CN103864817B - A kind of preparation method of Thienopyridines - Google Patents
A kind of preparation method of Thienopyridines Download PDFInfo
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- CN103864817B CN103864817B CN201410097772.1A CN201410097772A CN103864817B CN 103864817 B CN103864817 B CN 103864817B CN 201410097772 A CN201410097772 A CN 201410097772A CN 103864817 B CN103864817 B CN 103864817B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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Abstract
The present invention relates to the preparation method of pharmaceutical intermediate 2-oxo-2,4,5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine hydrochloride, this compound can be used as the synthetic intermediate of anti-platelet aggregation medicine prasugrel.The thienopyridine that the present invention protects with <i>N</iGreatT.Gr eaT.GT-is for starting raw material; 2-acyl thiophene is obtained and pyridine by Friedel-Crafts acylation reaction; reset through Backmenn and obtain 2-aminothiophene and pyridine, then through amino diazotization, the obtained target compound of hydrolysis.Instant invention overcomes the shortcoming of existing method, adopt the raw materials for production be easy to get, gentle reaction conditions and easy operating process, be applicable to the suitability for industrialized production of prasugrel.
Description
Technical field
The present invention relates to a kind of preparation method of pharmaceutical intermediate, be specifically related to a kind of Thienopyridines 2-oxo-2,4,5,6,7,7a-six hydrogen thieno-[3,2-c] pyridine hydrochloride (or 2-hydroxyl-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride also)
(1) preparation method, the compound of preparation can be used as the synthetic intermediate of anti-platelet aggregation medicine prasugrel.
Background technology
Prasugrel (prasugre1), chemistry 2-acetoxyl group-5-(α-cyclopropyl carbonyl-2-luorobenzyl)-4 by name, 5,6,7-tetramethylene sulfide is [3,2-c] pyridine also, the oral antidiabetic cohesion medicine jointly researched and developed by Lilly Co., Eli. and Japanese first pharmacy Sankyo Co., Ltd, in September, 2009, through FDA approval listing, is used for the treatment of atherosclerosis and acute coronary syndrome.
The synthetic method of classical prasugrel is: 2-halo-2-(2-fluorophenyl)-1-cyclopropyl or 2-alkylsulfonyl-2-(2-fluorophenyl)-1-cyclopropyl and 1(or its hydrochloride) condensation obtains intermediate 2, then obtains prasugrel through acetylize.
2-oxo-2,4,5 in above-mentioned synthetic method, 6,7,7a-six hydrogen thieno-[3,2-c] pyridine (or 2-hydroxyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine) (1) be its key intermediate, current intermediate 1 commercially there is no cheap industrial goods and sells, and the synthetic method of its comparative maturity is for disclosed in US Patent No. 470510, and its synthetic route is:
The defect of the method is severe reaction conditions, and be wherein oxidized single step reaction and carry out under absolute, anaerobic and cold condition, and employ inflammable and explosive butyllithium in reaction, reaction yield is also not high, and the large production of mass-producing has certain difficulty.
Chinese patent CN101985451A, CN101245073A etc. disclose another synthetic method of intermediate 1, that is:
Aforesaid method still also exists the shortcomings, particularly 2-methoxythiophene such as complex operation, yield are unstable, reaction poor reproducibility and the defect such as hydrolysis one step of pyridine needs to use hydrogen chloride gas, long reaction time, product purity difference.
Therefore, the economy of intermediate 1, safety and the synthetic method of applicable commercial scale production is very necessary is researched and developed.
Summary of the invention
The invention provides a kind of 2-oxo-2,4,5,6 of novelty, 7,7a-six hydrogen thieno-[3,2-c] pyridine (or 2-hydroxyl-4,5, the preparation method of 6,7-tetramethylene sulfide also [3,2-c] pyridine, the method overcome existing 2-oxo-2,4,5,6,7,7a-six hydrogen thieno-[3,2-c] shortcoming of pyridine synthetic method, adopt the raw materials for production be easy to get, gentle reaction conditions and operating process, be applicable to suitability for industrialized production.
