CN101845017A - Preparation method of atracurium besilate intermediates - Google Patents
Preparation method of atracurium besilate intermediates Download PDFInfo
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- CN101845017A CN101845017A CN200910068233A CN200910068233A CN101845017A CN 101845017 A CN101845017 A CN 101845017A CN 200910068233 A CN200910068233 A CN 200910068233A CN 200910068233 A CN200910068233 A CN 200910068233A CN 101845017 A CN101845017 A CN 101845017A
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- dimethoxy
- tetrahydroisoquinoline
- bian
- methyl acrylate
- racemize
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- 239000000543 intermediate Substances 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229950008951 atracurium besilate Drugs 0.000 title claims abstract description 10
- XXZSQOVSEBAPGS-UHFFFAOYSA-L atracurium besylate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 XXZSQOVSEBAPGS-UHFFFAOYSA-L 0.000 title claims abstract description 10
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 20
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims abstract description 10
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 238000001556 precipitation Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- 125000004494 ethyl ester group Chemical group 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 6
- YXWQTVWJNHKSCC-INIZCTEOSA-N (1s)-1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1C[C@H]1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-INIZCTEOSA-N 0.000 claims description 4
- YXWQTVWJNHKSCC-MRXNPFEDSA-N (R)-tetrahydropapaverine Chemical compound C1=C(OC)C(OC)=CC=C1C[C@@H]1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-MRXNPFEDSA-N 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- IDVPSOYNHUMTLJ-UHFFFAOYSA-N oxalic acid;propan-2-one Chemical class CC(C)=O.OC(=O)C(O)=O IDVPSOYNHUMTLJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000006957 Michael reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 abstract description 6
- YXWQTVWJNHKSCC-UHFFFAOYSA-N 1-[(3,4-dimethoxyphenyl)methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=C(OC)C(OC)=CC=C1CC1C2=CC(OC)=C(OC)C=C2CCN1 YXWQTVWJNHKSCC-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 239000003960 organic solvent Substances 0.000 abstract description 2
- 235000006408 oxalic acid Nutrition 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract 2
- 239000003513 alkali Substances 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 238000013019 agitation Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- YXSLJKQTIDHPOT-UHFFFAOYSA-N Atracurium Dibesylate Chemical compound C1=C(OC)C(OC)=CC=C1CC1[N+](CCC(=O)OCCCCCOC(=O)CC[N+]2(C)C(C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 YXSLJKQTIDHPOT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229960001862 atracurium Drugs 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 150000001993 dienes Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229960000970 cisatracurium besylate Drugs 0.000 description 1
- XXZSQOVSEBAPGS-DONVQRBFSA-L cisatracurium besylate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1.[O-]S(=O)(=O)C1=CC=CC=C1.C1=C(OC)C(OC)=CC=C1C[C@H]1[N@+](CCC(=O)OCCCCCOC(=O)CC[N@+]2(C)[C@@H](C3=CC(OC)=C(OC)C=C3CC2)CC=2C=C(OC)C(OC)=CC=2)(C)CCC2=CC(OC)=C(OC)C=C21 XXZSQOVSEBAPGS-DONVQRBFSA-L 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000028161 membrane depolarization Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 230000002232 neuromuscular Effects 0.000 description 1
- 239000000842 neuromuscular blocking agent Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of atracurium besilate intermediates, comprising the following steps of: reacting tetrahydropapaverine with methyl acrylate or ethyl acrylate in an organic solvent, then reacting the tetrahydropapaverine with pentanediol under alkali catalysis, and finally reacting with oxalic acid addition salts to prepare (1R, 1'R), (1S, 1'S) and (1R, 1'S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-bi-[1-(3,4-dimethoxy benzyl) -6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline] dioxalate. Because an intermediate 4,10-dioxy-3,11-dioxo-1,12-tridecylene with large synthesis difficulty is avoided in the method, the preparation method has the advantages of simple process, mild condition, high purity of products, high yield, lower cost and convenient industrial production.
Description
Technical field
The present invention relates to a kind of atracurium besilate intermediates preparation, particularly relate to a kind of (1R, 1`R), (1S, 1`S) and (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] preparation method of dioxalic acid salt.
Background technology
Cisatracurium besylate is a kind of neuromuscular blocking agents with highly selective, non-depolarization type of exploitation after the Phenylsulfonic acid atracurium, it is mainly through non-enzyme decomposition course (Huffman elimination) natural degradation, and decomposes under blood plasma pH value and body temperature and produce active substance.The termination of this blocker neuromuscular effect does not also rely on hepatic and/or renal metabolism, drainage, therefore do not damage influenced action time because of kidney, liver and circulorespiratory system function, be mainly used in the skeletal muscle relaxation when anaesthetizing in the various surgical operations, be convenient to control breathing, and drop into clinical application.(1R, 1`R)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] dioxalic acid salt is the key intermediate of synthesizing cis Phenylsulfonic acid atracurium.
