CN114746399A - 羧甲司坦的制备方法 - Google Patents
羧甲司坦的制备方法 Download PDFInfo
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- CN114746399A CN114746399A CN201980102544.XA CN201980102544A CN114746399A CN 114746399 A CN114746399 A CN 114746399A CN 201980102544 A CN201980102544 A CN 201980102544A CN 114746399 A CN114746399 A CN 114746399A
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- carbocisteine
- cysteine
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- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 title claims abstract description 123
- 229960004399 carbocisteine Drugs 0.000 title claims abstract description 121
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 claims abstract description 102
- 238000006482 condensation reaction Methods 0.000 claims abstract description 52
- 239000012535 impurity Substances 0.000 claims abstract description 46
- 239000004201 L-cysteine Substances 0.000 claims abstract description 35
- 235000013878 L-cysteine Nutrition 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 25
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 142
- 239000000243 solution Substances 0.000 claims description 119
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 111
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 102
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 99
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 97
- 229940106681 chloroacetic acid Drugs 0.000 claims description 68
- 229960002433 cysteine Drugs 0.000 claims description 65
- 238000010438 heat treatment Methods 0.000 claims description 50
- LJPYJRMMPVFEKR-UHFFFAOYSA-N prop-2-ynylurea Chemical compound NC(=O)NCC#C LJPYJRMMPVFEKR-UHFFFAOYSA-N 0.000 claims description 50
- 238000001816 cooling Methods 0.000 claims description 39
- 238000001914 filtration Methods 0.000 claims description 36
- LEVWYRKDKASIDU-IMJSIDKUSA-N L-cystine Chemical compound [O-]C(=O)[C@@H]([NH3+])CSSC[C@H]([NH3+])C([O-])=O LEVWYRKDKASIDU-IMJSIDKUSA-N 0.000 claims description 34
- 229960003067 cystine Drugs 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 34
- ZCITVSIKDJSWSS-VKHMYHEASA-N (3r)-5-oxothiomorpholine-3-carboxylic acid Chemical compound OC(=O)[C@@H]1CSCC(=O)N1 ZCITVSIKDJSWSS-VKHMYHEASA-N 0.000 claims description 31
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 31
- 235000018417 cysteine Nutrition 0.000 claims description 31
- 239000002585 base Substances 0.000 claims description 17
- 238000001953 recrystallisation Methods 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 125000002496 methyl group Chemical class [H]C([H])([H])* 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052783 alkali metal Inorganic materials 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000012847 fine chemical Substances 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- VDQVEACBQKUUSU-UHFFFAOYSA-M disodium;sulfanide Chemical compound [Na+].[Na+].[SH-] VDQVEACBQKUUSU-UHFFFAOYSA-M 0.000 claims description 4
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 229910052979 sodium sulfide Inorganic materials 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000003889 chemical engineering Methods 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 238000007865 diluting Methods 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 238000005086 pumping Methods 0.000 claims description 3
- 150000008538 L-cysteines Chemical class 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 3
- 239000002994 raw material Substances 0.000 description 81
- 238000001514 detection method Methods 0.000 description 73
- 239000007788 liquid Substances 0.000 description 69
- 239000000047 product Substances 0.000 description 48
- 239000012295 chemical reaction liquid Substances 0.000 description 47
- 239000012043 crude product Substances 0.000 description 41
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 38
- 238000004128 high performance liquid chromatography Methods 0.000 description 32
- 239000000126 substance Substances 0.000 description 31
- VLSOAXRVHARBEQ-UHFFFAOYSA-N [4-fluoro-2-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=C(F)C=C1CO VLSOAXRVHARBEQ-UHFFFAOYSA-N 0.000 description 30
- 238000005070 sampling Methods 0.000 description 26
- 238000005406 washing Methods 0.000 description 17
- 239000000706 filtrate Substances 0.000 description 16
- 238000012545 processing Methods 0.000 description 16
- 239000008213 purified water Substances 0.000 description 16
- 238000000967 suction filtration Methods 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 15
- 229920002472 Starch Polymers 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 14
- 230000014759 maintenance of location Effects 0.000 description 14
- 235000019698 starch Nutrition 0.000 description 14
- 239000008107 starch Substances 0.000 description 14
