KR100819759B1 - Method for preparing 1,2-diamino compound or addition salt thereof by using explosive process of azide compound - Google Patents

Abstract

The present invention provides 1,2-diamino compounds of the formula (1) or their compounds from 1,2-epoxides of the formula (2), which are intermediates in the process for preparing oseltamivir phosphate, which have excellent antiviral efficacy and particularly have an excellent effect on avian flu treatment. Provided is a multi-step process for preparing industrially stable pharmaceutically acceptable addition salts.

Oseltamivir phosphate, aminoalcohol, 1,2-epoxide, aziridine, 1,2-diamino

Description

 Method for preparing 1,2-diamino compound or addition salt thereof by using explosive process of azide compound {SYNTHETIC PROCESS OF 1,2-DIAMINO COMPOUNDS WITHOUT ANY EXPLOSION OF AZIDE COMPOUNDS}

The present invention relates to a 1,2-diamino compound of formula (I) from 1,2-epoxide of formula (II), which is an intermediate in the process for preparing oseltamivir addition salt, which is useful as a neuraminidase inhibitor of a virus or bacterium. A novel multistage process for the industrially stable preparation of pharmaceutically acceptable addition salts thereof.

PCT Patent Application No. 96/26933 discloses a large class of compounds useful as inhibitors of neuraminidase of viruses or bacteria and their preparation. Such compounds include partially unsaturated 6-membered carbocyclic or heterocyclic ring systems that may be substituted with several different substituents.

PCT Patent Application No. 98/07685 discloses various methods of preparing compounds of this class which are cyclohexene carboxylate derivatives. 10-step preparation of 1,2-diamino compounds starting with shikimic acid or 12-step preparation starting with quinic acid is described by Rohloff et al. Org. Chem., 1998, 63, 4545-4550.

The overall scheme is shown in Scheme 1 below.

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The 10-step method must pass through the steps of compound 7 and compound 9 using an azide reagent in the synthesis of the 1,2-diamino compound of compound 10 from the 1,2-epoxide of compound 6 , which is an intermediate. . Synthesis of compound 8 from compound 7 must satisfy anhydrous conditions, for which concentration is essential. However, azide compounds are potentially explosive at high concentrations, requiring dedicated manufacturing techniques and expensive equipment to perform these processes. If even a small amount of water is present, aminoalcohol, a compound 12 of Scheme 2, is produced.

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In order to solve this disadvantage, a method of synthesizing compound 8 via compound 13 obtained by converting an alcohol group of compound 7 to a methanesulfonyl group is disclosed in CU Kim et al. Am. Chem. Soc., 1997, 119, 681-690.

However, even in this method, when water is present, the aziridine production reaction by substitution reaction and the cyclic diene compound production reaction by removal reaction are competitive as in Scheme 3 below. Thus not only the desired compound 8 but also compounds 14 and 15, which are products of removal reactions, are produced. As a result, the yield and the difficulty of purification remain.

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U.S. Pat.No. 6,437,171 also discloses the preparation of oseltamivir phosphate from 1,2-epoxide by using allylamine-magnesium bromide etherate for ring opening epoxide and allylamine-Bwenstead for ring opening aziridine. An improved method is disclosed. Although the novel method solves the azide handling problem, the problem remains that the overall yield from epoxide to final drug substance is low.

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In view of the technical process, it is desirable to avoid the use of azide reagents and azide intermediates. However, the method of going through the azide intermediate is very easy to purify because of the high crystallinity of the intermediate azide compounds, which is obviously the most effective synthetic route if it can eliminate the explosiveness of the azide intermediate.

Therefore, the problem to be solved in the present invention is to find a manufacturing process that can remove the explosiveness of the azide intermediate.

The problem has been solved by the present invention, as disclosed in the following specification and the appended claims.

An object of the present invention is to provide a manufacturing process that can remove the explosiveness of the azide intermediate.

Hereinafter, the manufacturing method which can remove the explosive property of the azide intermediate of this invention is demonstrated in detail.

The present invention relates to an improved process for preparing 1,2-diamino compounds or addition salts thereof from 1,2-epoxide,

The present invention (a) by reacting 1,2-epoxide of compound 6 of Scheme 4 with azide reagent, omitting the concentration process, to synthesize compound 12 as an intermediate in the presence of water, and again to obtain compound 16 as an intermediate To form compound 17 ;

(b) converting compound 17 to compound 18 using dilute acid;

(c) reacting compound 18 with an azide reagent to form compound 10 in the presence of moisture.

