CN100335457C - 3,4-dihydroxy butyric ester of which 3 chiral hydroxyl group is protected, and its preparation method - Google Patents
3,4-dihydroxy butyric ester of which 3 chiral hydroxyl group is protected, and its preparation method Download PDFInfo
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- CN100335457C CN100335457C CNB2005100294928A CN200510029492A CN100335457C CN 100335457 C CN100335457 C CN 100335457C CN B2005100294928 A CNB2005100294928 A CN B2005100294928A CN 200510029492 A CN200510029492 A CN 200510029492A CN 100335457 C CN100335457 C CN 100335457C
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Abstract
The present invention relates to 3, 4-dihydroxy butyric ester whose 3-chiral hydroxyl group is protected, which belongs to the technical field of medicines. The structure of the 3, 4-dihydroxy butyric ester is shown in (IV), wherein R presents a straight chain of C1 to C5 or branch chain alkyl, a C1 to C5 alkyl group substituted by an aromatic group, and the aromatic group or an aromatic group with a substituent group. A method for preparing the 3, 4-dihydroxy butyric ester whose 3 chiral hydroxyl group is protected comprises the following steps: step 1, 4-carboxylic acid of cyclization lactonic acid (I) and alcohol react with each other to form ester (II); step 2, a lactone ring is hydrolyzed by zinc powder under the acid condition to form protected alpha- hydroxyl acid (III); step 3, carboxylic acid is reduced into the hydroxyl group in a selective reducing mode by BH3; thereby, a synthesis process of a target product (IV) is obtained. The whole synthesis process is simple and is easily operated. The 3, 4-dihydroxy butyric ester is suitable for industrial production, and has the high reaction yield rate.
Description
Technical field
What the present invention relates to is compound of a kind of medical technical field and preparation method thereof, specifically, is that 3-position chiral hydroxyl group is protected 3,4-dihydroxyl butyric ester and preparation method thereof.
Background technology
R (S)-3, the protected derivative of 4-dihydroxyl butyric ester and hydroxyl thereof is the important intermediate of chipal compounds.They are key intermediates of nerous sedative R-GABOB, brain metabolism improving agent (S)-Oxiracetam etc.The most important thing is the key intermediate as novel statins, because statins such as Atorvastatin etc. have the effect of reducing blood-fat, therefore the poly-function of anti-HMG-COA enzyme resistance has been widely used in blood lipid-lowering medicine synthetic at present.There are some biological methods of report to relate to R (S)-3 too at present, 4-dihydroxyl butyric ester synthetic.As make (S)-3 with carbohydrate, 4-dihydroxyl butyric ester, be by the 4-position being contained substituent carbohydrate of glucose such as 4-O-methyl-(D)-glucose, maltose, amylose starch, Cellulose lactose alkaline degradation, form dicarbonyl compound, dicarbonyl compound forms (S)-3 with alkali reaction again, 4-dihydroxyl butyric acid, but this reaction process yield is extremely low.Make R (S)-3 with biological method, 4-dihydroxyl butyric ester productive rate is extremely low, extracts purification difficult, is not suitable for suitability for industrialized production.
Find by prior art documents; document [Tetrahedron lett 2545-2548 (Vol.31); the tetrahedron communication] reported and protected 3; 4 hydroxyls in the 4-dihydroxyl butyric ester become ether; utilize R (S)-3; in the medicine processes such as the synthetic Statins of 4-dihydroxyl butyric ester; relate to 3 of this intermediate; 4 hydroxyls carry out the description of selective protection; after series reaction; thereby again protected hydroxyl is separated protection and obtain the finished product; because 3 of this intermediate; 4-position hydroxyl belongs to primary; competing reaction between secondary alcohol; between them, carry out the selective protection reaction; to blocking group; the selection of reaction conditions requires very harsh, reduces reaction yield thereby can produce by product simultaneously inevitably.United States Patent (USP) U.S.Pat.No.5,808,107, (Process for the preparation of hydroxy substituted gammabutyrolactones), wherein relate to (S)-3,4-dihydroxyl methyl-butyrate is controlled reductive agent LiCl/NaBH as the intermediate product of synthetic 3-hydroxyl-γ-Ding Suan lactone
4Amount control this reaction process, make one of them locational ester of diester be reduced into hydroxyl.Same content also is documented in: Chem.Lett., chemical communication 1389-1392 (1984).The consumption that above method need be controlled reductive agent carries out selective reduction, and the extremely difficult control of reaction end is not suitable for industrial production.
