CN101348490B - Preparation of clopidogrel and salt thereof - Google Patents
Preparation of clopidogrel and salt thereof Download PDFInfo
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- CN101348490B CN101348490B CN2008101423883A CN200810142388A CN101348490B CN 101348490 B CN101348490 B CN 101348490B CN 2008101423883 A CN2008101423883 A CN 2008101423883A CN 200810142388 A CN200810142388 A CN 200810142388A CN 101348490 B CN101348490 B CN 101348490B
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Abstract
The invention relates to a method for preparing an S type clopidogrel and a bisulphate of clopidogrel. A compound of R-2-chloromandelic acid shown in a formula(II) reacts with methanol to generate a compound of R-2-chloromandelic acid methyl ester shown in a formula(III), and the compound of R-2-chloromandelic acid methyl ester shown in the formula(III) reacts with a sulfonic acid chloride compound under the action of catalyst to generate a compound of 2-benzene sulfonic acid group-2(2-chlorphenyl)methyl acetate shown in a formula(IV), and the compound of 2-benzene sulfonic acid group-2(2-chlorphenyl)methyl acetate shown in the formula(IV) reacts with 4,5,6,7-tetrahydrothienopyridine hydrochloride under alkaline conditions to generate free alkalis of clopidogrel, which is acted under a concentrated sulphuric acid to generate the bisulphate of clopidogrel shown in a formula(I). The method of the invention has the advantages of saving costs, saving time, lowering energy consumption, improving product purity and reducing toxic and side effects, along with simple synthetic line.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate in particular to the preparation method of S-type clopidogrel and salt thereof.
Background technology
In China, cerebrovascular disease especially, morbidity has 490 people up to 100,000 philtrums.Studies show that atherosclerosis is the basic cause of disease of this type of disease, and platelet suppressant drug can be effectively to the atherosclerosis thrombotic disease.Though acetylsalicylic acid (Aspirin) and ticlopidine (Ticlopidine) are all effective aspect the inhibition thrombosis, the two all has the potential untoward reaction.For this reason, French Sano-Synth labo drugmaker has researched and developed anticoagulant of new generation---clopidogrel.This product took the lead in entering multinational markets such as Europe, North America, Australia, Singapore subsequently, and going on the market in China August calendar year 2001 in U.S.'s listing in March, 1998.Compare with other antiplatelet drugs, clopidogrel has advantages such as good effect, expense is low, untoward reaction is little.
Report about the SR-25990C synthetic route in the document is a lot, and summary is got up, and mainly contains 3 thinkings.Route 1: synthetic earlier back Split Method: patent US4529596 specifically describes 4,5,6,7-tetramethylene sulfide also [3,2-c] pyridine and α-chlorine (2-chlorine) methyl phenylacetate react the racemic modification that generates clopidogrel in the presence of salt of wormwood and tetrahydrofuran (THF), carry out chiral separation then, the yield of the clopidogrel of synthesising racemation only has 45% in this route.Patent US5036156 has reported above-mentioned route has been improved subsequently, replaces α-chlorine (2-chlorine) methyl phenylacetate to react with α-bromine (2-chlorine) methyl phenylacetate, and productive rate improves a lot.Though its technology is fairly simple, raw material is cheap and easy to get, relatively is fit to produce ticlopidine, and yield is also undesirable; Be placed in addition and carry out chiral separation at last, the yield of target product only is half.