Following document: [1] U.S.4,179,507; [2] U.S.5,454,510; [3] WO 92 00965; [4] Eur.J.Med.Chem.16 has all reported (1R in 515,1981,1`R)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] synthetic method of dioxalic acid salt, following formula is the synthetic route of this compound:
As can be seen from the above equation, relate to compound 4 in the above-mentioned synthetic method as intermediate, 10-dioxy-3,11-dioxo-1,12-13 diene, because the synthetic difficulty of this intermediate is big, therefore synthetic route is longer, the operational condition harshness, and labour intensity is big, post-reaction treatment difficulty, and equipment requirements and raw materials cost height.
Summary of the invention
In order to address the above problem, to the object of the present invention is to provide that technology is simple, mild condition, product purity height, yield height, cost be lower, and be convenient to the atracurium besilate intermediates preparation of suitability for industrialized production.
In order to achieve the above object, atracurium besilate intermediate provided by the invention (chemical name be (1R, 1`R), (1S, 1`S) and (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline] dioxalic acid salt) the preparation method comprise the following step that carries out in order:
1) with racemize, Michael reaction so that take place between the two in R or S tetrahydropapaverine and methyl acrylate or ethyl propenoate in methyl alcohol or alcohol solvent reflux 1.5-3 hour, be cooled to room temperature then, precipitation filters, filtrate is washed with ether, get the white solid racemize, R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline]-methyl acrylate or ethyl ester;
2) with potassium tert.-butoxide as catalyzer, with above-mentioned racemize, R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-methyl acrylate or ethyl ester and pentanediol in toluene solvant reflux 2-4 hour, so that carry out transesterify between the two, steam the azeotrope that removes methyl alcohol or ethanol and toluene simultaneously, be cooled to room temperature then, washing, organic phase drying, precipitation gets yellow dope; This dope is dissolved in the proper amount of acetone, drips saturated oxalic acid acetone soln then and do not separate out, filter to there being precipitation again, drying can obtain (1R, 1`R), (1S, 1`S) and (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt, chemical equation is:
Racemize in the described step 1), the mol ratio of R or S tetrahydropapaverine and methyl acrylate or ethyl propenoate is 1: 2.0-4.0.
Described step 2) racemize in, R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline]-mol ratio of methyl acrylate or ethyl ester and pentanediol is 1.8-2.2: 1, and the mol ratio of potassium tert.-butoxide and pentanediol is 0.08-0.12: 1.
Atracurium besilate intermediates preparation provided by the invention is to make tetrahydropapaverine and methyl acrylate or ethyl propenoate reaction in organic solvent, and then reacts under highly basic catalysis with pentanediol, last and oxalic acid salify and make (1R, 1`R), (1S is 1`S) with (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt.Owing to avoided the big intermediate of synthetic difficulty 4 among this preparation method, 10-dioxy-3,11-dioxo-1,12-13 diene, so technology is simple, mild condition, product purity height, yield height, cost are lower, and are convenient to suitability for industrialized production.
Embodiment
Embodiment 1:
11.5g R-tetrahydropapaverine-N-ethanoyl-L-L-glutamic acid is added the suitable quantity of water dissolving, regulate pH value to 11 with ammoniacal liquor then, the toluene extraction, precipitation adds 5.8g methyl acrylate and 70ml methyl alcohol afterwards, and reflux is 1.5 hours under agitation condition, be cooled to room temperature then, precipitation filters, filtrate is washed with ether, get white solid R-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline]-methyl acrylate 8.9g;
At above-mentioned 3.5g R-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-add the 0.43g pentanediol in the methyl acrylate, add 0.05g potassium tert.-butoxide and 100ml toluene then, reflux is 3 hours under agitation condition, steams the azeotrope that removes methyl alcohol and toluene simultaneously, is cooled to room temperature then, washing, the organic phase drying, precipitation gets yellow dope.This dope is dissolved in the proper amount of acetone, drips saturated oxalic acid acetone soln then and do not separate out, filter to there being precipitation again, drying can obtain (1R, 1`R)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt 3.6g.
Embodiment 2:
12.0g S-tetrahydropapaverine-N-ethanoyl-L-L-glutamic acid is added the suitable quantity of water dissolving, regulate pH value to 11 with ammoniacal liquor then, the toluene extraction; precipitation adds 6.2g ethyl propenoate and 70ml methyl alcohol afterwards, and reflux is 1.5 hours under agitation condition; be cooled to room temperature then, precipitation filters; filtrate is washed with ether, get white solid S-3-[1-(3,4-dimethoxy Bian Ji)-6; 7-dimethoxy-1; 2,3, the 4-tetrahydroisoquinoline]-ethyl propenoate 9.2g.
