CN101462947A - Preparation of (R) -4-phenyl-2-hydroxybutyrate - Google Patents
Preparation of (R) -4-phenyl-2-hydroxybutyrate Download PDFInfo
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- CN101462947A CN101462947A CNA2009100448657A CN200910044865A CN101462947A CN 101462947 A CN101462947 A CN 101462947A CN A2009100448657 A CNA2009100448657 A CN A2009100448657A CN 200910044865 A CN200910044865 A CN 200910044865A CN 101462947 A CN101462947 A CN 101462947A
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Abstract
The invention relates to a preparation method of (R)-4-phenyl-2-hydroxy-butanoic acid, comprising the following steps: bromohydrin reaction is carried out on 4- phenyl-1- butylenes for obtaining 4-phenyl-1-bromine-2-butanol and then 4-phenyl-1, 2-epoxy butane is obtained by cyclization under alkalescence condition; epoxy hydrolytic ferment ECU1040 is utilized for splitting the 4- phenyl-1, 2-epoxy butane to obtain the (R)-4-phenyl, -2-butanediol; finally, the (R)-4-phenyl, -2-butanediol is oxidized by the concentrated nitric acid for obtaining the target product of (R)-4-phenyl-2-hydroxy-butanoic acid. The method is simple and practical, the operation is simple and convenient, the raw material source is wide, the cost is low, and the yield is high; the product optical purity can reach more than 99 percent e.e; therefore, the method has good industrialization prospect.
Description
Technical field
The invention belongs to the preparation field of nervous plain converting enzyme inhibitor (ACEI) intermediate of synthetic vessel, particularly relate to the preparation method of a kind of (R)-4-phenyl-2-hydroxybutyric acid.
Background technology
(R)-4-phenyl-2-3-hydroxyethyl butyrate is the important intermediate of nervous plain converting enzyme inhibitor (ACEI) class treatment hypertension of synthetic vessel and congestive heart failure (CHF) medicine.Especially for enalapril (Enalapril), Zinadril Briem (Benazepril), delapril (Delapril), quinapril (Quinapril), lisinopril (Lisinapril), Yipingshu (Cilazapril), Ramipril (Ramipril), moexipril (Moexipril), imidapril (Imidapril), spirapril (Spirapril), indolapril (Indolapril), synthesizing of alacepril angiotensin-convertion enzyme inhibitors (ACEI) such as (Alacepril).
4-phenyl-2-the hydroxybutyric acid of Japanese Patent (JP04200391) report in 1992 racemization splits through lipase and can obtain (R)-4-phenyl-2-hydroxybutyric acid and (S)-4-phenyl-2-3-hydroxyethyl butyrate, yield 19%, and optical purity reaches 97%e.e.Nineteen ninety-five Chadha, A. wait the people at Tetrahedron Lett.1995,6 (3), 651 pages of 4-phenyl-2-hydroxybutyric acids of also having reported racemization split through lipase can obtain (R)-4-phenyl-2-hydroxybutyric acid and (S)-4-phenyl-2-3-hydroxyethyl butyrate, and optical purity reaches 99%e.e.1992 Japanese Patent (JP05335886) use the enzyme Leuconostoc that produces by L.Dextranicum IFO 27310 in the presence of NADPH, asymmetric reduction 4-phenyl-2-ketobutyric acid is (R)-4-phenyl-2-hydroxybutyric acid in phosphate buffer soln, yield 68%.Also phenyl-the 2-ketobutyric acid is (R)-4-phenyl-2-hydroxybutyric acid to Japanese Patent in the same year (JP0471494) with enzyme process reduction 4-, and optical purity reaches 100%e.e, yield 95%.1993, world patent (WO9313215) obtained (R)-4-phenyl-2-hydroxybutyric acid with serum lactic dehydrogenase reduction 4-phenyl-2-hydroxybutyronitrile, and optical purity reaches 97%e.e.Japanese Patent in the same year (JP05192190) obtains (R)-4-phenyl-2-hydroxybutyric acid, optical purity 95%e.e with the 4-phenyl-2-hydroxybutyronitrile of