Synthesis Method for Candesartan Cilexetil Intermediate

Abstract

A synthesis method for a candesartan cilexetil intermediate represented by formula (II) is provided. The method includes (1) dissolving a compound represented by formula (IV) to an aprotic solvent to obtain a first mixed solution, and dissolving a phase transfer catalyst and an azidation reagent to water to obtain a second mixed solution; (2) dropping the first mixed solution to the second mixed solution for azidation reaction, and after the reaction is ended, standing and layering same to obtain an organic phase containing a compound represented by formula (V); (3) dropping the obtained organic phase containing the compound represented by formula (V) to tertiary butyl alcohol for rearrangement reaction, and after the reaction is ended, concentrating same to obtain a solid or oily material, then adding a crystallizing solvent to the obtained solid or oily material for recrystallization, and separating same to obtain a crystal.

Claims

1. A method for synthesizing candesartan cilexetil intermediate represented by formula (II), ##STR00007## comprising: (1) dissolving a compound represented by formula (IV) in an aprotic solvent to obtain a first mixed solution; and dissolving a phase transfer catalyst and an azidation reagent in water to obtain a second mixed solution; (2) adding the first mixed solution dropwise to the second mixed solution to perform an azidation reaction; after the azidation reaction is completed, standing and layering to obtain an organic phase containing a compound represented by formula (V); and (3) adding the organic phase containing the compound represented by formula (V) dropwise to tertiary butyl alcohol to perform a rearrangement reaction; after the rearrangement reaction is completed, concentrating to obtain a solid or an oily material, then adding a crystallizing solvent to the solid or the oily material for recrystallization, and separating to obtain a crystal, i.e., the candesartan cilexetil intermediate represented by formula (II); ##STR00008## wherein, R is methyl or ethyl.

2. The method according to claim 1, wherein the aprotic solvent is selected from the group consisting of toluene, chlorobenzene, xylene, chloroform, 1,2-dichloroethane and 1,2-dibromoethane, or any combination thereof.

3. The method according to claim 1, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium fluoride and tetrabutylammonium iodide, or any combination thereof.

4. The method according to claim 1, wherein a molar ratio of the phase transfer catalyst to the compound represented by formula (IV) is 0.01-0.08:1.

5. The method according to claim 1, wherein the azidation reaction is carried out at −3° C. to 10° C.

6. The method according to claim 1, wherein the rearrangement reaction is carried out at 75° C. to 95° C.

7. The method according to claim 1, wherein a molar ratio of tertiary butyl alcohol to the compound represented by formula (IV) is 1.0-5.0:1.

8. The method according to claim 1, wherein the crystallizing solvent is selected from the group consisting of ethanol, methanol, isopropanol and ethyl acetate, or any combination thereof, or the crystallizing solvent is a mixed solution of at least one of ethanol, methanol, isopropanol or ethyl acetate with water.

9. The method according to claim 1, wherein the compound represented by formula (IV) is synthesized by the following method: (a) subjecting 3-nitrophthalic acid to an esterification reaction to obtain a compound represented by formula (III); and (b) subjecting the compound represented by formula (III) to an acyl chlorination reaction to obtain a compound represented by formula (IV); ##STR00009## wherein, R is methyl or ethyl.

10. The method according to claim 9, wherein in step (a), the esterification reaction is carried out by using methanol or ethanol; and in step (b), the acyl chlorination reaction is carried out by using thionyl chloride.

11. The method according to claim 1, wherein the azidation reagent is sodium azide or potassium azide.

12. The method according to claim 2, wherein the aprotic solvent is toluene or chloroform.

13. The method according to claim 3, wherein the phase transfer catalyst is tetrabutylammonium bromide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0036] For the sake of clarity of the purpose, technical solutions and advantages of the present application, the application is further described in detail in combination with specific examples. Obviously, the specific examples are only a part of the examples of the present application, rather than all the examples. Based on the examples in the present application, all other examples obtained by those of ordinary skill in the art without creative work shall fall within the protection scope of the present application.

