CN1202100C - Synthetic method for (S)-3-hydroxy-gamma-butyrolactone - Google Patents
Synthetic method for (S)-3-hydroxy-gamma-butyrolactone Download PDFInfo
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- CN1202100C CN1202100C CN 01129190 CN01129190A CN1202100C CN 1202100 C CN1202100 C CN 1202100C CN 01129190 CN01129190 CN 01129190 CN 01129190 A CN01129190 A CN 01129190A CN 1202100 C CN1202100 C CN 1202100C
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- butyrolactone
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Abstract
The present invention relates to a synthetic method for (S)-3-hydroxy-gamma-butyrolactone. Optically active malic acid generates acid anhydride under the action of acyl chloride compounds, and the acid anhydride is reduced to obtain (S)-3-hydroxy-gamma-butyrolactone with hydrochloric acid treatment and without separation by using tetrahydrofuran as a solvent, using metal borohydride as a reducing agent and using lewis acid as a catalyst. The S)-3-hydroxy-gamma-butyrolactone reacts with sulfuryl chloride compounds for activation, and openloop is carried out in an acidic aqueous solution. (R)-3, 4-poxy butyrate with reverse configuration is generated in an alkaline solution and acts with a 25 % trimethylamine aqueous solution to obtain L-carnitine. The method of the present invention has high yield, avoids the occurrence of over-reduced products and reduces the production cost.
Description
Technical field
The invention belongs to the organic synthesis field, specifically is the synthetic method of (S)-3-hydroxyl-gamma-butyrolactone.
Background technology
(S)-3-hydroxyl-gamma-butyrolactone is a kind of very important organic synthesis intermediate, also is very important chiral source (Chiral Pool).For example, it is the key intermediate of synthetic neuroregulator (R)-GABOB [(R)-GABOB)], (R)-GABOB is used for treating hyperlipidemia, (S)-and Oxiracetam (N-carbamyl methyl-(S)-3-hydroxyl-butyrolactam) be the metabolic promotor of brain, also synthetic by it; Can obtain (S)-3-hydroxyl tetrahydrofuran from (S)-3-hydroxyl-gamma-butyrolactone, the latter is the indispensable intermediate of AIDS-treating medicine, is the potential tranquilizer by its synthetic (S)-3-hydroxyl-4-bromo-butyric acid.Can also synthesize a lot of natural products by (S)-3-hydroxyl-gamma-butyrolactone, especially synthetic L-carnitine.The L-carnitine is present in the animal tissues, also is DL-carnitine chloride, has epochmaking physiologically active.In the past mainly with the raceme administration, but bibliographical information D-carnitine has opposite physiologically active with the L-carnitine, therefore now generally all with the administration of L-carnitine.The application of L-carnitine is quite extensive.Can be aid digestion, promote appetite; But as the treatment reducing blood-fat of carntine deficiency, fat-reducing and treatment vascular disease; Can treat acute ammonia poisoning as nutrition agent, stupor and nervous system disorders.The L-carnitine can also be used for infant formula as Functional Food Additives, to promote infants growth and development; Be used for the sports drink, to improve motion stamina and explosive power.The L-carnitine can make the fat of body accumulation change energy into, has functions of lowering blood-fat and reducing weight, can be used for defatting beauty food, and this based food quite is in great demand in American-European market.In addition, the L-carnitine adds the growth that can promote animal in animal-feed and the bait to.At present, L-carnitine demand at home is very big.
(S)-and present synthetic the mainly containing of 3-hydroxyl-gamma-butyrolactone: 1. be raw material with the L MALIC ACID, through esterification, reduction, acidolysis become cyclization to become; 2. get through oxidation by glucide or other chipal compounds.L MALIC ACID can make in a large number with microbial process, price is very cheap, make raw material with L MALIC ACID and can make (S)-3-hydroxyl-gamma-butyrolactone [United States Patent (USP) 5,808,107 (1990) Chem.Lett., 1389～1392 (1984)], this method is converted into oxysuccinic acid dimethyl ester or diethyl ester with oxysuccinic acid, adopt the reduction of borine or metal borohydride and obtain (S)-3-hydroxyl-gamma-butyrolactone, but there is the over reduction product inevitably in these methods, and borine is poisonous, costs an arm and a leg, and should not operate.Carbohydrate also is the very cheap compound of price, has recently with barley-sugar [US4,855,232A (1989)], lactose (WO 98/04543), starch (WO 00/05399) etc. to be synthetic (the S)-3-hydroxyl-gamma-butyrolactone of raw material.But these methods all have a shortcoming, because the reaction mixture composition is quite complicated, isolate needed lactone not a duck soup from the composition of complexity.