Summary of the invention
The objective of the invention is to overcome deficiency of the prior art, a kind of 3-position chiral hydroxyl group protected 3 is provided, 4-dihydroxyl butyric ester and preparation method thereof can be used as compound and synthesizes R (S)-3, the synthetic intermediate of statinses such as 4-dihydroxyl butyric ester; At synthetic R (S)-3,4-dihydroxyl butyric ester and the generation protected R of chiral hydroxyl group (S)-3 during 4-dihydroxyl butyric ester, can carry out selective reaction effectively, have improved reaction yield preferably.
The present invention is achieved by the following technical solutions, and 3-of the present invention position chiral hydroxyl group is protected 3,4-dihydroxyl butyric ester, and structure is:
R represents C
1-C
5Straight chain or the C that the alkyl of side chain is arranged, replaced by aromatic base
1-C
5Alkyl, aromatic base or be with substituent aromatic base.
3-of the present invention position chiral hydroxyl group is protected 3, the preparation method of 4-dihydroxyl butyric ester, and concrete steps are as follows:
1. the 4-position carboxylic acid with cyclization lactonic acid (I) becomes ester (II) with alcohol;
Step is 1. with cyclization lactonic acid and pure at H
+Carry out esterification under the condition, make cyclization oxysuccinic acid 4-position carboxylic acid become ester.
Alcohol roh in described esterification, R are C
1-C
5Straight chain or the C that the alkyl of side chain is arranged, replaced by aromatic base
1-C
5Alkyl, aromatic base or be with substituent aromatic base; Esterification cyclization oxysuccinic acid is 1 with the mol ratio of alcohol: 1-10.
2. form shielded alpha hydroxy acid (III) with zinc powder hydrolysis of lactone ring under acidic conditions then;
Step is 2. specifically: under solutions of weak acidity, zinc powder catalytic hydrolysis ring-opening reaction obtains the protected R of chiral hydroxyl group (S)-3-(2, the 2-dichloro) vinyloxy group-4-carboxylic acid-1-butyric ester.
Described zinc powder catalytic hydrolysis ring-opening reaction, the acid of its use can be the 1%-100% glacial acetic acid, 0.1-2.0N HCL and other organic acids and mineral acid; Zinc powder and lactone ratio are 1-20: 1; This hydrolysising reacting temperature is controlled between-10 ℃ to 100 ℃ and carries out; Reaction times was controlled at 1-24 hour.
3. use BH at last
3The selective reduction carboxylic acid becomes hydroxyl, obtains a synthesis route of target product (IV), and described synthesis route is as follows:
3. step uses BH at last
3The selective reduction carboxylic acid becomes hydroxyl, is meant: at last in organic solvent, and N
2Protection is used BH down
3Make reductive agent carboxylic acid is carried out selective reduction reaction, it is protected 3 to obtain target product 3-position chiral hydroxyl group, and 4-dihydroxyl butyric ester is R (S)-3-(2,2-Ethylene Dichloride oxygen base)-4 hydroxybutyric acid ester.
Described reduction reaction, the organic solvent of its use is: tetrahydrofuran (THF), ethyl acetate, ether, CH
2Cl
2, CHCl
3, CCl
4, alcohol, organic bases; Temperature of reaction is controlled at-20-100 ℃; Reaction times was controlled at 0.5-24 hour, and this reaction must be at N
2Carry out the proportioning of reactant and borine: 1: 1-10 under the protection.
