CN102584814A - Preparation method for 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-base)-8-azabicyclo[3.2.1]octane - Google Patents

Abstract

8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane disclosed in the present invention The preparation method of alkane comprises the steps successively: taking N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutyramide as raw material, in an aprotic solvent with a vulcanization reagent Heated to reflux to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide, then react with sodium alkoxide and halogenated hydrocarbon or sulfuric acid ester to obtain N-( 8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester, and then heated to reflux with acetylhydrazide in C2~C5 alcohol to obtain 8-benzyl- The crude product of 3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane was finally treated with n-heptane and Ethyl acetate was refined to obtain the high-purity target product. Adopt the present invention to prepare 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane The alkane avoids the interference of water on the intermediate reaction process, the yield is high, and the product purity is good.

Description

Preparation method of 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane

technical field

The invention relates to the key intermediate 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4- The preparation method of -8-azabicyclo [3.2.1] octane.

Background technique

Maraviroc was approved by the US FDA and the European Commission in August and September 2007, respectively, for the treatment of patients with CCR5-tropic HIV-1 infection in combination with other antiretroviral drugs. A CCR5 antagonist and first oral entry inhibitor with significant first-to-market advantage. 8-Benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane is a new anti- The key intermediate of the AIDS drug Maraviroc, the current route to synthesize this intermediate has in common that N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl ) isobutyramide is converted into N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutyric acid chloride by chlorination, and then converted into N-( 8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyrimidic acid hydrazide, and then obtain 8-benzyl-3-(3-isopropyl-5 -Methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane (WO2008063600; WO2010040272; Organic Process Research & Development 2008,12,1094–1103) , the methods of different documents are only slightly different in the specific implementation of the route. Since N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyrimidic acid chloride is very sensitive to water, and acetylhydrazide is very absorbent, it is difficult to completely remove water , so there is always a part of N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutyrimidic acid chloride reacts with the moisture in acetylhydrazide to be converted into N-( 8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide chloride, so that the crude product 8-benzyl-3-(3-isopropyl-5-methyl-4H- 1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane contains 7-8% N-(8-benzyl-8-azabicyclo[3.2. 1] Oct-3-yl) isobutyramide chloride. The existence of N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide chloride seriously interferes with the recrystallization of the product, resulting in low product yield and purity.

Contents of the invention

The purpose of the present invention is to provide a method that avoids the interference of water to the intermediate reaction process, has high yield and good product purity to prepare 8-benzyl-3-(3-isopropyl-5-methyl-4H-1, 2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane method.

8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane of the present invention The preparation method comprises the following steps in turn:

The first step is to use N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide as raw material, heat and reflux with vulcanization reagent in an aprotic solvent for 2~6h, reduce Evaporate to dryness under pressure, dissolve the obtained solid with _CH2Cl2 and OH ^- water solution, and adjust the pH of the aqueous layer to be _greater than 9, separate the organic layer, extract the aqueous layer with _CH2C2 , combine the _organic layers, and evaporate to dryness under reduced pressure to obtain N -(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfuramide, the sulfurization reagent used is the same as N-(8-benzyl-8-azabicyclo[3.2 .1] Oct-3-yl)isobutyramide molar ratio is 0.3～0.6:1, the aprotic solvent used and N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl ) The weight ratio of isobutyramide is 5-10:1;

In the second step, N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutylsulfamide obtained in the first step is mixed with halogenated hydrocarbon in the alcoholic solution of sodium alkoxide Or react sulfuric acid ester at room temperature for 5-8 hours, distill under reduced pressure, dissolve the obtained yellow oil with CH ₂ Cl ₂ and H ₂ O, separate the organic layer, extract the water layer with CH ₂ Cl ₂ , combine the organic layers, and the organic layer Evaporate to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester, sodium alkoxide and N-(8-benzyl Base-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide molar ratio is 1.0～1.3:1, halogenated hydrocarbon or sulfuric acid ester and N-(8-benzyl-8 -Azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide molar ratio is 1.0～1.2:1.

