TW200902510A - Regio-specific synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid - Google Patents

Abstract

This invention is directed to a five step regio-specific synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid compound of formula 16 comprising the steps of acetalating 3-methyl-thiophene-2-carbaldehyde in an alcohol solvent; iodinating the acetaleted 3-methyl-thiophene-2-carbaldehyde in an non-protic polar or hydrocarbon solvent to yield the corresponding iodinated and acetalated 3-methyl-thiophene-2-carbaldehyde product; treating the iodinated and acetalated product with water to yield the corresponding 5-iodo-3-methyl-thiophene-2-carbaldehyde; oxidizing the 5-iodo-3-methyl-thiophene-2-carbaldehyde to the corresponding 5-iodo-3-methyl-thiophene-2-carboxylic acid in ketone solvent; Ullmann coupling of the 5-iodo-3-methyl-thiophene-2-carboxylic acid with alkalimetal propoxide salt using a copper catalyst in propanol to yield 3-methyl-5-propoxy-thiophene-2-carboxylic acid; Esterifying 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 3-methyl-5-propoxy-thiophene-2-carboxylate; Brominating the 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate; and Basic hydrolyzing the alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate with base to yield 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid.

Description

200902510 IX. Description of the Invention: [Technical Field of the Invention] The present invention relates to a two-step position-selective Buchmann synthesis of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid. The invention also relates to several intermediates which are capable of producing 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid. [Prior Art] W02001/13811 discloses certain compounds, including [(phenylhydrazine)-piperidin-1-yl](aryl or heteroaryl)fluorenone as a tryptase inhibitor, ίο and describes the cause Tryptase involves various biological processes including the degradation of neuropeptides that cause vasodilation and bronchial relaxation (Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi, et al. , J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; and Tam, et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, 15 pages 27-32) and The regulation of bronchial-histamine reactivity (Sekizawa, et al., J. Clin. Invest., 1989, 83, pages 175-179), thereby determining the potential use of such compounds. W02005/097780 discloses more specifically the (benzoguanamine)-piperidin-1-ylthienyl fluorenone compound of formula A,

20 200902510 Its preparation, and its use in the treatment of diseases which can be treated by inhibition of tryptase. W02005/097780 also discloses that the compound of formula A is prepared by the coupling reaction of compound 16 with compound 10 below, and the subsequent deprotection of the coupling product. Compound 16 was prepared according to the following multi-step preparation method KOH cs « Λ〇, ο

NaH 41% 11

I η N 6 J-O MeONa Everyone ^ ° r.. 0^~B 13 77%

Ο Ο 14 100%

Ct^CH MeO,

Ο

UOH β1% 15 16 Although the above procedure enables the preparation of intermediate 16, it employs a wide variety of procedures, using an acyclic intermediate having an unpleasant odor characteristic, and is not prepared starting from a readily available thiophene-based starting material. SUMMARY OF THE INVENTION The present invention is directed to a specific positional synthesis of a 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid compound of formula 16, comprising the steps of: 3-mercaptoyl in an alcohol solvent Thiophene-2-furaldehyde is acetalized; 10 200902510 A non-sub-polar solvent or a hydrocarbon spray, which breaks down the 3_^ pathway to form the corresponding deuterated and condensed 3-a The thiophene-2-methyl waking product; the water is used in the Wei and the secreted silk to form the corresponding 5_Moth-3_methylthiophene-2-carbaldehyde; in the ketone solvent, the 5-methyl thiophene-2- Oxidation of formic acid to the corresponding 5-indole-3-indenyl porphin-2_ tacrotic acid; 10 15 using a copper-based scavenger to make 5_峨_3_methylthiophene-2-indole in propanol The metal propanolate is subjected to a Neumann coupling to produce "3_mercapto-5-propoxyphene-2-hypoacid; acetate 3-methyl-5-propoxy. Cephene to form (tetra)(tetra)yl 3-methyl-5-propoxythiophene-2-carboxylate; desertification 3_methyl_5-propoxysin_2_(tetra)' to generate the corresponding alkyl group 4 &gt Odor-3-methyl-5-propoxy σ-septene-2_acid-acid; and base 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid The ester undergoes alkaline hydrolysis to form 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid. The invention further relates to the following compounds 〇

