CN1903852A - New technology of synthesizing lipoamide - Google Patents
New technology of synthesizing lipoamide Download PDFInfo
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- CN1903852A CN1903852A CN 200610041248 CN200610041248A CN1903852A CN 1903852 A CN1903852 A CN 1903852A CN 200610041248 CN200610041248 CN 200610041248 CN 200610041248 A CN200610041248 A CN 200610041248A CN 1903852 A CN1903852 A CN 1903852A
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Abstract
The present invention relates to a new process for synthesizing lipoamide, belonging to the field of organics synthesis technology. Said process includes the following steps: dissolving raw material lipoic acid in solvent, under the catalysis of amine making the raw material lipoic acid and halogenated manthanoate implement condensation reaction, introducing ammonia gas to make ammonolysis, using acid to make neutralization, using alkaline solution to wash, decoloring in ethyl alcohol and recrystallizing obtain lipoamide.
Description
Technical field
The present invention relates to a kind of new technology of synthesizing lipoamide, belong to the organism synthesis technical field.
Background technology
The Thioctamide chemistry is called 1,2-dithiolane-3-valeramide.Its structural formula is as follows:
Thioctamide is the same with Thioctic Acid all to be liposoluble vitamin, be to have the medicine of physiologically active preferably, external clinical liver protecting therapy and the foodstuff additive of being widely used in already, also be used for hepatopathy prevention, treatment and tetter simultaneously, just trying out in recent years in diabetes, also relevant for being used for anticancer and the report beauty treatment aspect.The document that has claims the curative effect of Thioctamide to be better than Thioctic Acid.Several years ago, domestic existing how tame plant produced also exports to states such as America and Europe and Japan in a large number.
The synthetic method of Thioctamide is broadly divided into back cyclization and two routes of first cyclization at present.Back cyclization is with 6, and 8-dihalo-octanoate is that raw material synthesizes 6,8-dihalo-decoylamide, and cyclization becomes Thioctamide again; Elder generation's cyclization then is raw material with the Thioctic Acid, generates sulphur capryl(yl)chloride, regeneration Thioctamide earlier.The chemical equation of back cyclization and first cyclization is as follows:
Be first cyclization route
R is alkyl or benzyl
X1, X2 are fluorine, chlorine, bromine, iodine
The disclosed synthetic method of English Patent GB935962 is exactly first cyclization route, promptly is that raw material is made the sulphur capryl(yl)chloride through the sulfur oxychloride chlorination with the Thioctic Acid in benzole soln, and ammonia is separated into Thioctamide again.This technology will be through three-step reaction, and total recovery is low, the cost height; The synthetic method that U.S. Pat 3231590 is recommended is a back cyclization route, promptly with 6,8-dichloro octanoate is a raw material, in rare pure ammonia solution, stir, place a couple of days again, carry out amidation, obtain Thioctamide through the sodium disulfide cyclization again, this method reaction time long (reaction times need reach five days) is unfavorable for suitability for industrialized production; The synthetic route that Chinese patent Granted publication CN1065534C delivers also is a back cyclization route, and with 6,8-dichloro octanoate is a raw material, under sodium alkoxide catalysis, do solvent and the reaction of low alkyl group acid amides with tetrahydrofuran (THF), get 6,8-dichloro decoylamide, cyclization becomes Thioctamide again.The final product quality that this technology obtains is poor, is embodied in fusing point: 127-128 ℃, liquid content (HPLC) 97.5-98.5%, clarity lack transparent; Yield is low, only is 48-52%.
Summary of the invention
The object of the present invention is to provide a kind of new technology of synthesizing lipoamide, this technology is simple, yield is high, good product quality, preparation cost are low.
The objective of the invention is to reach like this: a kind of new technology of synthesizing lipoamide, the raw material Thioctic Acid is dissolved in the solvent, under the catalysis of amine,, feeds ammonia then and carry out ammonia and separate with the haloformate condensation, through acid neutralization, alkaline solution washing, decolouring, recrystallization make Thioctamide in the ethanol again.
Thioctic Acid of the present invention is any one in racemization Thioctic Acid, R type Thioctic Acid, the S type Thioctic Acid.
Haloformate of the present invention, its halogen comprises fluorine, chlorine, bromine, iodine, its ester comprises fatty alkane ester and fragrant alkane ester.
Haloformate of the present invention is the carbonochloridic acid ester.
Fatty alkane ester of the present invention is any one in Vinyl chloroformate, methyl-chloroformate, methyl chloroacetate, the ethyl chloroacetate; And described fragrant alkane ester is a chloroformic acid benzyl ester.
Of the present invention in acid and the acid of indication comprise organic acid or mineral acid.
Organic acid of the present invention is any one in formic acid, acetate, the propionic acid; And described mineral acid is in sulfuric acid, hydrochloric acid, nitric acid, the phosphoric acid any one.
The alkali of alkaline solution washing indication of the present invention comprises organic bases or mineral alkali.
Organic bases of the present invention is a diethylamine; And described mineral alkali is in sodium hydroxide, potassium hydroxide, the yellow soda ash any one.
