CN101289417A - Process for preparing D-3-thioacetyl-2-methylpropionyl-L-proline - Google Patents
Process for preparing D-3-thioacetyl-2-methylpropionyl-L-proline Download PDFInfo
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- CN101289417A CN101289417A CNA2008101238064A CN200810123806A CN101289417A CN 101289417 A CN101289417 A CN 101289417A CN A2008101238064 A CNA2008101238064 A CN A2008101238064A CN 200810123806 A CN200810123806 A CN 200810123806A CN 101289417 A CN101289417 A CN 101289417A
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Abstract
The invention relates to a method for preparing D-3-thioacetyl-2-methylpropionyl-L-proline. The method is that: the pH values of two diastereoisomer water solutions of D type and L type of the 3-thioacetyl-2-methylpropiony-proline are adjusted to 0.01 to 3.0, and a reservoir is precipitated; ethyl acetate is used for extracting water layers after separating the reservoir, and the 3-thioacetyl-2-methylpropiony-proline is transferred to the ethyl acetate layer; then the reservoir and the ethyl acetate layer are merged; and the temperature is reduced to crystallize, and the crystal obtained by the separation is the D-3-thioacetyl-2-methylpropionyl-L-proline, and the structural formula is as above. The purity and the yield of the D-3-thioacetyl-2-methylpropionyl-L-proline prepared by the method are both higher than those of the separation method which utilizes the solubility differences of the D type and the L type 3-thioacetyl-2-methylpropionyl-L-proline in water.
Description
Technical field
The present invention relates to the method for a kind of D-3-of preparation acetylthio-2-methyl propionyl-L-proline(Pro).
Background technology
D-3-acetylthio-2-methyl propionyl-L-proline(Pro), it be the preparation captopril its structural formula of intermediate as follows:
Captopril claims captopril again, and its chemical name is (2S)-1-(3-sulfydryl-2-methyl isophthalic acid=oxo-propyl group)-L-proline(Pro), and its structural formula is as follows:
Captopril is mainly used in the various essential hypertensions of treatment, has advantages such as onset is rapid, step-down is steady, late result is outstanding, simultaneously in heart failure and diabetes, ephrosis is also had good therapeutic action.As the D-3-acetylthio-2-methyl propionyl-L-proline(Pro) of preparation captopril intermediate, its purity direct relation the quality of captopril.The method for preparing at present D-3-acetylthio-2-methyl propionyl-L-proline(Pro) mainly is to be raw material with 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro), makes 3-acetylthio-2-methyl propionyl-L-proline(Pro) earlier.The 3-acetylthio that makes-2-methyl propionyl-L-proline(Pro) is the mixture of D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (I) and L-3-acetylthio-2-methyl propionyl-two kinds of diastereomers of L-proline(Pro).Seeking out D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (I) just must split 3-acetylthio-2-methyl propionyl-L-proline(Pro).U.S. Pat 4046889 is to adopt dicyclohexyl amine as resolving agent, with the 3-acetylthio-2-methyl propionyl-L-proline(Pro) that makes, with the dicyclohexylamine salify, obtain the dicyclohexyl amine salt of D configuration after the separation, free with sal enixum again, obtain D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (I).This method for splitting step is many, the production cost height; Chinese patent ZL89108856 (CN1021044C) utilizes D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (I) and L-3-acetylthio-2-methyl propionyl-two kinds of diastereomers of L-proline(Pro) difference of solubleness in water to split.But lower and purity is also not high with the yield of this method gained D-3-acetylthio-2-methyl propionyl-L-proline(Pro) (I), therefore, the purity of the captopril for preparing with its hydrolysis also is affected.
Summary of the invention
The objective of the invention is: the method for preparing D-3-acetylthio-2-methyl propionyl-L-proline(Pro) that provides a kind of purity and yield all to be improved.
The technical scheme that realizes the object of the invention is: the method for a kind of D-3-of preparation acetylthio-2-methyl propionyl-L-proline(Pro), be characterized in the aqueous solution with 3-acetylthio-2-methyl propionyl-L-proline(Pro), adjusting pH is 0.01～3.0, separate out oil reservoir, with the water layer behind the ethyl acetate extraction separation oil reservoir, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, merge oil reservoir and ethyl acetate layer then, decrease temperature crystalline, separating obtained crystallization is D-3-acetylthio-2-methyl propionyl-L-proline(Pro), and its structural formula is as follows:
Described 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type.
