis B.
• entecavir contains a chiral five-membered ring and a guanine nucleus.
• the chiral five-membered carbocyclic ring has three chiral centers and one methylene ring outside the ring.
• the structure is more complicated, although it has been reported that There are few synthetic methods, but existing synthetic methods have difficulties in preparation. At present, there are mainly the following methods for preparing entecavir.
• the preparation method of entecavir is disclosed in Chinese patent ZL91110831.9 and international application WO98/09964.
• the method comprises the steps of: reacting cyclopentadiene as a raw material, and sequentially reacting with chloromethylbenzyl ether and a di-enyl borane complex (Ipc 2 BH) prepared from (+)- ⁇ -olefin to obtain a chiral intermediate iii.
• Vi is protected by a single p-methoxytriphenylchloromethane (MMTC1) protecting group, and then oxidized to a keto group by the Dess-Martin reagent to give viii.
• Viii is subjected to a methyleneation reaction under the action of Nysted reagent and titanium tetrachloride to obtain ix.
• the problems in the preparation method should be complicated, and some reagents are expensive.
• the starting materials require expensive chiral boron reagents, and some intermediates are difficult to synthesize, the reaction conditions are harsh, and the final debenzylation is highly toxic.
• the boron trichloride is highly polluting to the environment and requires high equipment.
• WO2010/074534 uses the following reaction to prepare entecavir via Intermediate II, but the reaction conditions are harsh, the reagents used are expensive, and it is difficult to apply to industrial production.
• alkyl denotes a straight or branched monovalent saturated hydrocarbon group consisting of carbon and hydrogen atoms.
• Cw alkyl means a branched or straight-chain alkyl group having 1 to 6 ⁇ , such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, Is the base.
• alkylene denotes a straight or branched divalent saturated hydrocarbon group consisting of carbon and hydrogen atoms.
• d_ 6 alkylene denotes a ⁇ 1-6, child Branched or linear alkylene, such as methylene, ethylene, and the like.
• alkane alone or in combination with other groups, denotes a radical R,-0-, wherein R is an alkyl radical as defined above.
• d- 6 alkoxy denotes a radical R,-0-, wherein R, Is as described above
• Halogen means fluorine, chlorine, bromine or iodine.
• Haloalkyl means an alkyl group as defined above substituted by one or more halogens, for example trifluoromethyl.
• Aryl means a monocyclic or fused bicyclic aromatic ring containing a carbon atom.
• C 5 _ 1Q aryl means an aryl group having 5 to 10 carbon atoms.
• the C 5 _ 1() aryl group can be phenyl or naphthyl.
• Alkyl means an alkyl group as described above substituted with an aryl group as described above.
• Alkyloxy means an alkoxy group as described above substituted with an aryl group as described above.
• Grubbs catalyst refers to a Grubbs catalyst that catalyzes the metathesis of olefins.
• the first generation of Grubbs catalyst is, for example, benzylidene-bis(tricyclohexylphosphine) dichloro ruthenium
• the second generation catalyst of Grubbs is, for example, benzylidene-[1,3-di(2,4,6-three) Methylphenyl)-2-imidazolinium iododi-(tricyclohexylphosphine) ruthenium.
• Dioxane wire means "compound 2, wherein R" are each independently of formula NR 6 alkyl or C 3 _ 7 cycloalkyl is selected D_, e.g. N, N- diisopropylamine, N, N- Dicyclohexylamine.
• the dioxane further includes two R" together with the N atom to which they are attached forms an optionally substituted heterocyclic ring, for example, 2,2,6,6-tetramethylhexahydropyridine.
• the present invention provides a novel process for the preparation of intermediate II in the entecavir synthesis of formula I which has a higher yield, lower cost and less environmental pollution than existing processes.
• the invention provides a novel method of synthesizing intermediate II, characterized by Asymmetric catalytic reaction
• the chiral five-membered carbocyclic intermediate II of entecavir was prepared in high yield.
