CN102382053A - Method for preparing tolvaptan intermediate - Google Patents
Method for preparing tolvaptan intermediate Download PDFInfo
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- CN102382053A CN102382053A CN2011102724127A CN201110272412A CN102382053A CN 102382053 A CN102382053 A CN 102382053A CN 2011102724127 A CN2011102724127 A CN 2011102724127A CN 201110272412 A CN201110272412 A CN 201110272412A CN 102382053 A CN102382053 A CN 102382053A
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Abstract
The invention relates to a method for preparing a tolvaptan intermediate, namely 7-chlorine-5-oxo-1-(2-methyl-4-nitrobenzene formyl)-1,2,3,4-tetrahydro-benzo-azepine. The tolvaptan intermediate which is a compound as shown in the formula (1) is obtained by 7-chlorine-5-oxo-2,3,4,5-tetrahydro-1H-1-benzo-azepine (2) reacting with 4-nitryl-2-methylbenzene formyl chloride (3). The tolvaptan intermediate prepared by the method has the advantages of high purity, high yield and short reaction time, thereby being suitable for large-scale industrialized production.
Description
Technical field
The present invention relates to prepare tolvaptan midbody 7-chloro-5-oxo-1-(2-methyl-4-nitro benzoyl)-1,2,3, the method for 4-tetrahydro benzo azatropylidene.
Background technology
Tolvaptan (Tolvaptan trade(brand)name: be Samsca), can be used to treat the hyponatremia that causes by congestive heart failure, liver cirrhosis and vassopressin hyposecretion syndrome by the non-peptide class AVP2 receptor antagonist of Otsuka company exploitation.Up to now, in the compound method of having reported about tolvaptan, only the basic patent route expires.
Bioorganic & Medicinal Chemistry, 1999,7 (8); Reported oxo-2,3 among the 1743-1757,4 by 7-chloro-5-; 5-tetrahydrochysene-1H-1-benzazepine and 4-nitro-2-methyl benzoyl chloride synthetic intermediate (1) in the presence of the acid binding agent triethylamine, its synthetic route is as follows:
This method prepares midbody (1) document and has only 32% yield, and the raw material unreacted is intact, and influence is purified and yield.The prolongation reaction times can increase yield, but can produce a very big enol form impurity (4), and this impurity is difficult to recrystallization and removes.
Summary of the invention
The object of the invention provides a kind of improved preparation tolvaptan midbody 7-chloro-5-oxo-1-(2-methyl-4-nitro benzoyl)-1,2,3, the method for 4-tetrahydro benzo azatropylidene (1).
Concrete scheme provided by the invention is following:
A kind of preparation tolvaptan midbody 7-chloro-5-oxo-1-(2-methyl-4-nitro benzoyl)-1,2,3; The method of 4-tetrahydro benzo azatropylidene; Comprise following steps: in the presence of mineral alkali and non-proton organic solvent, 7-chloro-5-oxo-2,3; 4,5-tetrahydrochysene-1H-1-benzazepine (2) and 4-nitro-2-methyl benzoyl chloride (3) reaction obtains formula (1) compound; Synthetic route is as follows:
In the scheme of the present invention, wherein mineral alkali can be selected from sodium hydroxide, Pottasium Hydroxide, and salt of wormwood, saleratus, yellow soda ash, sodium hydrogencarbonates etc. are preferably sodium hydroxide; Formula (2) was generally 1: 1～1: 4 with the mol ratio of mineral alkali, was preferably 1: 1～1: 2; Non-proton organic solvent is preferably THF, acetonitrile, and DMSO 99.8MIN., N, dinethylformamide or their mixture further are preferably acetonitrile; Temperature of reaction generally is controlled at 0 ℃～40 ℃ carries out, preferably 15 ℃～25 ℃ scope; Reaction times generally was controlled at 1～3 hour, and preferably at 1～1.5 hour, the time surpasses 3 hours, and it is big that enol form impurity (4) also can become.
This bright 7-chloro-5-oxo-1-(2-methyl-4-nitro benzoyl)-1,2,3 that provides, the preparation method of 4-tetrahydro benzo azatropylidene compared with prior art yield significantly improve and obtain the product purity height, are fit to very much large-scale industrial production.
Embodiment
Below in conjunction with specific embodiment the present invention is described further, but protection scope of the present invention is not limited thereto.