The third step is to dissolve the N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester obtained in the second step in a C ₂ ~C ₅ alcohol , then heated to reflux with acetylhydrazide for 20-26h, distilled under reduced pressure, dissolved the resulting residue with CH ₂ Cl ₂ and H ₂ O, separated the organic layer, extracted the water layer with CH ₂ Cl ₂ , combined the organic layers, and Layers were distilled under reduced pressure to obtain 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1] Octane crude product, this crude product is dissolved in n-heptane and ethyl acetate, heated to 70-80°C, kept stirring for 1.5-3h, cooled to room temperature, filtered, the C ₂ ～C ₅ alcohol used and N-(8-benzyl Base-8-azabicyclo[3.2.1]oct-3-yl)isobutyl imidic acid thioester weight ratio is 18～22:1, the acetylhydrazide and N-(8-benzyl-8- The molar ratio of azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester is 1.5～2.5:1, and the n-heptane and N-(8-benzyl-8-azabis The weight ratio of cyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester is 2～5:1, and the ethyl acetate and N-(8-benzyl-8-azabicyclo[3.2 .1] The weight ratio of oct-3-yl)isobutylimidic acid thioester is 2-5:1.

Concrete synthetic route is as follows:

。 In the formula, R can be CH ₃ , CH ₃ CH ₂ , CH ₃ CH ₂ CH ₂ , CH ₃ CHCH ₃ or

.

In the preparation method of the present invention:

The aprotic solvent used in the first step is acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or methyl tert-butyl ether; the vulcanization reagent used is phosphorus pentasulfide or lawesson reagent; the OH ^- water solution is KOH aqueous solution or NaOH aqueous solution.

The alcohol solution of sodium alkoxide used in the second step is methanol solution of sodium methoxide or ethanol solution of sodium ethoxide, and the halogenated hydrocarbon used is methyl iodide, ethyl iodide, ethyl bromide, ethyl chloride, chloropropane, bromopropane, chlorine Benzyl or bromobenzyl; the sulfate used is methyl sulfate or ethyl sulfate.

The C ₂ -C ₅ alcohol used in the third step is n-butanol, tert-amyl alcohol, isoamyl alcohol, n-amyl alcohol, ethanol, isopropanol, isobutanol or tert-butanol.

The present invention uses N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide as raw material to prepare 8-benzyl-3 -(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane, simple operation, mild reaction, avoiding Water interferes with the intermediate reaction process, the yield is high, and the product purity is good.

Detailed ways

Example 1

Mix N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and _P2S5 ( _0.47g , 2.1mmol), add acetonitrile (12.6mL), heated to reflux for 6h, evaporated to dryness under reduced pressure, dissolved the obtained solid with CH ₂ Cl ₂ (20mL) and NaOH aqueous solution, controlled the pH to be greater than 9, separated the organic layer, and used CH ₂ Cl ₂ (10mLx2 ) extraction, the combined organic layers were evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (1.99g, yield 94.0% ).

Dissolve Na (0.15g, 6.6mmol) in methanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), after complete dissolution, add methyl sulfate (0.83g, 6.6mmol), stir at room temperature, react for 8h and distill under reduced pressure, dissolve the obtained yellow oil in CH ₂ Cl ₂ (50mL) and H ₂ O (50mL) , the organic layer was separated, the aqueous layer was extracted with CH ₂ Cl ₂ (50mLx2), the organic layers were combined, and the organic layer was evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]octane -3-yl) methylthioisobutylimidate (2.03g, yield 97.1%).

N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid methylthio ester (2.09g, 6.6mmol) and acetylhydrazine (0.73 g, 9.9mmol) was dissolved in ethanol (44mL), heated to reflux for 26h, and distilled under reduced pressure. The residue was added with CH ₂ Cl ₂ (50mL) and H ₂ O (50mL), and the layers were separated. The water layer was washed with CH ₂ Cl ₂ ( 50mLx2) extraction, combined the organic layers, and distilled under reduced pressure to obtain the yellow oil 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)- Crude 8-azabicyclo[3.2.1]octane, the yellow oil was dissolved in n-heptane (14.7mL) and ethyl acetate (4.5mL), heated to 70°C, kept stirring for 1.5h, cooled to room temperature , and the filtered solid was high-purity 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2 .1] Octane (1.75 g, 81.9% yield).