Among the above-mentioned preparation method, the aqueous solution of described 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the product that 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro) react in water or water-containing solvent.
The concrete operations step of above-mentioned preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) method is as follows:
1. be raw material with 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro), with alkali is condensing agent, regulating and controlling pH is 7～12, temperature of charge is-5 ℃～+ 20 ℃, after in water, reacting 0.5～3 hour, promptly make the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro), its 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type;
The aqueous solution of the 3-acetylthio that 2. 1. step is made-2-methyl propionyl-L-proline(Pro), adjusting the pH value is 0.01～3.0, separate out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separate the oil reservoir and the reservation of separating out;
3. 2. step is separated the water layer ethyl acetate extraction behind the oil reservoir, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, keep gained ester layer;
4. the oil reservoir that 2. ester layer that 3. step is kept and step keep merges;
5. lower the temperature behind 0 ℃ to-20 ℃ crystallization 3～6h under stirring, leave standstill 3h at least at 0 ℃ to-20 ℃ again;
6. filtering separation is washed and drying crystalline, promptly obtains D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro).
Among the above-mentioned preparation method, 2. described step is the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro) of earlier 1. step being made, with ethyl acetate washing and remove impure ester layer, adjusting the pH value then is 0.01～3.0, separate out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separate the oil reservoir and the reservation of separating out.Because washing through ethyl acetate, in the aqueous solution of the 3-acetylthio that 1. step makes-2-methyl propionyl-L-proline(Pro), the impurity that part dissolves in ethyl acetate is removed, thereby reduced impurity for the influence that splits with ethyl acetate extraction, be more conducive to improve the yield and the purity of product.
Among the above-mentioned preparation method, the 2. described adjustment of step pH value is 1.0～2.0 better.
Among the above-mentioned preparation method, described step 3. 2. step is separated behind the oil reservoir water layer with ethyl acetate extraction at least once, the weight ratio of the aqueous solution of the 3-acetylthio that 1. total consumption of its ethyl acetate and step make-2-methyl propionyl-L-proline(Pro) is 0.2: 1 to 1: 1.Extraction times is how favourable to improving percentage extraction.
Among the above-mentioned preparation method, 2. 3. described step separate step the water layer behind the oil reservoir, add sodium-chlor make it dissolving reach sodium-chlor saturated after, use ethyl acetate extraction, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, kept gained ester layer.Favourable to improving percentage extraction.
Among the above-mentioned preparation method, 4. described step is after the ester layer that 3. step extracts gained is carried out underpressure distillation and concentrates, and the oil reservoir that 2. keeps with step merges again.Owing to ethyl acetate layer has been carried out concentrating of appropriateness, has been more conducive to improve product yield.
Among the above-mentioned preparation method, 5. described step is to add D-3-acetylthio-2-methyl propionyl-L-proline(Pro) as crystal seed, lowers the temperature behind 0 ℃ to-20 ℃ crystallization 3～6h under stirring, and leaves standstill 3h at least at 0 ℃ to-20 ℃ again.Owing to added crystal seed, be more conducive to improve the purity of product.
Technique effect of the present invention is: the present invention adopts ethyl acetate to make resolving agent, 3-acetylthio-2-methyl propionyl-L-proline(Pro) (mixtures of D type and two kinds of diastereomers of L type) is transferred to ethyl acetate layer from water, make part impurity soluble in water be removed, thereby reduced the influence that impurity splits crystallization; Because adjusting the pH of 3-acetylthio-2-methyl propionyl-L-proline(Pro) (mixtures of D type and two kinds of diastereomers of L type) aqueous solution before splitting is 0.01～3.0, be beneficial to 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and the transfer in ethyl acetate from water of two kinds of non-enantiomer mixtures of L type, behind the decrease temperature crystalline, improved D-3-acetylthio-2-methyl propionyl-L-proline(Pro) crystalline yield and purity.The data declaration of table 1 aspect the yield and purity of product, the present invention all is better than utilizing D type and L type 3-acetylthio-2-methyl propionyl-two kinds of diastereomer methods that dissolubility difference splits in water of L-proline(Pro).Therefore, the D-3-acetylthio-2-methyl propionyl-L-proline(Pro) that obtains with the inventive method can make more highly purified captopril.
