CN103664990A - Preparation method of Vicagrel - Google Patents
Preparation method of Vicagrel Download PDFInfo
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- CN103664990A CN103664990A CN201210333184.4A CN201210333184A CN103664990A CN 103664990 A CN103664990 A CN 103664990A CN 201210333184 A CN201210333184 A CN 201210333184A CN 103664990 A CN103664990 A CN 103664990A
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- 0 COC(*=C(c1ccccc1Cl)N(CCC1S2)CC1=CC2=O)=O Chemical compound COC(*=C(c1ccccc1Cl)N(CCC1S2)CC1=CC2=O)=O 0.000 description 1
- JBSAZVIMJUOBNB-WUJWULDRSA-N COC([C@H](c1ccccc1Cl)N(CCC1S2)CC1=CC2=O)=O Chemical compound COC([C@H](c1ccccc1Cl)N(CCC1S2)CC1=CC2=O)=O JBSAZVIMJUOBNB-WUJWULDRSA-N 0.000 description 1
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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Abstract
The invention relates to the field of pharmaceuticals and particularly relates to a preparation method of Vicagrel. By using the method, (2S)-2-(2-oxo-7, 7a-dihydrothieno[3, 2-c]pyridine-5(2H, 4H, 6H)-yl)-2-(2-chlorphenyl)-methyl acetate is prepared in a chiral resolution way, and the Vicagrel is synthesized on the basis. The method is low in cost, simple and convenient in operation and suitable for industrial production, and the Vicagrel is high in chemical purity and optical purity. The invention also provides a method for preparing Vicagrel with high optical purity by using Vicagrel with low optical purity.
Description
Technical field
The present invention relates to pharmacy field, be specifically related to dimension card Gray's preparation method.Dimension card Gray is a kind of novel medicament for resisting platelet aggregation.
Background technology
(S)-2-(2-acetoxyl group-6 shown in formula (I), 7-dihydro-thiophene also [3,2-c] pyridine-5 (4H)-yl) 201010624329.7) and PCT patent application (application number: disclose PCT/CN2011/000138)-2-(2-chloro-phenyl-)-methyl acetate (dimension card Gray) is at Chinese patent application (application number:, dimension card Gray can be used for preparing novel antiplatelet drug (J Med Chem, 2012,55,3342), in order to overcome the clinical application defect of existing antiplatelet drug, as High risk of bleeding of " clopidogrel Resistant " and prasugrel etc.Dimension card Gray has now entered the preclinical study stage, and being expected to exploitation becomes safer, effective antiplatelet new drug.
The described method of preparing dimension card Gray of Chinese patent application 201010624329.7 is shown below:
The shortcoming of aforesaid method is: the semi-annular jade pendant acid esters of (1) optically pure 2-chloro mandelic acid methyl esters is expensive, has greatly increased the production cost of medicine, is unfavorable for that the commercialization of product is promoted; (2) the semi-annular jade pendant acid esters of optically pure 2-chloro mandelic acid methyl esters is very unstable, easily racemization occurs and affects the optical purity of product.
In order to overcome the deficiency of above-mentioned technological method, the inventor, through a large amount of research and probes, successfully adopts method for splitting to prepare optically pure dimension card Gray.The method chemical cost is low, and yield is high, and chemical purity and the optical purity of product are high, and easy and simple to handle, are suitable for suitability for industrialized production, thereby will be conducive to promote dimension card Gray's industrialization.
Summary of the invention
The invention provides a kind of preparation method who ties up card Gray, be shown below:
Specifically comprise the following steps:
(1) racemic formula II compound reacts under alkali exists with formula III compound or its salt, obtains racemic formula IV compound;
(2) racemic formula IV compound splits through chiral acid, obtain (2S)-2-(2-oxygen-7,7a-dihydro-thiophene also [3,2-c] pyridine-5 (2H, 4H, 6H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (formula V compound), the chiral acid adopting is the acid of camphor semi-annular jade pendant, tartrate or dibenzoyl tartaric acid;
(3) formula V compound or its salt reacts under alkali exists with acetic anhydride or Acetyl Chloride 98Min., obtains dimension card Gray;
In above-mentioned reaction formula, R
1be the phenyl of alkyl, trifluoromethyl, pentafluoroethyl group, seven fluoropropyls, phenyl or the X replacement of 1～6 carbon, wherein X is alkyl, halogen, itrile group, nitro or the trifluoromethyl of 1～3 carbon, and X group is positioned at 2,3 or 4 of phenyl ring.
