KR820001160B1 - Synthesis of Carbocysteine - Google Patents
Synthesis of Carbocysteine Download PDFInfo
- Publication number
- KR820001160B1 KR820001160B1 KR1019810000163A KR810000163A KR820001160B1 KR 820001160 B1 KR820001160 B1 KR 820001160B1 KR 1019810000163 A KR1019810000163 A KR 1019810000163A KR 810000163 A KR810000163 A KR 810000163A KR 820001160 B1 KR820001160 B1 KR 820001160B1
- Authority
- KR
- South Korea
- Prior art keywords
- carbocysteine
- cystine
- synthesis
- cysteine
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- GBFLZEXEOZUWRN-VKHMYHEASA-N S-carboxymethyl-L-cysteine Chemical compound OC(=O)[C@@H](N)CSCC(O)=O GBFLZEXEOZUWRN-VKHMYHEASA-N 0.000 title claims description 10
- 229960004399 carbocisteine Drugs 0.000 title claims description 9
- 230000015572 biosynthetic process Effects 0.000 title claims description 4
- 238000003786 synthesis reaction Methods 0.000 title claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 11
- 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 10
- 229960003067 cystine Drugs 0.000 claims description 10
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000011701 zinc Substances 0.000 claims description 3
- 229910052725 zinc Inorganic materials 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 3
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- QIJRTFXNRTXDIP-UHFFFAOYSA-N (1-carboxy-2-sulfanylethyl)azanium;chloride;hydrate Chemical compound O.Cl.SCC(N)C(O)=O QIJRTFXNRTXDIP-UHFFFAOYSA-N 0.000 description 3
- 229960001305 cysteine hydrochloride Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000003139 buffering effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
내용 없음.No content.
Description
본 발명은 복용시 일반항생제와는 달리 습관성, 알레르기성 반응, 내성등의 부작용을 유발함이 없이 감기나 독감, 기관지염등 호흡기 질환의 치료제, 거담제 및 코점막의 감염 예방재로 유용한 다음 일반식(I)의 S-카복시메틸-ℓ-시스테인(이하 "카보시스테인"이라 칭한다)의 보다 효율적이고 저렴한, 그리고 의약품 성분으로 합당한 순도로 얻는 합성법에 관한 것이다.Unlike general antibiotics, the present invention is useful for preventing respiratory diseases such as colds, flu, bronchitis, expectorants and nasal mucosa infections without causing side effects such as addictive, allergic reactions, and resistance. A method for synthesizing S-carboxymethyl-L-cysteine (hereinafter referred to as "carbocysteine") of I), which is obtained with reasonable purity as a pharmaceutical ingredient.
종래, 카보시스테인의 제조 방법으로는 시스테인 염산염을 출발물질로 하여 제조하는 방법이 알려져 있다.Background Art Conventionally, a method for producing carbocysteine has been known which uses cysteine hydrochloride as a starting material.
[참조, Fr 1,288,907(1962)][Reference, Fr 1,288,907 (1962)]
그러나, 시스테인 염산염은 쉽게 산화되어 반응시 불활성 기체의 사용이 요구될뿐 아니라, 시스테인 염산염 자체가 물에 대한 용해도가 크기 때문에 시스틴으로 부터 제조시 그 분리 공정에서 공기(산소)의 차단과 용매의 농축공정을 요하며, 그 합성 설비 및 에너지가 많이 소요될 뿐만 아니라 그 수율도 65%를 넘지 못하고 있어[참조, 미국특허 제2,376,186호(1945)], 미국특허 제2,414,303호(1947), 독일특허 제804,808호(1949) 및 미국특허 제2,907,703호(1959)]이로 부터 카보시스테인을 합성할 경우, 그 수율은 시스틴으로부터 55%를 넘지 못하는 단점이 있었다.However, cysteine hydrochloride is easily oxidized and requires the use of an inert gas in the reaction, and because cysteine hydrochloride itself has a high solubility in water, blocking of air (oxygen) and concentration of solvent in its separation process from the production of cystine The process requires a lot of synthesis equipment and energy, and the yield does not exceed 65% (see US Patent No. 2,376,186 (1945)), US Patent No. 2,414,303 (1947), and German Patent No. 804,808. (1949) and US Pat. No. 2,907,703 (1959)], the synthesis of carbocysteine from this, the yield was a disadvantage that does not exceed 55% from cystine.
또한, 시스틴으로부터 가성소다 용액에서의 환원과 카복시메틸화 반응이 이미 시도된바 있으나 [참조 미국특허 제2,460,785호(1949)]시스테인과 시스틴 및 카보시스테인이 모두 알칼리성 용액에서 불안정하여 반응 온도를 낮게 유지해야 하는데, 상기 방법에서는 반응열이 커서 열의 처리가 용이하지 않아, 공업화에 큰 장애가 되고 있을 뿐만 아니라 상기 방법대로 얻어지는 생성물의 순도도 매우 낮아 [융점 : 188-91°(분해)]본 출원인들이 상기 제법으로 얻은 90%의 생성물은 재결정후 수율이 60%에 미달되었음을 발견하였다.In addition, reduction and carboxymethylation reaction in caustic soda solution from cystine have already been attempted [see US Patent No. 2,460,785 (1949)], but both cysteine and cystine and carbocysteine are unstable in alkaline solution to keep the reaction temperature low. However, in this method, the heat of reaction is not easy to process the heat, which is not only an obstacle to industrialization, but also a very low purity of the product obtained according to the above method [melting point: 188-91 ° (decomposition)] The obtained 90% of the product was found to have a yield of less than 60% after recrystallization.