Route 2: first condensation is the method for cyclization again: patent US5204469 has reported with o-chlorobenzaldehyde and sodium cyanide and azanol reaction generation alpha-amino group (2-chlorine) toluylic acid, with tosic acid thiophene-2-ethyl ester reaction, has carried out chiral separation then after the esterification.Use this route, the reaction times is grown (40 hours), yield also low (50%).An other route is to generate α-bromine (2-chlorine) toluylic acid by the reaction of o-Chloromelic acid and bromo-phosphonium, after the esterification again with the thiophene ethamine reaction, split at last this chiral intermediate; Patent US6080875 has reported the alpha-amino group in the aforesaid method (2-chlorine) methyl phenylacetate has been split earlier, reacts this intermediate of generation with thiophene-2-glycidic acid sodium and cyaniding sodium borohydride under the catalysis of acetate then.Though it is higher that this route respectively goes on foot yield, agents useful for same cyaniding sodium borohydride is not easy to obtain, and influences its industrialization.Calendar year 2001 patent US6180793 has reported with 2 thiophene ethyl amine and o-chlorobenzaldehyde and sodium cyanide reaction generation 2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) acetonitrile, then generate 2-(2 thiophene ethyl amine base) (2-chloro-phenyl-) ethanamide with hydrogenchloride and methyl alcohol reaction, be hydrolyzed to thiophene ethamine base chlorophenylacetic acid methyl esters with the vitriolic methanol solution again, with (+)-camphor-10-sulfonic acid or (+)-tartrate split this intermediate.Adopt this operational path, can avoid using lacrimatory irritating alpha-halo acetogenin as intermediate, and yield also improves a lot.But total recovery has only about 50%, and it is not high to split the purity that obtains intermediate.So in the big production of technology of reality, do not adopt this route.
Route 3: split back synthetic method earlier: patent US5132435 is raw material with the o-Chloromelic acid, at first splits, and esterification and benzene sulfonyl chloride reaction generate has strong leavings group (OSO
2Ph) chiral intermediate, then with 4,5,6, bimolecular nucleophilic substitution takes place in 7-tetramethylene sulfide also [3,2-c] pyridine under the katalysis of salt of wormwood, configuration reversal generates clopidogrel, reaction scheme is as follows:
After the esterification of R-o-Chloromelic acid, very low among the patent US5132435 with the sulfonylation yield of benzene sulfonyl chloride, only be 45%; In addition the final step reaction times long partially, all more than 20 hours, use methylene dichloride to make solvent in this patent, the boiling point of methylene dichloride has only 40 ℃, the temperature of reflux is limited.So more than comprehensive, we determine to adopt the 3rd kind of synthetic schemes, and it is carried out corresponding improvement.
Summary of the invention
The object of the present invention is to provide a kind of route simple, save cost, save time, cut down the consumption of energy, improve product purity, reduce the method for preparing S-type clopidogrel and pharmacologically acceptable salt thereof of toxic side effect.
In order to achieve the above object, the invention provides following technical scheme: a kind of method of synthetic clopidogrel hydrosulphuric acid salt, proceed step by step in same reactor or in a plurality of reactor, described reaction process is as follows:
1) formula (II) compound R-o-Chloromelic acid is reacted acquisition formula (III) compound R-o-Chloromelic acid methyl esters at acidic conditions and methyl alcohol;
2) with formula (III) compound R-o-Chloromelic acid methyl esters under alkaline condition, catalyzer exists down, with sulfonyl chloride compound reaction production (IV) compound 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate;
3) with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride are dissolved in organic solvent, and in alkaline condition and the reaction of formula (IV) compound 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate, product adds vitriol oil production (I) compound clopidogrel hydrosulphuric acid salt;
Reaction scheme is:
Wherein step 1) is reflected under the acid existence and carries out, and reaction conditions is a normal pressure, and temperature is 60～80 ℃, and the reaction times is 2.5～5 hours, R-o-Chloromelic acid: methyl alcohol: the mol ratio of acid is 1.0:12～30:0.1～0.5; The mol ratio of preferred R-o-Chloromelic acid, methyl alcohol, acid is 1.0:18:0.2, and temperature of reaction is 65 ℃.Wherein said acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, sulfur oxychloride, methylsulphonic acid, iron(ic) chloride, ferric ammonium sulfate and sodium pyrosulfate.
