CN104829533A - Preparation method of tolvaptan key intermediate - Google Patents

Preparation method of tolvaptan key intermediate Download PDF

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Publication number
CN104829533A
CN104829533A CN201510256562.7A CN201510256562A CN104829533A CN 104829533 A CN104829533 A CN 104829533A CN 201510256562 A CN201510256562 A CN 201510256562A CN 104829533 A CN104829533 A CN 104829533A
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chloro
amino
phenyl
acid
synthetic method
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王廷圣
游洪全
周旭东
邹鑫
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Guang'an Kingday Pharm & Chemical Co Ltd
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Guang'an Kingday Pharm & Chemical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines

Abstract

The invention discloses a preparation method of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydro-benzazepine. The preparation method comprises the steps of condensing parachloroaniline, which is taken as a starting raw material, with 4-chlorobutyric acid methyl ester, carrying out hydrolysis de-esterification and acylating chlorination, and carrying out ring closure under an acidic condition, so as to obtain a target product, wherein the total yield of the target product can reach above 80%, and the HPLC (High Performance Liquid Chromatography) purity reaches above 99.5%.

Description

A kind of preparation method of tolvaptan key intermediate
Technical field
The present invention relates to field of pharmaceutical chemistry technology, specifically, relate to a kind of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method.
Background technology
Tolvaptan is the one oral selectivity non-peptide class Novel arginine vassopressin V developed by Japanese great Zhong company 2receptor antagonist, within 2009, through FDA approval listing, its structural formula is as follows:
Tolvaptan structural formula
As key intermediate prepared by tolvaptan, 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza synthesis have more bibliographical information, such as, Chinese Journal of Pharmaceuticals, 2009, report following synthesis technique in 40 (9): 648-650:
The shortcoming of this preparation technology is that yield is lower, and an in the end step PPA, high, the easy moisture absorption of viscosity, and cost is higher, is unsuitable for suitability for industrialized production.
Chinese patent application CN102093293A discloses 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza synthesis technique, as follows:
This route with to amino-chloro-benzene for raw material, first with Tosyl chloride condensation by amido protecting, then with the coupling of 4-bromobutyrate, by products therefrom hydrolysis, chloride, Cheng Huanhou Deprotection again, obtain target product through six-step process.The yield fluctuation of the method products obtained therefrom is comparatively large, and unstable is strong.
Summary of the invention
The invention provides a kind of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza the novel method of synthesis, the method has the advantages such as easy and simple to handle, with short production cycle, yield is high.
The object of this invention is to provide a kind of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza the method of synthesis.
The invention provides a kind of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza the method of synthesis, comprises the steps:
(1), mix amino-chloro-benzene, acid binding agent and non-proton organic solvent, drip 4-chlorobutanoate, be obtained by reacting 4-((4-chloro-phenyl-) is amino) methyl-butyrate;
(2) 4-((4-chloro-phenyl-) the is amino) methyl-butyrate, by step (1) obtained is hydrolyzed in the presence of a mineral acid, obtains 4-((4-chloro-phenyl-) is amino) butyric acid;
(3), step (2) is obtained 4-((4-chloro-phenyl-) is amino) butyric acid sulfur oxychloride and carry out chloride; Then cyclization under Lewis acid existent condition, obtains target product 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza .
In a kind of preferred embodiment of the present invention, the invention provides a kind of tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza the method of synthesis, is realized by following steps:
(1), mix amino-chloro-benzene, acid binding agent and non-proton organic solvent, 4-chlorobutanoate is dripped at 10-20 DEG C, then be warmed up to 40-50 DEG C of insulation reaction 3-8 hour, obtain 4-((4-chloro-phenyl-) is amino) methyl-butyrate;
(2) 4-((4-chloro-phenyl-) is amino) methyl-butyrate and water, is mixed, mineral acid is dripped at 10-20 DEG C, be warmed up to 90-100 DEG C of reaction 2-5 hour, be down to 0-15 DEG C again, through extraction, concentrate and obtain 4-((4-chloro-phenyl-) is amino) butyric acid;
(3), by 4-((4-chloro-phenyl-) is amino) butyric acid, sulfur oxychloride mixing, be warming up to 40-50 DEG C of reaction 4 hours, concentrated removing sulfur oxychloride, add dichloromethane solvent, be cooled to-5-5 DEG C, adding sulfuric acid keeps the pH value of system at 2.0-3.0, drip Lewis acid insulation reaction 2-3 hour, add alkaline solution stirring reaction 2-3 hour, concentrated removing methylene dichloride after stratification, through crystallization, obtain the chloro-5-oxo-1 of target product 7-, 2,3,4-tetrahydrochysene-benzo-aza .
