CN103204810B - A kind of tolvaptan intermediate and preparation method thereof - Google Patents

A kind of tolvaptan intermediate and preparation method thereof Download PDF

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CN103204810B
CN103204810B CN201210008911.XA CN201210008911A CN103204810B CN 103204810 B CN103204810 B CN 103204810B CN 201210008911 A CN201210008911 A CN 201210008911A CN 103204810 B CN103204810 B CN 103204810B
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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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Jiangsu Kanion Pharmaceutical Co Ltd
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Abstract

The invention discloses a kind of 7 chlorine 5 oxos 2,3,4,5 tetrahydrochysene 1H 1 benzazepine carboxylic acid ester compounds and preparation method thereof, and utilize this compounds to prepare tolvaptan another kind intermediate 7 chlorine 5 oxo 2,3, the method of 4,5 tetrahydrochysene 1H 1 benzazepines.The method of the invention is utilized to prepare 7 chlorine 5 oxo 2,3,4,5 tetrahydrochysene 1H 1 benzazepine productivity high; can prepare through one kettle way, significantly simplify operation, and raw materials used, reagent is cheap and easy to get; reaction gentleness, environmentally friendly, it is suitable for large-scale production.

Description

A kind of tolvaptan intermediate and preparation method thereof
Technical field
The present invention relates to medicinal chemistry art, particularly to a kind of tolvaptan intermediate 7-chloro-5-oxo-2,3,4,5- Tetrahydrochysene-1H-1-benzazepine carboxylate and preparation method thereof, and utilize this intermediate to prepare in the middle of tolvaptan another kind Body 7-chloro-5-oxo-2, the method for 3,4,5-tetrahydrochysene-1H-1-benzazepines.
Background technology
Tolvaptan (Tolvaptan), chemical entitled 7-chloro-5-hydroxyl-1-[2-methyl-4-[(2-toluyl Base)-amino] benzoyl] 2,3,4,5-tetrahydrochysene-1H-1-benzazepines, its structural formula is as shown in formula IV:
Formula IV
Tolvaptan is that a kind of new oral developed by Otsuka Pharmaceutical Co., Ltd. of Japan (Otsuka Pharm) is non-peptide Class arginine vasopressin (AVP) V2 receptor antagonist.AVP V2 receptor antagonist is not affecting electrolyte balance in the patient Under premise, moisture excretion in the patient can be promoted, so this medicine is used for treating by congestive heart failure, cirrhosis clinically And the hyponatremia that antidiuresis kinases diacrisis syndrome causes.This medicine obtained in FDA approval on May 19th, 2009 City.
Containing a benzo nitrogen Zhuo Huan, document Bioorg.Med.Chem, 1999,7 (8): 1743-in tolvaptan molecule Prepared acid amides is reacted through nitro reduction and 2-methyl benzoyl chloride after compound and acyl chloride reaction shown in 1754 employing formula IIIs, Tolvaptan is prepared again through carbonyl reduction.Compound shown in formula III is a key intermediate of synthesis tolvaptan.Its system The method of standby tolvaptan is as follows:
The existing method (Bioorg.Med.Chem, 1999,7 (8): 1743-1754) preparing compound shown in formula III It is to be former with the chloro-2-of the 5-shown in Formula V [N-(3-ethoxycarbonylpropyl)-N-(p-toluenesulfonyl)] Methyl anthranilate Material, prepares compound shown in Formula II through Claisen condensation, then concentrated hydrochloric acid, acetic acid effect under prepare shown in Formula IV after decarboxylation Compound, then with polyphosphoric acids react removing p-toluenesulfonyl prepare compound shown in formula III.
Formula V Formula II Formula IV formula III
There is shortcoming will be apparent below in the method: (1) to use substantial amounts of hydrochloric acid and acetic acid, and environmental pollution is big and acetic acid Reclaim more difficult;(2) polyphosphoric acids viscosity is very big, and the transfer of industrialized production material and operation are difficult to;(3) reaction yield The highest, in terms of compound shown in Formula V, 3 step reaction yields totally 48.6%.
It is excellent that poplar wonderful (Chinese Journal of Pharmaceuticals, 2009,40 (9): 648-650) et al. has carried out technique to said method Changing, the yield of this 3 step reaction is 53.6%, and yield slightly improves, but does not overcomes disadvantages mentioned above yet.
