CN103204810A - Tolvaptan intermediate and preparation method thereof - Google Patents

Tolvaptan intermediate and preparation method thereof Download PDF

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CN103204810A
CN103204810A CN201210008911XA CN201210008911A CN103204810A CN 103204810 A CN103204810 A CN 103204810A CN 201210008911X A CN201210008911X A CN 201210008911XA CN 201210008911 A CN201210008911 A CN 201210008911A CN 103204810 A CN103204810 A CN 103204810A
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formula
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CN103204810B (en
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张福利
梁小敏
萧伟
吴泰志
郭庆明
姜学书
肖立
张伟
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Kanion Pharmaceutical Co Ltd
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Kanion Pharmaceutical Co Ltd
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Abstract

The invention discloses a 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine carboxylic ester compound, its preparation method, and a method of utilizing the compound to prepare another tolvaptan intermediate 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine. The 7-chloro-5-oxo-2, 3, 4, 5-tetrahydro-1H-1-benzoazepine prepared by the method provided in the invention has a high yield, and can be prepared by a one-pot process, thus greatly simplifying the reaction operation. Also, the used materials and reagents are cheap and commercially available, the reaction is mild and environment-friendly, so that the method is suitable for large-scale production.

Description

A kind of tolvaptan intermediate and preparation method thereof
Technical field
The present invention relates to the pharmaceutical chemistry field, be particularly related to a kind of tolvaptan intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine carboxylicesters and preparation method thereof, and utilize the another kind of intermediate 7-of this intermediate preparation tolvaptan chloro-5-oxo-2,3, the method of 4,5-tetrahydrochysene-1H-1-benzazepine.
Background technology
Tolvaptan (Tolvaptan), chemistry 7-chloro-5-hydroxyl by name-1-[2-methyl-4-[(2-methyl benzoyl)-amino] benzoyl] 2,3,4,5-tetrahydrochysene-1H-1-benzazepine, its structural formula is suc as formula shown in the IV:
Formula IV
Tolvaptan is the non-peptide class of a kind of new oral arginine vasopressin (AVP) the V2 receptor antagonist by Japanese Otsuka Pharmaceutical Co., Ltd. (Otsuka Pharm) exploitation.AVP V2 receptor antagonist is under the prerequisite that does not influence patient's cylinder electrolyte balance, can promote that moisture is drained in patient's body, so this medicine is used for treating the hyponatremia that is caused by congestive heart failure, liver cirrhosis and antidiuresis kinases diacrisis syndromes clinically.This medicine obtains FDA approval listing on May 19th, 2009.
Contain a benzo nitrogen Zhuo Huan in the tolvaptan molecule, document Bioorg.Med.Chem, 1999,7 (8): 1743-1754 adopts behind compound shown in the formula III and the acyl chloride reaction through nitroreduction, makes acid amides with the reaction of 2-methyl benzoyl chloride, passes through carbonyl reduction again and makes tolvaptan.Compound shown in the formula III is a key intermediate of synthetic tolvaptan.Its method for preparing tolvaptan is as follows:
Existing method (the Bioorg.Med.Chem for preparing compound shown in the formula III; 1999; 7 (8): be with the 5-chloro-2-[N-shown in the formula V (3-ethoxycarbonyl propyl group)-N-(p-toluenesulfonyl) 1743-1754)] Methyl anthranilate is raw material; make compound shown in the formula II through the claisen ester condensation; after decarboxylation under the effect of concentrated hydrochloric acid, acetic acid, make compound shown in the formula VI again, remove p-toluenesulfonyl with the polyphosphoric acid reaction again and make compound shown in the formula III.
Formula V formula II formula VI formula III
There is following significant disadvantages in this method: (1) will use a large amount of hydrochloric acid and acetic acid, and environmental pollution recovery big and acetic acid is difficult; (2) polyphosphoric acid viscosity is very big, and the industrialized production material shifts and operation is difficult for; (3) reaction yield is not high, in compound shown in the formula V, and 3 step reaction yields totally 48.6%.
Poplar is wonderful, and (Chinese Journal of Pharmaceuticals, 2009,40 (9): 648-650) wait the people that aforesaid method has been carried out process optimization, the yield of this 3 step reaction is 53.6%, and yield has raising slightly, but does not overcome above-mentioned shortcoming yet.
Summary of the invention
The objective of the invention is for a kind of midbody compound new in preparation tolvaptan process and preparation method thereof is provided, and utilize this compound 7-chloro-5-oxo-2,3,4, the method for 5-tetrahydrochysene-1H-1-benzazepine.
The invention provides a kind of suc as formula the 7-chloro-5-oxo-2,3,4 shown in the I, 5-tetrahydrochysene-1H-1-benzazepine carboxylic acid ester compound,
Formula I
Wherein R is alkyl, substituted-phenyl, benzyl or the substituted benzyl of C1~C6.
Wherein said substituted-phenyl, substituted benzyl are phenyl and the benzyl that replaces arbitrarily, as halogenophenyl, halogeno-benzyl.
The present invention also provides the method for a kind of preparation suc as formula compound shown in the I, and compound removes p-toluenesulfonyl shown in the formula II under the effect of acid, obtains compound shown in the formula I,
Formula II formula I