In above-mentioned steps (1), preferred formula II compound is: 2-(2-chloro-phenyl-)-2-(4-oil of mirbane sulfonyloxy) methyl acetate, 2-(2-chloro-phenyl-)-2-(4-chlorobenzene sulfonyloxy) methyl acetate, 2-(2-chloro-phenyl-)-2-phenylsulfonyloxy methyl acetate, 2-(2-chloro-phenyl-)-2-mesyloxy methyl acetate, 2-(2-chloro-phenyl-)-2-trifluoro-methanesulfonyl oxy methyl acetate or 2-(2-chloro-phenyl-)-2-(2-oil of mirbane sulfonyloxy) methyl acetate; The alkali adopting is salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, triethylamine, diisopropylethylamine or 1,8-diazacyclo [5,4,0] hendecene-7; The solvent adopting is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1, the mixed solvent of one or more in 2-ethylene dichloride, methyl tertiary butyl ether, tetracol phenixin, ethyl acetate, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ether, acetonitrile, DMF or methyl-sulphoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃; The salt of formula III compound is selected from its hydrochloride, tosilate, acetate, vitriol, phosphoric acid salt, fluoroform sulphonate, oxalate, mesylate, benzene sulfonate or hydrobromate.
In above-mentioned steps (2), preferred resolving agent is L-(-)-camphorsulfonic acid; The solvent adopting is the mixture of one or more solvents in methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetonitrile, acetone, ethyl acetate, and preferably acetone is as solvent.
In above-mentioned steps (3), the alkali adopting is selected from triethylamine, sodium hydride, potassium hydride KH, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, diisopropylethylamine, diisopropylamine lithium, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium tert.-butoxide or sodium tert-butoxide; Reaction solvent used is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1, the mixed solvent of one or more in 2-ethylene dichloride, methyl tertiary butyl ether, tetracol phenixin, ethyl acetate, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ether, acetonitrile, DMF or methyl-sulphoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃.
Another object of the present invention is to provide a kind of high-optical-purity dimension card Gray's preparation method.It is characterized in that, the dimension card Gray of low optical purity can be improved to its optical purity by making beating or the method for recrystallization, finally obtain highly purified dimension card Gray.
The inventor is surprised to find in the process of the pilot scale amplification to end product and process optimization, can be by suitable purification process raising optical purity the dimension card Gray of the low optical purity owing to obtaining under various factors (ee value < 88%) (ee value represents optical purity).The inventor is by a large amount of tests, for influence factors such as the dimension card Gray of different e e. value, the recrystallisation solvent of different volumes and Tcs, carried out investigating (specifically seeing embodiment 4,5), be surprised to find low ee value (< 88%) dimension card Gray in solvent, particularly special solubility behavior in alcohol solvent.When dimension card Gray's ee value is lower than 88% time, no matter whether control temperature or change solvent volume, all will be lower than initial ee value by separating out the solid dimension card Gray's who obtains ee value after making beating or recrystallization, the dimension card Gray's of dissolving in mother liquor ee value will be higher than initial ee value, but can be higher than 90%.When dimension card Gray's ee value is in 88%～90% time, the temperature during by crystallization control and solvent volume, the ee value of the solid chemical compound of separating out after recrystallization can be higher than initial ee value, and can pass through repeatedly recrystallization, obtains the dimension card Gray of higher ee value.
According to such test-results, we have designed schema as shown in Figure 1, by this flow process, can be the product of high ee value by the dimension card Gray purifying of low ee value.
