CN110845347A - Preparation method of chloro-homoserine alkyl ester - Google Patents
Preparation method of chloro-homoserine alkyl ester Download PDFInfo
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- CN110845347A CN110845347A CN201911145686.2A CN201911145686A CN110845347A CN 110845347 A CN110845347 A CN 110845347A CN 201911145686 A CN201911145686 A CN 201911145686A CN 110845347 A CN110845347 A CN 110845347A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of chlorinated homoserine alkyl ester. The technical scheme adopted by the invention is to provide a preparation method of chlorinated homoserine alkyl ester, wherein a compound shown in formula (I) or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof is mixed with alcohol ROH and thionyl chloride for reaction to obtain a compound shown in formula (II) or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, namely the target chlorinated homoserine alkyl ester. The invention solves the problems of lower product yield, larger three wastes, unfavorable industrial operation and the like in the existing preparation method.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of chlorinated homoserine alkyl ester.
Background
The glufosinate-ammonium is used as an efficient, low-toxicity and broad-spectrum contact-type organic phosphorus herbicide, and the speed of the glufosinate-ammonium playing the active action is slower than that of paraquat and is better than that of glyphosate. But has resulted in the continued development of resistant weeds due to the large area use of glyphosate; due to the severe toxicity of paraquat, a large number of toxic death events occur, so that paraquat is withdrawn from the market; the glufosinate-ammonium serving as a second major transgenic crop tolerance herbicide glufosinate-ammonium has a very wide development prospect.
L-glufosinate developed by Japan Ming Guo manufacturing company is of a single L-configuration, and it was experimentally verified that glufosinate has a D-configuration which is biologically inactive and a L-configuration which is 2 times as active as the racemate.
A method for synthesizing L-glufosinate-ammonium using amino-protected (S) -4-chloro-2-aminobutyrate as a key intermediate is reported in patent US5442088 published in 1994. Subsequently, as reported in patent US20060135602, L-homoserine and thionyl chloride are utilized to directly synthesize (S) -4-chloro-2-aminobutyrate, which can be used for the subsequent synthesis of L-glufosinate-ammonium, but the problems of excessive consumption of thionyl chloride, high cost and environmental pollution caused by more waste acid and waste water are solved.
Patent CN109369432A discloses that (S) -4-chloro-2-aminobutyrate is prepared in two steps from (S) -2-aminobutyrolactone hydrochloride, and (S) -homoserine ester is obtained under acid catalysis, and then the target compound is obtained by chlorination, and the yield of the two steps is up to 80.6%. The method is divided into two steps for synthesis, so that the operation flow is increased, and impurities generated in the middle process of reaction are unknown, so that the overall yield of the product is not high.
Therefore, there is a need to develop a method which can effectively control the generated impurities and improve the yield of the product, and is convenient to operate and reduce the amount of the three wastes in the industrial production process.
Disclosure of Invention
In order to solve the problems, the technical scheme of the invention is to provide a compound of formula (II)
Or a salt, an enantiomer or a mixture of enantiomers in all ratios thereof, comprising the steps of:
mixing the compound of formula (I) or the salt, the enantiomer or the mixture of the enantiomers in all proportions with alcohol ROH and thionyl chloride for reaction to obtain a compound of formula (II) or the salt, the enantiomer or the mixture of the enantiomers in all proportions;
wherein R represents an alkyl group having a carbon number of 1 to 4.
The reaction temperature of the reaction is 0 to 60 ℃, preferably 25 to 45 ℃, and more preferably 35 ℃. When the reaction temperature is too low or too high, both ether impurities and ester impurities increase, the selectivity of the target product decreases, and the reaction is unfavorable.
The molar ratio of the compound of the formula (I) to thionyl chloride is 1: 1-5, preferably 1: 1.5-4, more preferably 1: 2-4. The thionyl chloride is used as a chlorinating agent in the reaction process, and the dosage is not too high or too low. In addition, the inventors tried to replace thionyl chloride with other chlorinating agents such as hydrogen chloride (gas), triphosgene, phosphorus oxychloride, sulfuryl chloride, the reaction did not proceed as expected, with very little product.
The alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
The molar ratio of the compound of the formula (I) to the alcohol is 1: 1-20, preferably 1: 5-15. The alcohol serves as both a reactant and a solvent in the reaction system. Alcohol is used as a reactant in an amount of at least 1 eq. The amount of the alcohol used as a solvent is not so small as 1 to 20eq, preferably 5 to 15 eq. The inventors tried to change the alcohol solvent to another solvent (e.g. 1, 2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran), i.e. only alcohol as reactant, but surprisingly found that only a few target products were obtained after changing to another solvent. It can be seen that the specific reaction of the present invention achieves better effect only under the condition that the specific chlorinating agents thionyl chloride and alcohol are used as solvents.
The preparation method of the compound of the formula (II) comprises the steps of mixing the compound of the formula (I) with alcohol and then adding thionyl chloride. The compound of the formula (I) is partially dissolved in alcohol, the whole system is in a suspension state, the suspension system is gradually clear along with the dropwise addition of thionyl chloride, a small amount of solid still exists after the LC-MS monitoring reaction is finished, and the solid is detected to be the unreacted raw material compound of the formula (I).
The system temperature in the thionyl chloride adding process needs to be maintained at 5-15 ℃, after the thionyl chloride is added, the mixture is continuously stirred for a certain time at 5-15 ℃ and then heated to the reaction temperature, so that the reaction process is effectively controlled, and impurities are controlled. As a preferred embodiment, the inventors chose to add thionyl chloride at 10 ℃ and continue stirring for 30 min.
The preparation method also comprises the steps of reduced pressure distillation, solvent addition washing and filtration. The solvent used for washing is a mixed solvent composed of n-hexane and ethyl acetate, a mixed solvent composed of petroleum ether and ethyl acetate, and tert-butyl methyl ether or toluene. And (3) a reduced pressure distillation process for removing thionyl chloride and ethanol. And washing residual solid after reduced pressure distillation by using a solvent and filtering to obtain the target product.
The invention further provides a compound of formula (II)
Or an enantiomer thereof or a mixture of enantiomers in all ratios, comprising the steps of:
the hydrochloride of the compound of formula (II) is obtained according to the preparation method described above, and the hydrochloride of the compound of formula (II) in the simultaneous presence of an inorganic base and water gives the compound of formula (II) or its enantiomers or a mixture of enantiomers in all ratios.
The inorganic base is one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and the pH of the reaction system is finally 7-8 under the combined action of the intermediate product, the inorganic base and water.
The preparation method also comprises the following post-treatment steps of adding an organic solvent for extraction, and concentrating the organic phase to obtain the oily compound of the formula (II). The organic solvent may be ethyl acetate.
When the reactants are compound hydrochloride of formula (I), ethanol and thionyl chloride, the target product, compound of formula (II), is chloro-homoserine ethyl ester.
Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
C1-C4 alkyl is a straight or branched, saturated hydrocarbon chain containing 1 to 4 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
The invention has the beneficial effects that:
(1) effectively controlling the generated impurities and improving the yield of the product;
(2) simple operation and convenient industrialization.
(3) Effectively reduces the amount of the generated three wastes.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The invention is further explained and illustrated by the following test examples and examples, which refer to the intermediate product as compound hydrochloride of formula (II), i.e. chloro-homoserine ethyl ester hydrochloride.
Example 1
10g of the hydrochloride salt of the compound of the formula (I) (L-homoserine lactone hydrochloride, ee value 99%, 137.56g/mol, 0.073mol) was weighed into a reaction vessel, 50mL of ethanol (46.07g/mol, 0.886mol, 0.816g/mL) was added, and the molar ratio of homoserine lactone hydrochloride to ethanol was 1: 12.1. The temperature of the system is reduced to 10 ℃, 21.7g of thionyl chloride (118.97g/mol, 0.182mol) is slowly added dropwise, and the molar ratio of L-homoserine lactone hydrochloride to thionyl chloride is 1: 2.5. The temperature of the system is maintained at 10 ℃, and the stirring reaction is carried out for 30 min. Gradually heating to 35 ℃, stirring for reaction for 20h, continuously generating bubbles in the process, monitoring the reaction progress by using LC-MS, and stopping the reaction. Wherein, the intermediate product (chloro-homoserine ethyl ester hydrochloride), ester impurities and ether impurities are LC detection values. The temperature of the system is reduced to room temperature, the residual thionyl chloride and ethanol are removed by reduced pressure distillation, the solid residue is pulped by 30mL of mixed solvent of n-hexane and ethyl acetate (the volume ratio of the n-hexane to the ethyl acetate is 2:1), and the solid residue is filtered and dried to obtain 13.69g of chloro-homoserine ethyl ester hydrochloride (202.08g/mol, 0.0657mol), wherein the HPLC purity is 97%, and the yield based on the reactant L-homoserine lactone hydrochloride is 90%.
