CN103936825B - 邻苯二甲酰-l-丙氨酰-l-谷氨酰胺的绿色制备方法 - Google Patents
邻苯二甲酰-l-丙氨酰-l-谷氨酰胺的绿色制备方法 Download PDFInfo
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- CN103936825B CN103936825B CN201410196961.4A CN201410196961A CN103936825B CN 103936825 B CN103936825 B CN 103936825B CN 201410196961 A CN201410196961 A CN 201410196961A CN 103936825 B CN103936825 B CN 103936825B
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- alanyl
- glutamine
- phthaloyl
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- 229960002648 alanylglutamine Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- 239000003513 alkali Substances 0.000 claims description 21
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 10
- 239000011707 mineral Substances 0.000 claims description 10
- 235000010755 mineral Nutrition 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 230000004044 response Effects 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 18
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 abstract description 10
- 108010044940 alanylglutamine Proteins 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000001914 filtration Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 239000003960 organic solvent Substances 0.000 abstract description 6
- 231100000614 poison Toxicity 0.000 abstract description 4
- 230000007096 poisonous effect Effects 0.000 abstract description 4
- 239000002699 waste material Substances 0.000 abstract description 3
- 239000007864 aqueous solution Substances 0.000 abstract description 2
- 238000001035 drying Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 abstract description 2
- 231100001261 hazardous Toxicity 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 abstract description 2
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 150000007529 inorganic bases Chemical class 0.000 abstract 1
- 239000002912 waste gas Substances 0.000 abstract 1
- 239000002351 wastewater Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- 230000008569 process Effects 0.000 description 8
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- -1 regulate pH to 1.5 Substances 0.000 description 5
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- VHHHONWQHHHLTI-UHFFFAOYSA-N hexachloroethane Chemical compound ClC(Cl)(Cl)C(Cl)(Cl)Cl VHHHONWQHHHLTI-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 229910052736 halogen Inorganic materials 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
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- 231100000167 toxic agent Toxicity 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- 0 C[C@@](C(NCC(*)=O)=*)N(C(c1c2cccc1)=N)C2=O Chemical compound C[C@@](C(NCC(*)=O)=*)N(C(c1c2cccc1)=N)C2=O 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108010016626 Dipeptides Proteins 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 208000012826 adjustment disease Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FYXKZNLBZKRYSS-UHFFFAOYSA-N benzene-1,2-dicarbonyl chloride Chemical compound ClC(=O)C1=CC=CC=C1C(Cl)=O FYXKZNLBZKRYSS-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000003871 intestinal function Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 230000001473 noxious effect Effects 0.000 description 1
- 230000000050 nutritive effect Effects 0.000 description 1
- 235000016236 parenteral nutrition Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000008057 potassium phosphate buffer Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
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- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
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CN106946978A (zh) * | 2017-03-15 | 2017-07-14 | 江苏诚信药业有限公司 | 一种邻苯二甲酰丙氨酰谷氨酰胺合成的工艺方法 |
CN114957384B (zh) * | 2022-04-14 | 2023-11-14 | 湖北泓肽生物科技有限公司 | 一种二肽-4的合成方法 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102040651A (zh) * | 2009-10-14 | 2011-05-04 | 北京和诚先锋医药技术有限公司 | 一种邻苯二甲酰-l-丙氨酰-l-谷氨酰胺的制备方法 |
CN102838656A (zh) * | 2012-09-29 | 2012-12-26 | 德州诚瑞达生物科技有限公司 | 一种l-丙氨酰-l-谷氨酰胺的制备方法 |
CN103626839A (zh) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | 一种n(2)-l-丙氨酰-l-谷氨酰胺的制备方法 |
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Publication number | Priority date | Publication date | Assignee | Title |
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CN102040651A (zh) * | 2009-10-14 | 2011-05-04 | 北京和诚先锋医药技术有限公司 | 一种邻苯二甲酰-l-丙氨酰-l-谷氨酰胺的制备方法 |
CN102838656A (zh) * | 2012-09-29 | 2012-12-26 | 德州诚瑞达生物科技有限公司 | 一种l-丙氨酰-l-谷氨酰胺的制备方法 |
CN103626839A (zh) * | 2013-12-19 | 2014-03-12 | 济南诚汇双达化工有限公司 | 一种n(2)-l-丙氨酰-l-谷氨酰胺的制备方法 |
Non-Patent Citations (1)
Title |
---|
10 t/a中试规模制备二肽L-丙氨酰-L-谷氨酰胺;陈然等;《精细化工》;20051215;第22卷(第12期);958-960 * |
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Inventor after: Ma Nan Inventor before: Kong Kaiming Inventor before: Wang Wei Inventor before: Zheng Beibei |
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Effective date of registration: 20170313 Address after: Nan Loudi Xiang Mao Shan Wei Cun Ping An Jie Anguo City, Hebei province 071000 Baoding city 9 Road No. 5 Patentee after: Ma Nan Address before: 312000 Zhejiang province Shaoxing City Chengnan Street East Village No. 55 Patentee before: Kong Kaiming |
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Effective date of registration: 20190916 Address after: 246700 Laozhou Town, Zongyang County, Tongling City, Anhui Province Patentee after: Anhui Xinke Bio-Environmental Co., Ltd. Address before: Nan Loudi Xiang Mao Shan Wei Cun Ping An Jie Anguo City, Hebei province 071000 Baoding city 9 Road No. 5 Patentee before: Ma Nan |