Example 2

N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and Lawesson's reagent (1.27g, 3.2mmol) were mixed, tetrahydrofuran (16.8 mL), heated to reflux for 4h, evaporated to dryness under reduced pressure, dissolved the obtained solid with CH ₂ Cl ₂ (20mL) and KOH aqueous solution, controlled the pH to be greater than 9, separated the organic layer, and extracted the aqueous layer with CH ₂ Cl ₂ (10mLx2) , combined the organic layers, and evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2.04g, yield 96.3%).

Dissolve Na (0.18g, 7.6mmol) in ethanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), add benzyl chloride (0.92g, 7.3mmol) after complete dissolution, stir at room temperature, react for 6h and distill under reduced pressure, dissolve the obtained yellow oil in CH ₂ Cl ₂ (50mL) and H ₂ O (50mL) , the organic layer was separated, the aqueous layer was extracted with CH ₂ Cl ₂ (50mLx2), the organic layers were combined, and the organic layer was evaporated to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]octane -3-yl) crude product of benzylthioisobutylimidate (2.53g, yield 97.8%).

N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid benzylthioester (2.59g, 6.6mmol) and acetylhydrazide (0.98 g, 13.2mmol) was dissolved in isopropanol (51mL), heated to reflux for 24h, distilled under reduced pressure, the residue was added with CH ₂ Cl ₂ (50mL), H ₂ O (50mL), the layers were separated, and the aqueous layer was washed with CH ₂ Cl ₂ (50mLx2) extraction, combined the organic layers, and distilled under reduced pressure to give yellow oil 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl )-8-Azabicyclo[3.2.1]octane crude product, the yellow oil was dissolved in n-heptane (10.3mL) and ethyl acetate (7.8mL), heated to 75°C, kept stirring for 3h, cooled to At room temperature, the solid obtained by filtration was high-purity 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[ 3.2.1] Octane (1.77g, yield 82.8%).

Example 3

Mix N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide (2g, 7mmol) and _P2S5 ( _0.93g , 4.2mmol), add toluene (23mL), heated to reflux for 2h, evaporated to dryness under reduced pressure, dissolved the obtained solid with CH ₂ Cl ₂ (20mL) and KOH aqueous solution, controlled the pH to be greater than 9, separated the organic layer, and used CH ₂ C ₂ (10mLx2) for the aqueous layer Extract, combine the organic layers, and evaporate to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2.02g, yield 95.6%) .

Dissolve Na (0.2g, 8.6mmol) in methanol (20mL), add N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide (2g, 6.6mmol), after complete dissolution, add iodomethane (1.22g, 8.6mmol), stir at room temperature, react for 5h and distill under reduced pressure, dissolve the obtained yellow oil in CH ₂ Cl ₂ (50mL) and H ₂ O (50mL), Separate the organic layer, extract the aqueous layer with CH ₂ Cl ₂ (50mLx2), combine the organic layers, and evaporate the organic layer to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]octyl- 3-yl) crude product of methylthioisobutylimidate (2.05g, yield 98.2%).

N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid methylthio ester (2.59g, 6.6mmol) and acetylhydrazide (1.22 g, 16.5mmol) was dissolved in n-pentanol (54mL), heated to reflux for 20h, and distilled under reduced pressure. The residue was added with CH ₂ Cl ₂ (50mL) and H ₂ O (50mL), and the layers were separated. The water layer was washed with CH ₂ Cl ₂ (50mLx2) extraction, combined organic layers, and distillation under reduced pressure to obtain a yellow oily substance 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl) - Crude 8-azabicyclo[3.2.1]octane, the yellow oil was dissolved in n-heptane (5.9mL) and ethyl acetate (11mL), heated to 80°C, kept stirring for 2h, cooled to room temperature, The solid obtained by filtration is high-purity 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2. 1] Octane (1.75g, yield 81.8%).