L-carnitine synthetic mainly contains following method:
1. Split Method: utilize chemistry to split; a DL-carnitine or derivatives thereof raceme and an optically active resolving agent reaction generate diastereomer; utilize the different mining of diastereomer solubleness in a certain solvent to separate with the method for recrystallization; the common resolving agent that adopts has the D-camphorsulfonic acid, and [US 4; 254; 053 (1981)]; L-tartrate [European patent 157; 315 (1985)], dibenzoyl-D-tartrate [United States Patent (USP) 4,933; 490 (1990)]; dibenzoyl-L-tartrate [United States Patent (USP) 4,610,828 (1986)] etc.But chemistry splits important disadvantages is arranged: used resolving agent costliness, need to reclaim resolving agent, often to just can obtain pure individual isomer through the re-crystallization step of complexity.
2, utilize the biochemical method of microorganism or enzyme: make raw material with 4-trimethylammonium amino-butyric acid salt, obtain L-carnitine [United States Patent (USP) 4 through enzymatic stereoselectivity hydroxylation, 371,618 (1983), 5,187,093 (1999)], or make [United States Patent (USP) 4 through suitable enzyme catalysis hydroxylation with the amino 2-butylene acid of 4-trimethylammonium, 650,759 (1987), 5,248,601 (1993), European patent 457,735 (1991)], biochemical process is consuming time oversize, and the reaction mixture concentration requirement is very low.
3, make raw material with chipal compounds: (S)-3-hydroxyl-gamma-butyrolactone is through the synthetic L-carnitine [United States Patent (USP) 5,473,104 (1995)] of series reaction.This method is not mentioned yield, and we do not obtain any L-carnitine when repeating this patent.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of (S)-3-hydroxyl-gamma-butyrolactone and be used to prepare the method for L-carnitine, this method yield height avoids the transition reduzate to occur, and reduces production costs.
The objective of the invention is to be achieved through the following technical solutions.
Optically active oxysuccinic acid is generated acid anhydrides under the acyl chloride compound effects, it is reductive agent that acid anhydrides is done under the solvent with metal borohydride at tetrahydrofuran (THF), Lewis acid is reduced for catalyzer, promptly gets (S)-3-hydroxyl-gamma-butyrolactone without separating with the salt acid treatment.
(S)-and the reaction of 3-hydroxyl-gamma-butyrolactone and SULPHURYL CHLORIDE compounds activates, and open loop in acidic aqueous solution generates (R)-3 of configuration inversion in the basic solution, and 4-epoxy butyrates is that 25% trimethylamine aqueous solution effect promptly gets the L-carnitine with mass ratio again.
In the such scheme, used acyl chloride compound is Acetyl Chloride 98Min. or Benzoyl chloride, and reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride, and catalyzer is zinc chloride or lithium chloride.
In the such scheme, used SULPHURYL CHLORIDE compounds is methane sulfonyl chloride or p-toluenesulfonyl chloride, and the separation and purification of L-carnitine is with the way of Zeo-karb or recrystallization.
In the such scheme, when generating acid anhydrides, oxysuccinic acid is 1: 1～1.5 with the ratio of the mole dosage of acyl chloride compound, and the reaction times is 1～5 hour; During reduction reaction, the consumption of solvent is every mole of acid anhydrides 1500ml, and reductive agent is 0.8～1.3: 1 with the ratio of the mole dosage of acid anhydrides, and reductive agent is 0.5: 1 with the ratio of the mole dosage of catalyzer, and the reaction times is 3～6 hours.
In the such scheme, with L MALIC ACID and acyl chloride compound is that 1: 1～1.5 ratio is made into mixture in molar ratio, stirred 1～5 hour, remove all solvents under reduced pressure, it is in 5～10 times the chloroform that the resistates that obtains is dissolved in volume multiple with respect to acid anhydrides, toward wherein adding volume multiple with respect to acid anhydrides is 25～50 times sherwood oil, and low temperature stirs promptly separates out crystal, acyloxy apple acid anhydrides; In being 8～12 times THF, the volume multiple with respect to acid anhydrides adds catalyzer, reductive agent and acyloxy apple acid anhydrides successively, the mole dosage ratio is 1: 1: 0.5, stirred 3～6 hours, steaming desolventizes, and with hydrochloric acid furnishing acidity, refluxing to steam after 1～2 hour desolventizes, with 60 times of ethyl acetate extractions, extraction liquid anhydrous Na 2SO4 drying, pressure reducing and steaming solvent, column chromatography get the pure product of (S)-3-hydroxyl-gamma-butyrolactone.