This step is characterised in that: utilize low ee value (< 88%) dimension card Gray special solubility behavior in ethanol, low ee value product is carried out to optical purity optimization, can obtain high ee value and tie up and block Gray.When dimension card Gray's ee value is lower than 88% time, under suitable temp by the making beating of appropriate ethanol, after filtering insoluble solids, acquisition contains ee value at 88%～90% dimension card Gray's solution, wherein ee value lower than 88% dimension card Gray's quality (with a gram calculating) and the volume of ethanol used (calculating with milliliter) than being selected from 1: 1 to 1: 30, preferably 1: 3 to 1: 20; Making beating or recrystallization temperature are subzero 20 ℃ to 100 ℃, and preferably temperature is 0 ℃ to 40 ℃; When dimension card Gray's ee value is 88%～90%, by appropriate ethyl alcohol recrystallization and control recrystallization temperature, can obtains ee value higher than 97% dimension card Gray, and can repeat this process acquisition ee value higher than 98% dimension card Gray.Wherein ee value at 88%～90% dimension card Gray's quality (with a gram calculating) and the volume of ethanol used (milliliter of take calculating) than as 1: 1 to 1: 10, preferably 1: 1 to 1: 7; During ethyl alcohol recrystallization, control recrystallization temperature at 0 ℃ to 50 ℃, preferably 30 ℃ to 40 ℃.
accompanying drawing explanation
Fig. 1 is to be the schema of high ee value product by the dimension card Gray purifying of low ee value.
embodiment
Below by embodiment, illustrate content of the present invention.In the present invention, the embodiment of the following stated is in order better to set forth the present invention, is not for limiting the scope of the invention.
Embodiment 1
2-(2-oxygen-7,7a-dihydro-thiophene is [3,2-c] pyridine-5 (2H, 4H, 6H)-yl also)-2-(2-chloro-phenyl-)-methyl acetate (IV)
By (±)-2-(2-chloro-phenyl-)-2-(4-oil of mirbane sulfonyloxy)-methyl acetate 58.0g (0.15mol), 5; 6; 7; 7a-tetramethylene sulfide also [3.2-c] pyridine-2 (4H)-one hydrochloride 32.4g (0.17mol) and 37.9g (0.38mol) saleratus joins in 500ml acetonitrile; reaction system nitrogen protection, stirring at room 24 hours.The standing rear filtration insolubles of reaction solution, evaporated under reduced pressure solvent, through rapid column chromatography (sherwood oil: ethyl acetate=4: 1) obtain oily matter (compound IV) 34.6g, yield 68%.
1H-NMR(300MHz，CDCl
3)δ1.78～1.92(m，1H)，2.31-2.40(m，1H)，2.55～2.71(m，1H)，3.01～3.26(m，2H)，3.71(s，3H)，3.78～3.92(m，1H)，4.11～4，18(m，1H)，4.90(d，1H，J＝5.5Hz)，6.01(d，1H，J＝5.3Hz)，7.25～7.51(m，4H)；ESI-MS m/z338.1[M+H]
+.
Embodiment 2
(2S)-2-(2-oxygen-7,7a-dihydro-thiophene is [3,2-c] pyridine-5 (2H, 4H, 6H)-yl also)-2-(2-chloro-phenyl-)-methyl acetate (V)
At room temperature, by 2-(2-oxygen-7,7a-dihydro-thiophene also [3,2-c] pyridine-5 (2H, 4H, 6H)-yl) 12.50 grams of-2-(2-chloro-phenyl-)-methyl acetates (compound IV) are dissolved in acetone (100mL), and then by L-(-)-camphorsulfonic acid, (5.20 grams, acetone 0.037moL) (20mL) solution is added drop-wise in above-mentioned solution.By above-mentioned reaction solution reflux 6～8 hours, then be cooled to room temperature, add (2S)-2-(2-oxygen-7,7a-dihydro-thiophene also [3,2-c] pyridine-5 (2H, 4H, 6H)-yl) crystal seed (approximately 250 milligrams) of-2-(2-chloro-phenyl-)-methyl acetate-L-(-)-camsilate, at room temperature stir and spend the night, have a large amount of crystal to separate out.Filter, filter cake washing with acetone, obtains (2S)-2-(2-oxygen-7,7a-dihydro-thiophene is [3,2-c] pyridine-5 (2H, 4H, 6H)-yl also)-2-(2-chloro-phenyl-)-methyl acetate-L-(-)-camsilate (5.25 grams).In above-mentioned salt, add a small amount of water (approximately 15～20mL), at 5 ℃, with saturated sodium bicarbonate solution alkalization, then use ethyl acetate (50mL x3) to extract.Saturated aqueous common salt for acetic acid ethyl acetate extract (20mL) washing, dry, pressure reducing and steaming solvent, obtains (2S)-2-(2-oxygen-7,7a-dihydro-thiophene also [3,2-c] pyridine-5 (2H, 4H, 6H)-yl) (4.98 grams of-2-(2-chloro-phenyl-)-methyl acetates (compound V), oily matter), through ethyl alcohol recrystallization, obtain white solid product (compound V) 4.50g, mp:146～148 ℃, [α]
d 20=+113.9 ° (c0.5, MeOH), (ee value is with chirality HPLC, to measure after compound V is converted into dimension card Gray to ee=98.85% again, HPLC analysis condition: Chiralpak IC4.6mm * 250mm; Column temperature: 25 ℃; Moving phase: 92% normal hexane/8% tetrahydrofuran (THF)/0.1% diethylamine; Flow velocity: 0.5ml/min; Detect wavelength: UV254nm);
1h-NMR (300MHz, CDCl
3) δ 1.79～1.93 (m, 1H), 2.30-2.40 (m, 1H), 2.56～2.70 (m, 1H), 3.00～3.27 (m, 2H), 3.72 (s, 3H), 3.79～3.93 (m, 1H), 4.12～4,19 (m, 1H), 4.89 (d, 1H, J=5.6Hz), 6.00 (d, 1H, J=5.2Hz), 7.26～7.50 (m, 4H);
13c-NMR (75MHz, CDCl
3) δ 33.9,34.0,49.0,49.7,51.1,51.6,52.2,52.4,67.3,76.6,77.0,77.4,126.6,126.8,127.2,129.8,130.1,132.7,134.8,167.2,167.4,170.8,198.6.
Embodiment 3
(S)-2-(2-acetoxyl group-6,7-dihydro-thiophene is [3,2-c] pyridine-5 (4H)-yl also)-2-(2-chloro-phenyl-)-methyl acetate (dimension card Gray)
By (2S)-2-(2-chloro-phenyl-)-2-(2-oxygen-5, 6, 7, 7a-tetramethylene sulfide also [3, 2-c] pyridyl) methyl acetate (V) (6.0g) is dissolved in acetonitrile (50ml), add 10ml triethylamine, at 0 ℃, drip diacetyl oxide (3.2ml), after dropping finishes, be warming up to room temperature reaction 2 hours, reaction solution is poured in water (50ml), ethyl acetate (50mlx3) aqueous phase extracted, saturated sodium bicarbonate aqueous solution and saturated common salt water washing for organic phase, anhydrous sodium sulfate drying, evaporate to dryness organic phase obtains crude product, through rapid column chromatography (sherwood oil: ethyl acetate=20: 1) obtain (S)-2-(2-acetoxyl group-6, 7-dihydro-thiophene also [3, 2-c] pyridine-5 (4H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (dimension card Gray) is (6.20g), through ethyl alcohol recrystallization, obtain 5.81 grams of white solids, mp:73～75 ℃, ee=99.0% (chirality HPLC analysis condition: Chiralpak IC 4.6mm * 250mm, column temperature: 25 ℃, moving phase: 92% normal hexane/8% tetrahydrofuran (THF)/0.1% diethylamine, flow velocity: 0.5ml/min, detect wavelength: UV254nm), [α]
d 22=+45.1 ° of (c=1.0, CH
3oH),
1h-NMR (300MHz, CDCl
3) δ 2.26 (s, 3H), 2.65～2.90 (m, 4H), 3.47～3.69 (m, 2H), 3.72 (s, 3H), 4.92 (s, 1H), 6.26 (s, 1H), 7.24～7.70 (m, 4H),
13c-NMR (75MHz, CDCl
3) δ 20.2,24.5,47.6,49.8,51.6,67.3,111.5,125.3,126.6,128.8,128.9,129.3,129.4,133.3,134.2,149.1,167.2,170.7, ESI-MS m/z380.0 [M+H]
+.
