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

Abstract

The invention discloses a 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine carboxylate compound and a preparation method thereof, and the use of the compound A method for preparing another intermediate of tolvaptan, 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. Utilize the method of the present invention to prepare 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine with high yield, which can be prepared by one-pot method, greatly simplifying The reaction is operated, and the raw materials and reagents used are cheap and easy to obtain, the reaction is mild, the environment is friendly, and it is suitable for large-scale production.

Description

A kind of tolvaptan intermediate and preparation method thereof

technical field

The invention relates to the field of medicinal chemistry, in particular to a tolvaptan intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine carboxylate and Its preparation method, and the method for preparing another tolvaptan intermediate 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine by using this intermediate .

Background technique

Tolvaptan (Tolvaptan), the chemical name is 7-chloro-5-hydroxy-1-[2-methyl-4-[(2-methylbenzoyl)-amino]benzoyl] 2,3, 4,5-tetrahydro-1H-1-benzazepine, its structural formula is as shown in formula IV:

Formula IV

Tolvaptan is a novel oral non-peptide arginine vasopressin (AVP) V2 receptor antagonist developed by Otsuka Pharm. AVP V2 receptor antagonists can promote the excretion of water in the patient's body without affecting the electrolyte balance in the patient's body. of hyponatremia. The drug was approved by the FDA on May 19, 2009.

Tolvaptan molecule contains a benzazepine ring, document Bioorg.Med.Chem, 1999,7 (8): 1743-1754 adopts the compound shown in formula III to react with acid chloride and then through nitro reduction, and 2-methyl benzoyl chloride reaction to prepare amide, and then through carbonyl reduction to prepare tolvaptan. The compound shown in formula III is a key intermediate in the synthesis of tolvaptan. Its method for preparing tolvaptan is as follows:

The existing method (Bioorg.Med.Chem, 1999, 7(8):1743-1754) of the compound shown in the preparation formula III is 5-chloro-2-[N-(3-ethoxy) shown in the formula V Carbonylpropyl)-N-(p-toluenesulfonyl)]aminobenzoic acid methyl ester is used as raw material, and the compound shown in formula II is obtained through Claisen ester condensation, and then decarboxylated under the action of concentrated hydrochloric acid and acetic acid to obtain the formula The compound shown in VI is reacted with polyphosphoric acid to remove p-toluenesulfonyl to obtain the compound shown in formula III.

Formula V Formula II Formula VI Formula III

This method has following obvious shortcomings: (1) will use a large amount of hydrochloric acid and acetic acid, environmental pollution is big and the recovery of acetic acid is more difficult; (2) polyphosphoric acid is viscous extremely, and industrialized large-scale production material transfer and reaction operation are not easy; (3) The reaction yield is not high, based on the compound shown in formula V, the 3-step reaction yield is 48.6% in total.

Yang Miao (Chinese Journal of Pharmaceutical Industry, 2009, 40 (9): 648-650) and others have carried out process optimization to the above-mentioned method, and the yield of this 3-step reaction is 53.6%, and the yield has improved slightly, but still not overcome the above disadvantages.

Contents of the invention

The purpose of the present invention is to provide a new intermediate compound and its preparation method in the process of preparing tolvaptan, and to use the compound to prepare 7-chloro-5-oxo-2,3,4,5-tetra Method for Hydrogen-1H-1-Benzazepines.

The present invention provides a 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine carboxylate compound as shown in formula I,

Formula I

Wherein R is C1-C6 alkyl, substituted phenyl, benzyl or substituted benzyl.

Wherein said substituted phenyl and substituted benzyl are any substituted phenyl and benzyl, such as halogenated phenyl and halogenated benzyl.

The present invention also provides a method for preparing the compound shown in formula I, the compound shown in formula II removes the p-toluenesulfonyl group under the action of acid to obtain the compound shown in formula I,

Formula II Formula I

The reactants of this reaction are heated under the action of acid to remove p-toluenesulfonyl. Wherein the acid is one or more of phosphoric acid, polyphosphoric acid or concentrated sulfuric acid.

Preferably, the acid used in the reaction is concentrated sulfuric acid.

In the reaction, the molar ratio of the reactant to the acid used is 1:1-50, and the reaction temperature is 40°C-100°C.

Preferably, the molar ratio of the reactant to the acid used is 1:10-30, and the reaction temperature is 50°C-80°C.

