CN112830882A - 一种对羟基苯甘氨酸甲酯合成方法 - Google Patents
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- DKLZRLRMFNWRFB-UHFFFAOYSA-N methyl 2-(4-hydroxyanilino)acetate Chemical compound COC(=O)CNC1=CC=C(O)C=C1 DKLZRLRMFNWRFB-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000010189 synthetic method Methods 0.000 title claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 111
- SZBDOFWNZVHVGR-MRVPVSSYSA-N methyl (2r)-2-amino-2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)[C@H](N)C1=CC=C(O)C=C1 SZBDOFWNZVHVGR-MRVPVSSYSA-N 0.000 claims abstract description 51
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 22
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 claims abstract description 16
- 239000000243 solution Substances 0.000 claims abstract description 16
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 230000006837 decompression Effects 0.000 claims abstract description 7
- 230000002378 acidificating effect Effects 0.000 claims abstract description 6
- 238000000926 separation method Methods 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 230000002194 synthesizing effect Effects 0.000 claims description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 claims 2
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 claims 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 claims 1
- 229960002216 methylparaben Drugs 0.000 claims 1
- 238000011084 recovery Methods 0.000 abstract description 7
- 238000001308 synthesis method Methods 0.000 abstract description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005886 esterification reaction Methods 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- JFQVGWJWZVAPQO-OGFXRTJISA-N S(=O)(=O)(O)O.OC1=CC=C([C@@H](N)C(=O)O)C=C1 Chemical compound S(=O)(=O)(O)O.OC1=CC=C([C@@H](N)C(=O)O)C=C1 JFQVGWJWZVAPQO-OGFXRTJISA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
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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
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- 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
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
- C07C227/42—Crystallisation
-
- 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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提出了一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤:(1)将D‑对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在30‑50℃的条件下,滴加氯化亚砜,得到D‑对羟基苯甘氨酸甲酯的甲醇溶液;(2)对D‑对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,酸性条件下活性炭脱色,得到D‑对羟基苯甘氨酸甲酯的水溶液;(3)向D‑对羟基苯甘氨酸甲酯的水溶液中滴加15‑20wt%的氨水,调节pH为9‑10,氨水滴加时间为3‑6h,D‑对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D‑对羟基苯甘氨酸甲酯产品。本发明制备的D‑对羟基苯甘氨酸甲酯回收率高,纯度高。
Description
技术领域
本发明涉及医药合成技术领域,特别是指一种对羟基苯甘氨酸甲酯合成方法。
背景技术
对羟基苯甘氨酸甲酯是抗生素的重要中间体,用于合成β-内酰胺类半合成抗菌素的侧链。现有的对羟基苯甘氨酸甲酯制备方法存在反应时间过长,产品不易结晶提纯等问题。中国专利CN111153821A公开了一种D-对羟基苯甘氨酸甲酯的制备方法,在浓硫酸条件下,在浓硫酸存在下,在65-80℃条件下,D-对羟基苯甘氨酸与甲醇发生甲酯化反应,得到D-对羟基苯甘氨酸硫酸盐,然后减压蒸出甲醇和水,在20-25℃条件下,加入D-对羟基苯甘氨酸晶种和水,然后加入碱金属氢氧化物调节pH值,使其保持在7.5-8,然后进10-20℃条件下养晶,碱金属氢氧化物为氢氧化钠、氢氧化钾或氢氧化锂。该方法酯化反应温度较高,容易造成甲醇的氧化,影响酯化反应的进行;采用氢氧化钠、氢氧化钾等强碱调节pH值,容易造成D-对羟基苯甘氨酸晶体的水解,降低了产品的回收率。
发明内容
本发明提出一种对羟基苯甘氨酸甲酯合成方法,制备的D-对羟基苯甘氨酸甲酯回收率高,纯度高。
本发明的技术方案是这样实现的:一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤:
(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在30-50℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液;
(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液;