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the acid binding agent wherein described in step (1) is selected from sodium carbonate, sodium bicarbonate, salt of wormwood, triethylamine or pyridine.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, wherein in step (1), be 1:1.2-1.5 to the mol ratio of amino-chloro-benzene and 4-chlorobutanoate.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the molar weight that the acid binding agent wherein described in step (1) feeds intake is to the 2-4 of amino-chloro-benzene mole number doubly, preferably, be 2-3 doubly.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the non-proton organic solvent wherein described in step (1) is selected from DMF, methyl-sulphoxide or acetonitrile, preferably, is DMF.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, wherein the aftertreatment of step (1) after insulation reaction 3-8 hour is for dripping water, cools to 10-15 DEG C of crystallization 2.0 hours, filters and obtains 4-((4-chloro-phenyl-) amino) methyl-butyrate.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the mineral acid wherein described in step (2) is selected from hydrochloric acid or sulfuric acid.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the mol ratio of the mineral acid wherein described in step (2) and 4-((4-chloro-phenyl-) is amino) methyl-butyrate is 0.8-1.2:1, preferably, is 0.9-1.1:1.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the organic solvent used by extraction wherein described in step (2) is selected from methylene dichloride, ethylene dichloride, ethyl acetate, propyl acetate, ethyl formate, chloroform or its mixture.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the Lewis acid described in step (3) is selected from aluminum chloride, iron trichloride, tin tetrachloride or boron trifluoride diethyl etherate, preferably, is aluminum chloride.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the mol ratio of the Lewis acid wherein described in step (3) and 4-((4-chloro-phenyl-) is amino) butyric acid is 1.4-1.7:1.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, the alkaline solution wherein described in step (3) is selected from the sodium carbonate solution of 5-40 % by weight, sodium hydrogen carbonate solution or solution of potassium carbonate, preferably, is the sodium carbonate solution of 10-15 % by weight.The consumption of step (3) described alkaline solution is 3-7 times of 4-((4-chloro-phenyl-) is amino) butyric acid weight.
In embodiments of the invention, the invention provides tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, wherein step (3) described crystallization is: add organic solvent 1., drips organic solvent 2. after 50-55 DEG C of stirring and dissolving, then cools to-5-5 DEG C of stirring and crystallizing; Here, 1., be selected from ethyl acetate, methyl alcohol, methylene dichloride, chloroform, propyl acetate, ethyl formate etc., preferably, be ethyl acetate or methylene dichloride to described organic solvent; 2., be selected from sherwood oil, normal hexane, hexanaphthene, toluene etc., preferably, be sherwood oil or normal hexane to described organic solvent.
Compared with prior art, tolvaptan key intermediate 7-provided by the invention chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza preparation method, without the need to through amido protecting and deprotection steps, enormously simplify operation, shorten the production cycle, and easy and simple to handle, yield is high, purity is high, is particularly suitable for suitability for industrialized production.
Embodiment
By following examples, the present invention is better illustrated, but the present invention is not limited by the following examples.
Embodiment 1
(1) 100g is mixed to amino-chloro-benzene, 100g DMF (N, dinethylformamide), 266.5g salt of wormwood, 132.7g 4-chlorobutanoate is dripped at 10-20 DEG C, be warmed up to 40-50 DEG C of insulation reaction after 4 hours, be incubated 40-50 DEG C and drip 400g water, cool to 10-15 DEG C of crystallization 2.0 hours, filter and obtain 4-((4-chloro-phenyl-) is amino) methyl-butyrate 172.6g, yield 96.7%.
(2) by 4-((4-chloro-phenyl-) is amino) methyl-butyrate 161.7g, 161.7g water, 70.0g 98% sulfuric acid is dripped at 10-20 DEG C, be warmed up to 90-100 DEG C of reaction 3 hours, cool to 0-15 DEG C again, add 323.4g methylene dichloride, drip 30wt% sodium hydroxide solution again and regulate pH=9.0-10.0, leave standstill separatory, obtain dichloromethane layer, 40-60 DEG C, evaporated under reduced pressure under-0.09Mpa, obtain solid 4-((4-chloro-phenyl-) is amino) butyric acid 144.4g, yield 95.2%.
(3) in 136.5g 4-((4-chloro-phenyl-) is amino) butyric acid, 273.0g sulfur oxychloride is added, be warmed up to 40-45 DEG C of insulation reaction 4.0 hours, at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add 136.5g ethylene dichloride again at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, adding 409.5g ethylene dichloride, cool to 0-5 DEG C, add sulfuric acid 27.2g and preserve the pH of system at 2-3, slowly add 136.5g aluminum chloride, be warmed up to 15-20 DEG C of reaction 2.0 hours, reaction solution is added drop-wise in the 10wt% sodium carbonate solution 680.0g of 10-15 DEG C, at 15-20 DEG C of stirring reaction 2.0h, filter, filtrate separatory, by organic layer at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add 40.0g ethyl acetate, be warmed up to 75-80 DEG C of stirring clearly molten, drip 160.0g sherwood oil, cool to 0-5 DEG C of stirring and crystallizing 0.5 hour, suction filtration, 4.0 hours are dried at 50-60 DEG C of normal pressure, obtain the chloro-5-oxo-1 of tolvaptan intermediate 7-, 2, 3, 4-tetrahydrochysene-benzo-aza 110.9g, yield 88.6%, HPLC purity: 99.59%. 1H-NMR(400MHz，CDCl 3)：δ2.12(m，2H),2.62(m，2H)，3.70(m，2H)，6.92(d,1H),7.48(m,1H)，7.66(m，1H)。