Embodiment
Below in conjunction with embodiment the present invention is further described in detail, but is not limited to this.
The used raw material of embodiment unless otherwise indicated is the technical grade commercially available product, also can use more highly purified raw material such as effects such as pharmaceutical grade, chemical pure better certainly, specifically selects for use grades of raw materials to take all factors into consideration according to cost.
Embodiment 1 preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) A
The concrete operations step is as follows:
1. using 3-acetylthio-2-methyl-prop acyl chlorides 102.5g (0.55mol) and L-proline(Pro) 63.5g (0.55mol) is raw material, is condensing agent with 5mol/L NaOH solution.63.5g L-proline(Pro) (0.55mol) is dissolved in the 270ml water, regulate its pH 8～9 and be cooled to-5 ℃～0 ℃ with 5mol/L NaOH solution, Dropwise 5 mol/L NaOH solution and 3-acetylthio-2-methyl-prop acyl chlorides 102.5g (0.55mol), control pH 8～9 in the dropping process, temperature of charge is-5 ℃～0 ℃, after dropwising, continue stirring reaction after 0.5 hour, promptly make the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro), its 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type;
It is 1.0 that the aqueous solution of the 3-acetylthio that 2. 1. step is made-2-methyl propionyl-L-proline(Pro) is adjusted the pH value, separates out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separates the oil reservoir and the reservation of separating out;
3. the water layer that 2. step is separated behind the oil reservoir divides 3 extractions with the 300ml ethyl acetate, and 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, keeps gained ester layer and merges; The weight ratio of the aqueous solution that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) that 1. total consumption of its ethyl acetate and step make is 0.4: 1.
4. the oil reservoir that 2. ester layer that 3. step is merged and step keep merges;
5. lower the temperature behind 0 ℃ to-5 ℃ crystallization 3h under stirring, leave standstill 10h at-10 ℃ again;
6. ethyl acetate and water washing crystallization are used in filtering separation crystallization successively, again in 55 ℃ of drying crystallines, promptly obtain D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro) 52g, and yield is 36.5%, 70～76 ℃ of fusing points, specific optical rotation
Embodiment 2 preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) B
The concrete operations step is as follows:
Step is 1., 3., 4., 5. with 6. identical with embodiment 1;
2. step carries out by the following method: the first aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro) that 1. step is made, with ethyl acetate washing 3 times, each 50ml ethyl acetate, remove impure ester layer, adjusting the pH value with concentrated hydrochloric acid then is 1.0, separate out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separate the oil reservoir and the reservation of separating out.
Resultant D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro) 58g, yield is 40%, 78～80 ℃ of fusing points, specific optical rotation
Embodiment 3 preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) C
The concrete operations step is as follows:
Step is 1., 4., 5. with 6. identical with embodiment 1;
Step is 2. identical with embodiment 2;
3. step carries out by the following method: 2. step is separated water layer behind the oil reservoir, add sodium-chlor make it dissolving reach sodium-chlor saturated after, divide 5 extractions with the 500ml ethyl acetate again, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, kept gained ester layer and merging; The weight ratio of the aqueous solution of the 3-acetylthio that 1. total consumption of its ethyl acetate and step make-2-methyl propionyl-L-proline(Pro) is 0.7: 1.
