CN108003105B - Method for synthesizing micromolecular amino acid derivative ectoin - Google Patents
Method for synthesizing micromolecular amino acid derivative ectoin Download PDFInfo
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- CN108003105B CN108003105B CN201810002838.2A CN201810002838A CN108003105B CN 108003105 B CN108003105 B CN 108003105B CN 201810002838 A CN201810002838 A CN 201810002838A CN 108003105 B CN108003105 B CN 108003105B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
The invention relates to a synthesis method of a micromolecular amino acid derivative (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin), which is characterized in that cheap and easily available commercial L-acetyl asparagine is used as a raw material, and lactam is synthesized by condensation, upper protection, carbonyl reduction, amide hydrolysis, amino deprotection, hydrochlorination and cyclization to obtain the ectoin molecule. The method can conveniently obtain the high-purity (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) product with low cost and fewer steps, has mild reaction conditions, is easy to control, has little environmental pollution and is suitable for industrial production.
Description
Technical Field
The invention relates to a novel synthesis method of amino acid derivatives with physiological activity, in particular to a synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin).
Background
(S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) is derived from halophilic bacteria (Halomonas Elongata) and is a small molecule amino acid derivative with a chiral carbon atom.
Under the extreme conditions of high salt, high temperature and high ultraviolet radiation, the ectoin can prevent halophilic bacteria from being damaged. Ectoine is a compatible solute produced intracellularly by salt tolerant organisms in order to maintain osmotic pressure balance. In vitro and in vivo studies show that (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) can be accumulated in cells through two ways of in vivo synthesis and in vitro transport, and the osmotic pressure balance inside and outside the cells is regulated.
The (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) has the functions of osmotic pressure regulation, protein hydration layer stabilization, enzyme, DNA and other biomacromolecules and cell membrane structure protection, and can help cells, animals and plants to resist various adverse environments such as freezing, drought, high temperature, high salt, radiation and the like. Therefore, the compound has wide application prospect in the fields of medical treatment, health care and cosmetics.
The use of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) in oral care is disclosed in the world patent WO 0219978. Its use in skin care and disease prevention is disclosed in patent DE 102004016129. Its use in the treatment and prevention of gastrointestinal disorders is reported in the world patent WO 2006097263.
The first mass production technique for (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) is a biosynthetic process known as the "bacterial milking" technique. On the other hand, ｃA synthetic method using expensive 2, 4-diaminobutyric acid as ｃA raw material has been reported in terms of chemical synthesis (patent JP- ｃA-03031265 and patent US 20110178292).
Disclosure of Invention
The invention aims to overcome the defects and provides a novel method for artificially synthesizing the ectoin, which has low cost and simple synthesis process.
The invention provides a synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, which is characterized by comprising the following steps: a target product is obtained by taking a compound with the following structure as a raw material through cyclization reaction:
the process of the cyclization reaction is generally as follows: the compound with the structure is dissociated by alkali in a polar solvent such as alcohol, and then is heated to carry out intramolecular cyclization reaction to obtain the product molecule of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin).
In addition, the invention also provides another synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, which is characterized by comprising the following steps: a compound with the following structure is taken as a raw material, and a target product is obtained after carbonyl reduction, amide hydrolysis, amino deprotection, hydrochlorination and cyclization reactions in sequence:
wherein Pro is an amino protecting group.
For example: alkoxycarbonyl-type protecting groups: n-benzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl (Boc), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), trimethylsilethoxycarbonyl (Teoc);
acyl protecting groups: phthaloyl, p-toluenesulfonyl, trifluoroacetyl, pivaloyl amide, benzamide;
alkyl protecting groups: trityl, 2, 4-dimethoxybenzyl, p-methoxybenzyl, benzyl and the like.
The protecting group has the characteristic of recovering to an amino group after being removed from the protection group.
The specific reaction equation is as follows:
in addition, the invention also provides another synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, which is characterized by comprising the following steps: a target product is obtained by using a compound with the following structure as a raw material and sequentially carrying out condensation to obtain lactam, upper protection, carbonyl reduction, amide hydrolysis, amino deprotection, hydrochlorination and cyclization reactions:
wherein R is a group capable of being converted into an amino group. Such as: carboxyl, aldehyde group, halogen, acyl halide, amide and other groups.