• R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH 2 -, (iv An aralkoxyalkylene group, such as an aralkylmethyl group, such as a BnOCH 2 -, or a (V) silane group, such as a triphenyl 3 ⁇ 4, a triisopropylsilyl group, a tert-butyldimethyl group, a tertiary Butyl diphenyl ⁇ ⁇ group;
• R is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl group, a t-butyl dimethyl group: Uncle Ding ⁇ ! Benzene: base; the method comprises the following steps:
• compound 6 is epoxy-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,
• the reaction solvent may be a polar or non-polar aprotic solvent, and preferred solvents include, but are not limited to, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dioxane, diethyl ether.
• the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene or toluene.
• the catalyst for the reaction may be Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%, and the reaction temperature is from room temperature to 120 * €.
• a coordination reagent of metal vanadium is used as a catalyst, such as VO(acac) 2
• the epoxidizing reagent may be t-butyl hydroperoxide, hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid.
• the reaction solvent can be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene, toluene and other solvents; reaction temperature is 0" € ⁇ room temperature, reaction time is 1 ⁇ 48 hours.
• R is selected from the group consisting of BnOCH 2 -, MeOCH 2 -, t-Bu(Me) 2 Si -, i-Pr 3 Si- and t-BuPh 2 Si - X is a halogen, such as C1;
• the base used in the reaction may be triethylamine, diisopropylethylamine, DBU, imidazole, etc.;
• the reaction solvent may be dichloromethane, 1,2-dichloroethane, Chloroform, tetrahydrofuran, benzene, toluene, dimethylformamide;
• the temperature should be -10*C ⁇ 45X.
• the dialkyl aluminum chloride reagent is, for example, diethylaluminum chloride
• the N,N-dialkyllithium is prepared in situ from the corresponding dialkylamine by reaction with butyllithium, wherein the dialkyl group
• the amine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine and 2,2,6,6-tetramethylhexahydropyridine, preferably 2,2,6,6-tetramethyl-6 Hydropyridine; reaction temperature is -20" € ⁇ room temperature, reaction time is 1 ⁇ 48 hours.
• the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps c) to e) as a raw material.
• the compound of the formula (4) can be used as a raw material and the steps d) to f) as described above can be used to prepare the intermediate II, or the compound of the formula (5) can be used as a raw material and the step e) as described above can be carried out. f) to prepare intermediate II, and the like.
• R is a hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH 2 -, (iv ) aralkyloxy alkylene, e.g. methylene aralkyl * ⁇ , as BnOCH 2 -, or (V) silyl, such as triphenyl silicon, triisopropylsilyl, tert-butyldimethyl , tert-butyl diphenyl ⁇ ⁇ group;
• R is a hydroxy protecting group, selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group, such as a triphenyl group, a triisopropyl J3 ⁇ 4 group, a t-butyl dimethyl group , tert-butyl benzene ⁇ ⁇ base; the method comprises the following steps:
• X is a halogen or a cyano group
• compound 6 is epoxy-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,
• the reaction solvent may be a polar or non-polar aprotic solvent, and preferred solvents include, but are not limited to, tetrahydrofuran, dichloromethane, chloroform, dimethylformamide, dioxane, diethyl ether.
• the reaction solvent may be tetrahydrofuran, diethyl ether, dibutyl ether or dioxane.
• a preferred solvent may be tetrahydrofuran.
• the reaction time is from 1 to 48 hours, and the reaction temperature is from -78 to room temperature.
• the cuprous halide reagent can be Cul, CuBr or CuBr.Me 2 S.
• Compound 1 can be produced according to the method of the literature (Angew. Chem. Int. Ed. 2010, 49, 881).
• the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane.
• the reaction solvent may be dimethylformamide, dichloromethane, chloroform or toluene.
• the base includes an organic base such as triethylamine,
• the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of steps a) to e) as a raw material.
• a compound of the formula (4) can be used as a raw material and carried out as described above.
• the intermediates II are prepared by the steps d) to f), or the intermediates of the formula (2) are used as starting materials and the steps b) to f) as described above are carried out to prepare the intermediate II, and the like.
• the invention provides a compound of the formula V:
• R is a hydrogen or hydroxy protecting group selected from: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkylene group such as MeOCH 2 -, (iv An aralkoxyalkylene group, such as an aralkyloxymethylene group, such as a BnOCH 2 -, or a (V) silane group, such as triphenyl&, triisopropylsilyl, tert-butylmethyl, tert-butyl ⁇ phenyl;
• R which is a hydroxy protecting group, is selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group, a triisopropyl group, a tert-butyl group; Base, tert-butyl benzene ⁇ ⁇ base.
