CN107674039A - A kind of preparation method than his western intermediate - Google Patents

Abstract

The present invention relates to a kind of N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl) carbamic acid 5-thiazolyl methyl ester (I) Preparation. The method takes (2R,5R)-1,6-diphenyl-2,5-hexanediamine dihydrochloride (II) and 5-hydroxymethylthiazole (III) as raw materials, in carbonyl condensation reagent and organic Reaction in the presence of base can directly obtain compound (I) in one step with higher yield, which is N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl) amino The preparation of 5-thiazolylmethyl formic acid (I) provides a simple and practical new method.

Description

A kind of preparation method of copecistat intermediate

technical field

The present invention relates to the field of preparation of copecistat intermediates, in particular to N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl) carbamic acid 5-thiazolylmethyl The field of preparation of base esters.

Background technique

Cobicistat is a new type of synergist developed by Gilead Sciences that can improve the pharmacokinetic parameters of anti-HIV drugs, thereby increasing the efficacy of the drug; in August 2012, it was first approved by the US FDA for marketing. Copecistat is a cytochrome P450 3A inhibitor, which can inhibit the liver drug enzymes involved in the metabolism of other anti-HIV drugs, especially inhibit the metabolism of liver drug enzymes to eltgravir (HIV integrase inhibitor). After Evitagravir is used in combination with Cobicistat, it can achieve a higher plasma concentration at a lower dose, thereby improving the effect on virus suppression and reducing side effects.

5-thiazolylmethyl N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl)carbamate (I) is one of the key intermediates in the synthesis of copecistat. The compound of synthetic formula (I) has only the following one method at present.

Patents US20100256366A1 and WO2015083066A1 disclose a kind of (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride (II) and ((5-thiazolyl)methyl) -(4-Nitrophenyl)carbonate (IV) as raw material to prepare N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl)carbamic acid 5-thiazole The method of methyl ester (I). As in the example of US20100256366A1, using dichloromethane as solvent and diisopropylethylamine as base, N -((1 R ,4 R )-4-amino-5-phenyl can be obtained in 83% yield - 5-thiazolylmethyl 1-benzylpentyl)carbamate (I) hydrochloride.

Although this method seems relatively simple, ((5-thiazolyl) methyl)-(4-nitrophenyl)carbonate (IV) must be raw material with 5-hydroxymethylthiazole (III), first and The carbonyl condensation reagent can be reacted with p-nitrophenyl ester, and two steps are required to obtain the product N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl)carbamate 5- The hydrochloride salt of thiazolyl methyl ester (I) is slightly cumbersome to operate.

Contents of the invention

Contrast above-mentioned two-step method, the present invention provides a kind of N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl) carbamic acid 5-thiazolyl methyl ester (I ) of the new method.

The method is simple and practical, using (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride (II) and 5-hydroxymethylthiazole (III) as raw materials, in In an organic solvent, react in the presence of a carbonyl condensation reagent and an organic base to directly obtain N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl)carbamic acid 5-thiazole in one step Methyl esters (I).

Preferably, the carbonyl condensation reagent used is triphosgene and N,N'-disuccinimidyl carbonate (DSC).

Preferably, the reaction temperature is 0-30°C.

Preferably, the reaction solvent is acetonitrile, dichloromethane, tetrahydrofuran.

Preferably, the organic base used in the reaction is triethylamine and pyridine.

The present invention uses (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride (II) and 5-hydroxymethylthiazole (III) as raw materials , using safe and mild reaction conditions, is the Preparation provides a concise and practical new method.

detailed description

In order to understand the technical content of the present invention more clearly, the following examples are given in detail.

Example 1:

Add 150mL of dichloromethane into the dry reaction bottle, cool to 0°C, add 32.7 g of triphosgene, and slowly add dropwise 100mL of dichloromethane solution containing 38.0g of 5-hydroxymethylthiazole, and stir the system at 0°C for 30min stand-by. In another reaction flask, 102.4 g of (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride and 100.0 g of triethylamine were added to 600 mL of dichloromethane, cooled The solution prepared by the above-mentioned triphosgene was added dropwise at 0°C, and the dropwise addition was completed in 1 hour. The reaction system was slowly warmed up to room temperature (25°C) and then stirred for 4 hours; TLC detected that the reaction of the raw materials was complete.