Gained D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro) is 54g, and yield is 38%, 78～80 ℃ of fusing points, specific optical rotation
Embodiment 4 preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) D
The concrete operations step is as follows:
Step is 1., 5. with 6. identical with embodiment 1;
Step is 2. identical with embodiment 2;
Step is 3. identical with embodiment 3;
4. step carries out by the following method: the ester layer that 3. step is extracted gained carries out underpressure distillation, steams after the 200ml ethyl acetate concentrates, and the oil reservoir that 2. keeps with step merges again;
Gained D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro) is 59g, and yield is 41%, 78～80 ℃ of fusing points, specific optical rotation
Embodiment 5 preparation D-3-acetylthio-2-methyl propionyl-L-proline(Pro) E
The concrete operations step is as follows:
Step is 1., 3., 4. with 6. identical with embodiment 1;
Step is 2. identical with embodiment 2;
5. step carries out by the following method: stir decrease temperature crystalline and add 0.1g D-3-acetylthio-2-methyl propionyl-L-proline(Pro) crystal seed, lower the temperature behind 0 ℃ to-5 ℃ crystallization 3h under stirring, leave standstill 10h at-10 ℃ again;
Gained D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro) is 58g, and yield is 40%, 80～82 ℃ of fusing points, specific optical rotation
Comparative example 1 duplicates the embodiment 1 of CN1021044C
1. 63.5g L-proline(Pro) (0.55mol) is dissolved in the 270ml water, regulate its pH 8～9 and be cooled to-5 ℃～0 ℃ with 2mol/L NaOH solution, drip 2mol/L NaOH solution and 3-acetylthio-2-methyl-prop acyl chlorides 102.5g (0.55mol), control pH 8～9 in the dropping process, temperature of charge is-5 ℃～0 ℃, after dropwising, continued stirring reaction 0.5 hour, promptly make the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro), its 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type;
2. earlier with the 1. aqueous solution of the 3-acetylthio of gained-2-methyl propionyl-L-proline(Pro) of step, with ethyl acetate washing 3 times, each 50ml ethyl acetate.Remove the ester layer, keep water layer, with 6mol/L hydrochloric acid the pH value of water layer is adjusted into 2.0 then;
3. in stirring at room 5 hours, 10 ℃ left standstill 16 hours.
4. filter, collecting precipitation washes with water, obtains D-3-acetylthio-2-methyl propionyl-L-proline-4 0g after the drying, yield 28%, 55～63 ℃ of fusing points, specific optical rotation
Table 1
| Yield | Fusing point | Specific optical rotation [α] D 20 | |
| Comparative example 1 (pressing CN1021044C embodiment 1 repeats) | 28％ | 55～63℃ | -150° |
| Comparative example 2 (CN1021044C public data) | 36％ | 70～80℃ | -155～-170° |
| Embodiment 1 | 36.5％ | 70～76℃ | -165° |
| Embodiment 2 | 40％ | 78～80℃ | -170° |
| Embodiment 3 | 38％ | 78～80℃ | -170° |
| Embodiment 4 | 41％ | 78～80℃ | -170° |
| Embodiment 5 | 40％ | 80～82℃ | -170° |
Comparison sheet 1 data, illustrate with the inventive method (embodiment 1,2,3,4 and 5) to make D-3-acetylthio-2-methyl propionyl-L-proline(Pro) purity and yield as resolving agent, all be higher than D type and the L type 3-acetylthio-2-methyl propionyl-two kinds of diastereomer methods that dissolubility difference splits in water of L-proline(Pro) (comparative example 1 and 2) utilized with ethyl acetate.Proof the present invention adopts ethyl acetate to have obvious technique effect as resolving agent.
The inventive method is by the concrete preparation process of appropriate change, for example: increase the operation (embodiment 2) that contains the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro) with the ethyl acetate washing, perhaps use more ethyl acetate to carry out more repeatedly extraction, simultaneously ethyl acetate layer is carried out appropriateness and concentrate (embodiment 4), perhaps add crystal seed measures such as (embodiment 5) during crystallization, can obtain needed yield and purity to the actual needs of product/price ratio according to market.Therefore, the inventive method adaptability is very flexible, has good market outlook.
Claims (9)
1, a kind of method for preparing D-3-acetylthio-2-methyl propionyl-L-proline(Pro), it is characterized in that, the aqueous solution with 3-acetylthio-2-methyl propionyl-L-proline(Pro), adjusting pH is 0.01～3.0, separate out oil reservoir, with the water layer behind the ethyl acetate extraction separation oil reservoir, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, merge oil reservoir and ethyl acetate layer then, decrease temperature crystalline, separating obtained crystallization is D-3-acetylthio-2-methyl propionyl-L-proline(Pro), and its structural formula is as follows:
Described 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type.
2, preparation method according to claim 1 is characterized in that, the aqueous solution of described 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the product that 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro) react in water or water-containing solvent.