• the compound of formula V is selected from the group consisting of:
• the invention provides a method of preparing a compound of formula V,
• R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an alkyl group, (ii) an aralkyl group such as a benzyl group, (iii) an alkoxyalkylene group such as an alkoxymethylene group such as MeOCH 2 -, (iv) an aralkoxyalkylene group, such as an aralkyloxymethylene group, such as a BnOCH 2 -, or a (V) silane group, such as a triphenylsilyl group, a triisopropylsilyl group, a tert-butyl group ⁇ , ⁇ ;
• R which is a hydroxy protecting group, is selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as triphenyl, triisopropyl, tert-butyldimethyl, and tert-butylbenzene.
• the method includes the following steps:
• X is a halogen or an aryl group
• R is hydrogen, R, as defined above,
• R and R as defined above, and R is not hydrogen.
• reaction conditions of steps a), b), c), d) and e) are as described above.
• the intermediate product can be prepared by directly carrying out the subsequent reaction using the reaction product obtained in any of the steps a) to d) as a raw material.
• the compound of the formula (4) can be used as a raw material and the steps d) to e) as described above can be carried out to prepare the compound V, or the compound of the formula (2) can be used as a raw material and the steps b) to e as described above can be carried out.
• the invention provides a compound of formula 4:
• R is a hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as triphenyl & triisopropyl, tert-butyl & tert-butyldiphenyl ⁇ ⁇ ⁇ .
• the invention provides a method of preparing a compound of formula 4,
• R is a hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group: a trisyl group, a triisopropyl group, a tert-butyl group! M ⁇ : base, tert-butyl diphenyl ⁇ J3 ⁇ 4 base, the method comprises the following steps:
• X is a halogen or an aryl group
• reaction conditions of steps a), b), c) are as described above. It will be understood by those skilled in the art that in the above method of synthesizing the compound 4, the reaction product obtained in any of the steps a) to b) can be directly used as a starting material to carry out the subsequent reaction to prepare the intermediate II.
• compound 4 can be prepared by using the compound of formula (3) as a starting material and carrying out step c) as described above, or using the compound of formula (2) as a starting material and carrying out steps b) to c) as described above. Compound 4, and so on.
• the invention provides
• R is a hydrogen or hydroxy protecting group selected from: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl JJ3 ⁇ 4 group, a triisopropyl group, a tert-butyl group JJ3 ⁇ 4 base, tert-butyldiphenyl group.
• the compound of formula III is selected from the group consisting of:
• the invention provides a method
• R is a hydrogen or hydroxy protecting group selected from the group consisting of: (i) an aralkyl group such as a trityl group, or (ii) a silane group such as a triphenyl group, a triisopropyl group: a tert-butyl group M ⁇ 3 ⁇ 4 base, tert-butyl diphenyl silicon,
• the method includes the following steps:
• X is a halogen or a cyano group
• R is as defined above, and R is not hydrogen and X is halogen.
• reaction conditions of steps a), b) are as described above.
• the invention provides a method of synthesizing entecavir of formula I via intermediate II as described above, characterized in that entecavir is obtained by the Mitsunobu reaction of the intermediate II with a guanine derivative.
• the method for synthesizing entecavir of formula I comprises the steps of: c) subjecting compound 3 to the cyclic compound 4 via olefin metathesis in the presence of a Grubbs catalyst,
• R is as defined by the compound of formula II above,
• X is a compound, R and R, as defined by the compound of formula II above,
• compound 6 is epoxy-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,
• R and R are as defined by the compound of formula II above,
• the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene or toluene.
• the catalyst for the reaction may be Grubbs first or second generation catalyst in an amount of from 0.1 to 20 eq%, and the reaction temperature is from room temperature to 120 " €.
• a coordination reagent of metal vanadium is used as a catalyst, such as VO(acac) 2
• the epoxidizing reagent may be t-butyl hydroperoxide, hydrogen peroxide, m-chloroperoxybenzoic acid, peroxybenzoic acid.