/°

0 and

These intermediate systems were prepared by applying the above procedure for the preparation of 4_methyl-3-methyldioxythiophene-2-carboxylic acid. 20 200902510 DETAILED DESCRIPTION OF THE INVENTION The present invention will be better understood by reference to the following detailed description. Definitions 5 As used above and throughout the description of the invention, including the scope of the appended claims, the following abbreviations and terms are understood to have the following meanings unless otherwise indicated: "acetalization" means under acidic conditions of non-aqueous solutions For example, dry HCl or tetrabutyltribromide is used, and is reacted with an alcohol such as MeOH, EtOH or 1,2-10 ethylene glycol, or with an alcohol source such as trimethyl orthoformate. The "alcohol solvent" means MeOH, EtOH or 1,2-ethanediol or the like. "Metal" means chain, sodium, potassium or planer. "Alkali metal propoxide" means a salt obtained by treating propanol with a strong base. Examples of strong tests are Cs2C03, metal tests such as NaH, 15 NaHMDS, KHMDS, LiHMDS, diisopropylamine (LDA), or a base metal such as a burnt-chain, a ruthenium, a ruthenium, and a base. The alkyl group of the town is Cw alkyl, more preferably butyl, for example, CsOPr, NaOPr, LiOPr or KOPr. The "brominated organic solvent" means a polar or inert organic solvent which can be used for the bromination reaction, such as acetonitrile, an organic acid such as acetic acid or propionic acid, or a halogenated solvent such as dichlorohydrin or chloroform. "Bromide" means reacting with Br2 or a suitable source of bromine such as NBS. "Copper catalyst" means a copper catalyst capable of achieving a Neumann coupling reaction selected from the group consisting of CuSCN, CuBr, Cul, CuCn, CuBF4, CuPF6, 200902510

CuOTf, CuPF6, CuBr2, CuCl2, and . "Coupling cosolvent" means another inert organic solvent which can be used in combination with an internal alcohol coupling solvent, such as THF, toluene, 2-methylthene, or dimethoxyethane. The meaning of the green base is converted to its corresponding vinegar under the conditions of I, == reacting with an alcohol in the presence of an acid, or by using a baseing agent such as Me2S〇4, stupid methyl desert Treatment, the alkylation of the acid to its corresponding carboxylic acid anion. "Solvent" means an inert polar organic solvent such as ethyltrans and di(tetra).曱 曱 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验 验When the Wei agent is finely reacted under the conditions of 12, IC1 or hexane-based lithium, the second butyl group ..., an example of a strong base is an alkyl lithium base such as a ring "Shenghua-> 卞丨1, n-Butyllithium and lithium diisopropylamide, etc. Hardening agent means - 葙 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ A lie (TBME), isopropyl is benzene, xylene or heptane # or 1> 3-dioxol quinone 'hydrocarbon solvent "Γ solvent" is intended to be a C3-5 ketone such as acetone.