Step 2 wherein) be reflected under the protection of inert gas temperature at-10～15 ℃, alkali and catalyzer exist down earlier with R-o-Chloromelic acid methyl esters and sulfonyl chloride compound reaction 4～8 hours, are cooled to normal temperature then, add sour adjust pH to neutrality; R-o-Chloromelic acid methyl esters wherein: alkali: catalyzer: the mol ratio of sulfonyl chloride compound is: 1:1～2:0.1～0.8:1～3; The mol ratio of preferred R-o-Chloromelic acid methyl esters, alkali, catalyzer, sulfonyl chloride compound is 1:1.3:0.1:1.5, and temperature of reaction is-5 ℃.Wherein said rare gas element is nitrogen, argon gas; Described alkali is selected from a kind of or its combinations such as oxyhydroxide, carbonate, organic or inorganic aminated compounds, Pyrrolidine, piperidines, morpholine, piperazine; Described sulfonyl chloride compound is selected from Methanesulfonyl chloride, benzene sulfonyl chloride and p-methyl benzene sulfonic chloride; Described catalyzer is a trimethylamine hydrochloride.The sulfonylation of this step has also used catalyzer except that adding the alkali in reaction, make reaction rate accelerates react more thorough, but formula (IV) the compound yield that make reaction generate within a short period of time to be further enhanced.
Wherein in the step 3), with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride are dissolved in the organic solvent, stir in the presence of alkali 30～90 minutes, then with 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate reaction 5～10 hours, 50～80 ℃ of temperature, product add the vitriol oil and get clopidogrel hydrosulphuric acid salt; 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride: 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate mol ratio is 1～4:1.Described alkali is selected from 20%～80% wet chemical, 20%～80% aqueous sodium carbonate, 20%～80% potassium bicarbonate aqueous solution, 20%～80% sodium bicarbonate aqueous solution, 20%～80% potassium hydroxide aqueous solution and 20%～80% aqueous sodium hydroxide solution, and the pH of reaction solution is 8.0～11.0.
The raising of the molar equivalent number of alkali and reactant also can make the reaction times shorten in step 3), and reaction yield improves.
Preferred described 4,5,6, the mol ratio of 7-tetramethylene sulfide and pyridine hydrochloride and 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate is 3:1.
Organic solvent used in the above-mentioned steps can be selected from acetone, toluene, tetrahydrofuran (THF), ethyl acetate etc.Ethyl acetate.
The present invention is raw materials used to be easy to get, and clopidogrel hydrosulphuric acid salt cost cheap, that make is lower, in the clopidogrel hydrosulphuric acid salt process for preparing, intermediate and end product quality are controlled easily, and product yield is higher, and yield is about 78%, purity is better, is easy to separate purify; And all recyclable utilization of organic solvent that the present invention is used reduces cost; The present invention does not have, and special, toxic reagent uses, and helps environmental protection; Atmospheric operation in the building-up process, the reaction conditions gentleness, technology is easy, and equipment is simple, and cost is low, is easy to industrialized production.
Embodiment
Now in conjunction with the embodiments, the present invention is further described.Used various chemical and reagent are commercially available purchase if no special instructions among the embodiment.
[embodiment 1]
Synthesizing of R-o-Chloromelic acid methyl esters (III)
In reaction flask, add R-o-Chloromelic acid (II) and (0.11mol) be dissolved in the methanol solution (133.3ml), slowly add the vitriol oil (2.93ml), heat 75 ℃ of reactions 5 hours, be cooled to room temperature, decompression.In the buttery residuum, add methylene dichloride and 10% wet chemical, tell organic phase, organic phase washing, anhydrous sodium sulfate drying.Steaming desolventize after the vacuum-drying colourless oil liquid, i.e. formula (III) compound, yield 90.3%.
Synthesizing of 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate (IV)
In three-necked bottle, add successively R-o-Chloromelic acid methyl esters (III) (0.11mol), triethylamine (0.22mol), trimethylamine hydrochloride (0.088mol), add anhydrous methylene chloride then.Be cooled to 0 ℃ under the nitrogen protection, stir down and drip benzene sulfonyl chloride (0.33mol), reacted 4 hours.Remove nitrogen protection, add 1N hydrochloric acid (12ml) and transfer Ph=7, pour into then in the water, fully stir, dichloromethane extraction, standing demix merges organic layer, steam desolventize light yellow liquid, i.e. formula (IV) compound, yield 85.3%.