Summary of the invention
The invention aims to provide a kind of midbody compound new during preparing tolvaptan and system thereof Preparation Method, and utilize this compound to prepare 7-chloro-5-oxo-2, the method for 3,4,5-tetrahydrochysene-1H-1-benzazepines.
The invention provides a kind of 7-shown in formula I chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine carboxylics Acid esters compound,
Formulas I
Wherein R is the alkyl of C1~C6, substituted-phenyl, benzyl or substituted benzyl.
Wherein said substituted-phenyl, substituted benzyl are any substituted phenyl and benzyl, such as halogenophenyl, halogeno-benzyl.
Present invention also offers a kind of method preparing compound shown in formula I, compound shown in Formula II is in the effect of acid Lower removing p-toluenesulfonyl, obtains compound shown in Formulas I,
Formula II Formulas I
The reactant of this reaction heats the reaction that removing p-toluenesulfonyl occurs under the action of an acid.Wherein said acid is One or more in phosphoric acid, polyphosphoric acids or the concentrated sulfuric acid.
As preferably, the acid that reaction is used is the concentrated sulfuric acid.
In this reaction, reactant is 1: 1~50 with the mol ratio of acid used, and reaction temperature is 40 DEG C~100 DEG C.
As preferably, reactant is 1: 10~30 with the mol ratio of acid used, and reaction temperature is 50 DEG C~80 DEG C.
It is raw that the method for the invention uses high concentrated acid that compound shown in Formula II carries out de-p-toluenesulfonyl protection group Becoming compound shown in Formulas I, this law is the quickest.If using low concentration acid, removing p-toluenesulfonyl can not completely or root This does not reacts.
Present invention also offers and a kind of utilize the method for compound shown in preparation of compounds of formula III described in Formulas I, shown in Formulas I There is decarboxylic reaction in compound under the effect of diluted acid, obtains compound shown in formula III,
Formulas I formula III
The reactant of this reaction heats under the effect of diluted acid, and decarboxylic reaction occurs.Wherein said diluted acid is hydrochloric acid, hydrogen bromine One or more in acid, nitric acid, phosphoric acid, polyphosphoric acids, sulfuric acid, formic acid, acetic acid, propionic acid, halogenated acid or sulfonic acid.Reaction temperature It it is 50 DEG C~150 DEG C.
As preferably, reaction temperature is 80 DEG C~120 DEG C.
Main advantages of the present invention are as follows:
1) the method applied in the present invention prepares the yield of compound shown in formula III compared with in prior art the 53.6% of report Height, average yield is more than 80%;
2) in the present invention, compound shown in Formula II removes p-toluenesulfonyl under the effect of concentrated acid, after reaction completely, Shown in the Formulas I arrived, compound is without isolation, directly addition suitable quantity of water dilute reaction solution in reaction vessel, more in a heated condition Decarboxylation occurring, can prepare compound shown in formula III through one kettle way, the method significantly simplifies operation, improves instead Answer yield;
3) raw material, reagent used in the present invention are cheap and easy to get, reaction gentleness, easy and simple to handle, environmentally friendly, are suitable for rule Modelling produces.
Detailed description of the invention
The invention discloses a kind of tolvaptan intermediate and preparation method thereof, and it is chloro-to utilize this compound to prepare 7- 5-oxo-2, the method for 3,4,5-tetrahydrochysene-1H-1-benzazepines.Those skilled in the art can use for reference present disclosure, suitably Improvement technological parameter realizes.Special needs to be pointed out is, all similar replacements and change are for a person skilled in the art It will be apparent that they are considered as being included in the present invention.Method and the application of the present invention are carried out by preferred embodiment Describe, related personnel substantially can in without departing from present invention, spirit and scope to method described herein and apply into Row is changed or suitably change and combination, realizes and applies the technology of the present invention.
The invention provides a kind of 7-shown in formula I chloro-5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine carboxylics Acid esters compound,
Formulas I
Wherein R is the alkyl of C1~C6, substituted-phenyl, benzyl or substituted benzyl.
Wherein said substituted-phenyl, substituted benzyl are any substituted phenyl and benzyl, such as halogenophenyl, halogeno-benzyl.