HPLC purity testing condition and method (lower same): chromatographic condition: liquid chromatography system adopts UV-detector, determined wavelength is the stainless steel column that a 230nm and C18 fills, and flow velocity is 1.0ml/min; Moving phase: 0.03mol/L phosphate buffer salt (4.08g potassium primary phosphate is dissolved in 1000ml water, phosphoric acid adjust pH to 3.0)-acetonitrile (30:70); Determination step: get this product and be about 25mg, accurately weighed, put in 25ml measuring bottle, add acetonitrile 5ml ultrasonic dissolution, with moving phase dilution and quantitative to scale, shake up to obtain need testing solution, inject the blank solution of equal-volume (20ul), need testing solution respectively, record trial-product collection of illustrative plates, 60 minutes working times, deduction is blank, the chloro-5-oxo-1 of tolvaptan intermediate 7-is calculated by area normalization method, 2,3,4-tetrahydrochysene-benzo-aza chromatographic purity and maximum list mix.
Embodiment 2
(1) 100g is mixed to amino-chloro-benzene, 100g DMSO (dimethyl sulfoxide (DMSO)), 266.5g sodium carbonate, 132.7g 4-chlorobutanoate is dripped at 10-20 DEG C, be warmed up to 40-50 DEG C of insulation reaction after 4 hours, be incubated 40-50 DEG C and drip 400g water, cool to 10-15 DEG C of crystallization 2.0 hours, filtration obtains 4-((4-chloro-phenyl-) is amino) methyl-butyrate 173.3g, yield 97%.
(2) by 4-((4-chloro-phenyl-) is amino) methyl-butyrate 162.0g, 162.0g water, 70.0g 98% sulfuric acid is dripped at 10-20 DEG C, be warmed up to 90-100 DEG C of reaction 3 hours, cool to 0-15 DEG C again, add 323.4g methylene dichloride, drip 30% sodium hydroxide solution again and regulate pH=9-10, leave standstill separatory, obtain dichloromethane layer, 40-60 DEG C, evaporated under reduced pressure under-0.09Mpa, obtain solid 4-((4-chloro-phenyl-) is amino) butyric acid 145.9g, yield 96%.
(3) in 135.9g 4-((4-chloro-phenyl-) is amino) butyric acid, 272.0g sulfur oxychloride is added, be warmed up to 40-45 DEG C of insulation reaction 4.0 hours, at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add 135.9g ethylene dichloride again at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, adding 407.7g ethylene dichloride, cool to 0-5 DEG C, add sulfuric acid 27.2g and preserve the PH of system at 2-3, slow dropping 136.5g aluminum chloride, reaction solution is added drop-wise in the 10 % by weight sodium carbonate solution 680.0g of 10-15 DEG C, at 15-20 DEG C of stirring reaction 2.0h, filter, filtrate separatory, by organic layer at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add ethyl acetate 40.0g, be warmed up to 60-65 DEG C of stirring clearly molten, drip 160.0g sherwood oil, cool to 0-5 DEG C of stirring and crystallizing 0.5 hour, suction filtration, 4.0 hours are dried at 50-60 DEG C of normal pressure, obtain the chloro-5-oxo-1 of tolvaptan intermediate 7-, 2, 3, 4-tetrahydrochysene-benzo-aza 109.1g, yield 87.5%, HPLC purity: 99.62%.
Embodiment 3
(1) 100g is mixed to amino-chloro-benzene, 100g DMF, 266.5g salt of wormwood, 132.7g4-chlorobutanoate is dripped at 10-20 DEG C, be warmed up to 40-50 DEG C of insulation reaction after 4 hours, be incubated 40-50 DEG C and drip 400g water, cool to 10-15 DEG C of crystallization 2.0 hours, filtration obtains 4-((4-chloro-phenyl-) is amino) methyl-butyrate 174.6g, yield 97.8%.
(2) by 4-((4-chloro-phenyl-) is amino) methyl-butyrate 161.7g, 161.7g water, 70.0g 98% sulfuric acid is dripped at 10-20 DEG C, be warmed up to 90-100 DEG C of reaction 3 hours, cool to 0-15 DEG C again, add 323.4g methylene dichloride, drip 30% sodium hydroxide solution again and regulate pH=9-10, leave standstill separatory, obtain dichloromethane layer, 40-60 DEG C, evaporated under reduced pressure under-0.09Mpa, obtain solid 4-((4-chloro-phenyl-) is amino) butyric acid 147.8g, yield 97.5%.
(3) in 136.5g 4-((4-chloro-phenyl-) is amino) butyric acid, 273.0g sulfur oxychloride is added, be warmed up to 40-45 DEG C of insulation reaction 4.0 hours, at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add 136.5g ethylene dichloride again at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, adding 409.5g ethylene dichloride, cool to 0-5 DEG C, add sulfuric acid 27.2g and preserve the PH of system at 2-3, slowly add 158.5g tin tetrachloride, be warmed up to 15-20 DEG C of reaction 2.0 hours, reaction solution is added drop-wise in the 10 % by weight sodium carbonate solution 680.0g of 10-15 DEG C, at 15-20 DEG C of stirring reaction 2.0h, filter, filtrate separatory, by organic layer at 50-55 DEG C, evaporated under reduced pressure under-0.09Mpa, add ethyl acetate 40.0g, be warmed up to 75-80 DEG C of stirring clearly molten, drip 160.0g sherwood oil, cool to 0-5 DEG C of stirring and crystallizing 0.5 hour, suction filtration, 4.0 hours are dried at 55-60 DEG C of normal pressure, obtain the chloro-5-oxo-1 of tolvaptan intermediate 7-, 2, 3, 4-tetrahydrochysene-benzo-aza 110.7g, yield 89.0%, HPLC purity: 99.65%.