(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15-20wt%的氨水,调节pH为9-10,氨水滴加时间为3-6h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。
进一步地,步骤(1)中,D-对羟基苯甘氨酸、甲醇和氯化亚砜的摩尔比为1:6:1.02。
进一步地,步骤(2)中,加水量为D-对羟基苯甘氨酸甲酯重量的3-6倍。
本发明的有益效果:
本发明将反应温度控制在30-50℃,降低了反应温度,既确保酯化反应的效率,也避免甲酯的氧化;采用减压蒸出过量的甲醇,真空度≤0.090MPa,加快了蒸发的速率,降低甲醇消耗,此时得到的为D-对羟基苯甘氨酸甲酯的酸盐,可溶于水,采用氨水调pH值9-10,氨水滴加时间为3-6h,保证D-对羟基苯甘氨酸甲酯充分析出,提到回收率,若是滴加速度过快,则D-对羟基苯甘氨酸甲酯未能充分析出,回收率较低。本发明合成方法的回收率≥106%(合成的D-对羟基苯甘氨酸甲酯与D-对羟基苯甘氨酸的质量比),D-对羟基苯甘氨酸甲酯的纯度≥98.5%。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有付出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例一
一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤:
(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在30℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液,D-对羟基苯甘氨酸、甲醇和氯化亚砜的摩尔比为1:6:1.02;
(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,加水量为D-对羟基苯甘氨酸甲酯重量的6倍,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液;
(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15wt%的氨水,调节pH为9-10,氨水滴加时间为3h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。
实施例二
一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤:
(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在40℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液,D-对羟基苯甘氨酸、甲醇和氯化亚砜的摩尔比为1:6:1.02;
(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,加水量为D-对羟基苯甘氨酸甲酯重量的5倍,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液;
(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15wt%的氨水,调节pH为9-10,氨水滴加时间为5h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。
实施例三
一种对羟基苯甘氨酸甲酯合成方法,包括以下步骤:
(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在50℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液,D-对羟基苯甘氨酸、甲醇和氯化亚砜的摩尔比为1:6:1.02;
(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,加水量为D-对羟基苯甘氨酸甲酯重量的3倍,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液;
(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15wt%的氨水,调节pH为9-10,氨水滴加时间为6h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。
实施例一至三的合成方法的回收率≥106%(合成的D-对羟基苯甘氨酸甲酯与D-对羟基苯甘氨酸的质量比),D-对羟基苯甘氨酸甲酯的纯度≥98.5%。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (3)
1.一种对羟基苯甘氨酸甲酯合成方法,其特征在于,包括以下步骤:
(1)将D-对羟基苯甘氨酸加入到甲醇中,搅拌均匀,然后在30-50℃的条件下,滴加氯化亚砜,得到D-对羟基苯甘氨酸甲酯的甲醇溶液;
(2)对D-对羟基苯甘氨酸甲酯的甲醇溶液减压整出甲醇,减压条件为真空度≤0.090MPa,然后加水搅拌,酸性条件下活性炭脱色,得到D-对羟基苯甘氨酸甲酯的水溶液;
(3)向D-对羟基苯甘氨酸甲酯的水溶液中滴加15-20wt%的氨水,调节pH为9-10,氨水滴加时间为3-6h,D-对羟基苯甘氨酸甲酯结晶析出,最后通过离心分离,得到D-对羟基苯甘氨酸甲酯产品。
2.根据权利要求1所述的一种对羟基苯甘氨酸甲酯合成方法,其特征在于,步骤(1)中,D-对羟基苯甘氨酸、甲醇和氯化亚砜的摩尔比为1:6:1.02。
3.根据权利要求1所述的一种对羟基苯甘氨酸甲酯合成方法,其特征在于,步骤(2)中,加水量为D-对羟基苯甘氨酸甲酯重量的3-6倍。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994000509A1 (en) * | 1992-06-30 | 1994-01-06 | Legomer Partners, L.P. | Oxazolone derived materials |
CN104744281A (zh) * | 2013-12-25 | 2015-07-01 | 河南新天地药业股份有限公司 | 一种d-对羟基苯甘氨酸甲酯的合成方法 |
CN111153821A (zh) * | 2019-12-25 | 2020-05-15 | 国药集团大同威奇达中抗制药有限公司 | D-对羟基苯甘氨酸甲酯的制备方法 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994000509A1 (en) * | 1992-06-30 | 1994-01-06 | Legomer Partners, L.P. | Oxazolone derived materials |
CN104744281A (zh) * | 2013-12-25 | 2015-07-01 | 河南新天地药业股份有限公司 | 一种d-对羟基苯甘氨酸甲酯的合成方法 |
CN111153821A (zh) * | 2019-12-25 | 2020-05-15 | 国药集团大同威奇达中抗制药有限公司 | D-对羟基苯甘氨酸甲酯的制备方法 |
Non-Patent Citations (1)
Title |
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孙国富等: "左旋对羟基苯甘氨酸甲酯盐酸盐结晶工艺研究", 《许昌学院学报》 * |
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