The specific reaction equation is as follows:
further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, the L-acetyl asparagine is taken as a raw material, and the target product is obtained by the following processes in sequence:
s1: performing intramolecular condensation on the L-acetyl asparagine;
s2: carrying out Boc protection on a nitrogen atom of lactam formed by condensing L-acetyl asparagine, and reducing a carbonyl group of the lactam into a methylene group by using sodium borohydride and triethylhydrosilane;
s3: hydrolyzing amide bond of the reduced lactam by using lithium hydroxide, and then reacting the hydrolyzed lactam with hydrogen chloride to remove Boc protection to obtain a hydrochloride intermediate;
s4: obtaining the target product through intramolecular cyclization reaction.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, the specific preparation method is as follows:
step one, under the condition of alkalescence, stirring and reacting L-acetyl asparagine for 1-5 hours at the temperature of 10-35 ℃ under the condition of adding condensing agents such as DCC, EDCI or HOBT and the like to obtain a lactam product;
secondly, under the action of strong base, reacting the product of the first step with Boc anhydride to protect the nitrogen atom of lactam, and reacting for 2-10 hours at the temperature of more than 0 ℃ by using sodium borohydride, triethylsilane hydrogen and the like as reducing agents to obtain an intermediate of which lactam carbonyl is reduced into methylene;
step three, hydrolyzing amido bonds of the product obtained in the step two by using lithium hydroxide, and then reacting the product with hydrogen chloride to remove Boc protection to obtain a hydrochloride intermediate;
and step four, reacting the product obtained in the step three for 5 to 24 hours at the temperature of between 50 and 120 ℃ under the action of alkali to obtain an intramolecular cyclization product.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: that is, in step one, the molar ratio of the L-acetyl asparagine to DCC or EDC I or HOBT is 1: 1.5; the molar ratio of the weak base to the L-acetyl asparagine is 1: 1.5;
further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, in the second step, the molar ratio of the product of the first step and Boc anhydride is 1: 1-1.5;
the molar ratio of the strong base to the Boc anhydride is 1: 1-1.5;
the molar ratio of the reducing agent sodium borohydride to the reducing agent triethylhydrosilicon to the product obtained in the first step is 2-3: 1.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, in the third step, the molar ratio of the product of the second step to the lithium hydroxide is 1: 1-1.5;
further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, in the fourth step, the molar ratio of the base to the product of the third step is 1:1 to 1.3.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, the solvent-free reaction or the solvent reaction is carried out in the steps from the first step to the fourth step;
the solvent is selected from ethers, esters, alcohols, aromatics and alkanes;
the weak base is selected from triethylamine and diisopropylethylamine, and the strong base is selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride and the like.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, the steps from the first step to the fourth step are continuous reaction; i.e., reactions that do not require separate processing;
or
One or more steps of the first step to the fourth step are carried out, and purification is carried out after the reaction is finished;
the procedure for the above purification is as follows:
the purification process is as follows:
the purification method of the product in the first step comprises the following steps: adjusting the pH value of the reaction solution to be neutral, extracting, and evaporating to remove the solvent to obtain a product in the first step;
the purification method of the product in the second step comprises the following steps: washing the reaction solution with acid, drying, and evaporating to remove the solvent to obtain a product in the second step;
the purification method of the product in the third step comprises the following steps: filtering;
the purification method of the product in the fourth step comprises the following steps: the target product is obtained after evaporation of the solvent and recrystallization.
The reagents for extraction and recrystallization may be selected from: esters (ethyl acetate, ethyl formate), alcohols (ethanol, methanol, propanol, isopropanol), ethers (diethyl ether, methyl tert-butyl ether), ketones (acetone, etc.).
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: that is, in the fourth step, trimethyl orthoacetate is further added to carry out the reaction.
Further, the synthesis method of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid provided by the invention also has the following characteristics: namely, the molar ratio of the product of the third step to trimethyl orthoacetate is 1: 0.1-1.5.
The invention has the following functions and effects:
the invention provides a synthesis method of a micromolecular amino acid derivative (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin). The method can conveniently obtain the (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid (ectoin) with high purity and high yield by using fewer steps at low cost, has mild reaction conditions, is easy to control, has little environmental pollution, improves the yield by at least 30 percent compared with the traditional process, has the cost which is less than 10 percent of the traditional process, and is extremely suitable for industrial production.
Detailed Description
Example 1
The first step is as follows: 500 g of L-acetoacetamide as a starting material was added to a solution of 300 g of DCC in 3L of dichloromethane, and 210 g of triethylamine was added dropwise. Then, the reaction mixture was reacted at room temperature for 2 hours, and after the reaction was completed, the reaction mixture was adjusted to pH 2 with hydrochloric acid. After the product is extracted with ethyl acetate, 1420 g of lactam are obtained after drying and evaporation to remove the solvent, and the yield is 78%.
