WO2021098712A1 - 一种氯代高丝氨酸烷基酯的制备方法 - Google Patents

一种氯代高丝氨酸烷基酯的制备方法 Download PDF

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WO2021098712A1
WO2021098712A1 PCT/CN2020/129701 CN2020129701W WO2021098712A1 WO 2021098712 A1 WO2021098712 A1 WO 2021098712A1 CN 2020129701 W CN2020129701 W CN 2020129701W WO 2021098712 A1 WO2021098712 A1 WO 2021098712A1
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formula
preparation
compound
enantiomers
thionyl chloride
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French (fr)
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周磊
刘永江
曾伟
刘俊强
程柯
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利尔化学股份有限公司
广安利尔化学有限公司
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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of chlorohomoserine alkyl ester.
  • Glufosinate-ammonium is a high-efficiency, low-toxicity, broad-spectrum contact-killing organophosphorus herbicide, and its active effect is slower than paraquat and better than glyphosate.
  • the large-scale use of glyphosate has led to the continuous development of resistant weeds; paraquat has been withdrawn from the market due to its high toxicity and caused a large number of poisoning deaths; glufosinate is the second largest genetically modified crop tolerant weeding
  • the agent glufosinate-ammonium has very broad development prospects.
  • the L-glufosinate-ammonium developed by Japan Meiji Confectionery Co., Ltd. is a single L-configuration, and it has been verified by experiments that the D-configuration of glufosinate-ammonium has no biological activity, while the biological activity of the L-configuration is racemic. 2 times.
  • Patent US5442088 published in 1994 reported a method for synthesizing L-glufosinate ammonium using amino-protected (S)-4-chloro-2-aminobutyrate as a key intermediate. Subsequent, as reported in the patent US20060135602, the use of L-homoserine and thionyl chloride to directly synthesize (S)-4-chloro-2-aminobutyrate can be used for the subsequent synthesis of L-glufosinate-ammonium, but there are two The excessive amount of thionyl chloride and the high cost result in more environmental pollution problems of waste acid wastewater.
  • Patent CN109369432A discloses that (S)-4-chloro-2-aminobutyrate is prepared in two steps by (S)-2-aminobutyrolactone hydrochloride, and (S)-homoserine ester is firstly obtained under acid catalysis , And then chlorination to obtain the target compound, the two-step yield is the highest 80.6%.
  • the method is divided into two-step synthesis, and the operation process is added, and the impurities generated in the intermediate process of the reaction are unknown, resulting in the overall yield of the product is not high.
  • the technical solution of the present invention is to provide a compound of formula (II)
  • the compound of formula (I) or its salt, enantiomer, or a mixture of enantiomers in all ratios is mixed with alcohol ROH and thionyl chloride to react to obtain a compound of formula (II) or its salt, enantiomer Isomers or mixtures of enantiomers in all ratios;
  • R represents a C1-C4 alkyl group.
  • the reaction temperature of the aforementioned reaction is 0 to 60°C, preferably 25 to 45°C, and more preferably 35°C.
  • the reaction temperature is too low or too high, both ether impurities and ester impurities increase, and the selectivity of the target product decreases, which is unfavorable to the reaction.
  • the molar ratio of the compound of formula (I) to thionyl chloride is 1:1-5, preferably 1:1.5-4, more preferably 1:2-4.
  • the amount of thionyl chloride should not be too high or too low.
  • the inventors tried to replace the thionyl chloride with other chlorinating agents, such as hydrogen chloride (gas), triphosgene, phosphorus oxychloride, and sulfonyl chloride, but the reaction did not proceed as expected and the products were very few.
  • the aforementioned alcohol is methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or tert-butanol.
  • the molar ratio of the compound of formula (I) to the alcohol is 1:1-20, preferably 1:5-15.
  • the aforementioned alcohol acts as both a reactant and a solvent in the reaction system. Alcohol is used as a reactant, and its amount is at least 1 eq. As a solvent, the amount of alcohol should not be too small, ranging from 1 to 20 eq, preferably 5 to 15 eq.
  • the inventor tried to replace the alcohol solvent with other solvents (for example: 1,2-dichloroethane, dichloromethane, acetonitrile, tetrahydrofuran), that is, only alcohol was used as the reactant, but unexpectedly found that only very good results were obtained after changing to other solvents. Few target products. It can be seen that the specific reaction of the present invention only achieves better results when the specific chlorinating agent thionyl chloride and alcohol are used as solvents.