NaCIO Milk H is made with Can 1〇2/ NaH2P〇4.H2〇/Amino-Rhein, 2 P ''', 1~10 Additive, ΚΜη04, Silver Oxide, H2〇2 or -10· 200902510 Ozone deal with. [Embodiment] In a specific embodiment of the method according to the present invention, the brominated organic solvent is acetic acid. In a specific embodiment of the method according to the invention, the acetalization is carried out at a temperature of from about -10 ° C to about 20 ° C. In a particular embodiment of the method according to the invention, the iodination is carried out in THF. Ίο In a specific embodiment of the method according to the invention, the strong base used for iodination is n-butyllithium. In a specific embodiment of the method according to the invention, the iodinating agent is 12, diiodoethylene, 1C or NIS. In a specific embodiment of the method according to the invention, the iodination is carried out at a temperature of from about 15 ° C to about 0 ° C. In a particular embodiment of the process according to the invention, the oxidation reaction is carried out as 'NaC102/NaH2P04.H20/sulfamic acid. In a specific embodiment of the method according to the invention, the ketone solvent is propylene ketone. In a specific embodiment of the method according to the invention, the oxidation is at a temperature of from about -10 ° C to about 30 ° C. Go on. In another embodiment of the method according to the invention, the alkali metal propoxides are CsOPr, NaOPr, LiOPr and KOPr. In another embodiment of the method according to the invention, the copper catalyst -11 - 200902510 is CuOTf, CuSCN, CuBr or CuI. In another embodiment of the process according to the invention, the coupling reaction is carried out under heating conditions of from about 70 ° C to about 120 ° C, depending on the solvent and pressure employed. 5 In another embodiment of the method according to the invention, the bromination is carried out at a temperature of from about 0 ° C to about 100 ° C, more preferably 750 ° C. In another embodiment of the method according to the invention, the bromination is carried out as Br2. In another embodiment of the method according to the invention, the alkali metal propoxide is sodium propoxide. In another embodiment of the method according to the invention, the copper catalyst is CuSCN, CuBr or Cul. In another embodiment of the method according to the invention, the hydrolysis is carried out at a temperature of from about 0 ° C to about 50 ° C. In another embodiment of the process according to the invention, the coupling reaction is carried out as a coupling cosolvent such as THF, toluene, 2-mercapto THF or dimethoxyethane. 20 EXAMPLES Preparation Details The starting materials can be purchased or prepared by applying or modifying known methods, or utilizing their apparent chemical equivalents. The invention is better understood by reference to the following non-limiting examples of typical inventions of the invention. The following examples are provided to more fully illustrate the specific embodiments of the invention. However, they should not be construed as limiting the broad scope of the invention in any way. In the nuclear magnetic resonance spectroscopy (NMR) listed below, the chemical shift is represented by 5 ppm, and the tetramethyl zephyr is used as an internal standard. The abbreviations have the following meanings: br = width ** %, dd = doublet, s = singlet; m = multiplet. The synthesis of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid described in the following examples can be represented by the following scheme I.