Claims (10)

1. tolvaptan key intermediate 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza synthetic method, comprise the steps:
(1) mixing is to amino-chloro-benzene, acid binding agent and non-proton organic solvent, drips 4-chlorobutanoate, is obtained by reacting 4-((4-chloro-phenyl-) is amino) methyl-butyrate;
(2) 4-((4-chloro-phenyl-) is amino) methyl-butyrate step (1) obtained is hydrolyzed in the presence of a mineral acid, obtains 4-((4-chloro-phenyl-) is amino) butyric acid;
(3) step (2) is obtained 4-((4-chloro-phenyl-) is amino) butyric acid sulfur oxychloride and carry out chloride; Then cyclization under Lewis acid existent condition, obtains target product 7-chloro-5-oxo-1,2,3,4-tetrahydrochysene-benzo-aza
2. synthetic method according to claim 1, comprises the steps:
(1) mixing is to amino-chloro-benzene, acid binding agent and non-proton organic solvent, 4-chlorobutanoate is dripped at 10-20 DEG C, then be warmed up to 40-50 DEG C of insulation reaction 3-8 hour, obtain 4-((4-chloro-phenyl-) is amino) methyl-butyrate;
(2) 4-((4-chloro-phenyl-) is amino) methyl-butyrate and water is mixed, drip mineral acid at 10-20 DEG C, be warmed up to 90-100 DEG C of reaction 2-5 hour, then be down to 0-15 DEG C, through extraction, concentrate and obtain 4-((4-chloro-phenyl-) is amino) butyric acid;
(3) by 4-((4-chloro-phenyl-) is amino) butyric acid, sulfur oxychloride mixing, be warming up to 40-50 DEG C of reaction 4 hours, concentrated removing sulfur oxychloride, add dichloromethane solvent, be cooled to-5-5 DEG C, adding sulfuric acid keeps the pH value of system at 2.0-3.0, drip Lewis acid insulation reaction 2-3 hour, add alkaline solution stirring reaction 2-3 hour, concentrated removing methylene dichloride after stratification, through crystallization, obtain the chloro-5-oxo-1 of target product 7-, 2,3,4-tetrahydrochysene-benzo-aza
3. synthetic method according to claim 1 and 2, wherein, the acid binding agent described in step (1) is selected from sodium carbonate, sodium bicarbonate, salt of wormwood, triethylamine or pyridine.
4. synthetic method according to claim 1 and 2, wherein, in step (1), is 1:1.2-1.5 to the mol ratio of amino-chloro-benzene and 4-chlorobutanoate.
5. synthetic method according to claim 1 and 2, wherein, the molar weight of the acid binding agent described in step (1) is 2-4 times to the mole number of amino-chloro-benzene, preferably, is 2-3 times.
6. synthetic method according to claim 1 and 2, wherein, the non-proton organic solvent described in step (1) is selected from DMF, methyl-sulphoxide or acetonitrile, preferably, is DMF.
7. synthetic method according to claim 1 and 2, wherein, the mineral acid described in step (2) is selected from hydrochloric acid or sulfuric acid.
8. synthetic method according to claim 1 and 2, wherein, the mol ratio of the mineral acid described in step (2) and 4-((4-chloro-phenyl-) is amino) methyl-butyrate is 0.8-1.2:1, preferably, is 0.9-1.1:1.
9. synthetic method according to claim 2, wherein, the organic solvent used by extraction described in step (2) is selected from methylene dichloride, ethylene dichloride, ethyl acetate, propyl acetate, ethyl formate, chloroform and composition thereof.
10. synthetic method according to claim 1 and 2, wherein, the Lewis acid described in step (3) is selected from aluminum chloride, iron trichloride, tin tetrachloride or boron trifluoride diethyl etherate, preferably, is aluminum chloride.
CN201510256562.7A 2015-05-19 2015-05-19 Preparation method of tolvaptan key intermediate Pending CN104829533A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400533A (en) * 2018-11-07 2019-03-01 亳州学院 A kind of synthetic method of hydrochloric acid conivaptan key intermediate
CN110274966A (en) * 2019-03-08 2019-09-24 常州市阳光药业有限公司 Method in relation to substance in high effective liquid chromatography for measuring tolvaptan bulk pharmaceutical chemicals