microbial hydrolytic racemization.European patent in 1989 (EP329156) splits the 4-phenyl-2-hydroxybutyric acid of racemization, yield 61%, optical purity 99%e.e respectively with optically pure 1-p-methylphenyl ethamine and N-hydroxyethylbenzene ethamine.4-phenyl-2-hydroxybutyric acid that Spain's patent (ES2035800) of Spain's patent (ES2019241) in 1991 and 1993 all uses cheap paraxin intermediate to split racemization gets (R)-4-phenyl-2-hydroxybutyric acid.But this method is difficult to repeat.2000, Bachvall, people such as J-E be at Org.Lett.2000, and 2 (8), reported with chirality ruthenium complex kinetic resolution Alpha-hydroxy acid esters for 1037 pages, but this method is not suitable for the fractionation of 4-phenyl-2-hydroxybutyric acid, optical purity is 18%e.e only.1987, Yamamoto, H. etc. are at J.Med.Chem.1987,30 (11), reported for 1984 pages 4-phenyl-2-oxo-3-butenoic acid has been made the alcohol in the Meng of chirality, again through synthetic (the R)-4-phenyl of palladium carbon asymmetric induction reduction-2-hydroxybutyric acid, three step total recoverys 25%.But the Meng, the alcohol price was very expensive.1993, Pedrosa, people such as R. be at Tetrahedron Lett.1993, and 34 (51), 8325 leaves have also been reported with synthetic (the R)-4-phenyl of chiral induction-2-hydroxybutyric acid, yield 64%, optical purity 94%e.e.The same year, the Blaser of vapour Bagong department, H.U. etc. be at Stud.Surf.Sci.Catal.1993, and 78,139 pages of reports obtain (R)-4-phenyl-2-3-hydroxyethyl butyrate with heterogeneous catalyst hydro-reduction 4-phenyl-2-ketobutyric acid ethyl ester, and optical purity has only 80%e.e.1992 Japanese Patent (JP0418050) in the presence of the L-proline(Pro), obtain (R)-4-phenyl-2-hydroxyl-3-butenoic acid with sodium borohydride reduction 4-phenyl-2-oxo-3-butenoic acid, yield 73%, optical purity 94%. further catalytic hydrogenations obtain (R)-4-phenyl-2-hydroxybutyric acid.
2002 Chinese patent (CN1370767) reported that with the D-oxysuccinic acid be raw material, be dehydrated into acid anhydrides through hydroxyl protection, obtain (R)-4-phenyl-4-oxo-2-hydroxybutyric acid through Friedel-Crafts reaction, obtain (R)-4-phenyl-2-hydroxybutyric acid through hydro-reduction again.But the D-oxysuccinic acid costs an arm and a leg.
But simple general-purpose, operation is convenient, cost is low, selectivity is high synthetic technology route are convenient to suitability for industrialized production (R)-4-phenyl-2-hydroxybutyric acid and are still waiting further research up to now.
Summary of the invention
The present invention will solve to such an extent that technical problem provides the preparation method of a kind of (R)-4-phenyl-2-hydroxybutyric acid, and present method is simple and practical, and is easy and simple to handle, used starting material wide material sources, cost is low, the yield height, optical purity of products reaches more than the 99%e.e, has good industrial prospect.
The synthetic route of a kind of (R)-4-phenyl of the present invention-2-hydroxybutyric acid is as follows:
Said synthesis route of the present invention is specially:
1. 4-phenyl-1-butylene is carried out oxidation, bromination generates 1-bromo-4-phenyl-2-butanols;
2.1-bromo-4-phenyl-2-butanols generates 4-phenyl-1,2-butylene oxide ring at alkaline condition ShiShimonoseki ring;
3. receive epoxide hydrolase with racemization 4-phenyl-1, the 2-butylene oxide ring splits and obtains (R)-4-phenyl-1,2-butyleneglycol;
With nitric acid to (R)-4-phenyl-1, the oxidation of 2-butyleneglycol obtains (R)-4-phenyl-2-hydroxybutyric acid.
