CN101823974A - Preparation method by adopting (R)-(-)-glycerinchlorohydrin as chirality starting material to synthetize L-carnitine - Google Patents

Abstract

The invention proposes a preparation method for synthesizing L-carnitine by using (R)-(-)-chloroglycerol as a chiral starting material, which belongs to the field of medicinal chemistry. The invention comprises the steps of: taking the by-product (R)-(-)-chloroglycerol as the chiral starting material when preparing L-carnitine by chiral resolution of racemic epichlorohydrin, first making (R) -(-)-Chloroglycerin reacts with thionyl chloride to generate a cyclic sulfinate intermediate; this cyclic intermediate reacts with KCN or NaCN to generate chlorobutyl nitrile; chlorobutyl nitrile Reaction in trimethylamine solution to produce cyanide salt; the final cyanide salt is hydrolyzed in acidic solution, and the chloride ion is removed by ion exchange to obtain the final product L-carnitine. The advantage of the present invention is that the by-product (R)-(-)-chloroglycerol when using cheap and easy-to-get chiral resolution racemic epichlorohydrin to prepare L-carnitine is the chiral starting material, so that The raw materials used in the preparation of L-carnitine are easily available, the process route is short, and the reaction operation is simple and easy.

Description

A preparation method for synthesizing L-carnitine with (R)-(-)-chloroglycerol as chiral starting material

technical field

The invention belongs to the field of medicinal chemistry, and relates to a preparation method for synthesizing L-carnitine by using (R)-(-)-chloroglycerol as a chiral starting material, in particular to a method for splitting a racemic ring by chirality A method for synthesizing L-carnitine by using the by-product (R)-(-)-chloroglycerin when L-carnitine is prepared from oxychloropropane as a chiral starting material.

Background technique

L-carnitine is also called L-carnitine or vitamin B _T , its chemical name is (R)-(-)-3-hydroxy-4-trimethylammonium butyric acid, and its chemical structure is:

L-carnitine is a compound with extensive physiological activities and broad physiological prospects. Since it was launched in the United States in the 1980s, it has been widely used in clinical treatment of heart failure, enhancement of muscle endurance and rapid recovery. Because only R-configuration carnitine has normal physiological effects, and its enantiomer S-configuration not only has no effect, but is also a competitive inhibitor of R-configuration carnitine in some metabolic processes, so for many years, Numerous researchers have reported the synthetic technique of L-carnitine (for example: 1. U.S. Patent US 5473104, 1995. 2. Robert, V.; Jean-Claude, P.; et.al., Helv.Chim.Acta, 1987,70 , 2058).

Since E.N.Jacobsen reported in 1997 (Tokunaga, M.; Larrow, J.F.; Kakiuchi, F.; Jacobsen, E.N., Science, 1997, 277, 936-938.), racemic epichlorohydrin can be resolved on a large scale to prepare chiral "block" substances (S)-(+)-epichlorohydrin and (R)-(-) - Chloroglycerin. Numerous L-carnitine production enterprises mostly adopt (S)-(+)-epichlorohydrin to be the chiral starting raw material system L-carnitine (for example, Gu Song Lin, Rui Liqin, Zhou Bin, etc., Synthetic Chemistry, 2004, 12, 383-384.).

From the above, it can be seen that the by-product (R)-(-)-chloroglycerin produced by chiral resolution of racemic epichlorohydrin to prepare L-carnitine is also a cheap and easy-to-obtain chiral "building block" substance . Utilizing this chiral "block" substance to directly prepare L-carnitine has very practical industrial significance.

Contents of the invention

The purpose of the present invention is to provide a kind of preparation method using (R)-(-)-chloroglycerin as chiral starting material to synthesize L-carnitine, the method is to split racemic epoxy chloride by chirality The by-product (R)-(-)-chloroglycerol used in the production of L-carnitine from propane is used as a chiral starting material, which can be directly and efficiently converted to produce L-carnitine. The method route for preparing L-carnitine with (R)-(-)-chloroglycerol chiral starting material proposed by the present invention is as follows:

The synthetic method of the present invention specifically comprises the steps:

(1) Carry out cyclization reaction of (R)-(-)-chloroglycerol with thionyl chloride at low temperature, and remove low boiling point substances by distillation to obtain a cyclic sulfinate intermediate, which does not need to be purified Refined, it can be directly used in the next step of synthesis reaction.

(2) In the temperature range of 10°C to 110°C, add the cyclic sulfinate intermediate prepared in step (1) into a polar solvent, react with cyanide inorganic salt to open the ring, and obtain the cyclic sulfinate intermediate After sulfonate ring opening and acid hydrolysis, the chlorobutyl nitrile intermediate is obtained.