  • the compound of formula (I) is mixed with alcohol first, and then thionyl chloride is added.
  • the compound of formula (I) is partially dissolved in alcohol, and the entire system is in a suspension state. With the addition of thionyl chloride, the suspension system gradually becomes clear. After the reaction is monitored by LC-MS, there is still a small amount of solid Exist, it was tested that this solid was the raw material compound of formula (I) that did not participate in the reaction.
  • the system temperature of the aforementioned thionyl chloride addition process needs to be maintained at 5-15°C. After the addition is completed, continue stirring at 5-15°C for a certain period of time and then raise the temperature to the reaction temperature, so as to effectively control the reaction process and control impurities.
  • the inventor chose to add thionyl chloride at 10°C and continue stirring for 30 minutes.
  • the aforementioned preparation method also includes the steps of distillation under reduced pressure, addition of solvent for 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, tert-butyl methyl ether or toluene.
  • Vacuum distillation process to remove thionyl chloride and ethanol. After distillation under reduced pressure, the residual solid is washed with a solvent and filtered to obtain the target product.
  • the present invention further provides a compound of formula (II)
  • the hydrochloride salt of the compound of formula (II) is obtained.
  • the hydrochloride salt of the compound of formula (II) can obtain the compound of formula (II) or its enantiomers or all ratios in the presence of an inorganic base and water. A mixture of enantiomers.
  • the aforementioned inorganic base is one of sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Under the joint action of the intermediate product, inorganic base and water, the pH of the above reaction system is finally 7-8.
  • the aforementioned preparation method also includes the following post-processing steps, adding an organic solvent for extraction, and concentrating the organic phase to obtain an oily compound of formula (II).
  • the aforementioned organic solvent may be ethyl acetate.
  • the target product of the compound of formula (II) is ethyl chlorohomoserine.
  • the C1-C4 alkyl group is straight or branched and contains a saturated hydrocarbon chain of 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
  • the present invention is further explained and illustrated by test examples and examples below.
  • the intermediate product mentioned in the following examples is the hydrochloride of the compound of formula (II), that is, chlorohomoserine ethyl ester hydrochloride.
  • the temperature of the system was lowered to 10°C, and 21.7 g of thionyl chloride (118.97 g/mol, 0.182 mol) was slowly added dropwise, and the molar ratio of L-homoserine lactone hydrochloride to thionyl chloride was 1:2.5. Maintain the temperature of the system at 10°C, stir and react for 30 minutes. The temperature was gradually raised to 35°C, and the reaction was stirred for 20 hours. During the process, bubbles continued to be generated. The progress of the reaction was monitored by LC-MS, and the reaction was terminated.
  • the intermediate product chlorohomoserine ethyl ester hydrochloride
  • ester impurities ester impurities
  • ether impurities are all LC detection values.
  • the temperature of the system was lowered to room temperature, and the remaining thionyl chloride and ethanol were removed by distillation under reduced pressure.
  • the chlorohomoserine ethyl ester hydrochloride solid was reacted with saturated sodium carbonate solution, the pH of the system was adjusted to 7-8, and ethyl acetate was added for extraction, and the total extraction was 3 times.
  • the amount of ethyl acetate for the 3 extraction processes was 30 mL. , 10mL and 10mL.
  • Example 1 According to the method described in Example 1, without adding thionyl chloride, and directly passing through dry hydrogen chloride (gas), only a small amount of intermediate products were generated, and the reaction did not proceed as expected.
  • the reaction solvent was screened according to the method described in Example 1, wherein the amount of ethanol was 6.73g (0.146mol), and the amount of solvent (1,2-dichloroethane, dichloromethane, acetonitrile or tetrahydrofuran) was 50mL , The reaction results are shown in Table 4, "-" means not detected.