- 238000004042 decolorization Methods 0.000 description 12
- 230000004580 weight loss Effects 0.000 description 10
- 230000000694 effects Effects 0.000 description 6
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 206010036790 Productive cough Diseases 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010062717 Increased upper airway secretion Diseases 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 208000026435 phlegm Diseases 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 125000000415 L-cysteinyl group Chemical group O=C([*])[C@@](N([H])[H])([H])C([H])([H])S[H] 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- -1 iodomethyl Chemical group 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000003754 machining Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000011085 pressure filtration Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种羧甲司坦的制备方法。该制备方法包括以下步骤：在连续流反应器中，在碱存在的条件下，在溶剂中，将如式I所示的L‑半胱氨酸和如式II所示的化合物进行如下所示的缩合反应，得到如式III所示的羧甲司坦。该方法在制备羧甲司坦时，产生的杂质量较少，从而经过常规的后处理即可获得符合CEP注册标准的产品。
Description
PCT国内申请，说明书已公开。
Claims (13)
- PCT国内申请，权利要求书已公开。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2019/122003 WO2021102918A1 (zh) | 2019-11-29 | 2019-11-29 | 羧甲司坦的制备方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114746399A true CN114746399A (zh) | 2022-07-12 |
| CN114746399B CN114746399B (zh) | 2024-05-24 |
Family
ID=76129026
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201980102544.XA Active CN114746399B (zh) | 2019-11-29 | 2019-11-29 | 羧甲司坦的制备方法 |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP4067341B1 (zh) |
| JP (1) | JP7429292B2 (zh) |
| CN (1) | CN114746399B (zh) |
| WO (1) | WO2021102918A1 (zh) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114394976B (zh) * | 2022-02-11 | 2023-05-02 | 广东工业大学 | 2-((s)-1-苯乙基)-6-氧杂-2-氮杂双环[3.2.1]辛烷-7-酮 |
Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5846064A (ja) * | 1981-08-28 | 1983-03-17 | デグツサ・アクチエンゲゼルシヤフト | ラセミ化合物ｓ−（カルボキシメチル）−（ｒｓ）−システインの分割法 |
| CN103102294A (zh) * | 2012-03-28 | 2013-05-15 | 新沂市汉菱生物工程有限公司 | 一种羧甲基半胱氨酸的生产方法 |
| CN103588662A (zh) * | 2013-11-06 | 2014-02-19 | 浙江大学 | 连续流微反应器中合成倍他米隆的方法 |
| CN106083673A (zh) * | 2016-06-29 | 2016-11-09 | 罗江晨明生物制品有限公司 | 一种羧甲司坦的制备工艺 |
| CN106565565A (zh) * | 2016-10-19 | 2017-04-19 | 武汉远大弘元股份有限公司 | 一种羧甲司坦的制备方法 |
| CN106748926A (zh) * | 2015-11-19 | 2017-05-31 | 江苏新汉菱生物工程股份有限公司 | 一种醋硫丙氨酸的生产方法 |
| CN206587716U (zh) * | 2017-03-20 | 2017-10-27 | 中国石油化工股份有限公司 | 一种管道连续式缩合反应装置 |
| CN108299174A (zh) * | 2017-12-29 | 2018-07-20 | 上海化学试剂研究所有限公司 | 一种利用微通道反应器制备含氟查尔酮衍生物的方法 |
| CN109053508A (zh) * | 2018-09-19 | 2018-12-21 | 山西云鹏制药有限公司 | 一种羧甲司坦的制备方法 |
| CN109970639A (zh) * | 2018-11-23 | 2019-07-05 | 重庆康乐制药有限公司 | 一种连续流微反应器中合成哌喹中间体的方法 |
| CN110452142A (zh) * | 2019-09-10 | 2019-11-15 | 云鹏医药集团有限公司 | 一种高纯度s-(羧甲基)-半胱氨酸的制备方法 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62135455A (ja) * | 1985-12-09 | 1987-06-18 | Kyowa Hakko Kogyo Co Ltd | Ｓ−カルボキシメチル−ｌ−システインの精製法 |
| CN1159474C (zh) * | 2000-12-14 | 2004-07-28 | 刘德海 | 在碱性介质中电解l-胱氨酸直接合成s-羧甲基-l-半胱氨酸的生产方法 |
| CN105418471B (zh) * | 2015-12-24 | 2017-09-05 | 宜昌三峡制药有限公司 | 一种羧甲司坦的合成方法 |
-
2019
- 2019-11-29 CN CN201980102544.XA patent/CN114746399B/zh active Active
- 2019-11-29 WO PCT/CN2019/122003 patent/WO2021102918A1/zh unknown
- 2019-11-29 EP EP19954373.7A patent/EP4067341B1/en active Active
- 2019-11-29 JP JP2022532162A patent/JP7429292B2/ja active Active
Patent Citations (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5846064A (ja) * | 1981-08-28 | 1983-03-17 | デグツサ・アクチエンゲゼルシヤフト | ラセミ化合物ｓ−（カルボキシメチル）−（ｒｓ）−システインの分割法 |
| CN103102294A (zh) * | 2012-03-28 | 2013-05-15 | 新沂市汉菱生物工程有限公司 | 一种羧甲基半胱氨酸的生产方法 |
| CN103588662A (zh) * | 2013-11-06 | 2014-02-19 | 浙江大学 | 连续流微反应器中合成倍他米隆的方法 |
| CN106748926A (zh) * | 2015-11-19 | 2017-05-31 | 江苏新汉菱生物工程股份有限公司 | 一种醋硫丙氨酸的生产方法 |
| CN106083673A (zh) * | 2016-06-29 | 2016-11-09 | 罗江晨明生物制品有限公司 | 一种羧甲司坦的制备工艺 |
| CN106565565A (zh) * | 2016-10-19 | 2017-04-19 | 武汉远大弘元股份有限公司 | 一种羧甲司坦的制备方法 |
| CN206587716U (zh) * | 2017-03-20 | 2017-10-27 | 中国石油化工股份有限公司 | 一种管道连续式缩合反应装置 |
| CN108299174A (zh) * | 2017-12-29 | 2018-07-20 | 上海化学试剂研究所有限公司 | 一种利用微通道反应器制备含氟查尔酮衍生物的方法 |
| CN109053508A (zh) * | 2018-09-19 | 2018-12-21 | 山西云鹏制药有限公司 | 一种羧甲司坦的制备方法 |
| CN109970639A (zh) * | 2018-11-23 | 2019-07-05 | 重庆康乐制药有限公司 | 一种连续流微反应器中合成哌喹中间体的方法 |
| CN110452142A (zh) * | 2019-09-10 | 2019-11-15 | 云鹏医药集团有限公司 | 一种高纯度s-(羧甲基)-半胱氨酸的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| 杨晓云等: "羧甲司坦合成工艺改进", 齐鲁药事, vol. 23, no. 3, pages 43 - 44 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021102918A1 (zh) | 2021-06-03 |
| JP2022550628A (ja) | 2022-12-02 |
| EP4067341A1 (en) | 2022-10-05 |
| JP7429292B2 (ja) | 2024-02-07 |
| CN114746399B (zh) | 2024-05-24 |
| EP4067341A4 (en) | 2023-04-12 |
| EP4067341B1 (en) | 2024-07-03 |
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