The preparation method of a kind of (R)-4-phenyl of the present invention-2-hydroxybutyric acid comprises:
(1) with 4-phenyl-1-butylene, sodium chlorate (NaClO
3), an amount of water adds reaction flask, stir, be heated to 50～100 ℃, drip Sodium Bromide and the mixed aqueous solution vitriol oil then, dropwised, continue reaction 1～5 hour at 1～5 hour, pour separating funnel into after naturally cooling to room temperature, tell layer oily matter, obtain product 4-phenyl-1-bromo-2-butanols, the weight proportion of its material is: 4-phenyl-1-butylene: sodium chlorate (NaClO
3): Sodium Bromide: the vitriol oil=1～5:1～3:1～3:1～4;
(2) 4-of above-mentioned gained phenyl-1-bromo-2-butanols does not need purifying, directly add 20% caustic-soda aqueous solution, 30～60 ℃ of following stirring reactions 2～8 hours, be cooled to room temperature, standing demix, tell the upper strata product, obtain product 4-phenyl-1,2-butylene oxide ring, molecular distillation purifying, product purity reaches more than 98%, and its material mole proportioning is: 4-phenyl-1-bromo-2-butanols: caustic soda=1～3:1;
(3) 4-phenyl-1,2-butylene oxide ring are pressed Chinese patent ZL200510023852.3 method, suitably revise the back fractionation and obtain (R)-4-phenyl-1,2-butyleneglycol.Specific operation process is: with 4-phenyl-1, and 2-butylene oxide ring, epoxide hydrolase ECU1040 (preserving number: CGMCC No
1292, preservation date: on January 17th, 2005) drop into reaction flask, add entry under 0～10 ℃, react after 10～40 hours, stopped reaction, underpressure distillation goes out unhydrolysed 4-phenyl-1, and behind the 2-butylene oxide ring, the continuation molecular distillation goes out (R)-4-phenyl-1,2-butyleneglycol; The weight of material proportioning of its reaction is: 4-phenyl-1 ,-2-butylene oxide ring: epoxide hydrolase: water=1:0.5～2:1～4;
(4) add concentrated nitric acid in reaction flask, under 0～60 ℃, add (R)-4-phenyl-1 in batches, the 2-butyleneglycol finishes, insulation reaction 30～72 hours, the high pressure liquid chromatographic analysis starting material back termination reaction that reacts completely; Underpressure distillation goes out excessive nitric acid, use ethyl acetate extraction 3-5 time behind the bottle end residue dilute with water, ethyl acetate solvent is reclaimed in underpressure distillation again, bottle end solid gets (R)-4-phenyl-2-hydroxybutyric acid with the toluene recrystallization, the weight of material proportioning of reaction is: (R)-4-phenyl-1,2-butyleneglycol: concentrated nitric acid=1:4～10.
Beneficial effect
Present method is simple and practical, and is easy and simple to handle, used starting material wide material sources, and cost is low, the yield height, optical purity of products reaches more than the 99%e.e, has good industrial prospect.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.Should be understood that in addition after having read content of the present invention, those skilled in the art can make various changes or modifications the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Embodiment 1
(1) with 4-phenyl-1-butylene 66g (0.5mol), sodium chlorate (NaClO
3) 26.6g (0.5mol), 100g water add reaction flask, stirs, and is heated to 85～90 ℃, Dropwise 5 1.4g Sodium Bromide (0.5mol) and vitriol oil 25ml then, the mixing solutions of water 200ml.3.5 hour dropwise.Continue reaction 1.5 hours, pour separating funnel into after naturally cooling to room temperature, tell layer oily matter, obtain product 4-phenyl-about 110g of 1-bromo-2-butanols crude product.Product directly uses the bottom reaction without purifying.
(2) 110g4-of above-mentioned gained phenyl-1-bromo-2-butanols crude product directly joins 120 grams, 20% caustic-soda aqueous solution, 30～35 ℃ of following stirring reactions 4 hours, is cooled to room temperature, leaves standstill layering in 30 minutes.Tell the upper strata product.The molecular distillation purifying obtains colourless transparent liquid product 4-phenyl-1,2-butylene oxide ring 63 grams, and product purity reaches more than 98%.Two about 85% (to 4-phenyl-1-butylene) of yield.
(3) with 74 gram 4-phenyl-1, (preserving number: CGMCC No1292, preservation date: on January 17th, 2005) drop into reaction flask, ice-water bath is cooled under 0～5 ℃, Dropwise 50 gram water for 2-butylene oxide ring and 1 gram epoxide hydrolase ECU1040.Controlled temperature is no more than 5 ℃.Drip and finish, remove ice-water bath, be warming up to room temperature naturally.Continue reaction 30 hours, stopped reaction.Underpressure distillation goes out unhydrolysed low chirality (S)-4-phenyl-1, behind the 2-butylene oxide ring, continues molecular distillation and goes out (R)-4-phenyl-1, and 2-butyleneglycol 32 grams are become white solid after the cooling.Chemical purity 96%, optical purity 99%e.e.Yield 77%.
(4) concentrated nitric acid 360 grams, the reaction flask of input 500ml under the stirring at room, adds 32 gram (R)-4-phenyl-1, the 2-butyleneglycol in batches.Control reaction temperature is no more than 35 ℃.Finish insulation reaction 48 hours.Termination reaction after the high pressure liquid chromatographic analysis starting material react completely.Underpressure distillation goes out excessive nitric acid, and bottle end residue dilutes back 30ml ethyl acetate extraction 3 times with 50ml water.United extraction liquid, anhydrous sodium sulfate drying spends the night, and ethyl acetate solvent is reclaimed in underpressure distillation.Bottle end solid gets (R)-4-phenyl-2-hydroxybutyric acid 31 grams, chemical purity 98 above %, optical purity 99%e.e with 60ml toluene recrystallization.Yield 88.5%.