Embodiment one
12.04g (0.0664mol) 4-nitro-2-tolyl acid is added in the single neck flask of 100ml; Add 9.49g (1.2eq) thionyl chloride and 12ml toluene; Add 3 DMF again, back flow reaction 4 hours, decompression steams solvent and unnecessary thionyl chloride; Get the pale brown look oily matter of 13.3g, get solid after the condensation; Be dissolved in the 5ml acetonitrile subsequent use.
With 10g (0.051mol) 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine adds in the 100ml three-necked flask; With the 50ml acetonitrile it is dissolved, add 2.04g (1eq) NaOH again, stir, drip the 5ml acetonitrile solution of 13.3g4-nitro-2-methyl benzoyl chloride; Room temperature reaction, along with the carrying out of reaction, reaction solution becomes light green by deep green gradually gradually, has a large amount of white solids to separate out simultaneously; Dropwise behind the 60min, stopped reaction is concentrated to fast doing with reaction solution, adds the 100ml methylene dichloride it is dissolved; Add the 100ml water washing, separate organic layer, use organic layer of 100ml water washing again, separate organic layer once more; Add 3g silica gel stirring at room 2min to the light green organic layer, filter, get red-brown filtrating.Solvent evaporated gets brown oil.With 30ml acetonitrile reflux oily matter is dissolved entirely, and then add the 30ml MTBE, have solid to separate out after being cooled to room temperature; With stirring in its placement ice-water bath, filter, use the MTBE flush cake; Drain; Get 13.4g buff powder, yield 73%, HPLC purity 99.74% after the drying.
Embodiment two
In 24.08g (0.133mol) 4-nitro-single neck flask of 2-tolyl acid adding 250ml, add 63.26g (4eq) thionyl chloride, back flow reaction 5 hours, decompression steams unnecessary thionyl chloride, gets the pale brown look oily matter of 26.6g, gets solid after the condensation; Be dissolved in the 10ml acetonitrile subsequent use.
With 20g (0.102mol) 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine adds in the 250ml three-necked flask; With the 100ml acetonitrile it is dissolved, add 4.08g (1eq) NaOH again, stir, drip the 10ml acetonitrile solution of 26.6g4-nitro-2-methyl benzoyl chloride; Room temperature reaction, along with the carrying out of reaction, reaction solution becomes light green by deep green gradually gradually, has a large amount of white solids to separate out simultaneously; Dropwise behind the 60min, stopped reaction is concentrated to fast doing with reaction solution, adds the 200ml methylene dichloride it is dissolved; Add the 200ml water washing, separate organic layer, use organic layer of 200ml water washing again, separate organic layer once more; Add 5g silica gel stirring at room 2min to the light green organic layer, filter, get red-brown filtrating.Solvent evaporated gets brown oil.With 60ml acetonitrile reflux oily matter is dissolved entirely, and then add the 60ml MTBE, have solid to separate out after being cooled to room temperature; With stirring in its placement ice-water bath, filter, use the MTBE flush cake; Drain; Get 25.3g buff powder, yield 69%, HPLC purity 99.52% after the drying.
Claims (10)
1. one kind prepares the 5-of compound 7-chloro-shown in the formula (1) oxo-1-(2-methyl-4-nitro benzoyl)-1,2,3, and the method for 4-tetrahydro benzo azatropylidene comprises following steps:
In the presence of mineral alkali and non-proton organic solvent, 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine (2) and 4-nitro-2-methyl benzoyl chloride (3) reaction obtains formula (1) compound.
2. preparation method according to claim 1, mineral alkali is a sodium hydroxide, Pottasium Hydroxide, salt of wormwood, saleratus, yellow soda ash, sodium hydrogencarbonate.
3. like the said preparation method of claim 2, mineral alkali is a sodium hydroxide.
4. preparation method according to claim 1, formula (2) is 1: 1～1: 4 with the mol ratio of mineral alkali.
5. like the said preparation method of claim 4, formula (2) is 1: 1～1: 2 with the mol ratio of mineral alkali.
6. preparation method according to claim 1, non-proton organic solvent is a THF, acetonitrile, DMSO 99.8MIN., N, dinethylformamide or their mixture.
7. like the said preparation method of claim 6, non-proton organic solvent is an acetonitrile.
8. preparation method according to claim 1, temperature of reaction is controlled at 0 ℃～40 ℃ and carries out.
9. like the said preparation method of claim 8, temperature of reaction is controlled at 15 ℃～25 ℃ scope.