In the such scheme, (S)-3-hydroxyl-gamma-butyrolactone is dissolved in 12～25 times the methylene dichloride (in (S)-3-hydroxyl-gamma-butyrolactone), add N, N '-dimethyl aminopyridine, Trimethylamine 99 and methylsulfonyl chloride, the mol ratio consumption is respectively 1: 1.2～1.6: 1.5～1.8, stirred 8～16 hours, and used anhydrous Na SO with behind frozen water, 1NHCl and the saturated NaCl solution washing successively after having reacted
4Drying, solvent evaporated get yellow oily liquid (S)-3-mesyloxy-gamma-butyrolactone; (S)-volume multiple that 3-mesyloxy-gamma-butyrolactone is dissolved in respect to (S)-3-mesyloxy-gamma-butyrolactone is in 8～12 times of water, adding is 1: 0.005～0.006 times vitriol oil with respect to the volume multiple of (S)-3-mesyloxy-gamma-butyrolactone, stirred 2～4 hours, using volume multiple with respect to (S)-3-mesyloxy-gamma-butyrolactone is 8～12 times CH
2Cl
2Extracting twice, the volume multiple that solution adds with respect to (S)-3-mesyloxy-gamma-butyrolactone is 3 times of amount 3mol/L NaOH solution, stir, adding is that the mass ratio of 1.3～2.0 times of amounts is 25% trimethylamine aqueous solution with respect to the volume multiple of (S)-3-mesyloxy-gamma-butyrolactone, stirred 1～2 hour, the pressure reducing and steaming solvent, with Zeo-karb handle the L-carnitine.
The present invention is converted into the acetyl-malic acid acid anhydride with L MALIC ACID, thereby has improved the reductive regioselectivity and avoided the transition reduction by the catalytic reduction to the acetyl-malic acid acid anhydride.
It is as follows to the reaction formula of L-carnitine to make (S)-3-mesyloxy-gamma-butyrolactone from oxysuccinic acid:
The present invention is a raw material with the L MALIC ACID of cheapness, is translated into acetyl-malic acid, is reductive agent with the metal hydride, and (S)-3-mesyloxy-gamma-butyrolactone has been synthesized in Lewis acid with high yield for catalyzer.This method in existing document still is patent of invention all not between the report, have original innovation, compare with prior art, greatly reduce cost, avoided the appearance of transition reduzate.(S)-open loop in methylsulfonylization, acidic aqueous solution of 3-mesyloxy-gamma-butyrolactone, alkalescence become the epoxy butyrates and can generate the L-carnitine with the trimethylamine aqueous solution effect.Whole process does not need special reagent, reaction temperature and, the existing patent height of yield.The L MALIC ACID price is very cheap, does raw material with L MALIC ACID, has synthesized very important chiral synthon (S)-3-hydroxyl-gamma-butyrolactone and L-carnitine in organic synthesis easily.
Embodiment
Be embodiments of the invention below.
Embodiment one
13.4 the mixture of gram L MALIC ACID and 50ml Acetyl Chloride 98Min. stirred 3 hours, removed all solvents under reduced pressure, the resistates that obtains is dissolved in the 20ml chloroform, and toward wherein adding the 100ml sherwood oil, low temperature stirs promptly separates out crystal, gets (S)-3-acetoxyl group apple acid anhydrides.
Embodiment two
In 200ml THF, add the anhydrous LiCl of 2.1g (45mmol), 2.7g KBH successively
4(50mmol) and 7.9g (S)-3-acetoxyl group apple acid anhydrides (50mmol), stirred 5 hours, steaming desolventizes, and with hydrochloric acid furnishing acidity, refluxing to steam after 2 hours desolventizes, and uses the 200ml ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, pressure reducing and steaming solvent, column chromatography get the pure product of 4.2 grams, yield: 82%.[α]
D 25＝-85°(c＝1，EtOH)。
Get the 102mg product and be dissolved in 10ml CH
2Cl
2In, add triethylamine 1ml, a small amount of 4-N, N '-Dimethylamino pyridine is chilled to 0 ℃ and adds the 0.5ml Acetyl Chloride 98Min..Room temperature reaction is water after 6 hours, and anhydrous Na is used in dilute hydrochloric acid and saturated common salt water washing
2SO
4Column chromatography gets acetyl derivative behind the dry evaporate to dryness, and the gas chromatographic analysis optical purity is greater than 99%.