Present invention also offers a kind of method preparing compound shown in formula I, compound shown in Formula II is in the effect of acid Lower generation removes p-toluenesulfonyl, obtains compound shown in Formulas I,
Formula II Formulas I
Present invention also offers and a kind of utilize the method for compound shown in preparation of compounds of formula III described in Formulas I, shown in Formulas I There is decarboxylic reaction in compound under the effect of diluted acid, obtains compound shown in formula III,
Formulas I formula III
In order to make those skilled in the art be more fully understood that technical scheme, below in conjunction with specific embodiment pair The present invention is described in further detail.Wherein compound shown in Formula II is referred to document Bioorg.Med.Chem, and 1999,7 (8): 1743-1754 and Chinese Journal of Pharmaceuticals 2009,40 (9): 648-650 are prepared.
Embodiment 1:7-chloro-5-oxo-2, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl esters
One equipped with magnetic stirrer, thermometer tetra-mouthfuls of round-bottomed flasks of 500mL in, add 7-chloro-5-oxo-1-to first Benzenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.1g, concentrated sulfuric acid 2.0g.40 DEG C of reactions 2 are little Time, with cryosel bath cooling after TLC display reaction completely, it is slowly added dropwise saturated sodium bicarbonate solution, regulates pH7~8,100mL second Acetoacetic ester extracts, and organic phases washed with brine after separatory, anhydrous magnesium sulfate is dried, and solvent is evaporated off after filtration, and silica gel column chromatography obtains To compound 4.4g shown in Formulas I, pale yellow oily liquid body, yield 87.6%.
ESI-MS (m/z): 254 (M+H), 277 (M+Na), 293 (M+K)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl esters
One equipped with magnetic stirrer, thermometer tetra-mouthfuls of round-bottomed flasks of 500mL in, add 7-chloro-5-oxo-1-to first Benzenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl ester 8.4g, 80% phosphatase 11 22.5g.100 DEG C of reactions 2 hours, with cryosel bath cooling after TLC display reaction completely, it is slowly added dropwise saturated sodium bicarbonate solution, regulates pH7~8,100mL Ethyl acetate extracts, and organic phases washed with brine after separatory, anhydrous magnesium sulfate is dried, and solvent, silica gel column chromatography are evaporated off after filtration Obtain compound 4.8g shown in Formulas I, pale yellow oily liquid body, yield 89.1%.
ESI-MS (m/z): 268 (M+H), 290 (M+Na), 306 (M+K)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl esters
One equipped with magnetic stirrer, thermometer tetra-mouthfuls of round-bottomed flasks of 500mL in, add 7-chloro-5-oxo-1-to first Benzenesulfonyl-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 8.1g, concentrated sulfuric acid 20.0g, polyphosphoric acids 33.8g.70 DEG C are reacted 2 hours, with cryosel bath cooling after TLC display reaction completely, are slowly added dropwise saturated sodium bicarbonate solution, adjust Joint pH7~8,100mL ethyl acetate extracts, and organic phases washed with brine after separatory, anhydrous magnesium sulfate is dried, and is evaporated off molten after filtration Agent, silica gel column chromatography obtains compound 4.2g shown in Formulas I, pale yellow oily liquid body, yield 83.6%.
ESI-MS (m/z): 254 (M+H), 277 (M+Na), 293 (M+K)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepines
One equipped with in tetra-mouthfuls of round-bottomed flasks of 100mL of magnetic stirrer, thermometer and reflux condensing tube, add 7-chloro- 5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 4.0g, 3N hydrochloric acid 50mL, 50 DEG C are reacted 3 hours, Reaction regulates pH to 7~8 with 10% sodium hydroxide solution after terminating, and 50mL dichloromethane extracts, organic phase salt solution after separatory Washing, anhydrous magnesium sulfate is dried, and filters silica gel column chromatography after dichloromethane is evaporated off and obtains compound 2.8g shown in formula III, yellowish Look solid, mp 101.0~102.0 DEG C, yield 90.3%.
MS:195 (M+H), 218 (M+Na)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepines
One equipped with in tetra-mouthfuls of round-bottomed flasks of 100mL of magnetic stirrer, thermometer and reflux condensing tube, add 7-chloro- 5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylic acid, ethyl ester 4.0g, formic acid 50mL, 150 DEG C react 3 hours, instead With 10% sodium hydroxide solution regulation pH to 7~8 after should terminating, 50mL dichloromethane extracts, and after separatory, organic phase salt is washed Washing, anhydrous magnesium sulfate is dried, and filters silica gel column chromatography after dichloromethane is evaporated off and obtains compound 2.6g shown in formula III, faint yellow Solid, mp 101.0~102.0 DEG C, yield 88.1%.