The whole synthetic route of the present invention is simple; easily go; be fit to suitability for industrialized production; all considered in each synthesis step not isoplastic protection has been reduced reaction yield with the selectivity competing reaction of avoiding identical group; and can directly obtain the protected R of 3-position chiral hydroxyl group (S)-3 by this route; 4-dihydroxyl butyric acid and derivative thereof; synthetic extremely beneficial to further statins; do not need 3; 4-position hydroxyl carries out selective protection; entire reaction course is simplified greatly; be beneficial in the course of industrialization and reduce cost, utilize this synthesis technique that reaction yield is improved.
Embodiment
The present invention is further described below by embodiment, so that better understand the present invention, but do not limit the scope of the invention:
Embodiment one:
Synthesizing of R (S)-3-(2,2-Ethylene Dichloride oxygen base)-4 hydroxybutyric acid methyl esters
1, the cyclization of D (L)-oxysuccinic acid: be with in the churned mechanically reaction flask at 250ml, add 6.5g (0.05mol) D (L)-oxysuccinic acid and 10g (0.06mol) Chloral Hydrate, thread drips the 10ml vitriol oil (98%) in the room temperature, and stirring reaction is after 5 hours, static spending the night.Second day, with the dilution of 100ml mixture of ice and water, stir after 30 minutes, filter, filter cake water repetitive scrubbing is constant to PH, gets crude product, mp.135-140 ℃ after the vacuum-drying; The toluene recrystallization gets white crystalline solid (I), 11.0g, and yield: 82%, mp.141 ℃.
2, esterification: with above-mentioned cyclization oxysuccinic acid (I) 5.3g (0.02mol) and 5mlCH
2CL
2, after the dispersed with stirring, add 2g (0.6mol) CH
3OH, 0.5mlH
2SO
4(dense) after the stirring and dissolving, is warming up to backflow, and back flow reaction is after 6 hours, and vacuum desolventizes and methyl alcohol, with the dilution of 50ml frozen water, stirs 30 minutes then, uses NaHCO
3Saturated solution is regulated PH to neutral, filters, and filter cake washes with water to neutrality, and drying gets white solid (II) 5.1g, yield: 90%mp. ℃.HNMR：[CDCl
3，ppm：3.03(m，2H)；3.75(s，3H)；4.85(m，1H)；5.90(s，1H)]。
3, hydrolysis:, add 30ml100%CH with above-mentioned cyclization oxysuccinic acid methyl esters (II) 5.0g (0.0177mol)
3COOH is stirred to whole dissolvings, slowly adds 2.0g (0.03mol) zinc powder then in the room temperature, stirring reaction 24 hours, filter, after vacuum desolventizes, get enriched material, add 20ml1N hydrochloric acid then, stirring at room dissolving is filtered, filtrate with extracted with diethyl ether after, it is constant to be washed to PH, the organic phase anhydrous Na
2SO
4Drying is filtered, and gets i.e. (III): the 2.4g of concentrated solution after vacuum desolventizes, yield: 91%.HNMR：[CDCl
3，ppm：2.95(m，2H)；3.75(s，3H)；4.75(m，1H)；6.67(s，1H)；9.09(s，1H)]。
4, reduction: in the 500ml four-hole boiling flask, add the anhydrous THF of 250ml and reach (III), magnetic agitation is to dissolving, N
2Under the protection, ice-water bath is cooled to 0 ℃, drips BH
3-THF (0.1mol/100ml, Acros) 50ml, T:-20-0 ℃, dropwised in 20 minutes, stirring reaction 1 hour is warming up to 20-30 ℃, stirring reaction 1 hour is warming up to 50-60 ℃, 50-60 ℃ the insulation 3 hours after, stop heating, be cooled to 20 ℃, after the dilution of dropping 100ml frozen water, vacuum is removed THF solution, use extracted with diethyl ether, the saturated NaHCO of organic phase
3The solution neutralization is washed 2 times, washes twice again with water, anhydrous Na
2SO
4Drying is filtered, and vacuum is removed ether, obtains (IV): 1.4g, yield: 64.5%.HNMR：[CDCl
3，ppm：2.65(dd，2H)；3.7(dd，1H)；3.69(s，1H)；4.29(m，1H)；6.7(s，1H)]。
Embodiment two:
(S)-3,4-dihydroxyl butyric acid benzene methyl is synthetic
1, the cyclization of L MALIC ACID; Make with reference to example one.