Embodiment three
In 6.8g (50mmol) zinc chloride, add 200mlTHF, go into 2.7g KBH after the dissolving
4(50mmol), add 7.9 grams (50mmol) (S)-3-acetoxyl group apple acid anhydrides, reaction mixture at room temperature stirred 3 hours, steaming desolventizes, with hydrochloric acid furnishing acidity, refluxing to steam after 2 hours desolventizes, and uses the 200ml ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, pressure reducing and steaming solvent, column chromatography get the pure product of 3.2 grams, yield: 63%.[α]
D 25＝-85°(c＝1，EtOH)。
Embodiment four
In 3.4g (25mmol) zinc chloride, add 150mlTHF, go into .1.9g NaBH after the dissolving
4(50mmol), add 7.9 grams (50mmol) (S)-3-acetoxyl group apple acid anhydrides, reaction mixture at room temperature stirred 3 hours, steaming desolventizes, with hydrochloric acid furnishing acidity, refluxing to steam after 2 hours desolventizes, and uses the 200ml ethyl acetate extraction, the extraction liquid anhydrous Na
2SO
4Drying, pressure reducing and steaming solvent, column chromatography get the pure product of 4.5 grams, yield: 88%.[α]
D 25＝-85°(c＝1，EtOH)。
Embodiment five
Add 150mlTHF in 5.4g (40mmol) zinc chloride, the dissolving back adds 4g KBH
4(74mmol), add 12g L MALIC ACID dimethyl ester (74mmol), reaction mixture at room temperature stirred 3 hours, and steaming desolventizes, and transfers to acidity with hydrochloric acid, reflux to steam in 2 hours and desolventize, use the 200ml ethyl acetate extraction, extraction liquid anhydrous sodium sulfate drying, pressure reducing and steaming solvent, column chromatography gets the pure product of 5.6 grams, yield: 73%.[α]
D 25＝-85°(c＝1，EtOH)。
Embodiment six
1.02g (10mmol) (S)-3-hydroxyl-gamma-butyrolactone is dissolved in the 20ml methylene dichloride, add a little N, N '-dimethyl aminopyridine and 2ml Trimethylamine 99, adding 1ml methylsulfonyl chloride also stirred 16 hours, had reacted the back with using anhydrous Na behind frozen water, 1NHCl and the saturated NaCl solution washing
2SO
4Dry.Solvent evaporated gets yellow oily liquid and is directly used in the next step.
Embodiment seven
4.5 gram (25mmol) (S)-3-mesyloxy-gamma-butyrolactone is dissolved in the 45ml water, adds the 0.25g vitriol oil, stirs 3 hours, uses 35ml CH
2Cl
2Collection twice, solution add 3mol/L NaOH solution 12.2ml and stirred 10 minutes, add the trimethylamine aqueous solution of 6.8ml 25%, stir 2 hours, and pressure reducing and steaming is fallen solvent, handle to such an extent that 2.1 restrain the L-carnitines with Zeo-karb.[α]
25 D=-30 ° of (c=1, H
2O), yield: 52%.
Claims (7)
1, the synthetic method of (S)-3-hydroxyl-gamma-butyrolactone, it is characterized in that L MALIC ACID is generated acid anhydrides under the acyl chloride compound effects, it is reductive agent that acid anhydrides is done under the solvent with metal borohydride at tetrahydrofuran (THF), Lewis acid is reduced for catalyzer, promptly gets (S)-3-hydroxyl-gamma-butyrolactone without separating with the salt acid treatment.
2, a kind of preparation method of L-carnitine, it is characterized in that, at first according to the method for claim 1 preparation (S)-3-hydroxyl-gamma-butyrolactone, then gained (S)-3-hydroxyl-gamma-butyrolactone and the reaction of SULPHURYL CHLORIDE compounds are activated, open loop in acidic aqueous solution, generate (R)-3 of configuration inversion in the basic solution, 4-epoxy butyrates is 25% trimethylamine aqueous solution effect again with mass ratio.
3, the synthetic method of (S)-3-hydroxyl-gamma-butyrolactone according to claim 1 is characterized in that used acyl chloride compound is Acetyl Chloride 98Min. or Benzoyl chloride, and reductive agent is POTASSIUM BOROHYDRIDE or sodium borohydride, and catalyzer is zinc chloride or lithium chloride.
4, the preparation method of L-carnitine according to claim 2 is characterized in that used SULPHURYL CHLORIDE compounds is a methane sulfonyl chloride or to the monomethyl benzene sulfonyl chloride, and the separation and purification of L one carnitine is with the way of Zeo-karb or recrystallization.