(3) React the chlorobutyl nitrile intermediate and trimethylamine solution prepared in step (2) at a temperature of 0°C to 100°C. After the reaction is completed, the solvent is evaporated under reduced pressure, and the recrystallization solvent is used Recrystallization was carried out to obtain a cyanide salt intermediate.

(4) The cyanide salt intermediate obtained in step (3) is first hydrolyzed under acidic conditions, then dechlorinated by ion exchange, recrystallized, and refined to obtain L-carnitine.

The low temperature range in the step (1) is -70°C to 0°C, and the (R)-(-)-chloroglycerin is obtained by chiral resolution of racemic epichlorohydrin to prepare L-carnitine When the by-product, the resulting cyclic sulfinate intermediate can be directly used in the next reaction without further purification, and its yield reaches 100%.

In the step (2), the polar solvent is methanol, ethanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, any solvent in water or a mixed solution of the above solvents , the cyanide inorganic salt is KCN or NaCN,

In the step (2), the yield of the obtained chlorobutyl nitrile intermediate reaches 85%.

In the step (2), the dilute acid used for the hydrolysis is dilute hydrochloric acid or dilute sulfuric acid.

In the step (3), the recrystallization solvent is water, methanol, ethanol, acetonitrile or tetrahydrofuran, and the yield of the prepared cyanide salt intermediate is 80%.

In the step (3), the recrystallization solvent is methanol or water.

In the step (4), the acid used for the hydrolysis of the cyanide salt intermediate is hydrochloric acid or sulfuric acid solvent.

The present invention has the advantages that: the by-product (R)-(-)-chloroglycerol when L-carnitine is prepared by using cheap and easy-to-obtain chiral resolution racemic epichlorohydrin as the chiral starting material, The transformation is carried out to synthesize L-carnitine. The raw materials used in the preparation of L-carnitine are easy to obtain, the process route is short, and the reaction operation is simple and easy.

Detailed ways

Example 1

(1) Put 19.19g (0.174mol) (R)-(-)-chloroglycerol and 50ml dichloromethane into a 250ml three-necked bottle, and slowly add 22.74g (0.191oml) dichloromethane dropwise under ice bath conditions sulfone. After reacting for 1 h, 40 ml of water was added, the organic layer was washed twice with saturated brine, the aqueous layer was washed twice with ethyl acetate, the organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 27.23 g of a colorless liquid. That is, the cyclic sulfinate intermediate was directly used in the next reaction without purification, and the yield was 100%.

(2) Throw 10g (0.064mol) cyclic sulfinate and 30ml methanol into a 100ml three-neck flask, add 5.21g (0.08mol) KCN at room temperature, stir for 10min, then rise to 50°C, and stir vigorously for 12h back. Concentrate under reduced pressure, add 15ml of ethyl acetate, and slowly add 20% H ₂ SO ₄ solution dropwise. After stirring for 5 h, dilute NaCO ₃ solution was added to wash twice, water was washed twice, saturated brine was washed once, the aqueous layer was washed with ethyl acetate, the organic layers were combined, and anhydrous sodium sulfate was added to dry. The 89-90° C./<1 mmHg fraction was collected by vacuum distillation to obtain 6.51 g of a colorless liquid, namely the chlorobutyl nitrile intermediate, with a yield of 85%. [α] _D ²⁵ =+6.90 (c 3.0, CHCl ₃ ); IR (KBr, liquor film): 3431(bs), 2960(m), 2934(m), 2258(m), 1415(s), 1307 (m), 1088(s), 1057(s), 860(m), 755(m)cm ^-1 ; ₁ H NMR (400M, CDCl ₃ ), δppm: 3.21(bs, 1H, OH), 2.72- 2.75 (t, 2H, -CH ₂ -), 3.65-3.67 (d, 2H, -CH ₂ -), 4.16-4.22 (br, 1H, -CH ₂ CH(OH)CH ₂ -).

(3) 19.2g (0.16mol) of chlorobutyl nitrile, 57.4g (0.34mol) of 33% trimethylamine aqueous solution were mixed uniformly and reacted for 5h at 40°C in a three-necked flask, the reaction was stopped, the solvent was evaporated under reduced pressure, and the obtained The crude product was recrystallized from methanol to obtain 22.85 g of white crystals, namely cyanide salt. Yield 80%. mp220-222°C (dec). [α] _D ²⁰ =-26.3 (c 1.0, H ₂ O); IR (KBr, liquor film): v 3260(s), 3197(s), 3018(m), 2979(m), 2906(m) , 2242(m), 1477(s), 1409(m), 1367(m), 1230(m), 1091(s), 965(s), 933(s), 688(s) cm ^-1 ; ¹ H NMR (400M, D ₂ O), δppm: 4.63 (m, 1H, -CH ₂ CH(OH)CH ₂ -), 3.47 (dd, 2H, -CH ₂ -), 3.20 (s, 9H, -( CH ₃ ) ₃ ), 2.75 (dd, 2H, -CH ₂ -).