Claims (7)

1. The preparation method of 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octane , including the following steps in turn: The first step is to use N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutyramide as raw material, heat and reflux with vulcanization reagent in an aprotic solvent for 2~6h, reduce Evaporate to dryness under pressure, dissolve the obtained solid with _CH2Cl2 and OH ^- water solution, and adjust the pH of the aqueous layer to be _greater than 9, separate the organic layer, extract the aqueous layer with _CH2C2 , combine the _organic layers, and evaporate to dryness under reduced pressure to obtain N -(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfuramide, the sulfurization reagent used is the same as N-(8-benzyl-8-azabicyclo[3.2 .1] Oct-3-yl)isobutyramide molar ratio is 0.3～0.6:1, the aprotic solvent used and N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl ) The weight ratio of isobutyramide is 5-10:1; In the second step, N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl) isobutylsulfamide obtained in the first step is mixed with halogenated hydrocarbon in the alcoholic solution of sodium alkoxide Or react sulfuric acid ester at room temperature for 5-8 hours, distill under reduced pressure, dissolve the obtained yellow oil with CH ₂ Cl ₂ and H ₂ O, separate the organic layer, extract the water layer with CH ₂ Cl ₂ , combine the organic layers, and the organic layer Evaporate to dryness under reduced pressure to obtain N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester, sodium alkoxide and N-(8-benzyl Base-8-azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide molar ratio is 1.0～1.3:1, halogenated hydrocarbon or sulfuric acid ester and N-(8-benzyl-8 -Azabicyclo[3.2.1]oct-3-yl)isobutylsulfamide molar ratio is 1.0～1.2:1; The third step is to dissolve the N-(8-benzyl-8-azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester obtained in the second step in a C ₂ ~C ₅ alcohol , then heated to reflux with acetylhydrazide for 20-26h, distilled under reduced pressure, dissolved the resulting residue with CH ₂ Cl ₂ and H ₂ O, separated the organic layer, extracted the water layer with CH ₂ Cl ₂ , combined the organic layers, and Layers were distilled under reduced pressure to obtain 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1] Octane crude product, this crude product is dissolved in n-heptane and ethyl acetate, heated to 70-80°C, kept stirring for 1.5-3h, cooled to room temperature, filtered, the C ₂ ～C ₅ alcohol used and N-(8-benzyl Base-8-azabicyclo[3.2.1]oct-3-yl)isobutyl imidic acid thioester weight ratio is 18～22:1, the acetylhydrazide and N-(8-benzyl-8- The molar ratio of azabicyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester is 1.5～2.5:1, and the n-heptane and N-(8-benzyl-8-azabis The weight ratio of cyclo[3.2.1]oct-3-yl)isobutylimidic acid thioester is 2～5:1, and the ethyl acetate and N-(8-benzyl-8-azabicyclo[3.2 .1] The weight ratio of oct-3-yl)isobutylimidic acid thioester is 2-5:1. 2. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] The preparation method of octane is characterized in that the aprotic solvent used in the first step is acetonitrile, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or methyl tert-butyl ether. 3. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] the preparation method of octane is characterized in that the vulcanization reagent used in the first step is phosphorus pentasulfide or lawesson reagent. 4. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] The preparation method of octane is characterized in that the OH ^- water solution used in the first step is KOH aqueous solution or NaOH aqueous solution. 5. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] the preparation method of octane is characterized in that the alcoholic solution of sodium alkoxide used in the second step is the methanol solution of sodium methylate or the ethanol solution of sodium ethylate. 6. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] the preparation method of octane is characterized in that the halogenated hydrocarbon used in the second step is methyl iodide, ethyl iodide, ethyl bromide, ethyl chloride, chloropropane, bromopropane, benzyl chloride or bromobenzyl, and the used sulfuric acid The ester is methyl sulfate or ethyl sulfate. 7. 8-benzyl-3-(3-isopropyl-5-methyl-4H-1,2,4-triazole-4-yl)-8-azabicyclo[ 3.2.1] The preparation method of octane is characterized in that the alcohol of _C2 ～ _C5 used in the third step is n-butanol, tert-amyl alcohol, isoamyl alcohol, n-amyl alcohol, ethanol, isopropanol, isobutanol or tert-butanol.