2, esterification: (I) and 20mlCH with 5.3g (0.02mol)
2Cl
2, after the stirring and dissolving, add 6.5g (0.06mol) phenylcarbinol, 0.5mlH
2SO
4(dense) after the stirring and dissolving, is warming up to backflow, and back flow reaction is after 6 hours, and vacuum desolventizes, and with the dilution of 50ml frozen water, has a large amount of white solids to produce then, uses NaHCO
3Saturated solution is regulated PH to neutral, filters, and filter cake washes with water to neutrality, and drying gets white solid (II) 6g, yield: 85%mp. ℃.HNMR：[CDCl
3，ppm：3.04(m，2H)；4.87(m，1H)；5.18(q，2H)；5.57(s，1H)；7.38(m，5H)]。
3, hydrolysis: with above-mentioned cyclization oxysuccinic acid benzene methyl (II) 6.0g (0.017mol), add 40ml2NHCl and 5mlTHF, be heated to 40 ℃ of dissolvings in the stirring, be cooled to room temperature then, slowly add 1.15g (0.017mol) zinc powder at room temperature, stirring at room reaction 3 hours is filtered, after vacuum desolventizes, get enriched material, add the dilution of 50ml water then, the stirring at room dissolving, after extracted with diethyl ether, use anhydrous Na
2SO
4Drying is filtered, and gets concentrated solution after vacuum desolventizes, and uses CH
2Cl
2And the methyl alcohol gradient elution, get i.e. (III): the 3.0g of oxysuccinic acid benzene methyl, yield: 79%.HNMR[CDCl
3，ppm：3.0(m，2H)；4.76(dd，1H)；5.19(d，2H)；6.65(s，1H)；7.36(m，5H)]。
4, reduction: in the 500ml four-hole boiling flask, add (III) and 300mlTHF (anhydrous), magnetic agitation is to dissolving, N
2Under the protection, ice-water bath is cooled to 0 ℃, drips BH
3-THF (0.1mol/100ml, Acros) 40ml, T:0-10 ℃, dropwised in 20 minutes, and removed ice-water bath, use water-bath stirring reaction 1 hour, be warming up to 50 ℃, after 3 hours, stop heating 50-60 ℃ of insulation, be cooled to 20 ℃, after dripping the dilution of 100ml frozen water, vacuum is removed THF solution, and the aqueous solution extracts repeatedly with ether, the saturated NaHCO of organic phase
3In the solution and layering, use saturated NaHCO
3Solution washing 2 times washes twice with water, anhydrous Na again
2SO
4Drying is filtered, and vacuum is removed ether, obtains (IV): 1.8g, yield: 68.5%.HNMR：[CDCl
3，ppm：2.75(m，2H)；3.75(m，2H)；4.32(m，1H)；5.15(s，2H)；6.67(s，1H)；7.35(m，5H)]。
Embodiment three:
(S)-3,4-dihydroxyl butyric acid benzene methyl is synthetic
1, the cyclization of L MALIC ACID: make with reference to example one.