Technology of the present invention compared with the prior art, technical process is brief, can be applicable to suitability for industrialized production; Yield can up to more than 75%, M.P.129-131 ℃, HPLC＞99%, clarity be transparent, so good product quality; Has the low advantage of preparation cost.
Embodiment
Embodiment 1
Specific operation process: in the 500ml three-necked bottle that stirring and thermometer are housed, add 180g chloroform and 25g racemization Thioctic Acid, start stirring, after treating that the racemization Thioctic Acid is molten entirely, to about 5 ℃, slowly drip the 12.4g triethylamine with ice bath cooling material temperature, control material temperature is no more than 5 ℃.After dripping, drip the mixed solution of 17.5g Vinyl chloroformate and 70g chloroform again, control material temperature dripped off at 2-7 ℃ in 1 hour, restir 10 minutes, and be yellow transparent solution this moment.Feed ammonia subsequently, feed liquid is muddy shape at once, and ventilation finishes about 1 hour.
Other one be equipped with stir and 1 liter, the three neck reaction flasks of reflux exchanger in, adding 90g chloroform.Start stirring, the feed liquid of the ammonia of will having friendly relations is put into wherein, cools to then about 45 ℃ reflux half an hour, slowly adds the hydrochloric acid 200ml of 1N, stirs 10 minutes, closes to stir static layering.Chloroform layer behind the branch vibration layer, is used anhydrous sodium sulfate dehydration with 200ml 5% sodium hydroxide water liquid and 200ml water washing, filters, and reclaims chloroform.After having treated that a large amount of solids are separated out, change underpressure distillation into, become dry, add 80g ethanol heating for dissolving, be as cold as 5 ℃ then and get rid of the filter material, obtain crude product until material.Crude product is with 5 times dissolve with ethanol and 1g decolorizing with activated carbon, filtered while hot, and crystallisation by cooling filters, dry finished product 19.5g.
M.P.129-131 ℃, yield 77%.
The principal reaction formula of the new technology of synthesizing lipoamide that present embodiment provided is:
X is fluorine, chlorine, bromine, iodine
R is alkyl or benzyl
Embodiment 2
In operating process with embodiment 1, change Vinyl chloroformate 17.5g into chloroformic acid benzyl ester 27.8g, with example 1 operation, reacting phenomenon is with embodiment 1, and yield is on the low side, gets finished product 15.4g.
M.P.129-131℃。
Embodiment 3
In operating process with embodiment 1, change hydrochloric acid the formic acid of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, and yield is on the low side 50%.
M.P.129-131℃。
Embodiment 4
In operating process with embodiment 1, change aqueous sodium hydroxide solution the diethylamine of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 65%.
M.P.129-131℃。
Embodiment 5
Be equipped with stir and the 500L reactor of thermometer in, add 180kg chloroform and 25kg racemization Thioctic Acid, start stirring, treat the racemization Thioctic Acid complete molten after, to about 5 ℃, slowly drip the 12.4kg triethylamine with ice bath cooling material temperature, control expects that temperature is no more than 5 ℃.After dripping, drip the mixed solution of 17.5kg Vinyl chloroformate and 70kg chloroform again, control material temperature dripped off at 2-7 ℃ in 1-1.5 hour, restir 10 minutes, and be yellow transparent solution this moment.Feed ammonia subsequently, feed liquid is muddy shape at once, and ventilation finishes about 1-1.5 hour.
Other one be equipped with stir and the 1000L reactor of reflux exchanger in, adding 450kg chloroform.Start stirring, the feed liquid of the ammonia of will having friendly relations is put into wherein, cools to then about 45 ℃ reflux half an hour, slowly adds the hydrochloric acid 200L of 1N, stirs 10 minutes, closes to stir static layering.Chloroform layer behind the branch vibration layer, is used anhydrous sodium sulfate dehydration with 200L 5% sodium hydroxide water liquid and 200L water washing, filters, and reclaims chloroform.After having treated that a large amount of solids are separated out, change underpressure distillation into, become dry, add 80kg ethanol heating for dissolving, be as cold as 5 ℃ then and get rid of the filter material, obtain crude product until material.Crude product decoloured with 5 times ethanol and 3kg activated carbon reflux in 0.5 hour, filtered while hot, crystallisation by cooling, filtration, the dry finished product 19.5kg that gets.
M.P.129-131 ℃, yield 77%.
Embodiment 6
In operating process with embodiment 1, change sodium hydroxide the potassium hydroxide of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 75%.
M.P.129-131℃。
Embodiment 7
In operating process with embodiment 1, change sodium hydroxide the yellow soda ash of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 72%.
M.P.129-131℃。
Embodiment 8
In operating process with embodiment 1, change hydrochloric acid the sulfuric acid of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 73%.
M.P.129-131℃。
Embodiment 9
In operating process with embodiment 1, change hydrochloric acid the nitric acid of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 70%.
M.P.129-131℃。
Embodiment 10
In operating process with embodiment 1, change hydrochloric acid the phosphoric acid of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 70.5%.