The second step is that: 1400 g of lactam and 500 g of BOC anhydride are added to 8 l of tetrahydrofuran, 120 g of sodium hydride is added at 0 ℃, and the reaction is carried out under the protection of nitrogen. After stirring and reacting for 2 hours at 0 ℃, 250 g of sodium borohydride is added in batches and then the reaction is carried out for 2 hours at 20 ℃. 400 g of triethylhydrosilane was added thereto, and the mixture was heated to 60 ℃ to react for 3 hours. After the reaction was completed, the reaction solution was washed with 1M hydrochloric acid. The solution was partially dried and the solvent evaporated to give intermediate 3670 g, 80% yield.
The third step: 500 g of BOC-protected intermediate 3 was dissolved in 3 l of ethanol and 1 l of water, and then solid sodium hydroxide was added to the reaction solution to react at 40 ℃ for 3 hours. After the reaction was complete, the ethanol was distilled off, 5 l of methyl tert-butyl ether was added and washed twice with clear water. The organic layer was dried over anhydrous sodium sulfate and then charged with hydrogen chloride gas to obtain 4360 g of a hydrochloride intermediate in 85% yield.
The fourth step: the hydrochloride intermediate 3360 g and sodium ethoxide 125 g were added to 5L of anhydrous ethanol, and the reaction was stirred with heating for 5 hours. The solvent was evaporated to give a crude product which was recrystallized from methanol (60mL) and ethyl acetate (300mL) to give 200 g of pure product in 85% yield.
Example 2
The first step is as follows: 500 g of the starting material L-acetoacetamide were added to a solution of 550 g EDCI in 4L of dichloromethane, followed by dropwise addition of 280 g of diisopropylethylamine. Then, the reaction mixture was reacted at room temperature for 2 hours, and after the reaction was completed, the reaction mixture was adjusted to pH 2 with hydrochloric acid. After the product was extracted with ethyl acetate, 1380 g of lactam was obtained at 67% yield by drying and evaporation of the solvent.
The second step is that: 1300 g of lactam and 400 g of BOC anhydride are added to 6 l of tetrahydrofuran, 150 g of sodium hydride is added at 0 ℃, and the reaction is carried out under the protection of nitrogen. Stirring the mixture at 0 ℃ for reaction for 2 hours, then adding sodium borohydride in batches, and reacting the mixture for 3 hours at 20 ℃. 400 g of triethylhydrosilane was added thereto, and the mixture was heated to 60 ℃ to react for 3 hours. After the reaction was completed, the reaction solution was washed with 1M hydrochloric acid. After partial drying of the solution and evaporation of the solvent, 3540 g of intermediate were obtained in 65% yield.
The third step: 500 g of BOC-protected intermediate 3 was dissolved in 5 l of methanol, and then a solid lithium hydroxide was added to the reaction solution to react at 40 ℃ for 2 hours. After the reaction was complete, the methanol was distilled off, 5 l of methyl tert-butyl ether was added and washed twice with clear water. The organic layer was dried over anhydrous sodium sulfate and then charged with hydrogen chloride gas to obtain 4360 g of a hydrochloride intermediate in 85% yield.
The fourth step: the hydrochloride intermediate 3300 g and sodium t-butoxide 130 g were added to 5 l of isopropanol and the reaction was stirred with heating for 4 hours. The solvent was evaporated to give a crude product which was recrystallized from methanol (60mL) and ethyl acetate (300mL) to give 200 g of pure product in 89% yield.
Example 3
The first step is as follows: 500 g of the starting material L-acetoacetamide were added to a solution of 560 g of HOBT in 4L of dichloromethane, followed by dropwise addition of 280 g of diisopropylethylamine. Then, the reaction mixture was reacted at room temperature for 2 hours, and after the reaction was completed, the reaction mixture was adjusted to pH 2 with hydrochloric acid. After the product was extracted with ethyl acetate, 1400 g of lactam was obtained after drying and evaporation of the solvent, with a yield of 74%.
The second step is that: 1300 g of lactam and 400 g of BOC anhydride are added to 6 l of tetrahydrofuran, 150 g of sodium hydride is added at 0 ℃, and the reaction is carried out under the protection of nitrogen. Stirring the mixture at 0 ℃ for reaction for 2 hours, then adding sodium borohydride in batches, and reacting the mixture for 3 hours at 20 ℃. 400 g of triethylhydrosilane was added thereto, and the mixture was heated to 50 ℃ to react for 3 hours. After the reaction was completed, the reaction solution was washed with 1M hydrochloric acid. The solution was partially dried and the solvent was evaporated to give 3440 g of intermediate in 65% yield.
The third step: 400 g of BOC-protected intermediate 3 were dissolved in 4 l of methanol and 1 l of water, and then solid lithium hydroxide was added to the reaction solution to react at 40 ℃ for 3 hours. After the reaction was complete, the methanol was distilled off, 5 l of methyl tert-butyl ether was added and washed twice with clear water. The organic layer was dried over anhydrous sodium sulfate and then charged with hydrogen chloride gas to obtain 4320 g of a hydrochloride intermediate in 86% yield.