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明属于有机合成技术领域，具体涉及一种氯代高丝氨酸烷基酯的制备方法。本发明采用的技术方案是提供了一种氯代高丝氨酸烷基酯的制备方法，式(I)化合物或其盐、对映异构体或所有比例的对映异构体的混合物与醇ROH、氯化亚砜混合发生反应，得式(II)化合物或其盐、对映异构体或所有比例的对映异构体的混合物，即目标氯代高丝氨酸烷基酯。本发明解决了现有制备方法中产品收率较低、三废量较大和不利于工业化操作等问题。

Description

一种氯代高丝氨酸烷基酯的制备方法 技术领域
本发明属于有机合成技术领域，具体涉及一种氯代高丝氨酸烷基酯的制备方法。
背景技术
草铵膦作为一种高效、低毒、广谱触杀型有机磷类除草剂，其发挥活性作用的速度比百草枯慢而优于草甘膦。但是由于草甘膦的大面积使用已经导致抗性杂草的不断的发展；百草枯由于剧毒，导致大量中毒死亡事件发生，因而退出市场；草铵膦作为第二大转基因作物耐受性除草剂草铵膦，具有非常广阔的发展前景。
日本明治制菓公司开发的L-草铵膦为单一的L-构型，并且经实验验证，草铵膦的D-构型是没有生物活性的，而L-构型生物活性为消旋体的2倍。
1994年公开的专利US5442088中报道了，利用氨基保护的(S)-4-氯-2-氨基丁酸酯作为关键中间体，合成L-草铵膦的方法。后续如专利US20060135602中报道了利用L-高丝氨酸和二氯亚砜直接合成(S)-4-氯-2-氨基丁酸酯，可用于后续的L-草铵膦的合成，但是其存在二氯亚砜用量过大，成本过高，产生较多的废酸废水的环境污染问题。
专利CN109369432A中公开了，通过(S)-2-氨基丁内酯盐酸盐分两步制备(S)-4-氯-2-氨基丁酸酯，先在酸催化下得到(S)-高丝氨酸酯，然后再氯化得到目标化合物，两步收率最高为80.6％。该方法分为两步合成，增加了操作流程，且反应中间过程产生的杂质未知，导致产品的整体收率并不高。
因此，目前亟需开发一种既能有效控制生成的杂质并提高产品的收率，又能在工业化生产过程中便于操作和降低“三废”量的方法。
发明内容
为解决上述问题，本发明的技术方案是提供一种式(II)化合物
Figure PCTCN2020129701-appb-000001
或其盐、对映异构体或所有比例的对映异构体的混合物的制备方法，前述方法包括以下步骤：
Figure PCTCN2020129701-appb-000002
将式(I)化合物或其盐、对映异构体或所有比例的对映异构体的混合物与醇ROH、氯化亚砜混合发生反应，得式(II)化合物或其盐、对映异构体或所有比例的对映异构体的混合物；
其中，R表示C1-C4的烷基。
前述反应的反应温度为0～60℃，优选25～45℃，更优选35℃。反应温度过低或过高时，醚杂质和酯杂质均增加，目标产物选择性下降，对反应不利。
前述式(I)化合物与氯化亚砜的摩尔比为1∶1～5，优选1∶1.5～4，更优选1∶2～4。氯化亚砜作为反应过程的氯化剂，用量不宜过高或过低。另外，发明人尝试将二氯亚砜更换为其他氯化剂，例如氯化氢(气体)、三光气、三氯氧磷、磺酰氯，反应未按预期进行，产物极少。
前述醇为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇或叔丁醇。
前述式(I)化合物与醇的摩尔比为1∶1～20，优选1∶5～15。前述醇在反应体系中既作为反应物，亦作为溶剂。醇作为反应物，其用量至少为1eq。醇作为溶剂，其用量不宜过小，为1～20eq，优选5～15eq。发明人尝试更换醇溶剂为其他溶剂(例如：1，2-二氯乙烷、二氯甲烷、乙腈、四氢呋喃)，即只以醇作为反应物，却意外发现，更换为其他溶剂后只得到很少的目标产物。可以看出，本发明的特定反应只有在特定氯化剂氯化亚砜与醇作为溶剂的条件下才取得较好的效果。
前述式(II)化合物的制备方法，先将式(I)化合物与醇混合，再加入氯化亚砜。式(I)化合物在醇中部分溶解，整个体系呈悬浊液状态，随着氯化亚砜 的滴加，悬浊液体系逐渐变清澈，利用LC-MS监测反应结束后，仍旧有少量固体存在，经检测此固体为未参与反应的原料式(I)化合物。
前述氯化亚砜加入过程的体系温度需维持在5～15℃，加入完成后，在5～15℃下继续搅拌一定时间后再升温至反应温度，从而有效控制反应过程，控制杂质。作为一种优选的实施方式，发明人选择在10℃加入氯化亚砜并继续搅拌30min。