Embodiment 4
The ee value that dimension is blocked to Gray is from being promoted to 88%～90% lower than 85%
In ee value, lower than 85% dimension card Gray, be promoted in the process of ee=88%～90% impact of the ethanol volume when investigating recrystallization temperature, recrystallization or making beating and stirring on this process:
(1) dimension card Gray (3g) heating of low ee value is dissolved in the ethanol of different volumes amount completely, is cooled to after room temperature (20 ℃～30 ℃), stir 8～10 hours, filter the solid of separating out, chirality HPLC detects the ee value of mother liquor and solid.
| Batch 1-1 | Batch 1-2 | Batch 1-3 | Batch 1-4 | |
| Complete molten rear initial ee value | 80.5％ | 80.5％ | 80.3％ | 80.3％ |
| Add amount of alcohol (mL) | 6 | 12 | 18 | 30 |
| Separate out mother liquor ee value after solid | 88.1％ | 88.7％ | 88.9％ | 80.3％ |
| Separate out solid ee value | 78.9％ | 76.5％ | 74.1％ | Without solid, separate out |
| Separate out solid weight | 2.8g | 2.2g | 1.8g | Without solid, separate out |
(2) the dimension card Gray (3g) who is 80.5% by ee value is room temperature making beating under the ethanol of different volumes amount, stirs 8～10 hours, filters remaining solid, and chirality HPLC detects the ee value of mother liquor and solid.
| Batch 2-1 | Batch 2-2 | Batch 2-3 | Batch 2-4 | Batch 2-5 | Batch 2-6 | |
| Add amount of alcohol (mL) | 6 | 12 | 18 | 30 | 45 | 60 |
| Rear mother liquor ee value is filtered in making beating | 87.7％ | 88.3％ | 88.7％ | 88.5％ | 89.9％ | 85.7％ |
| Rear solid ee value is filtered in making beating | 77.9％ | 74.9％ | 73.3％ | 43.5％ | 43.5％ | 3.7％ |
| Rear solid weight is filtered in making beating | 2.4g | 1.8g | 1.6g | 0.6g | 0.6g | 0.14g |
(3) 2g ee value is heated to 45～50 ℃ 73～75% dimension card Gray with 10mL ethanol and dissolves completely, stir lower nature and be down under differing temps and separate out solid, separate out start to clock from solid, stirs mistake filter solid after 4～5 hours, result is as following table.
| Cooling temperature | Initial ee. value | Separate out solid masses | Separate out solid ee value | Mother liquor ee value |
| 25℃ | 73.7％ | 1.6g | 65.9％ | 89.5％ |
| 30℃ | 72.7％ | 1.4g | 65.8％ | 88.7％ |
| 35℃ | 72.5％ | 0.4g | 5.3％ | 88.3％ |
Experiment conclusion: when dimension card Gray's ee. value is lower than 85% time, no matter be with ethyl alcohol recrystallization or making beating, the solid ee value of separating out is all lower than initial value, ties up the ee value of blocking Gray and is all stabilized in 88%～90% in mother liquor.Method compared to ethyl alcohol recrystallization, the optical purity efficiency that improves dimension card Gray with ethanol making beating stirring is higher, and especially, when the amount of ethanol increases, the amount of dissolving in mother liquor is increasing, but do not dissolve more low ee value material, the ee value of mother liquor does not reduce.
Embodiment 5
Dimension card Gray's ee value is brought up to > 97% from 88%～90%
Dimension card Gray's ee. value is brought up to > 97% this process from 88%～90%, the recrystallization temperature of investigation recrystallization, uses amount of alcohol, adds crystal seed on finally separating out the impact of solid:
(1) impact of different recrystallization temperatures on the weight of the solid finally obtaining and ee. value while investigating recrystallization
2g ee value is heated to 45～50 ℃ 88～89% dimension card Gray with 10mL ethanol and dissolves completely, stir lower nature and be down to crystallization under differing temps, separate out start to clock from solid, stirs mistake filter solid after 4～5 hours, result is as following table.
| Recrystallization temperature | Initial ee value | Separate out solid masses | Separate out solid ee value | Mother liquor ee value |
| 25℃ | 88.9％ | 1.5g | 90.3％ | 88.3％ |
| 30℃ | 89.5％ | 1.3g | 97.1％ | 78.3％ |
| 35℃ | 89.1％ | 1.3g | 97.1％ | 79.9％ |
(2) investigate the impact of different volumes ethyl alcohol recrystallization on the weight of the solid finally obtaining and ee under 20 ℃～30 ℃ recrystallization temperatures
3g ee value is heated to 45～50 ℃ 88～89% dimension card Gray with different volumes ethanol dissolves completely, be cooled to after room temperature (20 ℃～30 ℃), stir 15 hours, filter the solid of separating out, chirality HPLC detects the ee value of mother liquor and solid, and result is as following table.