Ίο Schematic I

HO •13- 200902510 Example 1: 5-indole-3-indolyl β-sentene-2-methylate to trimethylacetate orthoformate (367 g, 3.45 mol) and tetrabutyl tri-evolution (11.0 g, 0.024 mol) In a solution of methanol (2 〇L), add "5 thiophene-2-carbaldehyde (400 g, 2.85 mol) at a temperature between 2 and 1 〇〇C over a period of 50 minutes. After an hour, the acetalization of (GCMS) was completed. The reaction mixture was concentrated on a rotary evaporator to give 550 g of crude thiophene acetal as a dark yellow oil. 'Cool to _6〇〇c and in a ίο ear.) Stir the mixture at _60 °C for 45 minutes. Add iodine in THF at -60 °C over a period of 4 Torr. 871 g, 1.5 L THF, 3.42 mol. After 5 minutes, judge (Ηριχ) iodization has been completed. After quenching with decyl alcohol (0.350 L) at -60 °C, the reaction mixture is heated to 15 % and kept overnight. The dark yellow reaction mixture was concentrated on a rotary evaporator to give a dark yellow oil. After adding water (9 L·), dichloromethane (1×8) L, 1 x 2 L) extracting the mixture. The combined chloroformic solution was concentrated on a rotary evaporator to obtain 8 〇 8 g of 5 iodo-3-mercaptothiophene-2-furaldehyde as a dark yellow Solid. The crude 5-methyl-3-methyl-e-phen-2-pyrene was used directly in the next step. 20 H (CDC13) δ 2.5 (s, 3 Η), 7.2 (s, 1 Η), 9.9 ( s, 1Η). LCMS (ESI) m/z 296.87 (Μ-Η). Example 2: 5_ thiophene-2-carboxylic acid at 5 ° C for a period of 3 minutes to 5-iodo-3-methyl Thiophene-2-methyl-14- 200902510 A mixture of aldehyde (650 g, 2.58 mol), acetone (2.6 L) and water (1.5 L), adding sulfamic acid (277 g, 2.84 mol) and NaH2P04.H2 〇 (533 g, 3.86 mol). To this suspension was added a solution of NaC 102 (306 g in 1.3 L of water, 2.71 mol) over a period of 3 hours at 8 ° C. No yellow gas was observed during the addition. After 5 minutes, the reaction was judged to be complete (HPLC). After adding water (7.3 L) to 18 DC, the suspension was filtered, and 4 X 800 mL water, 1 X 800 mL acetone/n-heptane (1:5), and Wash the reactor and filter cake sequentially with 1 x 200 mL of n-heptane. Dry product To give 539 g (89%) 5- iodo-3-yl thiophene-2-carboxylic acid Yue as a solid. 1h NMR (DMSO-d6) δ 2.4 (s, 3H), 7.3 (s, 1 Π), 13.1 (s, 1 Η). Example 3: 4-Bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 1-propane (3.85 L), Cs2C03 (1.73 kg, 5.31 mol) and (CU〇Tf&gt;2·曱A mixture of benzene (35. 2 g, 〇〇68 mol) was heated to 90 ° C and 5-iodo-3-indolylthiophene-2-carboxylic acid (500 g ' 1.87 mol) was added over a period of 7 minutes. The resulting suspension was stirred at 95 ° C for 18 hours to determine the completion of the Neumann coupling reaction by HPLC. The reaction mixture was cooled to 40 ° C ' and added to dichloromethane (1 9 L). 40 ± 1 °C Me2S04 (350 mL, 3.60 moles) was added to the suspension over a period of 1.5 hours. At 40. (: stirring for an additional 1 hour, the suspension was cooled to warm. Add two gas methane (19 L) and filter the suspension with diatomaceous earth. Wash the reactor and filter cake with 5 x 700 mL dioxane. Concentrate the filtrate on a rotary evaporator to obtain 505 g3- Mercapto-5-propoxythia-15- 200902510 Methyl phen-2-carboxylate is a dark yellow oil. This material is dissolved in dichloromethane (4.2 L) / n-heptane (4.7 L). Then join in 3〇c in a minute 95 mL ' 1.88 moles. After a further 3 minutes, the reaction mixture was concentrated by rotary evaporation to give 587 g of dark yellow solid. 5 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> LiOH (223 g, 9.33 moles) was added at 3 ° C. The reaction mixture was stirred at room temperature for 20 hours. The reaction was quenched with HCl (1.4L, 6 N) at 2 ° C and water (1.1 L) was then added. , the suspension was filtered, and the reactor was washed with 11 〇〇 mL of hydrazine/water (2:3), 3×600 mL of n-heptane and 11 〇〇mL of acetone/n-heptane (j: 5 ) ίο The cake was dried and 318 g of crude 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid were obtained by recrystallization from acetonitrile (15 L) / water (18 L). The crude product was further purified and dried to give the desired 4-bromo-3-indolyl-5-propoxyindole as 248 g (yield: 46% of 3-methylthiophene-2-carbaldehyde). Phen-2-carboxylic acid, a pale yellow solid. 15 HPLC: about 98 ° / 〇 purity. C9 HuBr03S analytical value: c, 38.72; Η ' 3.97. Actual value: C, 38.98; Η, 3.77. MS (ESI+ m/z 279 [Μ] ° 1H-NMR(dmso-d6) δ 13.0 (s » 1 Η)» 4.2 (t &gt; 2Η)' 2.4 (s » 3H), 1.8 (m, 2H), 1.0 (t'3H). 13C-NMR (dmso-d6) 3 163, 20 162 , 143 , 113 , 96 , 77 , 22 , 16 , 11 . •16-

Claims (1)