The method of the present invention uses a high-concentration acid to remove the p-toluenesulfonyl protecting group of the compound shown in the formula II to generate the compound shown in the formula I, and the method is efficient and fast. If a low concentration of acid is used, removal of the p-toluenesulfonyl group is incomplete or does not occur at all.

The present invention also provides a method for preparing the compound shown in formula III by using the compound described in formula I. The compound shown in formula I undergoes a decarboxylation reaction under the action of dilute acid to obtain the compound shown in formula III.

Formula I Formula III

The reactants of this reaction are heated under the action of dilute acid, and a decarboxylation reaction occurs. Wherein the dilute acid is one or more of hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, polyphosphoric acid, sulfuric acid, formic acid, acetic acid, propionic acid, halogenated acid or sulfonic acid. The reaction temperature is 50°C to 150°C.

Preferably, the reaction temperature is 80°C to 120°C.

The main advantages of the present invention are as follows:

1) The yield of the compound represented by formula III prepared by the method adopted in the present invention is higher than the 53.6% reported in the prior art, and the average yield is above 80%;

2) The compound shown in formula II in the present invention removes the p-toluenesulfonyl group under the action of concentrated acid. After the reaction is complete, the compound shown in formula I obtained is not separated, and an appropriate amount of water is directly added to the reaction vessel to dilute the reaction solution, and then Decarboxylation occurs under heating conditions, and the compound shown in formula III can be prepared through a one-pot method, which greatly simplifies the reaction operation and improves the reaction yield;

3) The raw materials and reagents used in the present invention are cheap and easy to obtain, mild in reaction, easy to operate, friendly to the environment, and suitable for large-scale production.

detailed description

The invention discloses a tolvaptan intermediate and a preparation method thereof, and the preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine by using the compound Excellent method. Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and the relevant personnel can obviously make changes or appropriate changes and combinations to the method and application described herein without departing from the content, spirit and scope of the present invention to realize and Apply the technology of the present invention.

The present invention provides a 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine carboxylate compound as shown in formula I,

Formula I

Wherein R is C1-C6 alkyl, substituted phenyl, benzyl or substituted benzyl.

Wherein said substituted phenyl and substituted benzyl are any substituted phenyl and benzyl, such as halogenated phenyl and halogenated benzyl.

The present invention also provides a method for preparing the compound shown in formula I. The compound shown in formula II removes the p-toluenesulfonyl group under the action of an acid to obtain the compound shown in formula I.

Formula II Formula I

The present invention also provides a method for preparing the compound shown in formula III by using the compound described in formula I. The compound shown in formula I undergoes a decarboxylation reaction under the action of dilute acid to obtain the compound shown in formula III.

Formula I Formula III

In order to enable those skilled in the art to better understand the technical solutions of the present invention, the present invention will be further described in detail below in conjunction with specific examples. The compound represented by formula II can be prepared by referring to the literature Bioorg. Med. Chem, 1999, 7(8): 1743-1754 and Chinese Journal of Pharmaceutical Industry 2009, 40(9): 648-650.

Example 1: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylic acid methyl ester

In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.1 g of methyl azepine-4-carboxylate, 2.0 g of concentrated sulfuric acid. React at 40°C for 2 hours, TLC shows that the reaction is complete, then cool with an ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.4 g of the compound represented by formula I as a light yellow oily liquid with a yield of 87.6%.

ESI-MS(m/z): 254(M+H), 277(M+Na), 293(M+K)

¹ HNMR: (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).

Example 2: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylic acid ethyl ester

In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.4 g of ethyl azepine-4-carboxylate, 122.5 g of 80% phosphoric acid. React at 100°C for 2 hours, TLC shows that the reaction is complete, cool with ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, and anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.8 g of the compound represented by formula I as a pale yellow oily liquid with a yield of 89.1%.

ESI-MS(m/z): 268(M+H), 290(M+Na), 306(M+K)

¹ HNMR: (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).