본 발명에서는 염기로서 가성소다 대신 탄산소다를 사용함으로써, pH를 보다 낮추고 완충효과를 부여하여 아연에 의한 환원 속도를 완화시킴으로서 급격한 반응열의 발생을 막을 수 있었다.In the present invention, by using sodium carbonate instead of caustic soda as a base, it was possible to prevent the rapid generation of reaction heat by lowering the pH and providing a buffering effect to alleviate the rate of reduction by zinc.
따라서, 반응 온도도 20℃에서 시작하여 별다른 냉각이 없이 30℃를 넘지않고 반응이 완결되었다.Therefore, the reaction temperature also started at 20 ° C. and the reaction was completed without exceeding 30 ° C. without any cooling.
본 발명에서 사용되는 염기로는 탄산소다, 탄산카리, 아세트산소다등을 포함한 강알카리의 약산염을 들 수 있다.Examples of the base used in the present invention include weak acid salts of strong alkalis including sodium carbonate, potassium carbonate, sodium acetate and the like.
본 발명에서는 1부의 시스틴과 1.0-2.0부의 모노클로로 아세트산 소다와 물의 혼합액에 20%의 탄산소다 수용액과 2당량의 아연을 첨가하여 반응시킴으로써 시스틴을 환원하여 바로 카보시스테인을 85-90%의 수율로 얻는 방법을 기술한다.In the present invention, 20% aqueous solution of sodium carbonate and 2 equivalents of zinc are added to a mixture of 1 part of cystine, 1.0-2.0 parts of monochloroacetic acid, and water to react to reduce the cystine, thereby yielding a carbocysteine in a yield of 85-90%. Describe how to get it.
[실시예]EXAMPLE
30g의 시스틴, 31.5g 모노클로로 아세트산 소다, 100ml의 물을 혼합물에 20%탄산소다 수용액 135ml를 첨가한 다음 20g의 아연 분말을 넣어주고 3시간 동안 교반시켰다.30 g of cystine, 31.5 g of monochloroacetic acid and 100 ml of water were added to a mixture of 135 ml of 20% aqueous sodium carbonate solution, and then 20 g of zinc powder was added and stirred for 3 hours.
반응 온도는 20-30℃로 유지시킨 다음 침전된 아연 찌꺼기를 여과하여 제거하고, 그 여액과 세척액을 30℃이하에서 18ml의 진한 황산으로 산성으로 맞춘다음 10-15℃에서 생성물을 결정시켰다.The reaction temperature was maintained at 20-30 ° C. and the precipitated zinc residue was filtered off. The filtrate and washings were acidified with 18 ml of concentrated sulfuric acid below 30 ° C., and the product was determined at 10-15 ° C.
얻어진 일차 생성물을 120ml의 5몰 염산 수용액에 용해시킨 다음 5몰 암모니아수로 pH 2-2.5로 조정하여 생성물을 재침전시킨 후 여과, 세척후 건조시켜서 정제된 카보시스테인 39.5g을 얻었다.The obtained primary product was dissolved in 120 ml of 5 mol aqueous hydrochloric acid solution, adjusted to pH 2-2.5 with 5 mol ammonia water to reprecipitate the product, filtered, washed and dried to obtain 39.5 g of purified carbocysteine.
수율 : 88%, 융점 198-202℃(분해) 시스테인 0.05%이하, 시스틴 0.1 이하Yield: 88%, melting point 198-202 ° C (decomposition) cysteine 0.05% or less, cystine 0.1 or less
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019810000163A KR820001160B1 (en) | 1981-01-21 | 1981-01-21 | Synthesis of Carbocysteine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019810000163A KR820001160B1 (en) | 1981-01-21 | 1981-01-21 | Synthesis of Carbocysteine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR820001160B1 true KR820001160B1 (en) | 1982-06-28 |
Family
ID=19219994
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019810000163A Expired KR820001160B1 (en) | 1981-01-21 | 1981-01-21 | Synthesis of Carbocysteine |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR820001160B1 (en) |
-
1981
- 1981-01-21 KR KR1019810000163A patent/KR820001160B1/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PA0109 | Patent application |
Patent event code: PA01091R01D Comment text: Patent Application Patent event date: 19810121 |
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| PE0902 | Notice of grounds for rejection |
Comment text: Notification of reason for refusal Patent event date: 19820216 Patent event code: PE09021S01D |
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| PG1605 | Publication of application before grant of patent | ||
| PE0701 | Decision of registration |
Patent event code: PE07011S01D Comment text: Decision to Grant Registration Patent event date: 19820907 |
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| PR0701 | Registration of establishment |
Comment text: Registration of Establishment Patent event date: 19821106 Patent event code: PR07011E01D |
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| PR1001 | Payment of annual fee |
Payment date: 19821106 Start annual number: 4 End annual number: 12 Payment date: 19821106 Start annual number: 1 End annual number: 3 |
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| PR1002 | Payment of registration fee |
Payment date: 19821106 End annual number: 12 Start annual number: 4 Payment date: 19821106 End annual number: 3 Start annual number: 1 |
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| PC1801 | Expiration of term |
Termination date: 19951120 Termination category: Others |