| Batch 1-1 | Batch 1-2 | Batch 1-3 | |
| Initial ee value after dissolving | 89.1％ | 89.1％ | 89.1％ |
| Add amount of alcohol (mL) | 6 | 12 | 18 |
| Separate out mother liquor ee value after solid | 87.7％ | 88.9％ | 87.3％ |
| Solid ee value | 89.5％ | 89.7％ | 89.5％ |
| Solid weight | 2.4g | 2.2g | 1.9g |
(3) investigate the impact of different volumes ethyl alcohol recrystallization on the weight of the solid finally obtaining and ee. value under 30 ℃ of recrystallization temperatures
2g ee value is heated to 45～50 ℃ 88～89% dimension card Gray with different volumes ethanol and dissolves completely, stir lower nature and be down at 30 ℃ and separate out solid, separate out start to clock from solid, stirs mistake filter solid after 4～5 hours, result is as following table.
| Ethanol volume | Initial ee value | Separate out solid masses | Separate out solid ee value | Mother liquor ee value |
| 4mL | 88.7％ | 1.8g | 89.5％ | 86.9％ |
| 8mL | 88.7％ | 1.4g | 89.9％ | 86.5％ |
| 12mL | 89.3％ | 1.2g | 97.3％ | 79.3％ |
(4) under standing while investigating recrystallization, add the impact of crystal seed on the weight of the solid finally obtaining and ee value.
1g ee value is heated to 45～50 ℃ 88～89% dimension card Gray with 10mL ethanol dissolves completely, standingly naturally be down to 30 ℃, portion adds the dimension card Gray of 99%ee as crystal seed, and another part does not add crystal seed, observes time, weight, ee value that solid starts to separate out.Result is as following table.
| Crystal seed | Initial ee value | Start to separate out the solid time | Separate out solid masses | Separate out solid ee value | Mother liquor ee value |
| Add | 89.5％ | 6 hours | 0.53g | 96.7％ | 82.1％ |
| Do not add | 89.3％ | 17 hours | 0.47g | 96.7％ | 80.7％ |
Experiment conclusion: test (1) illustrates that ee value just can be separated out the solid of higher ee value 88～89% dimension card Gray when recrystallization temperature is when more than 30 ℃; Test (2), (3) have groped 30.℃ following and 30 ℃ time, different volumes ethanol, on separating out the impact of solid ee value, when ethanol is too much, cannot obtain higher ee value solid, necessary control ethanol usage quantity; Test (4) adds the crystal seed of high ee value can shorten the crystallization time when crystallization is described, but on the not impact of its ee value.
Claims (8)
1. tie up card Gray's a preparation method, as shown in following reaction formula:
Specifically comprise the following steps:
(1) racemic formula II compound reacts under alkali exists with formula III compound or its salt, obtains racemic formula IV compound;
(2) racemic formula IV compound splits through chiral acid, obtain (2S)-2-(2-oxygen-7,7a-dihydro-thiophene also [3,2-c] pyridine-5 (2H, 4H, 6H)-yl)-2-(2-chloro-phenyl-)-methyl acetate (formula V compound), the chiral acid adopting is the acid of camphor semi-annular jade pendant, tartrate or dibenzoyl tartaric acid;
(3) formula V compound or its salt reacts under alkali exists with acetic anhydride or Acetyl Chloride 98Min., obtains dimension card Gray;
In above-mentioned reaction formula, R
1be the phenyl of alkyl, trifluoromethyl, pentafluoroethyl group, seven fluoropropyls, phenyl or the X replacement of 1～6 carbon, wherein X is alkyl, halogen, itrile group, nitro or the trifluoromethyl of 1～3 carbon, and X group is positioned at 2,3 or 4 of phenyl ring.