2, esterification: (I) and 20mlCH with 5.3g (0.02mol)
2CL
2, after the stirring and dissolving, add 2.2g (0.02mol) phenylcarbinol, 0.5mlH
2SO
4(dense) after the stirring and dissolving, is warming up to backflow, and back flow reaction is after 6 hours, and vacuum desolventizes, and with the dilution of 50ml frozen water, has a large amount of white solids to produce then, uses NaHCO
3Saturated solution is regulated PH to neutral, filters, and filter cake washes with water to neutrality, and drying gets white solid (II) 6g, yield: 85%mp. ℃.HNMR：[CDCl
3，ppm：3.04(m，2H)；4.87(m，1H)；5.18(q，2H)；5.57(s，1H)；7.38(m，5H)]。
3, hydrolysis:, add 50ml1%CH with above-mentioned cyclization oxysuccinic acid benzene methyl (II) 6.0g (0.017mol)
3COOH and 5mlTHF, be heated to 40 ℃ of dissolvings in the stirring, be cooled to room temperature then, slowly add 23g (0.35mol) zinc powder at room temperature, stirring at room reaction 1 hour, filter, after vacuum desolventizes, get enriched material, add the dilution of 50ml water then, the stirring at room dissolving after extracted with diethyl ether, is used anhydrous Na
2SO
4Drying is filtered, and gets concentrated solution after vacuum desolventizes, and uses CH
2CL
2And the methyl alcohol gradient elution, get i.e. (III): the 3.0g of oxysuccinic acid benzene methyl, yield: 79%.HNMR[CDCl
3, ppm:3.0 (m, 2H); 4.76 (dd, 1H); 5.19 (d, 2H); 6.65 (s, 1H); 7.36 (m, 5H)].
4, reduction: in the 500ml four-hole boiling flask, add (III) and 300mlTHF (anhydrous), magnetic agitation is to dissolving, N
2Under the protection, ice-water bath is cooled to 0 ℃, drips BH
3-THF (0.1mol/100ml, Acros) 130ml, T:0-10 ℃, dropwised in 20 minutes, and removed ice-water bath, use water-bath stirring reaction 1 hour, be warming up to 50 ℃, after 3 hours, stop heating 50-60 ℃ of insulation, be cooled to 20 ℃, after dripping the dilution of 100ml frozen water, vacuum is removed THF solution, and the aqueous solution extracts repeatedly with ethyl acetate, the saturated NaHCO of organic phase
3In the solution and layering, use saturated NaHCO
3Solution washing 2 times washes twice with water, anhydrous Na again
2SO
4Drying is filtered, and vacuum is removed ethyl acetate, obtains (IV): 1.85g, yield: 70.4%.HNMR：[CDCl
3，ppm：2.75(m，2H；3.75(m，2H)；4.32(m，1H)；5.15(s，2H)；6.67(s，1H)；7.35(m，5H)；)。
Claims (8)
1, a kind of 3-position chiral hydroxyl group is protected 3, and 4-dihydroxyl butyric ester is characterized in that structure is:
R represents C
1-C
5Straight chain or the C that the alkyl of side chain is arranged, replaced by aromatic base
1-C
5Alkyl, aromatic base.
2, a kind of 3-as claimed in claim 1 position chiral hydroxyl group is protected 3, and the preparation method of 4-dihydroxyl butyric ester is characterized in that concrete steps are as follows:
1. the 4-position carboxylic acid with cyclization lactonic acid (I) becomes ester (II) with alcohol;
2. form shielded alpha hydroxy acid (III) with zinc powder hydrolysis of lactone ring under acidic conditions then;
3. use BH at last
3The selective reduction carboxylic acid becomes hydroxyl, obtains a synthesis route of target product (IV), and described synthesis route is as follows:
3,3-according to claim 2 position chiral hydroxyl group is protected 3, the preparation method of 4-dihydroxyl butyric ester, it is characterized in that step 1. with cyclization lactonic acid and alcohol at H
+Carry out esterification under the condition, make cyclization oxysuccinic acid 4-position carboxylic acid become ester.
4,3-according to claim 3 position chiral hydroxyl group is protected 3, and the preparation method of 4-dihydroxyl butyric ester is characterized in that, the alcohol roh in described esterification, R are C
1-C
5Straight chain or the C that the alkyl of side chain is arranged, replaced by aromatic base
1-C
5Alkyl, aromatic base; Esterification cyclization oxysuccinic acid is 1 with the mol ratio of alcohol: 1-10.
5,3-according to claim 2 position chiral hydroxyl group protected 3; the preparation method of 4-dihydroxyl butyric ester; it is characterized in that; step is 2. specifically: under solutions of weak acidity; zinc powder catalytic hydrolysis ring-opening reaction obtains the protected R of chiral hydroxyl group (S)-3-(2, the 2-dichloro) vinyloxy group-4-carboxylic acid-1-butyric ester.