[0037] General test methods of the present application:

[0038] Instrument: high performance liquid chromatograph (HPLC) equipped with UV detector;

[0039] Chromatographic column: Agilent XDB C8 250*4.6 mm 5 μm or an equivalent chromatographic column;

[0040] Buffer: 1.36 g potassium dihydrogen phosphate dissolved in 1000 ml water, the pH was adjusted to 2.5 with concentrated phosphoric acid;

[0041] Mobile phase A: buffer:acetonitrile=60:40 (v/v);

[0042] Mobile phase B: buffer:acetonitrile=15:85 (v/v);

[0043] Flow rate: 1.0 ml/min;

[0044] The temperature of the chromatographic column: 30° C.;

[0045] Sample size: 10 μl;

[0046] Detection wavelength: 210 nm;

[0047] Gradient table:

TABLE-US-00001 Mobile phase A Mobile phase B Time (min) (% v/v) (% v/v)  0.fwdarw.15 100.fwdarw.0 0.fwdarw.100 15.fwdarw.27  0 100   27.fwdarw.27.5   0.fwdarw.100 100.fwdarw.0   27.5.fwdarw.35   100  0

Preparation Example of Ethyl 2-chlorocarbonyl-3-nitrobenzoate

[0048] 35 g of 3-nitrophthalic acid, 300 mL ethanol and 20 mL concentrated sulfuric acid were added to a 500 mL four-necked flask, heated to reflux, reacted for 24 hours and concentrated to remove ethanol, then 300 mL saturated potassium carbonate aqueous solution was added, extracted with 50 mL of dichloromethane, and an organic layer was discarded; the pH of an water layer was adjusted to 1 with hydrochloric acid, and the water layer was extracted with 2×300 mL methylene chloride. The methylene chloride layers obtained by extracting the water layer twice were combined and concentrated to dryness to obtain 30.2 g of ethyl 3-nitro-2-carboxybenzoate with a yield of 76.2%.

[0049] 30.2 g of ethyl 3-nitro-2-carboxybenzoate, 19.5 g of thionyl chloride and 150 mL toluene were added to a 500 mL four-necked flask, heated to reflux, reacted for 2 hours and concentrated to dryness to obtain 32.2 g of ethyl 2-chlorocarbonyl-3-nitrobenzoate with a yield of 99%.

Preparation Example of Methyl 2-chlorocarbonyl-3-nitrobenzoate

[0050] According to the method described in the preparation example of ethyl 2-chlorocarbonyl-3-nitrobenzoate, the ethanol used in the esterification reaction was replaced by methanol to prepare methyl 2-chlorocarbonyl-3-nitrobenzoate.

Example 1 Preparation of ethyl 2-((tert-butoxycarbonyl) amino)-3-nitrobenzoate

[0051] 60 mL water, 6.5 g sodium azide (0.1 mol) and 1.6 g of tetrabutylammonium bromide (0.005 mol) were added to a 250 mL four-necked flask, cooled to 0° C. and a toluene solution formed by dissolving 25.7 g ethyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL toluene was added dropwise. After the dropwise addition was completed, the reaction was maintained at 0° C. for 1 h, left stand and layered to obtain a toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate. 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After an oily material was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 27.9 g of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 90% and a purity of 97.2%.

Example 2 Preparation of methyl 2-((tert-butoxycarbonyl) amino)-3-nitrobenzoate

[0052] 60 mL water, 6.5 g sodium azide (0.1 mol) and 1.6 g of tetrabutylammonium bromide (0.005 mol) were added to a 250 mL four-necked flask, cooled to 0° C. and a chlorobenzene solution formed by dissolving 24.2 g methyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL chlorobenzene was added dropwise. After the dropwise addition was completed, the reaction was maintained at 0° C. for 1 h, left stand and layered to obtain a chlorobenzene solution containing methyl 2-(azidocarbonyl)-3-nitrobenzoate.