Example 3: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate

In a 500mL four-neck round bottom flask equipped with a magnetic stirrer and a thermometer, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H-1-benzene 8.1 g of methyl azepine-4-carboxylate, 20.0 g of concentrated sulfuric acid, and 33.8 g of polyphosphoric acid. React at 70°C for 2 hours, TLC shows that the reaction is complete, then cool with an ice-salt bath, slowly add saturated sodium bicarbonate solution dropwise, adjust the pH to 7-8, extract with 100mL ethyl acetate, wash the organic phase with brine after liquid separation, anhydrous magnesium sulfate After drying, filtering and evaporating the solvent, silica gel column chromatography obtained 4.2 g of the compound represented by formula I as a light yellow oily liquid with a yield of 83.6%.

ESI-MS(m/z): 254(M+H), 277(M+Na), 293(M+K)

¹ HNMR: (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).

Example 4: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

In a 100mL four-neck round bottom flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 4.0g of azol-4-methyl carboxylate, 50mL of 3N hydrochloric acid, react at 50°C for 3 hours, adjust the pH to 7-8 with 10% sodium hydroxide solution after the reaction, extract with 50mL of dichloromethane, and use the organic phase after separation Washed with brine, dried over anhydrous magnesium sulfate, dichloromethane was distilled off by filtration, and silica gel column chromatography gave 2.8 g of the compound represented by formula III as a light yellow solid, mp 101.0-102.0°C, yield 90.3%.

MS: 195(M+H), 218(M+Na)

¹ HNMR: (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)

Example 5: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

In a 100mL four-neck round bottom flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 4.0g of azol-4-ethyl carboxylate, 50mL of formic acid, react at 150°C for 3 hours, adjust the pH to 7-8 with 10% sodium hydroxide solution after the reaction, extract with 50mL of dichloromethane, and separate the organic phase with brine After washing, drying over anhydrous magnesium sulfate, dichloromethane was distilled off by filtration, and silica gel column chromatography gave 2.6 g of the compound represented by formula III as a light yellow solid, mp 101.0-102.0°C, yield 88.1%.

MS: 195(M+H), 218(M+Na)

¹ HNMR: (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)

Example 6: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

In a 100mL four-neck round bottom flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine 4.0g of azol-4-methyl carboxylate, 50mL of hydrobromic acid, 5mL of acetic acid, react at 100°C for 3 hours, adjust the pH to 7-8 with 10% sodium hydroxide solution after the reaction, extract with 50mL of dichloromethane, and separate Finally, the organic phase was washed with brine, dried over anhydrous magnesium sulfate, dichloromethane was distilled off by filtration, and silica gel column chromatography gave 2.7 g of the compound represented by formula III as a pale yellow solid, mp 101.0-102.0°C, yield 87.1%.

MS: 195(M+H), 218(M+Na)

¹ HNMR: (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)

Example 7: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

In a 250mL four-neck round bottom flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H - 8.1g of methyl 1-benzazepine-4-carboxylate, 20.0g of concentrated sulfuric acid, and reacted at 50°C for 2 hours. After TLC confirmed that the conversion of the raw materials was complete, 20mL of water was added dropwise, a large amount of gas escaped, and the temperature was raised to After reacting at 80°C for 1 h, TLC confirmed that the conversion was complete, adding saturated aqueous sodium carbonate solution, filtering and washing to obtain 3.3 g of the compound represented by formula III, a light yellow solid, mp 101.0-102.0°C, yield 84.6%.

MS: 195(M+H), 218(M+Na)

¹ HNMR: (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)

Example 8: Preparation of 7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine

In a 250mL four-neck round bottom flask equipped with a magnetic stirrer, a thermometer and a reflux condenser, add 7-chloro-5-oxo-1-p-toluenesulfonyl-2,3,4,5-tetrahydro-1H - 8.4g of methyl 1-benzazepine-4-carboxylate, 60.0g of concentrated sulfuric acid, and reacted at 80°C for 2 hours. After TLC confirmed that the conversion of the raw materials was complete, 20mL of water was added dropwise, a large amount of gas escaped, and the temperature was raised to After reaction at 120°C for 1 h, TLC confirmed that the conversion was complete, then added saturated aqueous sodium carbonate solution, filtered and washed to obtain 3.2 g of the compound represented by formula III, a pale yellow solid, mp 101.0-102.0°C, yield 82.1%.

MS: 195(M+H), 218(M+Na)

¹ HNMR: (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 is only a preferred embodiment of the present invention, it should be pointed out that for those skilled in the art, without departing from the principle of the present invention, some improvements and modifications can also be made, and these improvements and modifications are also It should be regarded as the 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.