10. preparation method according to claim 1, the reaction times was controlled at 1～3 hour, spent preferred 1～1.5 hour an of step.
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| CN201110272412.7A CN102382053B (en) | 2011-08-31 | 2011-08-31 | A kind of method preparing tolvaptan intermediate |
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| CN201110272412.7A CN102382053B (en) | 2011-08-31 | 2011-08-31 | A kind of method preparing tolvaptan intermediate |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180009228A (en) * | 2016-07-18 | 2018-01-26 | (주)헥사파마텍 | Improved process for preparing synthetic intermediates of tolvaptan |
| IT202000013573A1 (en) | 2020-06-08 | 2021-12-08 | Cambrex Profarmaco Milano S R L | INTERMEDIATE AND PROCESSES FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES |
Citations (5)
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| US4009208A (en) * | 1970-08-07 | 1977-02-22 | Sterling Drug Inc. | N,n'-heptamethylenebis(4-methoxybenzamide) |
| CN1051038A (en) * | 1989-10-20 | 1991-05-01 | 大塚制药株式会社 | Benzoheterocyclic compounds |
| CN101273017A (en) * | 2005-09-02 | 2008-09-24 | 大塚制药株式会社 | Method of manufacturing benzoazepin compound or its salt |
| CN101817783A (en) * | 2010-05-12 | 2010-09-01 | 天津泰普药品科技发展有限公司 | Method for preparing tolvaptan intermediate |
| CN102060769A (en) * | 2010-12-20 | 2011-05-18 | 天津药物研究院 | Preparation method of tolvaptan |
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2011
- 2011-08-31 CN CN201110272412.7A patent/CN102382053B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4009208A (en) * | 1970-08-07 | 1977-02-22 | Sterling Drug Inc. | N,n'-heptamethylenebis(4-methoxybenzamide) |
| CN1051038A (en) * | 1989-10-20 | 1991-05-01 | 大塚制药株式会社 | Benzoheterocyclic compounds |
| CN101273017A (en) * | 2005-09-02 | 2008-09-24 | 大塚制药株式会社 | Method of manufacturing benzoazepin compound or its salt |
| CN101817783A (en) * | 2010-05-12 | 2010-09-01 | 天津泰普药品科技发展有限公司 | Method for preparing tolvaptan intermediate |
| CN102060769A (en) * | 2010-12-20 | 2011-05-18 | 天津药物研究院 | Preparation method of tolvaptan |
Non-Patent Citations (6)
| Title |
|---|
| ALEJANDRO CORDERO-VARGAS,等: "A flexible approach for the preparation of substituted benzazepines:Application to the synthesis of tolvaptan", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| KAZUMI KONDO,等: "7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A Potent, Orally Active Nonpeptide Arginine Vasopressin V2 Receptor Antagonist", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
| KAZUMI KONDO,等: "Novel Design of Nonpeptide AVP V2 Receptor Agonists: Structural Requirements for an Agonist Having 1-(4-Aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepine as a Template", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| YASUHIRO TORISAWA,等: "Aminocarbonylation route to tolvaptan", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 刘杨,等: "莫扎伐普坦的合成工艺研究", 《中国药物化学杂志》 * |
| 杨传伟,等: "托伐普坦的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20180009228A (en) * | 2016-07-18 | 2018-01-26 | (주)헥사파마텍 | Improved process for preparing synthetic intermediates of tolvaptan |
| KR102592555B1 (en) | 2016-07-18 | 2023-10-23 | (주)헥사파마텍 | Improved process for preparing synthetic intermediates of tolvaptan |
| IT202000013573A1 (en) | 2020-06-08 | 2021-12-08 | Cambrex Profarmaco Milano S R L | INTERMEDIATE AND PROCESSES FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES |
| WO2021249877A1 (en) | 2020-06-08 | 2021-12-16 | Cambrex Profarmaco Milano S.R.L. | Intermediates and processes for the preparation of tolvaptan and its derivatives |
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Effective date of registration: 20170926 Address after: 317024 flood bridge, Linhai City, Zhejiang Co-patentee after: Shanghai SynCores Technologies Inc. Patentee after: Zhejiang Huahai Pharmaceutical Co., Ltd. Address before: 317024 Development Zone of Linhai bridge, Linhai City, Zhejiang Patentee before: Zhejiang Huahai Pharmaceutical Co., Ltd. |