Claims (1)
1. the preparation method of (R)-4-phenyl-2-hydroxybutyric acid comprises:
(1) with 4-phenyl-1-butylene, NaClO
3, water adds reaction flask, stir, be heated to 50～100 ℃, drip the mixed aqueous solution of the Sodium Bromide and the vitriol oil then, dropwised, continue reaction 1～5 hour at 1～5 hour, pour separating funnel into after naturally cooling to room temperature, tell layer oily matter, obtain product 4-phenyl-1-bromo-2-butanols, the weight proportion of its material is: 4-phenyl-1-butylene: NaClO
3: Sodium Bromide: the vitriol oil=1～5:1～3:1～3:1～4;
(2) 4-of above-mentioned gained phenyl-1-bromo-2-butanols does not need purifying, directly add 20% caustic-soda aqueous solution, 30～60 ℃ of following stirring reactions 2～8 hours, be cooled to room temperature, standing demix, tell the upper strata product, obtain product 4-phenyl-1,2-butylene oxide ring, molecular distillation purifying, product purity reaches more than 98%, and its material mole proportioning is: 4-phenyl-1-bromo-2-butanols: caustic soda=1～3:1;
(3) with 4-phenyl-1, the 2-butylene oxide ring, epoxide hydrolase ECU1040 drops into reaction flask, adds entry under 0～10 ℃, react after 10～40 hours, stopped reaction, underpressure distillation goes out unhydrolysed 4-phenyl-1, behind the 2-butylene oxide ring, continue molecular distillation and go out (R)-4-phenyl-1,2-butyleneglycol; The weight of material proportioning of its reaction is: 4-phenyl-1 ,-2-butylene oxide ring: epoxide hydrolase: water=1:0.5～2:1～4;
(4) add concentrated nitric acid in reaction flask, under 0～60 ℃, add (R)-4-phenyl-1 in batches, the 2-butyleneglycol finishes, insulation reaction 30～72 hours, the high pressure liquid chromatographic analysis starting material back termination reaction that reacts completely; Underpressure distillation goes out excessive nitric acid, use ethyl acetate extraction 3-5 time behind the bottle end residue dilute with water, ethyl acetate solvent is reclaimed in underpressure distillation again, bottle end solid gets (R)-4-phenyl-2-hydroxybutyric acid with the toluene recrystallization, the weight of material proportioning of reaction is: (R)-4-phenyl-1,2-butyleneglycol: concentrated nitric acid=1:4～10.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391239A (en) * | 2011-09-14 | 2012-03-28 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN105669423A (en) * | 2016-01-08 | 2016-06-15 | 江西科技师范大学 | New synthesis method of two enantiomers of 4-(4-(benzyloxy)phenyl)-2-hydroxybutyric acid |
| CN110927278A (en) * | 2019-12-09 | 2020-03-27 | 湖南九典制药股份有限公司 | Improved method for separating imidapril hydrochloride related substances |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1370767A (en) * | 2001-02-27 | 2002-09-25 | 中国科学院成都有机化学研究所 | Synthesis of optically pure R-and S-2-hydroxyl-4-aryl butyric acid |
| CN100335645C (en) * | 2005-02-05 | 2007-09-05 | 上海科利生物医药有限公司 | Preparation of chiral epichlorohydrin |
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2009
- 2009-01-05 CN CN2009100448657A patent/CN101462947B/en not_active Expired - Fee Related
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391239A (en) * | 2011-09-14 | 2012-03-28 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN102391239B (en) * | 2011-09-14 | 2013-08-21 | 上海科利生物医药有限公司 | Preparation method of (R)-propene carbonate |
| CN105669423A (en) * | 2016-01-08 | 2016-06-15 | 江西科技师范大学 | New synthesis method of two enantiomers of 4-(4-(benzyloxy)phenyl)-2-hydroxybutyric acid |
| CN105669423B (en) * | 2016-01-08 | 2018-06-29 | 江西科技师范大学 | The novel synthesis of two kinds of enantiomters of 4- (4- (benzyloxy) phenyl) -2- hydroxybutyric acids |
| CN110927278A (en) * | 2019-12-09 | 2020-03-27 | 湖南九典制药股份有限公司 | Improved method for separating imidapril hydrochloride related substances |
| CN110927278B (en) * | 2019-12-09 | 2022-07-01 | 湖南九典制药股份有限公司 | Improved method for separating imidapril hydrochloride related substances |
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Application publication date: 20090624 Assignee: Keli Biological Medical Co., Ltd., Shanghai Assignor: Shanghai Baiding Pharmaceutical Technology Co., Ltd. Contract record no.: 2013990000332 Denomination of invention: Method for preparing (R) -4- phenyl -2- hydroxy butyric acid Granted publication date: 20120725 License type: Exclusive License Record date: 20130620 |
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