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Publication number Priority date Publication date Assignee Title
CN102093293A (en) * 2011-03-02 2011-06-15 宁波人健药业集团有限公司 Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone
WO2012046244A1 (en) * 2010-10-05 2012-04-12 Hetero Research Foundation Process for preparing tolvaptan intermediates
CN103012265A (en) * 2012-11-23 2013-04-03 天津药物研究院 Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
CN103012266A (en) * 2012-11-23 2013-04-03 天津药物研究院 Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012046244A1 (en) * 2010-10-05 2012-04-12 Hetero Research Foundation Process for preparing tolvaptan intermediates
CN102093293A (en) * 2011-03-02 2011-06-15 宁波人健药业集团有限公司 Method for preparing 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepino-5-ketone
CN103012265A (en) * 2012-11-23 2013-04-03 天津药物研究院 Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine
CN103012266A (en) * 2012-11-23 2013-04-03 天津药物研究院 Preparation method of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400533A (en) * 2018-11-07 2019-03-01 亳州学院 A kind of synthetic method of hydrochloric acid conivaptan key intermediate
CN110274966A (en) * 2019-03-08 2019-09-24 常州市阳光药业有限公司 Method in relation to substance in high effective liquid chromatography for measuring tolvaptan bulk pharmaceutical chemicals
CN110274966B (en) * 2019-03-08 2022-01-18 常州市阳光药业有限公司 Method for determining related substances in tolvaptan bulk drug by high performance liquid chromatography

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Application publication date: 20150812