The present invention with the thienopyridine of N-protected (2) for starting raw material; 2-acyl thiophene is obtained and pyridine (3) by Friedel-Crafts acylation reaction; reset through Backmenn and obtain 2-aminothiophene and pyridine (4), then through amino diazotization, the obtained target compound (1) of hydrolysis or its free alkali.Its synthetic route is as follows:
Step one:
Step 2:
Step 3:
Wherein: R
1=H, CPh
3, CH
2ph, COOR
3, C
1~ C
10fatty acyl group
R
2=H, C
1~ C
10alkyl
R
3=H, C
1~ C
10alkyl, containing the C of 1-3 halogen atom
1~ C
10haloalkyl, (substituting group is halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, C in replacement
1~ C
6alkyl) or unsubstituted C
6~ C
10aryl;
The acylating agent of above-mentioned steps one, Friedel-Crafts acidylate comprises: C
1~ C
10fatty carboxylic acid halides, C
1~ C
10(substituting group is halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, C for acid anhydrides, active ester, carboxylic acid, replacement
1-C
6alkyl) or unsubstituted C
6-C
10the acylating agent that aroyl etc. are common; Lwies acid comprises: AlX
3, ZnX
2, SnX
4, FeX
3, TiX
4, BF
3, (X=Cl, Br); Preferred acylating agent is Acetyl Chloride 98Min., diacetyl oxide; Preferred Lwies acid is AlCl
3, SnCl
4.
The catalyzer that Backemenn rearrangement reaction uses comprises: PCl
5, PCl
3, POCl
3, SOCl
2deng chlorizating agent, sulfuric acid, methylsulphonic acid, tosic acid, trifluoromethane sulfonic acid, phosphoric acid, polyphosphoric acid, the protonic acid such as Glacial acetic acid, trifluoroacetic acid, AlX
3, ZnX
2, SnX
2, FeX
3, TiX
4, BF
3, Lwies acid such as (X=Cl, Br).Preferred catalyzer comprises for PCl
5, POCl
3, SOCl
2, sulfuric acid, trifluoromethane sulfonic acid, AlCl
3, BF
3; More preferred protonic acid is: PCl
5, sulfuric acid, tosic acid, AlCl
3.
Above-mentioned steps two, amide hydrolysis alkali used comprises: KOH, NaOH, K
2cO
3, NaOR
4(R
4=C
1~ C
4alkyl); Amide hydrolysis acid used comprises: HX gas (X=Cl, Br) hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methylsulphonic acid; Amide hydrolysis solvent used comprises: water, C
1~ C
6various alcohols, C
1~ C
4various halo alkanes, tetrahydrofuran (THF), acetonitrile, DMF, DMSO etc. common are the mixed solvent of the different ratios of machine solvent and foregoing all kinds of SOLVENTS thereof; Wherein preferred solvent is: water, methyl alcohol, ethanol, propyl carbinol, methylene dichloride, chloroform, acetonitrile; More preferred solvent is: water, methyl alcohol, ethanol, propyl carbinol, and the consumption of solvent is: compound 4 (weight)/solvent (volume)=1g/1ml ~ 1g/30ml; Temperature of reaction is 0 DEG C ~ reflux temperature.
Above-mentioned steps three; slough acid used in the reaction of N-protected base to comprise: the protonic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methylsulphonic acid, tosic acid, trifluoromethane sulfonic acid, Glacial acetic acid, trifluoroacetic acid, wherein preferred acid is: hydrochloric acid, sulfuric acid, trifluoromethane sulfonic acid.Slough alkali used in the reaction of N-protected base to comprise: MOH(M=Li, Na, K), M
2cO
3(M=Li, Na, K), MHCO
3(M=Li, Na, K), C
1~ C
6various sodium alkoxide, C
1~ C
6various potassium alcoholates.Wherein preferred alkali is: KOH, NaOH, NaOCH
3, K
2cO
3, Na
2cO
3.
Not only raw materials for production are easy to get method of the present invention, reaction conditions gentle and operating process is simple, are applicable to suitability for industrialized production, and can significantly improve product yield.
Embodiment:
Contact following embodiment, will understand compound of the present invention and their preparation better, these embodiments are intended to set forth instead of limit the scope of the invention.