The fourth step: the hydrochloride intermediate 3300 g and potassium tert-butoxide 150 g were added to 5 l isopropanol and the reaction was stirred with heating for 4 hours. The solvent was evaporated to give a crude product which was recrystallized from methanol (50mL) and ethyl acetate (300mL) to give 220 g of pure product in 90% yield.
Claims (7)
1. A method for synthesizing (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid is characterized in that:
s1: performing intramolecular condensation on the L-acetyl asparagine;
s2: carrying out Boc protection on a nitrogen atom of lactam formed by condensing L-acetyl asparagine, and reducing a carbonyl group of the lactam into a methylene group by using sodium borohydride and triethylhydrosilane;
s3: hydrolyzing amide bond of the reduced lactam by using lithium hydroxide, and then reacting the hydrolyzed lactam with hydrogen chloride to remove Boc protection to obtain a hydrochloride intermediate;
s4: obtaining a target product through intramolecular cyclization reaction;
2. the method for synthesizing (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid according to claim 1, wherein the specific preparation method is as follows:
step one, under the condition of alkalescence, stirring and reacting L-acetyl asparagine for 1-5 hours at the temperature of 10-35 ℃ under the condition of adding DCC to obtain a lactam product;
step two, under the action of sodium hydride, reacting the product of the step one with Boc anhydride to protect the nitrogen atom of lactam, and reacting with sodium borohydride and triethylhydrosilane for 2-10 hours at the temperature of more than 0 ℃ to obtain an intermediate of which lactam carbonyl is reduced into methylene;
step three, hydrolyzing amido bonds of the product obtained in the step two by using lithium hydroxide, and then reacting the product with hydrogen chloride to remove Boc protection to obtain a hydrochloride intermediate;
and step four, reacting the product obtained in the step three for 5 to 24 hours at the temperature of between 50 and 120 ℃ under the action of alkali to obtain an intramolecular cyclization product.
3. The process of claim 2 for the synthesis of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, wherein:
in step one, the molar ratio of L-acetyl asparagine to DCC is 1: 1.5;
the molar ratio of the weak base to the L-acetyl asparagine is 1: 1.5;
in the second step, the molar ratio of the product of the first step to Boc anhydride is 1: 1-1.5;
the molar ratio of the sodium hydride to the Boc anhydride is 1: 1-1.5;
in the third step, the molar ratio of the product of the second step to the lithium hydroxide is 1: 1-1.5;
in step four, the molar ratio of the base to the product of step three is 1:1 to 1.3.
4. The process of claim 2 for the synthesis of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, wherein:
carrying out solvent-free reaction or solvent reaction in the first step to the fourth step;
the solvent is selected from ethers, esters, alcohols, aromatics and alkanes;
the weak base is selected from triethylamine and diisopropylethylamine.
5. The process of claim 2 for the synthesis of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, wherein:
the first step to the fourth step are continuous reactions;
or
One or more steps of the reaction from the first step to the fourth step are carried out, and purification is carried out after the reaction is finished;
the purification process is as follows:
the purification method of the product in the first step comprises the following steps: adjusting the pH value of the reaction solution to be neutral, extracting, and evaporating to remove the solvent to obtain a product in the first step;
the purification method of the product in the second step comprises the following steps: washing the reaction solution with acid, drying, and evaporating to remove the solvent to obtain a product in the second step;
the purification method of the product in the third step comprises the following steps: filtering;
the purification method of the product in the fourth step comprises the following steps: the target product is obtained after evaporation of the solvent and recrystallization.
6. A process as claimed in any one of claims 2 to 5 for the synthesis of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid, characterized in that:
in the fourth step, trimethyl orthoacetate is also added for reaction.
7. The process of claim 6 for the synthesis of (S) -2-methyl-1, 4,5, 6-tetrahydropyrimidine-4-carboxylic acid wherein:
the molar ratio of the product obtained in the third step to trimethyl orthoacetate is 1: 0.1-1.5.
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| KR102570658B1 (en) | 2022-10-12 | 2023-08-25 | 자경케미칼 주식회사 | Preparing method of heterocyclic amino acid and Heterocyclic amino acid by manufactured the method |
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| WO2004022536A1 (en) * | 2002-09-04 | 2004-03-18 | Glenmark Pharmaceuticals Limited | New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them |
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| WO2004022536A1 (en) * | 2002-09-04 | 2004-03-18 | Glenmark Pharmaceuticals Limited | New heterocyclic amide compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them |
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