5, the synthetic method of (S)-3-hydroxyl-gamma-butyrolactone according to claim 1, when it is characterized in that generating acid anhydrides, oxysuccinic acid is 1: 1～1.5 with the ratio of the mole dosage of acyl chloride compound, the reaction times is 1～5 hour; During reduction reaction, the consumption of solvent is every mole of acid anhydrides 1500ml, and reductive agent is 0.8～1.3: 1 with the ratio of the mole dosage of acid anhydrides, and reductive agent is 0.5: 1 with the ratio of the mole dosage of catalyzer, and the reaction times is 3～6 hours.
6, the synthetic method of (S)-3-hydroxyl-gamma-butyrolactone according to claim 1, it is characterized in that with L MALIC ACID and acyl chloride compound being that 1: 1～1.5 ratio is made into mixture in molar ratio, stirred 1～5 hour, remove all solvents under reduced pressure, it is in 5～10 times the chloroform that the resistates that obtains is dissolved in volume multiple with respect to acid anhydrides, toward wherein adding volume multiple with respect to acid anhydrides is 25～50 times sherwood oil, and low temperature stirs promptly separates out crystal, acyloxy apple acid anhydrides; In being 8～12 times THF, the volume multiple with respect to acid anhydrides adds catalyzer, reductive agent and acyloxy apple acid anhydrides successively, the mole dosage ratio is 1: 1: 0.5, stirred 3～6 hours, steaming desolventizes, with hydrochloric acid furnishing acidity, refluxing to steam after 1～2 hour desolventizes, with 60 times of ethyl acetate extractions, extraction liquid anhydrous Na
2SO
4Drying, pressure reducing and steaming solvent, column chromatography get the pure product of (S)-3-hydroxyl-gamma-butyrolactone.
7, the preparation method of L-carnitine according to claim 2, it is characterized in that it is in 12～25 times the methylene dichloride that (S)-3-hydroxyl-gamma-butyrolactone is dissolved in volume multiple with respect to (S)-3-hydroxyl-gamma-butyrolactone, add N, N '-dimethyl aminopyridine, Trimethylamine 99 and methylsulfonyl chloride, consumption is respectively 1: 1.2～1.6: 1.5～1.8, stirred 8～16 hours, after having reacted successively with using anhydrous Na behind frozen water, 1NHCl and the saturated NaCl solution washing
2SO
4Drying, solvent evaporated get yellow oily liquid (S)-3-mesyloxy-gamma-butyrolactone; (S)-volume multiple that 3-mesyloxy-gamma-butyrolactone is dissolved in respect to (S)-3-mesyloxy-gamma-butyrolactone is in 8～12 times of water, adding is 1: 0.005～0.006 times vitriol oil with respect to the volume multiple of (S)-3-mesyloxy-gamma-butyrolactone, stirred 2～4 hours, using volume multiple with respect to (S)-3-mesyloxy-gamma-butyrolactone is 8～12 times CH
2Cl
2Extracting twice, the volume multiple that solution adds with respect to (S)-3-mesyloxy-gamma-butyrolactone is 3 times of amount 3mol/L NaOH solution, stir, adding is that the mass ratio of 1.3～2.0 times of amounts is 25% trimethylamine aqueous solution with respect to the volume multiple of (S)-3-mesyloxy-gamma-butyrolactone, stirred 1～2 hour, the pressure reducing and steaming solvent, with Zeo-karb handle the L-carnitine.
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| CN101838212B (en) * | 2010-05-20 | 2013-03-13 | 北京科技大学 | Method for synthesizing L-carnitine by using (R)-(-)-3-chlorine-1,2-propylene glycol as chiral initiative raw material |
| CN102408402A (en) * | 2011-12-27 | 2012-04-11 | 上海立科药物化学有限公司 | Synthesis method of (R) or (S)-6-fluoro-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid |
| CN103044278B (en) * | 2012-12-07 | 2014-07-09 | 沈阳化工大学 | Method for synthesizing levocarnitine by taking D-(-)-tartaric acid as raw material |
| WO2017041228A1 (en) * | 2015-09-08 | 2017-03-16 | 浙江九洲药业股份有限公司 | Method for preparing hexahydrofurofuranol derivative, intermediate thereof and preparation method thereof |
| CN111333598B (en) * | 2019-12-30 | 2023-07-07 | 武汉利昌医药科技有限公司 | Synthesis method of R-3-propyl-gamma-butyrolactone |
| CN112939901B (en) * | 2021-02-09 | 2023-05-09 | 中国科学院福建物质结构研究所 | Preparation method of alpha-hydroxy-gamma-butyrolactone |
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