The preparation of embodiment 1:2,5-diacetyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
5-ethanoyl-4 is added in 250mL reaction flask; 5,6,7-tetramethylene sulfide also [3; 2-c] pyridine 18.2g (0.1mol); aluminum trichloride (anhydrous) 13.4g (0.1mol) and 80mL methylene dichloride, be cooled to-15 DEG C, stirs lower dropping Acetyl Chloride 98Min. 7.8g (0.1mol); drip and finish; synthermal lower stirring reaction 2 hours, rises to room temperature and continues stirring reaction 2 hours (TLC monitors reaction end, developping agent: petrol ether/ethyl acetate=1/1).By in reaction solution impouring 100g trash ice, separate organic layer, water layer is with dichloromethane extraction (30mL × 3); merge organic phase, spend the night with anhydrous sodium sulfate drying, filtering siccative; concentrating under reduced pressure reclaims methylene dichloride, and resistates room temperature is placed, solidification; obtain 2,5-diacetyl-4,5; also [3,2-c] pyridine is light is yellow solid for 6,7-tetramethylene sulfide; 19.6g must be measured, yield 88%, LC-MS [M+H]
+224.1.
The preparation of embodiment 2:2,5-diacetyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
5-ethanoyl-4 is added in 250mL reaction flask; 5; 6; 7-tetramethylene sulfide also [3; 2-c] pyridine 18.2g (0.1mol); Acetyl Chloride 98Min. 9.42g (0.12mol) and 80mL methylene dichloride; mix; be cooled to-5 DEG C; stir 30min, drip the mixed solution be made up of 31.3g (0.1mol) anhydrous stannic chloride and 70mL methylene dichloride, drip and finish; synthermal lower stirring reaction 4 hours (TLC monitors reaction end, developping agent: petrol ether/ethyl acetate=1/1).Reaction solution impouring contained in the 100g trash ice of 1mL concentrated hydrochloric acid, separate organic layer, water layer is with dichloromethane extraction (30mL × 3); merge organic phase, spend the night with anhydrous sodium sulfate drying, filtering siccative; concentrating under reduced pressure reclaims methylene dichloride, and resistates room temperature is placed, solidification; obtain 2,5-diacetyl-4,5; also [3,2-c] pyridine is light is yellow solid for 6,7-tetramethylene sulfide; 18.6g must be measured, yield 83%, LC-MS [M+H]
+224.1, [M+Na]
+246.0.
The preparation of embodiment 3:2-acetylaminohydroxyphenylarsonic acid 5-ethanoyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
11.2g (0.05mol) 2,5-diacetyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine is added, 11.1g (0.11mol) triethylamine, 60mL dehydrated alcohol in 250mL reaction flask.7.3g (0.11mol) oxammonium hydrochloride is dissolved in 10mL water, drips the aqueous solution of oxammonium hydrochloride in ice bath downhill reaction system, drips and finishes, back flow reaction 4 hours, and in reaction process, adularescent solid is separated out.Suction filtration, washes filter cake with water, and obtain white solid after drying, this white solid is hydroxyl oxime intermediate, and without the need to purifying, be hydrolyzed reaction.
Obtained hydroxyl oxime intermediate 6.3g (0.025mol) is mixed with 80mL tetrahydrofuran (THF), 6.2g (0.03mol) phosphorus pentachloride is added fast under ice bath cooling, stirring reaction 3 hours under equality of temperature, by in the mixed solution of reaction solution impouring 50g frozen water and 30mL methylene dichloride, organic layer is separated after abundant stirring, aqueous phase is again with dichloromethane extraction (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure reclaims methylene dichloride, resistates room temperature is placed, solidify to obtain yellow solid, for thick product, fine work is refined to obtain with ethyl acetate, 5.0g must be measured, yield 87%, LC-MS [M+H]
+239.1, [M+Na]
+261.1.
The preparation of embodiment 4:2-amino--5-acetyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
12g (0.05mol) 2-acetylaminohydroxyphenylarsonic acid 5-ethanoyl-4,5,6 is added in 250mL reaction flask; 7-tetramethylene sulfide is [3,2-c] pyridine also, 3.4g (0.06mol) potassium hydroxide (being dissolved in 10mL water); 30mL methyl alcohol; be heated to back flow reaction 4 hours, concentrating under reduced pressure, resistates is with re-crystallizing in ethyl acetate; obtaining product is yellow solid; 8.1g must be measured, yield 83%, LC-MS [M+H]
+197.07.
