CN111533695B - 一种依托咪酯的制备方法 - Google Patents
一种依托咪酯的制备方法 Download PDFInfo
- Publication number
- CN111533695B CN111533695B CN202010446607.8A CN202010446607A CN111533695B CN 111533695 B CN111533695 B CN 111533695B CN 202010446607 A CN202010446607 A CN 202010446607A CN 111533695 B CN111533695 B CN 111533695B
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- CN
- China
- Prior art keywords
- etomidate
- organic solvent
- mass ratio
- amino acid
- purifying
- 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.)
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- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 title claims abstract description 91
- 229960001690 etomidate Drugs 0.000 title claims abstract description 91
- 238000002360 preparation method Methods 0.000 title abstract description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 51
- 239000003960 organic solvent Substances 0.000 claims abstract description 35
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical group ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000000034 method Methods 0.000 claims abstract description 24
- 235000001014 amino acid Nutrition 0.000 claims abstract description 20
- 150000001413 amino acids Chemical class 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 19
- 238000003756 stirring Methods 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000008367 deionised water Substances 0.000 claims abstract description 11
- 229910021641 deionized water Inorganic materials 0.000 claims abstract description 11
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims abstract description 10
- 235000003704 aspartic acid Nutrition 0.000 claims abstract description 10
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- 238000001816 cooling Methods 0.000 claims abstract description 6
- 238000001035 drying Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 238000010438 heat treatment Methods 0.000 claims abstract description 6
- 238000000746 purification Methods 0.000 abstract description 11
- 238000002347 injection Methods 0.000 abstract description 6
- 239000007924 injection Substances 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- 230000001965 increasing effect Effects 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 230000003444 anaesthetic effect Effects 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 230000003204 osmotic effect Effects 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 239000012085 test solution Substances 0.000 description 3
- 238000004448 titration Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 229940125717 barbiturate Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000002960 lipid emulsion Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- BAXLBXFAUKGCDY-UHFFFAOYSA-N mebendazole Chemical compound [CH]1C2=NC(NC(=O)OC)=NC2=CC=C1C(=O)C1=CC=CC=C1 BAXLBXFAUKGCDY-UHFFFAOYSA-N 0.000 description 2
- 229960003439 mebendazole Drugs 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000029058 respiratory gaseous exchange Effects 0.000 description 2
- AWLILQARPMWUHA-UHFFFAOYSA-M thiopental sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC([S-])=NC1=O AWLILQARPMWUHA-UHFFFAOYSA-M 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- KJCVRFUGPWSIIH-UHFFFAOYSA-N 1-naphthol Chemical compound C1=CC=C2C(O)=CC=CC2=C1 KJCVRFUGPWSIIH-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-UHFFFAOYSA-N 3-(1-phenylethyl)-4-imidazolecarboxylic acid ethyl ester Chemical compound CCOC(=O)C1=CN=CN1C(C)C1=CC=CC=C1 NPUKDXXFDDZOKR-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 235000019766 L-Lysine Nutrition 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001780 adrenocortical effect Effects 0.000 description 1
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000003727 cerebral blood flow Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000003193 general anesthetic agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 230000036284 oxygen consumption Effects 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims (8)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN202010446607.8A CN111533695B (zh) | 2020-05-25 | 2020-05-25 | 一种依托咪酯的制备方法 |
Applications Claiming Priority (1)
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CN202010446607.8A CN111533695B (zh) | 2020-05-25 | 2020-05-25 | 一种依托咪酯的制备方法 |
Publications (2)
Publication Number | Publication Date |
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CN111533695A CN111533695A (zh) | 2020-08-14 |
CN111533695B true CN111533695B (zh) | 2021-01-08 |
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CN202010446607.8A Active CN111533695B (zh) | 2020-05-25 | 2020-05-25 | 一种依托咪酯的制备方法 |
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Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114195720B (zh) * | 2020-09-18 | 2023-10-31 | 燃点(南京)生物医药科技有限公司 | 一种依托咪酯的纯化方法 |
CN116265442B (zh) * | 2021-12-16 | 2024-08-06 | 燃点(南京)生物医药科技有限公司 | 一种依托咪酯的制备方法 |
CN115819267A (zh) * | 2022-12-15 | 2023-03-21 | 远大生命科学(武汉)有限公司 | 一种依托咪酯中间产物及其制备方法与应用 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3991072A (en) * | 1975-03-10 | 1976-11-09 | Janssen Pharmaceutica N.V. | Racemization of lower alkyl imidazole carboxylates |
US4770689A (en) * | 1986-03-10 | 1988-09-13 | Janssen Pharmaceutica N.V. | Herbicidal imidazole-5-carboxylic acid derivatives |
CN110922361B (zh) * | 2019-11-21 | 2021-01-08 | 武汉大安制药有限公司 | 一种依托咪酯氧化杂质及其制备方法 |
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- 2020-05-25 CN CN202010446607.8A patent/CN111533695B/zh active Active
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PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: 430000 Jinyin Lake Ecological Park, Dongxihu District, Wuhan City, Hubei Province Patentee after: Yuanda Life Science (Wuhan) Co.,Ltd. Address before: 430040 Jinyin Lake Ecological Park, Lake District, Wuhan City, Hubei Province Patentee before: WUHAN DOCAN PHARMACEUTICAL Co.,Ltd. |
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CP03 | Change of name, title or address | ||
CP03 | Change of name, title or address |
Address after: 430000 No.1 Xiaoxiang West Road, Dongxihu District, Wuhan City, Hubei Province Patentee after: Yuanda Medical Nutrition Science (Wuhan) Co.,Ltd. Country or region after: China Address before: 430000 Jinyin Lake Ecological Park, Dongxihu District, Wuhan City, Hubei Province Patentee before: Yuanda Life Science (Wuhan) Co.,Ltd. Country or region before: China |
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CP03 | Change of name, title or address |