Add 500 mL of 1 mol/L sodium hydroxide aqueous solution to quench the reaction, wash the organic phase with water and saturated sodium chloride solution successively, dry over anhydrous magnesium sulfate, concentrate the solvent, dissolve the obtained residue in isopropanol, and add isopropanol The hydrochloric acid solution of propanol forms a salt, a large amount of white solid appears, filter, rinse and dry to obtain the white powder product N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl ) 5-thiazolylmethyl carbamate hydrochloride (I) 118.5 g, yield 88.6%.

¹ H NMR (300 MHz, CD ₃ OD) δ 9.03 (s, 1H), 7.81 (s, 1H), 7.42-7.14(m,10H), 5.23 (d, J =4.5 Hz, 1H), 4.81 (s , 5H), 3.68 (m, 1H), 3.61 (m, 1H), 3.30(m, 1H), 2.81-2.63 (m, 2H), 1.82-2.39 (m, 4H); ¹⁹ F NMR (300 MHz, CDCl ₃ ): δ –197.2 (d, J = 48.5Hz, 1F).

MS (ESI) m/z = 410.2 (M ⁺ +1).

Example 2:

Add 50mL of acetonitrile into the dry reaction flask, cool to 0°C, add 28.2 g of N,N'-disuccinimidyl carbonate (DSC), and slowly dropwise add 12.7.0 g of 5-hydroxymethylthiazole 50 mL of acetonitrile solution, and the system was stirred at 0°C for 1 hour for use. In another reaction flask, add 34.1 g of (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride and 25.0 g of pyridine into 200 mL of acetonitrile, cool to 0°C and drop Add the solution prepared by DSC above, and the dropwise addition is completed in 1 hour. The reaction system is slowly warmed up to room temperature (25°C) and then stirred for 8 hours; TLC detects that the reaction of the raw materials is complete.

Concentrate to remove most of the acetonitrile, then add 150 mL of 1 mol/L sodium hydroxide aqueous solution, and extract three times with ethyl acetate, the combined organic phases are washed with water and saturated sodium chloride solution successively, dried over anhydrous magnesium sulfate, and the solvent is concentrated. The obtained residue was dissolved in isopropanol, and added with hydrochloric acid solution of isopropanol to form a salt, a large amount of white solid appeared, filtered, rinsed and dried to obtain a white powder product N -((1 R ,4 R )-4 -Amino-5-phenyl-1-benzylpentyl) carbamic acid 5-thiazolyl methyl ester hydrochloride (I) 36.0 g, yield 80.7%.

See Example 1 for spectrogram data.

In this specification, the invention has been described with reference to specific embodiments thereof. However, it is obvious that various modifications and changes can be made without departing from the spirit and scope of the invention. Accordingly, the specification should be regarded as illustrative rather than restrictive.

Claims (5)

1. Preparation of a copecistat intermediate N -((1 R ,4 R )-4-amino-5-phenyl-1-benzylpentyl)carbamate 5-thiazolylmethyl ester (I) The method uses (2 R ,5 R )-1,6-diphenyl-2,5-hexanediamine dihydrochloride (II) and 5-hydroxymethylthiazole (III) as raw materials. In a solvent, react in the presence of a carbonyl condensation reagent and an organic base to obtain a compound of formula (I). 2. The method according to claim 1, characterized in that, the carbonyl condensation reagent is triphosgene, N,N'-disuccinimidyl carbonate (DSC). 3. The method according to claim 1, characterized in that, the reaction temperature is 0-30°C. 4. method according to claim 1, is characterized in that, described organic solvent comprises acetonitrile, methylene dichloride, tetrahydrofuran. 5. method according to claim 1, is characterized in that, described organic base comprises triethylamine, pyridine.