Reacting the solid of the chloro-homoserine ethyl ester hydrochloride with a saturated sodium carbonate solution, adjusting the pH of the system to 7-8, adding ethyl acetate for extraction, and extracting for 3 times in total, wherein the dosage of the ethyl acetate in the 3-time extraction process is 30mL, 10mL and 10mL respectively. The organic phase was collected and concentrated to give 10.30g of the desired product, chloro-homoserine ethyl ester of formula (II) (165.62g/mol, 0.0591mol), as an oil, with an HPLC purity of 95%, ee of 99%, yield of 90% based on the intermediate chloro-homoserine ethyl ester hydrochloride.
Example 2
Following the procedure described in example 1, without addition of thionyl chloride, but directly by dry hydrogen chloride (gas), only traces of intermediate were formed and the reaction did not proceed as expected.
Examples 3 to 17
The reaction temperature was selected according to the method described in example 1, and the reaction results are shown in Table 1.
TABLE 1
Examples | Reactants and solvents | Temperature of | Thionyl chloride | Time of day | Intermediate product | Ester impurities | Ether impurities |
3 | Ethanol | 15℃ | 2.5eq | 20h | 76.2% | 6.9% | 3.9% |
4 | Ethanol | 25℃ | 2.5eq | 20h | 78.7% | 6.0% | 3.0% |
1 | Ethanol | 35℃ | 2.5eq | 20h | 86.4% | 2.0% | 3.6% |
5 | Ethanol | 45℃ | 2.5eq | 20h | 81.8% | 7.9% | 6.5% |
6 | Ethanol | 60℃ | 2.5eq | 20h | 76.0% | 13.5% | 8.4% |
The amount of thionyl chloride was selected as described in example 1, and the reaction results are shown in Table 2, "-" indicates no detection.
TABLE 2
Examples | Reactants and solvents | Temperature of | Thionyl chloride | Time of day | Intermediate product | Ester impurities | Ether impurities |
7 | Ethanol | 35℃ | 1.5eq | 20h | 81.6% | 3.4% | 5.4% |
8 | Ethanol | 35℃ | 2eq | 20h | 85.0% | 2.3% | 3.6% |
1 | Ethanol | 35℃ | 2.5eq | 20h | 86.4% | 2.0% | 3.6% |
9 | Ethanol | 35℃ | 3eq | 20h | 88.5% | 2.4% | 4.2% |
10 | Ethanol | 35℃ | 4eq | 20h | 88.4% | 2.2% | 3.4% |
11 | Ethanol | 35℃ | 5eq | 20h | 78.6% | 4.3% | 3.9% |
12 | Ethanol | 35℃ | 10eq | 20h | 35.5% | - | - |
The reaction time was extended according to the method described in example 1, and the reaction results are shown in Table 3.
TABLE 3
Examples | Reactants and solvents | Temperature of | Thionyl chloride | Time of day | Intermediate product | Ester impurities | Ether impurities |
1 | Ethanol | 35℃ | 2.5eq | 20h | 86.4% | 2.0% | 3.6% |
13 | Ethanol | 35℃ | 2.5eq | 24h | 87.9% | 1.6% | 4.3% |
The reaction solvent was screened according to the method described in example 1, wherein the amount of ethanol used was 6.73g (0.146mol), the amount of the solvent (1, 2-dichloroethane, dichloromethane, acetonitrile or tetrahydrofuran) used was 50mL, the reaction result was as shown in Table 4, and "-" indicates no detection.