• the reaction solvent can be dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, benzene, toluene and other solvents; reaction temperature is 0X ⁇ room temperature, reaction time is 1 ⁇ 48 hours .
• R is selected from the group consisting of BnOCH 2 -, MeOCH 2 -, t-Bu(Me) 2 Si -, i-Pr 3 Si- and t-BuPh 2 Si - X is a halogen, such as C1;
• the base used in the reaction may be triethylamine, diisopropylethylamine, DBU, imidazole, etc.;
• the reaction solvent may be dichloromethane, 1,2-dichloroethane, chloroform , tetrahydrofuran, benzene, toluene, dimethylformamide; reaction temperature is -10*C ⁇ 45X.
• the dialkyl aluminum chloride reagent is, for example, diethylaluminum chloride
• the N,N-dialkyllithium is prepared in situ from the corresponding dialkylamine by reaction with butyllithium, wherein the dialkyl group
• the amine is selected from the group consisting of N,N-diisopropylamine, N,N-dicyclohexylamine and 2,2,6,6-tetramethylhexahydropyridine, preferably 2,2,6,6-tetramethyl-6 Hydropyridine; reaction temperature is -20" € ⁇ room temperature, reaction time is 1 ⁇ 48 hours.
• the Mitsunobu reaction reagent is a phosphine catalyst such as triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate
• the reaction solvent may be an aprotic solvent such as tetrahydrofuran, dichloromethane, or Oxycyclohexane, diethyl ether, toluene, etc.; tetrahydrofuran is preferred.
• the reaction temperature is -23 "C ⁇ room temperature.
• the reaction time is 1 to 48 hours.
• the reaction solvent is an aprotic or protic solvent such as tetrahydrofuran, dioxane, methanol, ethanol or the like
• the acid used is a mineral acid such as hydrochloric acid, sulfuric acid or the like.
• the reaction temperature is room temperature ⁇ 120" €.
• the reaction time is 3 to 48 hours.
• the reaction product obtained in any of the steps c) to g ) can be directly used as a raw material to carry out the subsequent reaction to prepare entecavir of the formula (I).
• a compound of the formula (4) can be used as a raw material and carried out as described above.
• the method of synthesizing entecavir of Formula I comprises the steps of: a) intermediate compound 1 being reacted with an isopropenol Grignard reagent in the presence of a cuprous halide to provide a compound 2
• X is a halogen or an aryl group
• compound 6 is epoxy-opened to form intermediate II under the action of a dialkylaluminum chloride reagent and lithium N,N-dialkylamine,
• the reaction solvent is a polar or non-polar solvent, and preferred solvents are tetrahydrofuran, dichloromethane, chloroform, methanol, ethanol, dimethylformamide, dioxane, diethyl ether.
• the reaction solvent may be tetrahydrofuran, diethyl ether, dibutyl ether or dioxane.
• a preferred solvent may be tetrahydrofuran.
• the reaction time is from 1 to 48 hours, and the reaction temperature is from -78 to room temperature.
• the cuprous halide reagent can be Cul, CuBr or CuBr.Me 2 S.
• Compound 1 can be produced according to the method of the literature (Angew. Chem. Int. Ed. 2010, 49, 881).
• the primary hydroxyl protecting agent R, X is selected from the group consisting of triphenylsilyl chloride, triisopropylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldiphenylsilyl chloride, three Phenylchloromethane.
• the reaction solvent may be dimethylformamide, dichloromethane, chloroform or toluene.
• the base includes an organic base such as triethylamine,
• the synthetic route of entecavir is as follows,
• the synthetic route of entecavir is as follows,
• the reaction product obtained in any of steps a) to g ) can be used as a raw material to directly carry out the subsequent reaction to prepare entecavir of the formula (I).
• the compound of the formula (4) can be used as a raw material and the steps d) to h) as described above can be carried out to prepare entecavir of the formula (I), or the compound of the formula (2) can be used as a raw material and the steps as described above can be carried out.
• Example 7 According to the similar method of the above Example 7, the secondary hydroxysilicon-protected compound prepared in Example 5 was used to obtain the following product in a yield of 92.5%.
• the novel preparation method provided by the invention is easy to purify, the quality is controllable, and the raw materials are easy to obtain, the price is cheap, and the production cost is better reduced.

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