The preparation of embodiment 5:2-hydroxyl-5-ethanoyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
9.8g (0.05mol) 2-amino--5-acetyl-4 is added in 250mL reaction flask; 5; 6; 7-tetramethylene sulfide is [3,2-c] pyridine also, the vitriol oil 50mL of 20%; stirring is cooled to-5 DEG C after making it dissolving; drip 4.1g (0.06mol) nitrous acid solution (4.1g is dissolved in 10mL water), dropwise and react 1 hour between-5 DEG C ~ 0 DEG C, obtain diazonium salt solution for subsequent use.Separately get 500mL three-necked bottle, add 20% sulfuric acid 30mL, be heated to 100 DEG C, slowly drip above-mentioned obtained diazonium salt solution at such a temperature, finish, insulation reaction 1 hour, cool to room temperature, with extraction into ethyl acetate reaction solution (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure reclaims ethyl acetate, obtaining product is yellow oil, 7.9g must be measured, yield 81%, LC-M [M+H]
+198.05.
The preparation of embodiment 6:2-hydroxyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride
9.9g (0.05mol) 2-hydroxyl-5-ethanoyl-4 is added in 250mL reaction flask, 5, 6, 7-tetramethylene sulfide also [3, 2-c] pyridine, the potassium hydroxide solution 50mL of 20%, be heated with stirring between 100 DEG C and react 3 hours, cool to room temperature, with extraction into ethyl acetate reaction solution (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filtering siccative, filtrate is transferred in three-necked bottle, dry hydrogen chloride gas is passed into saturated under ice bath cooling, separate out white precipitate, suction filtration, a small amount of cold ethanol rinse filter cake, vacuum drying product, 8.1g must be measured, yield 85%, mp:209-211 DEG C, LC-M [M+H]
+192.02.
The preparation of embodiment 7:2-ethanoyl-5-(2,2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
5-(2 is added in 250mL reaction flask, 2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine 31.4g (0.1mol), Acetyl Chloride 98Min. 9.42g (0.12mol) and 80mL methylene dichloride, mix, be cooled to-5 DEG C, stir 30min, drip the mixed solution be made up of 31.3g (0.1mol) anhydrous stannic chloride and 70mL methylene dichloride, drip and finish, synthermal lower stirring reaction 4 hours (TLC monitors reaction end, developping agent: petrol ether/ethyl acetate=1/1).Reaction solution impouring contained in the 100g trash ice of 1mL concentrated hydrochloric acid, separate organic layer, water layer, with dichloromethane extraction (30mL × 3), merges organic phase; spend the night with anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure reclaims methylene dichloride; resistates room temperature is placed, and solidification, obtains 2-ethanoyl-5-(2; 2,2-tri-chloroethoxy) carbonyl-4,5; 6,7-tetramethylene sulfide also [3,2-c] pyridine is white solid; 27.8g must be measured, yield 83%, LC-MS [M+H]
+355.9.
The preparation of embodiment 8:2-acetylaminohydroxyphenylarsonic acid 5-(2,2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
17.8g (0.05mol) 2-ethanoyl-5-(2,2,2-tri-chloroethoxy) carbonyl-4 is added in 250mL reaction flask; 5,6,7-tetramethylene sulfide also [3; 2-c] pyridine, 11.1g (0.11mol) triethylamine, 60mL dehydrated alcohol.7.3g (0.11mol) oxammonium hydrochloride is dissolved in 10mL water, drips the aqueous solution of oxammonium hydrochloride in ice bath downhill reaction system, drips and finishes, back flow reaction 4 hours, and in reaction process, adularescent solid is separated out.Suction filtration, washes filter cake with water, and obtain white solid after drying, this white solid is hydroxyl oxime intermediate, and without the need to purifying, be hydrolyzed reaction.