3, preparation method according to claim 1 is characterized in that, the concrete operations step is as follows:
1. be raw material with 3-acetylthio-2-methyl-prop acyl chlorides and L-proline(Pro), with alkali is condensing agent, regulating and controlling pH is 7～12, temperature of charge is-5 ℃～+ 20 ℃, after in water, reacting 0.5～3 hour, promptly make the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro), its 3-acetylthio-2-methyl propionyl-L-proline(Pro) is the D type of 3-acetylthio-2-methyl propionyl-L-proline(Pro) and the mixture of two kinds of diastereomers of L type;
The aqueous solution of the 3-acetylthio that 2. 1. step is made-2-methyl propionyl-L-proline(Pro), adjusting the pH value is 0.01～3.0, separate out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separate the oil reservoir and the reservation of separating out;
3. 2. step is separated the water layer ethyl acetate extraction behind the oil reservoir, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, keep gained ester layer;
4. the oil reservoir that 2. ester layer that 3. step is kept and step keep merges;
5. lower the temperature behind 0 ℃ to-20 ℃ crystallization 3～6h under stirring, leave standstill 3h at least at 0 ℃ to-20 ℃ again;
6. filtering separation is washed and drying crystalline, promptly obtains D-3-acetylthio of the present invention-2-methyl propionyl-L-proline(Pro).
4, preparation method according to claim 3, it is characterized in that, 2. described step is the aqueous solution of 3-acetylthio-2-methyl propionyl-L-proline(Pro) of earlier 1. step being made, with ethyl acetate washing and remove impure ester layer, adjusting the pH value then is 0.01～3.0, separate out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separate the oil reservoir and the reservation of separating out.
5, according to claim 3 or 4 described preparation methods, it is characterized in that, the 2. described adjustment of step pH value is 1.0～2.0, separates out the oil reservoir that contains 3-acetylthio-2-methyl propionyl-L-proline(Pro) D type and two kinds of diastereomers of L type, separates the oil reservoir and the reservation of separating out.
6, preparation method according to claim 3, it is characterized in that, described step 3. 2. step is separated behind the oil reservoir water layer with ethyl acetate extraction at least once, the weight ratio of the aqueous solution of the 3-acetylthio that 1. total consumption of its ethyl acetate and step make-2-methyl propionyl-L-proline(Pro) is 0.2: 1 to 1: 1.
7, preparation method according to claim 3, it is characterized in that, 2. 3. described step separate step the water layer behind the oil reservoir, add sodium-chlor make it dissolving reach sodium-chlor saturated after, use ethyl acetate extraction, 3-acetylthio-2-methyl propionyl-L-proline(Pro) is transferred in the ethyl acetate layer, kept gained ester layer.
8, preparation method according to claim 3 is characterized in that, 4. described step is after the ester layer that 3. step extracts gained is carried out underpressure distillation and concentrates, and the oil reservoir that 2. keeps with step merges again.
9, preparation method according to claim 3 is characterized in that, 5. described step is to add D-3-acetylthio-2-methyl propionyl-L-proline(Pro) as crystal seed, lowers the temperature behind 0 ℃ to-20 ℃ crystallization 3～6h under stirring, and leaves standstill 3h at least at 0 ℃ to-20 ℃ again.
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Cited By (2)
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| CN102452970A (en) * | 2010-10-16 | 2012-05-16 | 华中药业股份有限公司 | Preparation method of D-3-bromine-2-methyl propionyl-L-proline |
| CN108373436A (en) * | 2017-06-14 | 2018-08-07 | 金溪斯普瑞药业有限公司 | The preparation method of acetyl captopril |
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| US4046889A (en) * | 1976-02-13 | 1977-09-06 | E. R. Squibb & Sons, Inc. | Azetidine-2-carboxylic acid derivatives |
| TW401421B (en) * | 1994-03-07 | 2000-08-11 | Syn Tech Chem & Pharm Co Ltd | A method of asymmeric synthezing of optically active peptides |
| CN1298873A (en) * | 1999-12-09 | 2001-06-13 | 国家医药管理局上海医药工业研究院 | Xiantuopuli-hydrate as inhibitor of angiotonin converzyme |
| WO2007099894A1 (en) * | 2006-02-27 | 2007-09-07 | Kaneka Corporation | General-purpose deprotecting method using sulfur oxide |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102452970A (en) * | 2010-10-16 | 2012-05-16 | 华中药业股份有限公司 | Preparation method of D-3-bromine-2-methyl propionyl-L-proline |
| CN108373436A (en) * | 2017-06-14 | 2018-08-07 | 金溪斯普瑞药业有限公司 | The preparation method of acetyl captopril |
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