前述制备方法还包括减压蒸馏、加入溶剂洗涤和过滤的步骤。用于洗涤的溶剂为正己烷与乙酸乙酯组成的混合溶剂、石油醚与乙酸乙酯组成的混合溶剂、叔丁基甲基醚或甲苯。减压蒸馏过程，用以除去二氯亚砜和乙醇。减压蒸馏后残留固体用溶剂洗涤并过滤，得目标物。
本发明进一步提供了一种式(II)化合物
Figure PCTCN2020129701-appb-000003
或其对映异构体或所有比例的对映异构体的混合物的制备方法，它包括以下步骤：
按照前述的制备方法得到式(II)化合物的盐酸盐，式(II)化合物的盐酸盐在无机碱和水同时存在下得到式(II)化合物或其对映异构体或所有比例的对映异构体的混合物。
前述无机碱为碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾中的一种，中间产物、无机碱和水共同作用下，上述反应体系pH最终为7-8。
前述制备方法还包括以下后处理步骤，加入有机溶剂萃取，浓缩有机相得到油状式(II)化合物。前述有机溶剂可以为乙酸乙酯。
前述反应物为式(I)化合物盐酸盐、乙醇和氯化亚砜时，目标产物式(II)化合物为氯代高丝氨酸乙酯。
除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。
C1-C4烷基是直链的或支链的，包含1至4个碳原子的饱和烃链。它可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基基团。
本发明的有益效果是：
(1)有效控制生成的杂质，提高产品的收率；
(2)操作简便，便于工业化。
(3)有效降低生成的“三废”量。
显然，根据本发明的上述内容，按照本领域的普通技术知识和惯用手段，在不脱离本发明上述基本技术思想前提下，还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
以下通过试验例和实施例对本发明作进一步的解释和说明，以下实施例提及的中间产物为式(II)化合物盐酸盐，即氯代高丝氨酸乙酯盐酸盐。
实施例1
Figure PCTCN2020129701-appb-000004
称量式(I)化合物盐酸盐(L-高丝氨酸内酯盐酸盐，ee值99％，137.56g/mol，0.073mol)10g到反应容器中，加入乙醇(46.07g/mol，0.886mol，0.816g/mL)50mL，高丝氨酸内酯盐酸盐与乙醇的摩尔比为1∶12.1。将体系温度降至10℃，开始缓慢滴加二氯亚砜(118.97g/mol，0.182mol)21.7g，L-高丝氨酸内酯盐酸盐与二氯亚砜的摩尔比为1∶2.5。维持体系温度10℃，搅拌反应30min。逐渐升温至35℃，搅拌反应20h，过程中持续有气泡产生，利用LC-MS监测反应的进程，终止反应。其中，中间产物(氯代高丝氨酸乙酯盐酸盐)、酯杂质、醚杂质均为LC检测值。将体系温度降至室温，减压蒸馏除去剩余的二氯亚砜和乙醇，固体残渣用30mL正己烷/乙酸乙酯混合溶剂打浆(正己烷和乙酸乙酯的体积比为2∶1)，过滤并烘干，得氯代高丝氨酸乙酯盐酸盐(202.08g/mol，0.0657mol)13.69g，HPLC纯度97％，基于反应物L-高丝氨酸内酯盐酸盐的收率为90％。
将氯代高丝氨酸乙酯盐酸盐固体与饱和碳酸钠溶液反应，体系pH调节至7-8， 加入乙酸乙酯萃取，总计萃取3次，3次萃取过程的乙酸乙酯的用量分别为30mL、10mL和10mL。收集有机相并浓缩，得油状目标产品式(II)化合物氯代高丝氨酸乙酯(165.62g/mol，0.0591mol)10.30g，HPLC纯度95％，ee值99％，基于中间产物氯代高丝氨酸乙酯盐酸盐的收率90％。
实施例2
按照实施例1中所述的方法，不加入二氯亚砜，而直接通如干燥氯化氢(气体)，仅有微量中间产物生成，反应并未如预期进行。
实施例3-17
按照实施例1中所述的方法，对反应温度进行筛选，反应结果如表1所示。
表1
实施例 反应物及溶剂 温度 二氯亚砜 时间 中间产物 酯杂质 醚杂质
3 乙醇 15℃ 2.5eq 20h 76.2％ 6.9％ 3.9％
4 乙醇 25℃ 2.5eq 20h 78.7％ 6.0％ 3.0％
1 乙醇 35℃ 2.5eq 20h 86.4％ 2.0％ 3.6％