M.P.129-131℃。
Embodiment 11
In operating process with embodiment 1, change hydrochloric acid the propionic acid of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 66%.
M.P.129-131℃。
Embodiment 12
In operating process with embodiment 1, change hydrochloric acid the acetate of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 60%.
M.P.129-131℃。
Embodiment 13
In operating process with embodiment 1, change Vinyl chloroformate the methyl-chloroformate of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 66%.
M.P.129-131℃。
Embodiment 14
In operating process with embodiment 1, change Vinyl chloroformate the methyl chloroacetate of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 64%.
M.P.129-131℃。
Embodiment 15
In operating process with embodiment 1, change Vinyl chloroformate the ethyl chloroacetate of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 66.5%.
M.P.129-131℃。
Embodiment 16
In operating process with embodiment 1, change the racemization Thioctic Acid R type Thioctic Acid (R-Thioctic Acid) of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 75%.
M.P.129-131℃。
Embodiment 17
In operating process with embodiment 1, change the racemization Thioctic Acid S type Thioctic Acid (S-Thioctic Acid) of identical mole into, with example 1 operation, reacting phenomenon is with embodiment 1, yield 74.5%.
M.P.129-131℃。
The clarity of the resulting product of the foregoing description 1-17 is transparent, and liquid content (HPLC) all＞99%.
Claims (9)
1, a kind of new technology of synthesizing lipoamide, it is characterized in that the raw material Thioctic Acid is dissolved in the solvent, under the catalysis of amine,, feed ammonia then and carry out ammonia and separate with the haloformate condensation, through acid neutralization, alkaline solution washing, decolouring, recrystallization make Thioctamide in the ethanol again.
2, new technology of synthesizing lipoamide according to claim 1 is characterized in that described Thioctic Acid is any one in racemization Thioctic Acid, R type Thioctic Acid, the S type Thioctic Acid.
3, new technology of synthesizing lipoamide according to claim 1 is characterized in that described haloformate, and its halogen comprises fluorine, chlorine, bromine, iodine, and its ester comprises fatty alkane ester and fragrant alkane ester.
4,, it is characterized in that described haloformate is the carbonochloridic acid ester according to claim 1 or 3 described new technology of synthesizing lipoamide.
5, new technology of synthesizing lipoamide according to claim 3 is characterized in that described fatty alkane ester is any one in Vinyl chloroformate, methyl-chloroformate, methyl chloroacetate, the ethyl chloroacetate; And described fragrant alkane ester is a chloroformic acid benzyl ester.
6, new technology of synthesizing lipoamide according to claim 1, it is characterized in that described in acid and the acid of indication comprise organic acid or mineral acid.
7, new technology of synthesizing lipoamide according to claim 6 is characterized in that described organic acid is any one in formic acid, acetate, the propionic acid; And described mineral acid is in sulfuric acid, hydrochloric acid, nitric acid, the phosphoric acid any one.
8, new technology of synthesizing lipoamide according to claim 1 is characterized in that the alkali of described alkaline solution washing indication comprises organic bases or mineral alkali.
9, new technology of synthesizing lipoamide according to claim 8 is characterized in that described organic bases is a diethylamine; And described mineral alkali is in sodium hydroxide, potassium hydroxide, the yellow soda ash any one.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100412488A CN100436444C (en) | 2006-07-29 | 2006-07-29 | New technology of synthesizing lipoamide |
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|---|---|---|---|
| CNB2006100412488A CN100436444C (en) | 2006-07-29 | 2006-07-29 | New technology of synthesizing lipoamide |
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| CN1903852A true CN1903852A (en) | 2007-01-31 |
| CN100436444C CN100436444C (en) | 2008-11-26 |
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Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB935962A (en) * | 1960-06-17 | 1963-09-04 | Fujisawa Pharmaceutical Co | Improvements in or relating to the production of 6.8-dithiooctanamides |
| CN1065534C (en) * | 1996-04-03 | 2001-05-09 | 中国科学院上海药物研究所 | Method for synthesizing thioctic acid amide |
| WO1998023606A1 (en) * | 1996-11-27 | 1998-06-04 | Fuji Kagaku Kogyo Kabushiki Kaisha | Cyclic dithio derivatives, remedies for diabetic kidney diseases, hypoglycemic agents, hypolipidemic agents, and lenitives for digestive disorders |
| CZ96798A3 (en) * | 1997-04-02 | 1998-10-14 | Sankyo Company Limited | Dithiolan derivatives, process of their preparation and their therapeutic effects |
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Owner name: SUZHOU FUSHILAI PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: CHANGSHU FUSHILAI MEDICINE CHEMICAL CO., LTD. |
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Address after: 215522 Jiangsu province Changshu New Material Industrial Park Haiwang Road No. 16 Patentee after: SUZHOU FUSHILAI PHARMACEUTICAL CO., LTD. Address before: 215558 southeast development zone, Jiangsu, Changshou City Patentee before: Changshu Fushilai Medicine Chemical Co., Ltd. |