(4) Add 20 g (0.11 mol) of cyanide salt and 45 mL of concentrated hydrochloric acid prepared in the above three steps into a three-neck flask, heat up to reflux, stop the reaction after 4 hours, freeze, and suction filter. The filtrate was neutralized with sodium hydroxide solution to pH=2.2, and the water was distilled off under reduced pressure. Add 35ml of ethanol, heat to reflux and then filter with suction, and the filtrate is concentrated. Add 130ml of deionized water to the solid obtained by concentrating, after fully dissolving, remove chloride ions by strongly basic anion exchange resin. The effluent liquid was concentrated to dryness under reduced pressure, and 25 ml of ethanol was added for recrystallization to obtain 15 g of white needle-like crystals, that is, L-carnitine. mp 194°C; [α] _D ²⁰ =30.9 (c 10, H ₂ O); IR (KBr, liquor film): v 3264(s), 2997(s), 2930(s), 2873(s), 1725 (s), 1487(m), 1413(m), 1185(s), 1096(m), 935(m), 878(m), 602(m)cm ^-1 ; ¹ H NMR (400M, D ₂ O), δppm, 4.66 (m, 1H, -CH ₂ CH(OH)CH ₂ -), 3.52-3.47 (dd, 2H, -CH ₂ -), 3.24 (s, 9H, -(CH ₃ ) ₃ ) , 2.67-2.63 (dd, 2H, -CH ₂ -).

Example 2

(1) Put 38.38g of (R)-(-)-chloroglycerin and 100ml of dichloromethane into a 500ml three-neck flask, and slowly add 45.5g of thionyl chloride dropwise under ice-bath conditions. After reacting for 1 h, 80 ml of water was added, the organic layer was washed twice with saturated brine, the aqueous layer was washed twice with ethyl acetate, the organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 54.5 g of a colorless liquid. That is, the cyclic sulfinate intermediate was directly used in the next reaction without purification, and the yield was 100%.

(2) Throw 20g of cyclic sulfinate and 60ml of ethanol into a 250ml three-neck flask, add 10.42g of KCN at room temperature, stir for 10min, then rise to 60°C, and stir vigorously for 12h. Concentrate under reduced pressure, add 30ml of ethyl acetate, and slowly add 20% HCl solution dropwise. After stirring for 5 h, dilute NaCO ₃ solution was added to wash twice, water was washed twice, saturated brine was washed once, the aqueous layer was washed with ethyl acetate, the organic layers were combined, and anhydrous sodium sulfate was added to dry. The 89-90°C/<1mmHg fraction was collected by distillation under reduced pressure to obtain 13 g of colorless liquid, namely the chlorobutyl nitrile intermediate, with a yield of 85%.

(3) 38.4g of chlorobutyl nitrile, 114.8g of 33% trimethylamine aqueous solution were mixed and reacted at 45°C in a three-necked flask for 4.5h, the reaction was stopped, the solvent was evaporated under reduced pressure, and the obtained crude product was recrystallized with ethanol, Obtained 45.7g of white crystals, namely cyanide salt. Yield 80%.

(4) Add 40 g of the cyanide salt and 50 mL of concentrated sulfuric acid obtained in the above three steps into a three-necked flask, heat up to reflux, stop the reaction after 4.5 hours, freeze, and suction filter. The filtrate was neutralized with sodium hydroxide solution to pH = 2.0, and water was distilled off under reduced pressure. Add 70ml of ethanol, heat to reflux and then filter with suction, and the filtrate is concentrated. Add 250ml of deionized water to the solid obtained by concentration, and after the solution is completely dissolved, chloride ions are removed by a strongly basic anion exchange resin. The effluent liquid was concentrated to dryness under reduced pressure, and 50 ml of ethanol was added for recrystallization to obtain 30 g of white needle-like crystals, that is, L-carnitine.

Example 3

(1) Put 28.79g of (R)-(-)-chloroglycerol and 75ml of dichloromethane into a 500ml three-neck flask, and slowly add 34.11g of thionyl chloride dropwise under ice-bath conditions. After reacting for 1 h, 60 ml of water was added, the organic layer was washed twice with saturated brine, the aqueous layer was washed twice with ethyl acetate, the organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 41 g of a colorless liquid. That is, the cyclic sulfinate intermediate was directly used in the next reaction without purification, and the yield was 100%.