5 乙醇 45℃ 2.5eq 20h 81.8％ 7.9％ 6.5％
6 乙醇 60℃ 2.5eq 20h 76.0％ 13.5％ 8.4％
按照实施例1中所述的方法，对二氯亚砜用量进行筛选，反应结果如表2所示，“-”表示未检出。
表2
实施例 反应物及溶剂 温度 二氯亚砜 时间 中间产物 酯杂质 醚杂质
7 乙醇 35℃ 1.5eq 20h 81.6％ 3.4％ 5.4％
8 乙醇 35℃ 2eq 20h 85.0％ 2.3％ 3.6％
1 乙醇 35℃ 2.5eq 20h 86.4％ 2.0％ 3.6％
9 乙醇 35℃ 3eq 20h 88.5％ 2.4％ 4.2％
10 乙醇 35℃ 4eq 20h 88.4％ 2.2％ 3.4％
11 乙醇 35℃ 5eq 20h 78.6％ 4.3％ 3.9％
12 乙醇 35℃ 10eq 20h 35.5％ - -
按照实施例1中所述的方法，对反应时间进行延长，反应结果如表3所示。
表3
实施例 反应物及溶剂 温度 二氯亚砜 时间 中间产物 酯杂质 醚杂质
1 乙醇 35℃ 2.5eq 20h 86.4％ 2.0％ 3.6％
13 乙醇 35℃ 2.5eq 24h 87.9％ 1.6％ 4.3％
按照实施例1中所述的方法，对反应溶剂进行筛选，其中，乙醇用量为6.73g(0.146mol)，溶剂(1，2-二氯乙烷、二氯甲烷、乙腈或四氢呋喃)用量为50mL，反应结果如表4所示，“-”表示未检出。
表4
实施例 反应物及溶剂 温度 二氯亚砜 时间 中间产物 酯杂质 醚杂质
1 乙醇 35℃ 2.5eq 20h 86.4％ 2.0％ 3.6％
14 乙醇/1，2-二氯乙烷 35℃ 2.5eq 20h ＜5％ - -
15 乙醇/二氯甲烷 35℃ 2.5eq 20h ＜5％ - -
16 乙醇/乙腈 35℃ 2.5eq 20h ＜5％ - -
17 乙醇/四氢呋喃 35℃ 2.5eq 20h ＜5％ - -

Claims (10)

  1. 一种式(II)化合物
    Figure PCTCN2020129701-appb-100001
    或其盐、对映异构体或所有比例的对映异构体的混合物的制备方法，其特征在于：所述方法包括以下步骤：
    Figure PCTCN2020129701-appb-100002
    以式(I)化合物或其盐、对映异构体或所有比例的对映异构体的混合物为原料，与醇ROH、氯化亚砜混合发生反应，得式(II)化合物或其盐、对映异构体或所有比例的对映异构体的混合物；
    其中，R表示C1-C4的烷基。
  2. 根据权利要求1所述的制备方法，其特征在于：所述反应的反应温度为0～60℃，优选25～45℃，更优选35℃。
  3. 根据权利要求1或2所述的制备方法，其特征在于：所述式(I)化合物与氯化亚砜的摩尔比为1∶1～5，优选1∶1.5～4，更优选1∶2～4。
  4. 根据权利要求1～3任一项所述的制备方法，其特征在于：所述醇为甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇或叔丁醇。
  5. 根据权利要求4所述的制备方法，其特征在于：所述式(I)化合物与醇的摩尔比为1∶1～20。
  6. 根据权利要求5所述的制备方法，其特征在于：所述式(I)化合物与醇的摩尔比为1∶5～15。
  7. 根据权利要求1～6任一项所述的制备方法，其特征在于：所述式(I)化合物先与醇混合，再加入氯化亚砜。
  8. 根据权利要求1所述的制备方法，其特征在于：所述制备方法还包括减压蒸馏、加入溶剂洗涤和过滤的步骤。
  9. 根据权利要求1～8任一项的制备方法，其特征在于：所述原料为式(I)化合物的盐酸盐。
  10. 根据权利要求9所述的制备方法，其特征在于：一种式(II)化合物
    Figure PCTCN2020129701-appb-100003
    或其对映异构体或所有比例的对映异构体的混合物的制备方法，其特征在于：所述方法包括以下步骤：
    按照权利要求1～9任一项所述的制备方法得到式(II)化合物的盐酸盐，式(II)化合物的盐酸盐在无机碱和水同时存在下得到式(II)化合物或其对映异构体或所有比例的对映异构体的混合物。
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