Obtained hydroxyl oxime intermediate 9.3g (0.025mol) is mixed with 80mL tetrahydrofuran (THF), 6.2g (0.03mol) phosphorus pentachloride is added fast under ice bath cooling, stirring reaction 3 hours under equality of temperature, by in the mixed solution of reaction solution impouring 50g frozen water and 30mL methylene dichloride, organic layer is separated after abundant stirring, aqueous phase is again with dichloromethane extraction (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure reclaims methylene dichloride, resistates room temperature is placed, solidify to obtain yellow solid, for thick product, fine work is refined to obtain with ethyl acetate, 7.3g must be measured, yield 79%, LC-MS [M+H]
+370.9.
The preparation of embodiment 9:2-amino-5-(2,2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride
9.3g (0.025mol) 2-acetylaminohydroxyphenylarsonic acid 5-(2,2,2-tri-chloroethoxy) carbonyl-4,5 is added in 250mL reaction flask, 6,7-tetramethylene sulfide is [3,2-c] pyridine also, 30mL anhydrous methylene chloride, ice-water bath cools, and passes into dry hydrogen chloride gas to saturated at 0 ~ 5 DEG C, logical complete, synthermal lower stirring reaction 1 hour, suction filtration, filter cake with a small amount of eluent methylene chloride, vacuum-drying, obtaining product is white solid, 7.4g must be measured, yield 81%, LC-MS [M+H]
+364.9.
The preparation of embodiment 10:2-hydroxyl-5-(2,2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine
9.15g (0.025mol) 2-amino-5-(2 is added in 250mL reaction flask, 2,2-tri-chloroethoxy) carbonyl-4,5,6,7-tetramethylene sulfide is [3,2-c] pyridine hydrochloride also, the vitriol oil 30mL of 20%, stirring is cooled to-5 DEG C after making it dissolving, drip 2.1g (0.03mol) nitrous acid solution (2.1g is dissolved in 5mL water), dropwise and react 1 hour between-5 DEG C ~ 0 DEG C, obtain diazonium salt solution for subsequent use.Separately get 500mL three-necked bottle, add 20% sulfuric acid 20mL, be heated to 100 DEG C, slowly drip above-mentioned obtained diazonium salt solution at such a temperature, finish, insulation reaction 1 hour, cool to room temperature, with extraction into ethyl acetate reaction solution (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filtering siccative, concentrating under reduced pressure reclaims ethyl acetate, obtaining product is yellow oil, 6.5g must be measured, yield 79%, LC-M [M+H]
+329.9.
The preparation of embodiment 11:2-hydroxyl-4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine hydrochloride
8.3g (0.025mol) 2-hydroxyl-5-(2 is added in 250mL reaction flask, 2, 2-tri-chloroethoxy) carbonyl-4, 5, 6, 7-tetramethylene sulfide also [3, 2-c] pyridine, the potassium hydroxide solution 20mL of 20%, be heated with stirring between 100 DEG C and react 3 hours, cool to room temperature, with extraction into ethyl acetate reaction solution (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filtering siccative, filtrate is transferred in three-necked bottle, dry hydrogen chloride gas is passed into saturated under ice bath cooling, separate out white precipitate, suction filtration, a small amount of cold ethanol rinse filter cake, vacuum drying product, 3.6g must be measured, yield 75%, mp:209-211 DEG C, LC-M [M+H]
+192.02.
Claims (13)
1. the preparation method of Thienopyridines; it is characterized in that; with 4 of N-protected, 5,6; 7-tetramethylene sulfide also [3; 2-c] pyridine is starting raw material, obtains 2-acyl thiophene and pyridine by Friedel-Crafts acylation reaction, reset through Backmenn and obtain 2-aminothiophene and pyridine; obtain through amino diazotization, hydrolysis, synthetic route is as follows again:
Step one:
Step 2:
Step 3:
Wherein: R
1=CPh
3, CH
2ph, COOR
3, C
1~ C
10fatty acyl group
R
2=H, C
1~ C
10alkyl
R
3=C
1~ C
10alkyl, containing the C of 1-3 halogen atom
1~ C
10haloalkyl, substituted or unsubstituted C
6~ C
10aryl; Described substituting group is halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, C
1~ C
6alkyl.