At above-mentioned 7.2g S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-add the 0.88g pentanediol in the ethyl propenoate, add 0.10g potassium tert.-butoxide and 200ml toluene then, reflux is 3 hours under agitation condition, steams the azeotrope that removes ethanol and toluene simultaneously, is cooled to room temperature then, washing, the organic phase drying, precipitation gets yellow dope.This dope is dissolved in the proper amount of acetone, drips saturated oxalic acid acetone soln then and do not separate out, filter to there being precipitation again, drying can obtain (1S, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt 7.1g.
Claims (3)
1. atracurium besilate intermediates preparation, the chemical name of this intermediate be (1R, 1`R), (1S, 1`S) and (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt, it is characterized in that: described preparation method comprises the following step that carries out in order:
1) with racemize, Michael reaction so that take place between the two in R or S tetrahydropapaverine and methyl acrylate or ethyl propenoate in methyl alcohol or alcohol solvent reflux 1.5-3 hour, be cooled to room temperature then, precipitation filters, filtrate is washed with ether, get the white solid racemize, R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline]-methyl acrylate or ethyl ester;
2) with potassium tert.-butoxide as catalyzer, with above-mentioned racemize, R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline]-methyl acrylate or ethyl ester and pentanediol in toluene solvant reflux 2-4 hour, so that carry out transesterify between the two, steam the azeotrope that removes methyl alcohol or ethanol and toluene simultaneously, be cooled to room temperature then, washing, organic phase drying, precipitation gets yellow dope; This dope is dissolved in the proper amount of acetone, drips saturated oxalic acid acetone soln then and do not separate out, filter to there being precipitation again, drying can obtain (1R, 1`R), (1S, 1`S) and (1R, 1`S)-4,10-dioxy-3,11-dioxo tridecylene-1,13-pair-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline] dioxalic acid salt, chemical equation is:
2. atracurium besilate intermediates preparation according to claim 1 is characterized in that: racemize in the described step 1), the mol ratio of R or S tetrahydropapaverine and methyl acrylate or ethyl propenoate is 1: 2.0-4.0.
3. atracurium besilate intermediates preparation according to claim 1, it is characterized in that: racemize described step 2), R or S-3-[1-(3,4-dimethoxy Bian Ji)-6,7-dimethoxy-1,2,3, the 4-tetrahydroisoquinoline]-mol ratio of methyl acrylate or ethyl ester and pentanediol is 1.8-2.2: 1, and the mol ratio of potassium tert.-butoxide and pentanediol is 0.08-0.12: 1.
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| CN200910068233A CN101845017A (en) | 2009-03-24 | 2009-03-24 | Preparation method of atracurium besilate intermediates |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
| US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
| US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
| US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| US8461338B2 (en) | 2007-03-08 | 2013-06-11 | Chemagis Ltd. | (1R, 1′R)-atracurium salts separation process |
| CN105348148A (en) * | 2015-11-30 | 2016-02-24 | 山东新华制药股份有限公司 | Method for preparing impurity oxalate of intermediate condensation compound of pradaxa |
| CN110724100A (en) * | 2019-11-26 | 2020-01-24 | 山东铂源药业有限公司 | Preparation method of cisatracurium besilate intermediate |
| CN111777554A (en) * | 2019-04-04 | 2020-10-16 | 山东瑞安药业有限公司 | Method for synthesizing cisatracurium besilate |
-
2009
- 2009-03-24 CN CN200910068233A patent/CN101845017A/en active Pending
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8461338B2 (en) | 2007-03-08 | 2013-06-11 | Chemagis Ltd. | (1R, 1′R)-atracurium salts separation process |
| US8293912B2 (en) | 2007-05-01 | 2012-10-23 | Chemagis Ltd. | Process for producing cisatracurium compounds and associated intermediates |
| US8357807B2 (en) | 2007-05-01 | 2013-01-22 | Chemagis Ltd. | Isoquinolinium compounds useful in the preparation of cisatracurium and associated intermediates |
| US8357805B2 (en) | 2007-06-18 | 2013-01-22 | Chemagis Ltd. | (1R,1′R)-atracurium salts separation process |
| US8354537B2 (en) | 2007-10-29 | 2013-01-15 | Chemagis Ltd. | R,R1-atracurium salts |
| CN105348148A (en) * | 2015-11-30 | 2016-02-24 | 山东新华制药股份有限公司 | Method for preparing impurity oxalate of intermediate condensation compound of pradaxa |
| CN105348148B (en) * | 2015-11-30 | 2017-12-26 | 山东新华制药股份有限公司 | The method for preparing the oxalates of the impurity of dabigatran etexilate intermediate condensation product |
| CN111777554A (en) * | 2019-04-04 | 2020-10-16 | 山东瑞安药业有限公司 | Method for synthesizing cisatracurium besilate |
| CN110724100A (en) * | 2019-11-26 | 2020-01-24 | 山东铂源药业有限公司 | Preparation method of cisatracurium besilate intermediate |
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Application publication date: 20100929 |