2. the method for claim 1, in step (1), preferred formula II compound is: 2-(2-chloro-phenyl-)-2-(4-oil of mirbane sulfonyloxy) methyl acetate, 2-(2-chloro-phenyl-)-2-(4-chlorobenzene sulfonyloxy) methyl acetate, 2-(2-chloro-phenyl-)-2-phenylsulfonyloxy methyl acetate, 2-(2-chloro-phenyl-)-2-mesyloxy methyl acetate, 2-(2-chloro-phenyl-)-2-trifluoro-methanesulfonyl oxy methyl acetate or 2-(2-chloro-phenyl-)-2-(2-oil of mirbane sulfonyloxy) methyl acetate; The alkali adopting is salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, triethylamine, diisopropylethylamine or 1,8-diazacyclo [5,4,0] hendecene-7; The solvent adopting is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1, the mixed solvent of one or more in 2-ethylene dichloride, methyl tertiary butyl ether, tetracol phenixin, ethyl acetate, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ether, acetonitrile, DMF or methyl-sulphoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃; The salt of formula III compound is selected from its hydrochloride, tosilate, acetate, vitriol, phosphoric acid salt, fluoroform sulphonate, oxalate, mesylate, benzene sulfonate or hydrobromate.
3. the method for claim 1, in step (2), preferred resolving agent is L-(-)-camphorsulfonic acid; The solvent adopting is the mixture of one or more solvents in methyl alcohol, ethanol, Virahol, ether, isopropyl ether, acetonitrile, acetone, ethyl acetate.
4. the method for claim 1, in step (3), the alkali adopting is selected from triethylamine, sodium hydride, potassium hydride KH, 1,8-diazacyclo [5,4,0] hendecene-7, pyridine, diisopropylethylamine, diisopropylamine lithium, salt of wormwood, sodium carbonate, saleratus, sodium bicarbonate, potassium tert.-butoxide or sodium tert-butoxide; Reaction solvent used is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, methylene dichloride, 1, the mixed solvent of one or more in 2-ethylene dichloride, methyl tertiary butyl ether, tetracol phenixin, ethyl acetate, propyl acetate, butylacetate, methyl alcohol, ethanol, acetone, tetrahydrofuran (THF), ether, acetonitrile, DMF or methyl-sulphoxide; Temperature of reaction is subzero 20 ℃ to 100 ℃.
5. from low optical purity dimension card Gray, prepare high-optical-purity dimension card Gray's method for one kind, it is characterized in that: utilize low optical purity dimension card Gray special solubility behavior in ethanol, method by low optical purity dimension card Gray by making beating or recrystallization obtains high-optical-purity dimension card Gray, specifically comprises the following steps:
(1) when dimension card Gray's optical purity (using ee value representation) is lower than 88% time, by pulling an oar or recrystallization with ethanol, after filtering insoluble solids, acquisition contains ee value at 88%～90% dimension card Gray's solution, more obtains ee value 88%～90% dimension card Gray through removing solvent under reduced pressure;
(2), when dimension card Gray's ee value is 88%～90%, by ethyl alcohol recrystallization and control recrystallization temperature, can obtains ee value higher than 97% dimension card Gray, and can repeat this process and obtain the more dimension card Gray of high-optical-purity.
6. method as claimed in claim 5, it is characterized in that, low optical purity dimension card Gray refers to that optical purity (ee value) is less than or equal to the dimension card Gray that 90% dimension card Gray, especially ee value are less than 88%, more refers in particular to the dimension card Gray that ee value is less than 80%.
7. method as claimed in claim 5, in step (1), ties up card Gray's (ee value is lower than 88%) quality (with a gram calculating) and the volume of ethanol used (with milliliter, calculating) than being selected from 1: 1 to 1: 30, preferably 1: 3 to 1: 20.
8. method as claimed in claim 5, in step (2), controls recrystallization temperature at 0 ℃ to 50 ℃ during ethyl alcohol recrystallization, and preferably temperature is 30 ℃ to 40 ℃; Tie up card Gray's (ee value is 88%～90%) quality (with a gram calculating) and the volume (milliliter of take calculating) of ethanol used ratio as 1: 1 to 1: 10, preferably 1: 1 to 1: 7.
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| CN201210333184.4A CN103664990A (en) | 2012-09-12 | 2012-09-12 | Preparation method of Vicagrel |
| PCT/CN2013/082510 WO2014040498A1 (en) | 2012-09-12 | 2013-08-29 | Method for preparing vicagrel |
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| CN108420798B (en) * | 2017-02-15 | 2021-03-02 | 江苏威凯尔医药科技有限公司 | Quick-release medicinal preparation of anticoagulant and preparation method thereof |
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