TABLE 4
Examples | Reactants and solvents | Temperature of | Thionyl chloride | Time of day | Intermediate product | Ester impurities | Ether impurities |
1 | Ethanol | 35℃ | 2.5eq | 20h | 86.4% | 2.0% | 3.6% |
14 | Ethanol/1, 2-dichloroethane | 35℃ | 2.5eq | 20h | <5% | - | - |
15 | Ethanol/dichloromethane | 35℃ | 2.5eq | 20h | <5% | - | - |
16 | Ethanol/acetonitrile | 35℃ | 2.5eq | 20h | <5% | - | - |
17 | Ethanol/tetrahydrofuran | 35℃ | 2.5eq | 20h | <5% | - | - |
Claims (10)
1. A compound of formula (II)
Or a salt, an enantiomer or a mixture of enantiomers in all ratios thereof, characterized in that: the method comprises the following steps:
taking a compound of a formula (I) or a salt thereof, an enantiomer or a mixture of enantiomers in all proportions as a raw material, mixing the raw material with alcohol ROH and thionyl chloride for reaction to obtain a compound of a formula (II) or a salt thereof, an enantiomer or a mixture of enantiomers in all proportions;
wherein R represents an alkyl group having a carbon number of 1 to 4.
2. The method of claim 1, wherein: the reaction temperature of the reaction is 0-60 ℃, preferably 25-45 ℃, and more preferably 35 ℃.
3. The production method according to claim 1 or 2, characterized in that: the molar ratio of the compound of the formula (I) to thionyl chloride is 1: 1-5, preferably 1: 1.5-4, and more preferably 1: 2-4.
4. The production method according to any one of claims 1 to 3, characterized in that: the alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
5. The method of claim 4, wherein: the molar ratio of the compound of the formula (I) to the alcohol is 1: 1-20.
6. The method of claim 5, wherein: the molar ratio of the compound of the formula (I) to the alcohol is 1: 5-15.
7. The production method according to any one of claims 1 to 6, characterized in that: the compound of formula (I) is first mixed with alcohol and then added with thionyl chloride.
8. The method of claim 1, wherein: the preparation method also comprises the steps of reduced pressure distillation, solvent addition washing and filtration.
9. The production method according to any one of claims 1 to 8, characterized in that: the raw material is hydrochloride of a compound shown in a formula (I).
10. The method of claim 9, wherein: a compound of formula (II)
Or an enantiomer thereof or a mixture of enantiomers in all ratios, characterized in that: the method comprises the following steps:
the method according to any one of claims 1 to 9, wherein the hydrochloride of the compound of formula (II) is obtained in the presence of an inorganic base and water to obtain the compound of formula (II) or an enantiomer thereof or a mixture of enantiomers in all proportions.
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WO2022077989A1 (en) | 2020-10-14 | 2022-04-21 | 利尔化学股份有限公司 | Method for preparing l-glufosinate |
WO2023051768A1 (en) * | 2021-09-30 | 2023-04-06 | 利尔化学股份有限公司 | Methods for preparing (s)-4-chloro-2-aminobutyric acid hydrochloride and (s)-4-chloro-2-aminobutyrate |
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CN111018728A (en) * | 2019-12-27 | 2020-04-17 | 暨南大学 | Method and device for preparing 3-chloro-alanine hydrochloride by using water as auxiliary agent |
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CN109369432A (en) * | 2018-11-02 | 2019-02-22 | 永农生物科学有限公司 | (S) preparation method of the chloro- 2-amino-butyric acid ester of -4- |
CN110386882A (en) * | 2019-08-12 | 2019-10-29 | 利尔化学股份有限公司 | (S) preparation method of the chloro- 2- of -4- ((ethoxy carbonyl) amino) ethyl butyrate |
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AU2003271811A1 (en) * | 2002-07-16 | 2004-02-02 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Novel derivatives of 4,4'-dithiobis-(3-aminobutane-1-sulphonates) and compositions containing same |
CN109641896B (en) * | 2016-06-29 | 2021-09-21 | 诺维拉治疗公司 | Diazepinone derivatives and their use in the treatment of hepatitis b infections |
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CN109369432A (en) * | 2018-11-02 | 2019-02-22 | 永农生物科学有限公司 | (S) preparation method of the chloro- 2-amino-butyric acid ester of -4- |
CN110386882A (en) * | 2019-08-12 | 2019-10-29 | 利尔化学股份有限公司 | (S) preparation method of the chloro- 2- of -4- ((ethoxy carbonyl) amino) ethyl butyrate |
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WO2022077989A1 (en) | 2020-10-14 | 2022-04-21 | 利尔化学股份有限公司 | Method for preparing l-glufosinate |
WO2023051768A1 (en) * | 2021-09-30 | 2023-04-06 | 利尔化学股份有限公司 | Methods for preparing (s)-4-chloro-2-aminobutyric acid hydrochloride and (s)-4-chloro-2-aminobutyrate |
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