Synthesizing of SR-25990C
In three-necked bottle, with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride (0.0.9mol) are dissolved in ethyl acetate, add 10% wet chemical (salt of wormwood is 14g) then.Stir after 45 minutes, formula (IV) compound (0.09mol) is dissolved in ethyl acetate to join in the reaction flask, 55 ℃ of reactions of two-phase medium heating 5 hours, remove solvent under reduced pressure, add entry, use ethyl acetate extraction, merge organic phase, washing to be washing away unnecessary inorganics, concentrate clopidogrel free alkali.
In free alkali, add ethyl acetate, cool off-5 ℃, slowly drip the vitriol oil, be warming up to 65 ℃ and stirred 1 hour, white solid occurs, and wash with ethyl acetate.40～45 ℃ of vacuum-dryings, get I type bisulfate clopidogrel finished product (I), yield 85%.185 ℃ of fusing points, 184 ℃ of literature values.Proton nmr spectra carbon spectrum test result is consistent with literature value:
[embodiment 2]
Synthesizing of R-o-Chloromelic acid methyl esters (III)
In reaction flask, add R-o-Chloromelic acid (II) and (0.11mol) be dissolved in the methanol solution (78.4ml), slowly add the vitriol oil (1.12ml), heat 65 ℃ of reactions 2.5 hours, be cooled to room temperature, decompression.In the buttery residuum, add methylene dichloride and 10% wet chemical, tell organic phase, organic phase washing, anhydrous sodium sulfate drying.Steaming desolventize after the vacuum-drying colourless oil liquid, i.e. formula (III) compound, yield 97%.
Synthesizing of 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate (IV)
In three-necked bottle, add successively R-o-Chloromelic acid methyl esters (III) (0.11mol), triethylamine (0.15mol), trimethylamine hydrochloride (0.011mol), add anhydrous methylene chloride then.Be cooled to 0～-5 ℃ under the argon shield, stir down and drip benzene sulfonyl chloride (0.17mol), reacted 4 hours.Remove argon shield, add 1N hydrochloric acid (8ml) and transfer Ph=7, pour into then in the water, fully stir, dichloromethane extraction, standing demix merges organic layer, steam desolventize light yellow liquid, i.e. formula (IV) compound, yield 91.1%.
Synthesizing of SR-25990C
In three-necked bottle, with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride (0.27mol) are dissolved in ethyl acetate, add 30% wet chemical (salt of wormwood is 42g) then.Stir after 45 minutes, formula (IV) compound (0.09mol) is dissolved in ethyl acetate to join in the reaction flask, 60 ℃ of reactions of two-phase medium heating 5 hours, remove solvent under reduced pressure, add entry, use ethyl acetate extraction, merge organic phase, washing to be washing away unnecessary inorganics, concentrate clopidogrel free alkali.
In free alkali, add ethyl acetate, cool off-5 ℃, slowly drip the vitriol oil, be warming up to 65 ℃ and stirred 1 hour, white solid occurs, and wash with ethyl acetate.40～45 ℃ of vacuum-dryings, get I type bisulfate clopidogrel finished product (I), yield 90%.185 ℃ of fusing points, 184 ℃ of literature values.Proton nmr spectra carbon spectrum test result is consistent with literature value:
1H-NMR(400MHz，DMSO-d
6)δ：2.89(m，2H，CH
2)，3.63-3.66(m，2H，CH
2)，3.76-3.79(m，2H，CH
2)，3.73(s，3H，OCH
3)，4.94(s，1H，CH)，6.68(d，J＝4.8Hz，1H，CH
2)，7.06(d，J＝4.8Hz，1H，CH
2)，7.26-7.32(m，2H，Ar-H)，7.41-7.43(m，1H，Ar-H)，7.71-7.72(m，1H，Ar-H)。
13C-NMR(100MHz，DMSO-d
6)δ：22.5(CH
2)，48.9(CH
2N)，50.4(CH
2N)，53.6(OCH
3)，65.7(CHN)，125.1(＝CH-S)，125.5(Ar-C)，128.5(Ar-C)，130.2(Ar-C)，130.6(＝C-C1)，131.7(＝C＝)，132.2(＝C＝)，134.3(＝C＝)，167.6(-C＝O)。
Concrete synthetic route is as follows:
Claims (6)
1. the preparation method of a clopidogrel hydrosulphuric acid salt, its step is as follows:
1) formula (II) compound R-o-Chloromelic acid is dissolved in the methanol solution, adds the vitriol oil, be heated to 60～80 ℃, reaction acquisition formula (III) compound R-o-Chloromelic acid methyl esters;
2) formula (III) compound R-o-Chloromelic acid methyl esters, triethylamine, trimethylamine hydrochloride add in the reaction vessel, add methylene dichloride then, be cooled to-10～15 ℃, with benzene sulfonyl chloride reaction production (IV) compound 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate;
3) with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride are dissolved in ethyl acetate, add 30% wet chemical, be heated to 50～80 ℃, with the reaction of formula (IV) compound 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate, product adds strong sulfuric acid response production (I) compound clopidogrel hydrosulphuric acid salt; Described 4,5,6, the mol ratio of 7-tetramethylene sulfide and pyridine hydrochloride and 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate is 3: 1;
Be reflected in same reactor or the different reactor and carry out, reaction scheme is:
2. preparation method as claimed in claim 1, wherein the mol ratio of the described R-o-Chloromelic acid of step 1), methyl alcohol, the vitriol oil is 1.0: 18: 0.2, temperature of reaction is 65 ℃.
3. preparation method as claimed in claim 1, step 2 wherein) be reflected under the protection of inert gas temperature at-10～15 ℃, under existing, alkali triethylamine and catalyzer trimethylamine hydrochloride earlier R-o-Chloromelic acid methyl esters and benzene sulfonyl chloride were reacted 4～8 hours, be cooled to normal temperature then, add sour adjust pH to neutral; R-o-Chloromelic acid methyl esters wherein: alkali: catalyzer: the mol ratio of benzene sulfonyl chloride is: 1: 1～2: 0.1～0.8: 1～3.
4. preparation method as claimed in claim 3, wherein said rare gas element is nitrogen, argon gas.
5. preparation method as claimed in claim 3, the mol ratio of wherein said R-o-Chloromelic acid methyl esters, alkali, catalyzer, benzene sulfonyl chloride is 1: 1.3: 0.1: 1.5, temperature of reaction is-5 ℃.
6. preparation method as claimed in claim 1, wherein in the step 3), with 4,5,6,7-tetramethylene sulfide and pyridine hydrochloride are dissolved in the ethyl acetate, in the presence of 30% salt of wormwood, stirred 30～90 minutes, reacted 5～10 hours with 2-Phenylsulfonic acid base-2 (2-chloro-phenyl-) methyl acetate then, 50～80 ℃ of temperature, product adds the vitriol oil and gets clopidogrel hydrosulphuric acid salt.
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| CN101864464B (en) * | 2010-04-29 | 2012-10-10 | 重庆凯乐尔生物催化技术有限公司 | Chemical-enzyme method for preparing (S)-2-chlorophenyl glycine methyl ester clopidogrel chiral intermediate |
| CN101845050A (en) * | 2010-06-01 | 2010-09-29 | 上虞京新药业有限公司 | Method for preparing clopidogrel |
| CN102250114B (en) * | 2011-04-27 | 2014-02-26 | 青岛黄海制药有限责任公司 | Preparation method of clopidogel and sulfate thereof |
| CN103435631B (en) * | 2013-08-29 | 2015-08-26 | 四川峨嵋山药业股份有限公司 | The preparation method of I-type clopidogrel hydrogen sulfate |
| CN103524528A (en) * | 2013-09-16 | 2014-01-22 | 吉林省博大伟业制药有限公司 | Improved preparation method of II-type clopidogrel hydrogen sulfate crystal |
| CN106928251B (en) * | 2015-12-30 | 2021-05-04 | 江苏天士力帝益药业有限公司 | Preparation method of high-purity clopidogrel |
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