6,3-according to claim 5 position chiral hydroxyl group protected 3, the preparation method of 4-dihydroxyl butyric ester is characterized in that, described zinc powder catalytic hydrolysis ring-opening reaction, the acid of its use is selected from the 1%-100% glacial acetic acid, 0.1-2.0N HCL and other organic acids and mineral acid; Zinc powder and lactone ratio are 1-20: 1; This hydrolysising reacting temperature is controlled between-10 ℃ to 100 ℃ and carries out; Reaction times was controlled at 1-24 hour.
7,3-according to claim 2 position chiral hydroxyl group is protected 3, and the preparation method of 4-dihydroxyl butyric ester is characterized in that, 3. step uses BH at last
3The selective reduction carboxylic acid becomes hydroxyl, is meant: at last in organic solvent, and N
2Protection is used BH down
3Make reductive agent carboxylic acid is carried out selective reduction reaction, it is protected 3 to obtain target product 3-position chiral hydroxyl group, and 4-dihydroxyl butyric ester is R (S)-3-(2,2-Ethylene Dichloride oxygen base)-4 hydroxybutyric acid ester.
8,3-according to claim 7 position chiral hydroxyl group is protected 3, and the preparation method of 4-dihydroxyl butyric ester is characterized in that, described reduction reaction, and the organic solvent of its use is: tetrahydrofuran (THF), ethyl acetate, ether, CH
2Cl
2, CHCl
3, CCl
4, alcohol or organic bases; Temperature of reaction is controlled at-20-100 ℃; Reaction times was controlled at 0.5-24 hour, and this reaction must be at N
2Carry out the proportioning of reactant and borine: 1: 1-10 under the protection.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0759424A1 (en) * | 1995-08-22 | 1997-02-26 | Ajinomoto Co., Inc. | Process for producing optically active 2-hydroxy-4-arylbutyric acid or its ester, and intermediate therefor |
| EP0841332A1 (en) * | 1996-11-07 | 1998-05-13 | Degussa Aktiengesellschaft | Method for preparing alpha-methylene-beta-methyl-gamma-butyrolactone and 4-hydroxy-butyric aldehyde as well as 2-hydroxa-3-methylene-4-methyltetrahydrofuran being valuable intermediates |
| US5808107A (en) * | 1997-10-31 | 1998-09-15 | Board Of Trustees Operating Michigan State University | Process for the preparation of hydroxy substituted gamma butyrolactones |
| WO2000006532A2 (en) * | 1998-07-31 | 2000-02-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Process for the preparation of r-(-)-carnitine |
| CN1273234A (en) * | 1999-05-11 | 2000-11-15 | 罗姆和哈斯公司 | Method for preparing substituted 3-hydroxybutyrate |
-
2005
- 2005-09-08 CN CNB2005100294928A patent/CN100335457C/en not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0759424A1 (en) * | 1995-08-22 | 1997-02-26 | Ajinomoto Co., Inc. | Process for producing optically active 2-hydroxy-4-arylbutyric acid or its ester, and intermediate therefor |
| EP0841332A1 (en) * | 1996-11-07 | 1998-05-13 | Degussa Aktiengesellschaft | Method for preparing alpha-methylene-beta-methyl-gamma-butyrolactone and 4-hydroxy-butyric aldehyde as well as 2-hydroxa-3-methylene-4-methyltetrahydrofuran being valuable intermediates |
| US5808107A (en) * | 1997-10-31 | 1998-09-15 | Board Of Trustees Operating Michigan State University | Process for the preparation of hydroxy substituted gamma butyrolactones |
| WO2000006532A2 (en) * | 1998-07-31 | 2000-02-10 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Process for the preparation of r-(-)-carnitine |
| CN1273234A (en) * | 1999-05-11 | 2000-11-15 | 罗姆和哈斯公司 | Method for preparing substituted 3-hydroxybutyrate |
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