The reactant of this reaction heats the reaction that removes p-toluenesulfonyl under the effect of acid.Wherein said acid is one or more in phosphoric acid, polyphosphoric acid or the vitriol oil.
As preferably, reacting employed acid is the vitriol oil.
In this reaction, the mol ratio of reactant and used acid is 1: 1~50, and temperature of reaction is 40 ℃~100 ℃.
As preferably, the mol ratio of reactant and used acid is 1: 10~30, and temperature of reaction is 50 ℃~80 ℃.
The method of the invention uses high concentrated acid that compound shown in the formula II is taken off compound shown in the p-toluenesulfonyl protecting group production I, and this law is efficiently quick.If use lower concentration acid, removing p-toluenesulfonyl can not react fully or not.
The present invention also provides a kind of method of utilizing compound shown in the described compound formula III of formula I, and compound shown in the formula I under the effect of diluted acid decarboxylic reaction takes place, and obtains compound shown in the formula III,
Formula I formula III
The reactant of this reaction heats under the effect of diluted acid, and decarboxylic reaction takes place.Wherein said diluted acid is one or more in hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, polyphosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, halogenated acid or the sulfonic acid.Temperature of reaction is 50 ℃~150 ℃.
As preferably, temperature of reaction is 80 ℃~120 ℃.
Major advantage of the present invention is as follows:
1) the method applied in the present invention prepare compound shown in the formula III yield than 53.6% height of reporting in the prior art, average yield is more than 80%;
2) compound removes p-toluenesulfonyl shown in the Chinese style II of the present invention under the effect of concentrated acid, after reacting completely, compound is without separation shown in the formula I that obtains, directly in reaction vessel, add the suitable quantity of water dilute reaction solution, under heating condition decarboxylation takes place again, can make compound shown in the formula III through one kettle way, this method has significantly been simplified operation, has been improved reaction yield;
3) the used raw material of the present invention, reagent are cheap and easy to get, reaction temperature and, easy and simple to handle, environmentally friendly, be fit to large-scale production.
Embodiment
The invention discloses a kind of tolvaptan intermediate and preparation method thereof, and utilize this compound 7-chloro-5-oxo-2,3,4, the method for 5-tetrahydrochysene-1H-1-benzazepine.Those skilled in the art can use for reference this paper content, suitably improve processing parameter and realize.Special needs to be pointed out is that all similarly replace and change apparent to those skilled in the art, they all are regarded as being included in the present invention.Method of the present invention and application are described by preferred embodiment, the related personnel obviously can change or suitably change and combination methods and applications as herein described in not breaking away from content of the present invention, spirit and scope, realizes and use the technology of the present invention.
The invention provides a kind of suc as formula the 7-chloro-5-oxo-2,3,4 shown in the I, 5-tetrahydrochysene-1H-1-benzazepine carboxylic acid ester compound,
Formula I
Wherein R is alkyl, substituted-phenyl, benzyl or the substituted benzyl of C1~C6.
Wherein said substituted-phenyl, substituted benzyl are phenyl and the benzyl that replaces arbitrarily, as halogenophenyl, halogeno-benzyl.
The present invention also provides the method for a kind of preparation suc as formula compound shown in the I, and compound removes p-toluenesulfonyl shown in the formula II under the effect of acid, obtains compound shown in the formula I,
Formula II formula I
The present invention also provides a kind of method of utilizing compound shown in the described compound formula III of formula I, and compound shown in the formula I under the effect of diluted acid decarboxylic reaction takes place, and obtains compound shown in the formula III,
Formula I formula III
In order to make those skilled in the art understand technical scheme of the present invention better, the present invention is described in further detail below in conjunction with specific embodiment.Compound shown in its Chinese style II can reference Bioorg.Med.Chem, and 1999,7 (8): 1743-1754 and Chinese Journal of Pharmaceuticals 2009,40 (9): 648-650 is prepared.
Embodiment 1:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester
Be equipped with in the 500mL four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.1g, vitriol oil 2.0g.40 ℃ were reacted 2 hours, after reacting completely, the TLC demonstration bathes cooling with cryosel, slowly drip saturated sodium bicarbonate solution, regulate pH7~8, the 100mL ethyl acetate extraction, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying filters the back steaming and desolventizes, and silica gel column chromatography obtains compound 4.4g shown in the formula I, the pale yellow oily liquid body, yield 87.6%.
ESI-MS(m/z):254(M+H),277(M+Na),293(M+K)
1HNMR:(400MHz,CDCl 3)2.10(2H,m),3.16(2H,m),3.77(1H,t),3.58(3H,s),6.54(1H,s),6.90(1H,d),7.55(1H,d),7.72(1H,s)。
Embodiment 2:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl ester