200902510 X. Patent application scope: 1. A method for preparing 4-bromo-3-indolyl-5-propoxythiophene-2-indanoic acid, comprising the following steps: 3-mercaptothiophene in an alcohol solvent _2_Formaldehyde is acetalized; the acetalized 3-mercaptothiophene-2-furaldehyde is iodinated in an aprotic polar solvent or a hydrocarbon solvent to form the corresponding iodinated and acetalized 3_曱a thiophene-2-furfural product; treating the iodinated and acetalized product with water to form the corresponding 5-iodo-3-indolyl thiophene-2-indole; in a ketone solvent, 5-iodine _3_Methylthiophene-2-formaldehyde is oxidized to the corresponding 5-iodo-3-indolylthiophene-2-carboxylic acid; 5-iodo-3-mercaptothiophene_2 is used in propanol using a copper catalyst The uranium is coupled with the metallopropoxide of the test metal, and the 3, fluorenyl _5_ propoxy β-cephen-2-pyruic acid; bismuth 3 methyl _5_propoxy porphin _carboxylic acid to form the corresponding alkyl 3-methyl-5-propoxythiophene-2-carboxylate; 3-methyl-5-propoxythiophene-2-carboxylic acid bromide to generate a corresponding Alkyl 4-bromo-3-methyl-5-propoxythiophene-2-carboxylate; and the use of the test to give a base 4-di-___ 曱 _5_ Oxygen. The vinegar vinegar is subjected to an in situ hydrolysis to form a 4-methyl-3-methyl-5-propoxy group. The phenotype 2_ slow acid. The method of the method of claim 1 of the patent of the invention, the shrinkage of the anti-μ疋 described in the towel, under the acidic conditions of the non-aqueous solution, using dry HC1 or tetrabutyltribromide and the species is selected from the group consisting of decyl alcohol, ethanol or 1,2- Ethylene glycol 'or-alcohol source -17· 10 15 20 200902510 That is, trimethyl orthoformate is reacted. 3. The method according to item 1 of the scope of application of the patent should be the use of tri-f-ester of formic acid and tetrabutyl. 4. According to the method of claim 1 of the patent scope, the solvent is methanol, ethanol or 1,2-ethanediol. The alcohol solvent according to the method of claim 1 is methanol. According to the method of applying for patent patent field No. 1, =^ jump to about, the temperature ^=. According to the scope of the patent application, H m , force to 'the iodination reaction species described above (4), such as the ring of the county clock (four) deferred from a - n ^ ^ ^ coin - butyl lithium, n-butyl lithium and - Lithium propyl hydrazide; the iodinating agent is Nbi.込L, diiodoethylene, IC1 and according to the scope of the patent application is to use the n-butyl axis and then use l2^ to 'the aforesaid Aihua reaction according to the scope of the patent application 〗 〖Aprotic polar solution (four) B _ , the first _ square; ^ which uses the (four) chemical reaction of the two base acetyl hydrazine 'according to the scope of the patent application 丨: 'dioxane. The aprotic polar solvent is the THF method' which is used for the oximation reaction. According to the scope of the patent application, the smoky solvent is a sputum, which is used to deuterate the 12-oxime or heptane. The method of applying the priming method of the first slave is carried out, wherein the (iv) deuteration reaction 5 6 9 is carried out by the acetalization reaction. Among them, an acid-reducing alcohol is used for the acetalization reaction, wherein the acetalization reaction -18-200902510 is carried out at a temperature of about -80 ° C to about 0 ° C. 13. The method of claim 1, wherein the oxidation reaction is carried out using NaC102/NaH2P04, H20/sulfamic acid, ΚΜη04, silver oxide, h2o2 or ozone. The method of claim 1, wherein the oxidation reaction is carried out using NaC102/NaH2PCVH20/sulfamic acid. 15. The method of claim 1, wherein the ketone solvent is acetone. 16. The method of claim 1, wherein the oxidation reaction is carried out at a temperature of from about -10 ° C to about 30 ° C. 17. The method of claim 1, wherein the metal alkoxide is CsOPr, NaOPr, LiOPr or KOPr. 18. The method of claim 1, wherein the metal alkoxide is NaOPr. The method according to claim 1, wherein the copper catalyst is CuSCN, CuBr, Cul, Cua, CuBF4, CuPF6, CuOTf, CuPF6, CuBr2, C\iCl2 and Cu20. 20. The method of claim 1, wherein the copper catalyst is CuOTf, CuSCN, CuBr or Cul. The method of claim 1, wherein the Ubermann coupling reaction is carried out under heating at a temperature of from about 70 ° C to about 120 μ. 22. The method of claim 1, wherein the esterification is carried out by treatment with Me2S04. 23. The method of claim 1, wherein the bromination reaction -19-200902510 is carried out in an organic glutamine acetic acid. 24. According to the scope of application for patents ^ is in #温(四)(4) full-time (4) 1 material of desertification reaction, where _ desertification is used -20 - 200902510 VII. Designated representative map: (1) The representative representative of the case is: (No) ) Figure. (2) A brief description of the symbol of the representative figure: None 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 16