[0053] 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the chlorobenzene solution containing methyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After a solid was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 27.5 g of methyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 92.9% and a purity of 95.4%.

Example 3 Preparation of methyl 2-((tert-butoxycarbonyl) amino)-3-nitrobenzoate

[0054] 60 mL water, 6.5 g sodium azide (0.1 mol) and 1.6 g of tetrabutylammonium bromide (0.005 mol) were added to a 250 mL four-necked flask, cooled to 0° C. and a 1,2-dichloroethane solution formed by dissolving 24.2 g methyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL 1,2-dichloroethane was added dropwise. After the dropwise addition was completed, the reaction was maintained at 0° C. for 1 h, left stand and layered to obtain a 1,2-dichloroethane solution containing methyl 2-(azidocarbonyl)-3-nitrobenzoate.

[0055] 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the 1,2-dichloroethane solution containing methyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After a solid was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 27.1 g of methyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 91.5% and a purity of 96.5%.

Example 4 Ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0056] 60 mL water, 6.5 g sodium azide (0.1 mol) and 1.6 g of tetrabutylammonium bromide (0.005 mol) were added to a 250 mL four-necked flask, cooled to −3° C. and a toluene solution formed by dissolving 25.7 g ethyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL toluene was added dropwise. After the dropwise addition was completed, the reaction was maintained at −3° C. for 2 h, left stand and layered to obtain a toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate. 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After an oily material was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 27.1 g of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 87.4% and a purity of 98.0%.

Example 5 Ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0057] 60 mL water, 6.5 g sodium azide (0.1 mol) and 1.6 g of tetrabutylammonium bromide (0.005 mol) were added to a 250 mL four-necked flask, cooled to 10° C. and a toluene solution formed by dissolving 25.7 g ethyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL toluene was added dropwise. After the dropwise addition was completed, the reaction was maintained at 10° C. for 1 h, left stand and layered to obtain a toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate.

[0058] 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After an oily material was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 26.8 g of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 86.5% and a purity of 96.8%.

Example 6 Ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0059] 60 mL water, 6.5 g sodium azide (0.1 mol) and 0.32 g of tetrabutylammonium bromide (0.001 mol) were added to a 250 mL four-necked flask, cooled to 0° C. and a toluene solution formed by dissolving 25.7 g ethyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL toluene was added dropwise. After the dropwise addition was completed, the reaction was maintained at 0° C. for 2 h, left stand and layered to obtain a toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate. 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After an oily material was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 27.2 g of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 87.8% and a purity of 97.8%.

Example 7 Ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate

[0060] 60 mL water, 6.5 g sodium azide (0.1 mol) and 2.57 g of tetrabutylammonium bromide (0.008 mol) were added to a 250 mL four-necked flask, cooled to 0° C. and a toluene solution formed by dissolving 25.7 g ethyl 2-chlorocarbonyl-3-nitrobenzoate in 140 mL toluene was added dropwise. After the dropwise addition was completed, the reaction was maintained at 0° C. for 1 h, left stand and layered to obtain a toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate. 11.1 g of tertiary butyl alcohol (0.15 mol) was added to a 250 mL four-necked flask and heated to 80° C. Then the toluene solution containing ethyl 2-(azidocarbonyl)-3-nitrobenzoate obtained above was added dropwise. During the addition process, a reaction temperature was controlled at 80 to 90° C. The reaction was maintained for 1 h after the addition was completed. After an oily material was obtained by concentration under reduced pressure, 80 mL ethanol was added and the temperature was reduced to 0° C. The mixture was stirred for 2 h, filtered and dried to obtain 28.2 g of ethyl 2-((tert-butoxycarbonyl)amino)-3-nitrobenzoate with a yield of 90.9% and a purity of 98.0%.

[0061] Examples mentioned above are only the preferred examples of the present application and are not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included within the protection scope of the present application.