Be equipped with in the 500mL four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl ester 8.4g, 80% phosphatase 11 22.5g.100 ℃ were reacted 2 hours, after reacting completely, the TLC demonstration bathes cooling with cryosel, slowly drip saturated sodium bicarbonate solution, regulate pH7~8, the 100mL ethyl acetate extraction, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying filters the back steaming and desolventizes, and silica gel column chromatography obtains compound 4.8g shown in the formula I, the pale yellow oily liquid body, yield 89.1%.
ESI-MS(m/z):268(M+H),290(M+Na),306(M+K)
1HNMR:(400MHz,CDCl 3)1.30(3H,t),2.15(2H,m),3.11(2H,m),3.85(1H,t),4.20(2H,m),5.84(1H,s),6.88(1H,d),7.65(1H,d),7.79(1H,s)。
Embodiment 3:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester
Be equipped with in the 500mL four-hole round-bottomed flask of magnetic stirrer, thermometer one, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.1g, vitriol oil 20.0g, polyphosphoric acid 33.8g.70 ℃ were reacted 2 hours, after reacting completely, the TLC demonstration bathes cooling with cryosel, slowly drip saturated sodium bicarbonate solution, regulate pH7~8, the 100mL ethyl acetate extraction, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying filters the back steaming and desolventizes, and silica gel column chromatography obtains compound 4.2g shown in the formula I, the pale yellow oily liquid body, yield 83.6%.
ESI-MS(m/z):254(M+H),277(M+Na),293(M+K)
1HNMR:(400MHz,CDCl 3)2.10(2H,m),3.16(2H,m),3.77(1H,t),3.58(3H,s),6.54(1H,s),6.90(1H,d),7.55(1H,d),7.72(1H,s)。
Embodiment 4:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine
Be equipped with in the 100mL four-hole round-bottomed flask of magnetic stirrer, thermometer and reflux condensing tube one, add 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 4.0g, 3N hydrochloric acid 50mL, 50 ℃ were reacted 3 hours, and reaction finishes the back and regulates pH to 7~8,50mL dichloromethane extraction with 10% sodium hydroxide solution, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying filters steaming and obtains the 2.8g of compound shown in the formula III, faint yellow solid except silica gel column chromatography behind the methylene dichloride, 101.0~102.0 ℃ of mp, yield 90.3%.
MS:195(M+H),218(M+Na)
1HNMR:(400MHz,CDCl 3)1.96(2H,m),2.40(2H,m),3.83(2H,m),6.88(1H,d),7.40(1H,m),7.59(1H,m),7.66(1H,m)
Embodiment 5:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine
Be equipped with in the 100mL four-hole round-bottomed flask of magnetic stirrer, thermometer and reflux condensing tube one, add 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl ester 4.0g, formic acid 50mL, 150 ℃ were reacted 3 hours, and reaction finishes the back and regulates pH to 7~8,50mL dichloromethane extraction with 10% sodium hydroxide solution, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying filters steaming and obtains the 2.6g of compound shown in the formula III, faint yellow solid except silica gel column chromatography behind the methylene dichloride, 101.0~102.0 ℃ of mp, yield 88.1%.
MS:195(M+H),218(M+Na)
1HNMR:(400MHz,CDCl 3)1.96(2H,m),2.40(2H,m),3.83(2H,m),6.88(1H,d),7.40(1H,m),7.59(1H,m),7.66(1H,m)
Embodiment 6:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine
One magnetic stirrer is housed, in the 100mL four-hole round-bottomed flask of thermometer and reflux condensing tube, add 7-chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 4.0g, Hydrogen bromide 50mL, acetic acid 5mL, 100 ℃ were reacted 3 hours, reaction finishes the back and regulates pH to 7~8 with 10% sodium hydroxide solution, the 50mL dichloromethane extraction, organic phase salt water washing behind the separatory, anhydrous magnesium sulfate drying, filter steaming and obtain the 2.7g of compound shown in the formula III except silica gel column chromatography behind the methylene dichloride, faint yellow solid, 101.0~102.0 ℃ of mp, yield 87.1%.
MS:195(M+H),218(M+Na)
1HNMR:(400MHz,CDCl 3)1.96(2H,m),2.40(2H,m),3.83(2H,m),6.88(1H,d),7.40(1H,m),7.59(1H,m),7.66(1H,m)
Embodiment 7:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine
One magnetic stirrer is housed; in the 250mL four-hole round-bottomed flask of thermometer and reflux condensing tube; add 7-chloro-5-oxo-1-p-toluenesulfonyl-2; 3; 4; 5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.1g; vitriol oil 20.0g; 50 ℃ were reacted 2 hours, and TLC confirms to splash into 20mL water after feedstock conversion fully, and a large amount of gases are overflowed; dropwise and be warming up to 80 ℃ of reaction 1h; TLC confirms to transform back adding saturated aqueous sodium carbonate fully, and filtration washing obtains the 3.3g of compound shown in the formula III, faint yellow solid; 101.0~102.0 ℃ of mp, yield 84.6%.
MS:195(M+H),218(M+Na)
1HNMR:(400MHz,CDCl 3)1.96(2H,m),2.40(2H,m),3.83(2H,m),6.88(1H,d),7.40(1H,m),7.59(1H,m),7.66(1H,m)
Embodiment 8:7-chloro-5-oxo-2,3,4, the preparation of 5-tetrahydrochysene-1H-1-benzazepine
One magnetic stirrer is housed; in the 250mL four-hole round-bottomed flask of thermometer and reflux condensing tube; add 7-chloro-5-oxo-1-p-toluenesulfonyl-2; 3; 4; 5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.4g; vitriol oil 60.0g; 80 ℃ were reacted 2 hours, and TLC confirms to splash into 20mL water after feedstock conversion fully, and a large amount of gases are overflowed; dropwise and be warming up to 120 ℃ of reaction 1h; TLC confirms to transform back adding saturated aqueous sodium carbonate fully, and filtration washing obtains the 3.2g of compound shown in the formula III, faint yellow solid; 101.0~102.0 ℃ of mp, yield 82.1%.
MS:195(M+H),218(M+Na)
1HNMR:(400MHz,CDCl 3)1.96(2H,m),2.40(2H,m),3.83(2H,m),6.88(1H,d),7.40(1H,m),7.59(1H,m),7.66(1H,m)
The above only is preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.