2. preparation method as claimed in claim 1, it is characterized in that, the acylating agent of the Friedel-Crafts acidylate of step one is selected from: C
1~ C
10fatty carboxylic acid halides, C
1~ C
10acid anhydrides, active ester, carboxylic acid, substituted or unsubstituted C
6-C
10aroyl, described substituting group are halogen, hydroxyl, amino, cyano group, nitro, trifluoromethyl, C
1-C
6alkyl; Lwies acid is selected from: AlX
3, ZnX
2, SnX
2, FeX
3, TiX
4, BF
3, wherein X=Cl, Br.
3. preparation method as claimed in claim 1, it is characterized in that, the acylating agent of the Friedel-Crafts acidylate of step one is selected from Acetyl Chloride 98Min. or diacetyl oxide.
4. preparation method as claimed in claim 1, it is characterized in that, the Lwies acid of step one is selected from AlCl
3or SnCl
4.
5. preparation method as claimed in claim 1 or 2 or 3 or 4, it is characterized in that, the catalyzer that described Backemenn rearrangement reaction uses is selected from: PCl
5, PCl
3, POCl
3, SOCl
2, sulfuric acid, methylsulphonic acid, tosic acid, trifluoromethane sulfonic acid, phosphoric acid, polyphosphoric acid, Glacial acetic acid, trifluoroacetic acid; AlX
3, ZnX
2, SnX
2, FeX
3, TiX
4, BF
3, wherein X=Cl, Br.
6. preparation method as claimed in claim 1 or 2 or 3 or 4, it is characterized in that, the catalyzer that described Backemenn rearrangement reaction uses is selected from PCl
5, POCl
3, SOCl
2, sulfuric acid, trifluoromethane sulfonic acid, AlCl
3or BF
3.
7. preparation method as claimed in claim 1, it is characterized in that, described step 2 is hydrolyzed catalyzer used and is selected from KOH, NaOH, K
2cO
3, NaOR
4, R
4=C
1~ C
4alkyl; HX gas, wherein X=Cl, Br, hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methylsulphonic acid.
8. preparation method as claimed in claim 1, it is characterized in that, described step 2 is hydrolyzed catalyzer used and is selected from KOH, NaOCH
3, HCl gas or sulfuric acid.
9. preparation method as claimed in claim 1, it is characterized in that, described step 2 is hydrolyzed solvent used and is selected from: water, C
1~ C
6alcohols, C
1~ C
4halo alkanes, tetrahydrofuran (THF), acetonitrile, one or more different ratioss in DMF, DMSO mixed solvent.
10. preparation method as claimed in claim 1, is characterized in that, it is one or more in water, methyl alcohol, ethanol, propyl carbinol that described step 2 is hydrolyzed solvent used.
11. preparation methods as claimed in claim 1, is characterized in that, the consumption of described step 2 hydrolysis reaction solvent is: the weightmeasurement ratio=1g/1ml ~ 1g/30ml of compound 4/ solvent; Temperature of reaction is 0 DEG C ~ reflux temperature.
12. preparation methods as claimed in claim 1; it is characterized in that; the catalyzer used in the reaction of N-protected base of sloughing of described step 3 is selected from: hydrochloric acid, sulfuric acid, phosphoric acid, polyphosphoric acid, methylsulphonic acid, tosic acid, trifluoromethane sulfonic acid, Glacial acetic acid, trifluoroacetic acid, MOH, M
2cO
3, MHCO
3, C
1~ C
6sodium alkoxide, C
1~ C
6potassium alcoholate, wherein M=Li, Na, K.
13. preparation methods as claimed in claim 1, is characterized in that, the catalyzer used in the reaction of N-protected base of sloughing of described step 3 is selected from: hydrochloric acid, KOH, NaOCH
3.
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| CN101289454B (en) * | 2008-06-10 | 2011-02-16 | 上海医药工业研究院 | Method for preparing 2-oxygen-2,4,5,6,7,7alpha-hexahydro thieno [3,2-c]pyridine |
| CN101985451B (en) * | 2010-11-02 | 2012-04-25 | 北京赛科药业有限责任公司 | Preparation method of prasugrel intermediate |
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