(2) Throw 15g of cyclic sulfinate and 45ml of methanol into a 250ml three-necked flask, add 7.82g of KCN at room temperature, stir for 7min, then rise to 55°C, and stir vigorously for 12h. Concentrate under reduced pressure, add 23ml of ethyl acetate, and slowly add 20% H ₂ SO ₄ solution dropwise. After stirring for 5 h, dilute NaCO ₃ solution was added to wash twice, water was washed twice, saturated brine was washed once, the aqueous layer was washed with ethyl acetate, the organic layers were combined, and anhydrous sodium sulfate was added to dry. The 89-90° C./<1 mmHg fraction was collected by vacuum distillation to obtain 9.78 g of colorless liquid, namely the chlorobutyl nitrile intermediate, with a yield of 85%.

(3) Mix 28.8g of chlorobutyl nitrile and 86.1g of 33% trimethylamine aqueous solution to react in a three-necked flask at 40°C for 5h, stop the reaction, evaporate the solvent under reduced pressure, and recrystallize the gained crude product with acetonitrile to obtain 34.28g white crystals, namely cyanide salt. Yield 80%.

(4) Add 30 g of the cyanide salt and 67.5 mL of concentrated sulfuric acid prepared in the above step (3) into a three-necked flask, heat up to reflux, stop the reaction after 4 hours, freeze, and suction filter. The filtrate was neutralized with sodium hydroxide solution to pH=2.2, and the water was distilled off under reduced pressure. Add 52.5ml of ethanol, heat to reflux and then filter with suction, and the filtrate is concentrated. Add 190ml of deionized water to the solid obtained by concentration, after complete dissolution, remove chloride ions by strongly basic anion exchange resin. The effluent liquid was concentrated to dryness under reduced pressure, and 37.5 ml of ethanol was added for recrystallization to obtain 22.5 g of white needle crystals, namely L-carnitine.

Claims (7)

1. a kind of preparation method taking (R)-(-)-chloroglycerol as chiral starting material synthetic L-carnitine, it is characterized in that, the synthetic steps of L-carnitine are: (1) Carry out cyclization reaction of (R)-(-)-chloroglycerol with thionyl chloride at low temperature, and remove low boiling point substances by distillation to obtain a cyclic sulfinate intermediate, which does not need to be purified Refined, it can be directly used in the next step of synthesis reaction; (2) In the temperature range of 10°C to 110°C, add the cyclic sulfinate intermediate prepared in step (1) into a polar solvent, react with cyanide inorganic salt to open the ring, and obtain the cyclic sulfinate intermediate After the ring-opening of the sulfonic acid ester and its acid hydrolysis, the chlorobutyl nitrile intermediate is obtained; (3) React the chlorobutyl nitrile intermediate and trimethylamine solution prepared in step (2) at a temperature of 0°C to 100°C. After the reaction is completed, the solvent is evaporated under reduced pressure, and the recrystallization solvent is used Carry out recrystallization, make cyanide salt intermediate; (4) The cyanide salt intermediate obtained in step (3) is first hydrolyzed under acidic conditions, then dechlorinated by ion exchange, recrystallized, and refined to obtain L-carnitine. 2. take (R)-(-)-chloroglycerol according to claim 1 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, the low temperature in described step (1) The range is from -70°C to 0°C. The (R)-(-)-chloroglycerin is a by-product of chiral resolution of racemic epichlorohydrin to prepare L-carnitine. The obtained cyclic sub The sulfonate intermediate can be directly used in the next reaction without further purification, and the yield reaches 100%. 3. take (R)-(-)-chloroglycerol according to claim 1 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, in described step (2), described The polar solvent is methanol, ethanol, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, any solvent in water or a mixed solution of the above solvents; the cyanide inorganic salt is KCN or NaCN. 4. take (R)-(-)-chloroglycerol according to claim 1 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, in described step (2), described The dilute acid used for hydrolysis is dilute hydrochloric acid or dilute sulfuric acid, and the yield of the obtained chlorobutyl nitrile intermediate reaches 85%. 5. take (R)-(-)-chloroglycerol according to claim 1 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, in described step (3), described The recrystallization solvent is water, methanol, ethanol, acetonitrile or tetrahydrofuran, and the yield of the prepared cyanide salt intermediate is 80%. 6. take (R)-(-)-chloroglycerol according to claim 5 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, in described step (3), described The recrystallization solvent is methanol or water. 7. take (R)-(-)-chloroglycerin according to claim 1 as the preparation method of chiral starting material synthetic L-carnitine, it is characterized in that, in described step (4), cyanide salt The acid used for the hydrolysis of the intermediate is hydrochloric acid or sulfuric acid solvent.