Claims (12)

1. compound shown by formula I,
Formula I
Wherein R is alkyl, substituted-phenyl, benzyl or the substituted benzyl of C1~C6.
2. one kind prepares the method for compound according to claim 1, it is characterized in that, compound shown in the formula II removes the tolysulfonyl radical reaction under the effect of acid, obtain compound shown in the formula I,
Formula II formula I
Wherein, Ts is
3. method according to claim 2 is characterized in that, described acid is to be selected from phosphoric acid, polyphosphoric acid or the vitriol oil one or more.
4. method according to claim 3 is characterized in that, described acid is the vitriol oil.
5. method according to claim 2 is characterized in that, the mol ratio of compound is 1~50: 1 shown in described acid and the formula II.
6. method according to claim 5 is characterized in that, described mol ratio is 10~30: 1.
7. method according to claim 2 is characterized in that, the temperature of described reaction is 40 ℃~100 ℃.
8. method according to claim 7 is characterized in that, the temperature of described reaction is 50 ℃~80 ℃.
9. a method of utilizing compound shown in the described compound formula III of claim 1 is characterized in that compound shown in the formula I under the effect of diluted acid decarboxylic reaction takes place, and obtains compound shown in the formula III,
Formula I formula III
10. method according to claim 9 is characterized in that, described diluted acid is to be selected from hydrochloric acid, Hydrogen bromide, nitric acid, phosphoric acid, polyphosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, halogenated acid or the sulfonic acid one or more.
11. method according to claim 9 is characterized in that, the temperature of described reaction is 50 ℃~150 ℃.
12. method according to claim 11 is characterized in that, the temperature of described reaction is 80 ℃~120 ℃.
CN201210008911.XA 2012-01-12 2012-01-12 A kind of tolvaptan intermediate and preparation method thereof Active CN103204810B (en)

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Cited By (2)

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CN105315212A (en) * 2014-07-31 2016-02-10 上海天慈生物谷生物工程有限公司 Preparation method for vasopressin antagonist
CN111995576A (en) * 2020-08-31 2020-11-27 三峡大学 Process for preparing polysubstituted nitrogen-containing heterocyclic compound

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Publication number Priority date Publication date Assignee Title
CN105315212A (en) * 2014-07-31 2016-02-10 上海天慈生物谷生物工程有限公司 Preparation method for vasopressin antagonist
CN105315212B (en) * 2014-07-31 2019-06-18 上海天慈生物谷生物工程有限公司 A kind of preparation method of vasopressin antagonistic drug
CN111995576A (en) * 2020-08-31 2020-11-27 三峡大学 Process for preparing polysubstituted nitrogen-containing heterocyclic compound

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