MS:195 (M+H), 218 (M+Na)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepines
One equipped with in tetra-mouthfuls of round-bottomed flasks of 100mL of magnetic stirrer, thermometer and reflux condensing tube, add 7-chloro- 5-oxo-2,3,4,5-tetrahydrochysene-1H-1-benzazepine-4-carboxylate methyl ester 4.0g, hydrobromic acid 50mL, acetic acid 5mL, 100 DEG C anti- Answering 3 hours, reaction regulates pH to 7~8 with 10% sodium hydroxide solution after terminating, and 50mL dichloromethane extracts, organic after separatory Washing with salt solution, anhydrous magnesium sulfate is dried, and filters silica gel column chromatography after dichloromethane is evaporated off and obtains compound shown in formula III 2.7g, faint yellow solid, mp 101.0~102.0 DEG C, yield 87.1%.
MS:195 (M+H), 218 (M+Na)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepines
One equipped with in tetra-mouthfuls of round-bottomed flasks of 250mL of magnetic stirrer, 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, the concentrated sulfuric acid 20.0g, 50 DEG C are reacted 2 hours, and TLC confirms that raw material instills 20mL water after converting completely, and a large amount of gases escape, and drip complete intensification Adding saturated aqueous sodium carbonate after confirming to convert completely to 80 DEG C of reactions 1h, TLC, filtration washing obtains chemical combination shown in formula III Thing 3.3g, faint yellow solid, mp 101.0~102.0 DEG C, yield 84.6%.
MS:195 (M+H), 218 (M+Na)
1HNMR:(400MHz, CDCl3) 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, the preparation of 3,4,5-tetrahydrochysene-1H-1-benzazepines
One equipped with in tetra-mouthfuls of round-bottomed flasks of 250mL of magnetic stirrer, 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, the concentrated sulfuric acid 60.0g, 80 DEG C are reacted 2 hours, and TLC confirms that raw material instills 20mL water after converting completely, and a large amount of gases escape, and drip complete intensification Adding saturated aqueous sodium carbonate after confirming to convert completely to 120 DEG C of reactions 1h, TLC, filtration washing obtains chemical combination shown in formula III Thing 3.2g, faint yellow solid, mp 101.0~102.0 DEG C, yield 82.1%.
MS:195 (M+H), 218 (M+Na)
1HNMR:(400MHz, CDCl3) 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 is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (9)

1. the preparation method of compound described in a Formulas I, it is characterised in that shown in Formula II, compound takes off under the action of an acid Except p-toluenesulfonyl reacts, obtain compound shown in Formulas I,
Described acid is one or more in phosphoric acid, polyphosphoric acids or the concentrated sulfuric acid;
Wherein, Ts is
Wherein, R is the alkyl of C1~C6, substituted-phenyl, benzyl or substituted benzyl.
Method the most according to claim 1, it is characterised in that described acid is the concentrated sulfuric acid.
Method the most according to claim 1, it is characterised in that the mol ratio of compound shown in described acid and Formula II be 1~ 50:1.
Method the most according to claim 3, it is characterised in that described mol ratio is 10~30:1.
Method the most according to claim 1, it is characterised in that the temperature of described reaction is 40 DEG C~100 DEG C.
Method the most according to claim 5, it is characterised in that the temperature of described reaction is 50 DEG C~80 DEG C.
7. the preparation method of compound shown in a formula III, it is characterised in that
Occur compound shown in Formula II under the action of an acid to remove p-toluenesulfonyl reaction, obtain compound shown in Formulas I,
Described acid is one or more in phosphoric acid, polyphosphoric acids or the concentrated sulfuric acid,
Wherein, Ts is
Wherein, R is the alkyl of C1~C6, substituted-phenyl, benzyl or substituted benzyl;
Under the effect of another kind of acid, be there is decarboxylic reaction in compound shown in Formulas I, obtains compound shown in formula III,
Described another kind of acid is selected from hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, polyphosphoric acids, sulfuric acid, formic acid, acetic acid, propionic acid, halo One or more in acid or sulfonic acid.
Method the most according to claim 7, it is characterised in that described by compound shown in Formulas I in the effect of another kind of acid The temperature of lower generation decarboxylic reaction is 50 DEG C~150 DEG C.
Method the most according to claim 8, it is characterised in that described by compound shown in Formulas I in the effect of another kind of acid The temperature of lower generation decarboxylic reaction is 80 DEG C~120 DEG C.
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JP4238978B2 (en) * 2003-04-22 2009-03-18 大塚製薬株式会社 Benzazepine compounds and process for producing the same
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