R ₁ in Scheme 4 is a tert-butyloxycarbonyl group, triphenyl methyl group or triphenyl methyl derivative group.

Step (a) reacts compound 6 with an azide reagent, extracts them with an organic solvent, omits a separate concentration process, and immediately reduces azide to synthesize compound 12 . Compound 12 , an amino alcohol, is concentrated and reacted with a compound having a R ₁ substituent to form compound 17 aziridine via intermediate 16 . In this case, R ₁ used is a tert-butyloxycarbonyl group, triphenyl methyl group, or triphenyl methyl derivative groups represented by the following general formula (3).

In the general formula _{3 R 2, R 3, R} 4 each independently is hydrogen, an alkoxy group of C ₁ ~ C ₁₀ alkyl group or a C ₁ ~ C ₁₀ of.

Step (a) is a very important step to omit the concentration of the azide compound and to reduce the azide in the presence of moisture. The solvent from which the azide compound is extracted is a common organic solvent and does not have to be mixed with water.

Step (b) comprises converting compound 17 to compound 18 by removing and acetylating R ₁ using dilute acid. The dilute acid used at this time may be an ordinary inorganic acid such as hydrochloric acid or sulfuric acid and an organic acid such as trifluoroacetic acid. The concentration of the dilute acid is 0.1 to 4 molar concentrations, preferably 0.5 to 2 molar concentrations.

In step (c), the acetylated aziridine compound 18 is reacted with an azide reagent, the azide is extracted with an organic solvent, a separate concentration process is omitted, and the azide is immediately reduced to synthesize compound 10 .

The invention is further illustrated by the following examples.

Example 1-1: Preparation of (3R, 4R, 5R) -4,5- (N-triphenylmethyl) imino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester

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Sodium in 76.2 ml of purified water in 25.4 g (100 mmol) solution of (3R, 4S, 5S) -4,5-epoxy-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester in 178 ml of acetonitrile Add a solution of 7.8 g (120 mmol) of azide and 6.4 g (120 mmol) of ammonium chloride. The solution was stirred at 75 ° C. for 6 hours. The temperature was lowered to room temperature, 400 ml of purified water was added, and extracted with 178 ml of methylene chloride. 31.5 g (120 mmol) of triphenylphosphine was added to the solution, followed by stirring at room temperature for 3 hours. 75 g of silica gel was added thereto, stirred for 1 hour, filtered to remove excess triphenylphosphine and triphenylphosphine oxide, and amino alcohol-adsorbed silica gel was added to 254 ml of ethanol and stirred for 1 hour. After filtration, ethanol was concentrated and 50 ml of methylene chloride and 34.4 g (340 mmol) of triethylamine were added thereto. 33.5 g (120 mmol) of triphenylmethyl chloride was dissolved in 50 ml of methylene chloride, slowly added dropwise, and stirred for 3 hours. When TLC confirmed that the amino group was protected, 13.7 g (120 mmol) of methanesulfonyl chloride was slowly added dropwise and stirred for 2 hours. 34 g of sodium bicarbonate was dissolved in 200 ml of water, and the reaction temperature was raised to 50 ° C. and stirred for 5 hours. The layers were separated and the organic layer was washed several times with water and recrystallized to give 41 g of solid.

Example 1-2 Preparation of (3R, 4R, 5R) -4,5- (N-t-butyloxycarbonyl) imino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester

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Sodium in 76.2 ml of purified water in 25.4 g (100 mmol) solution of (3R, 4S, 5S) -4,5-epoxy-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester in 50 ml of acetonitrile Add a solution of 7.8 g (120 mmol) of azide and 6.4 g (120 mmol) of ammonium chloride. The solution was stirred at 75 ° C. for 6 hours. The temperature was lowered to room temperature, 400 ml of purified water was added, and extracted with 178 ml of methylene chloride. 31.5 g (120 mmol) of triphenylphosphine was added to the solution, followed by stirring at room temperature for 3 hours. 75 g of silica gel was added thereto, stirred for 1 hour, filtered to remove excess triphenylphosphine and triphenylphosphine oxide, and amino alcohol-adsorbed silica gel was added to 254 ml of ethanol and stirred for 1 hour. After filtration, ethanol was concentrated and 127 ml of methylene chloride and 34.4 g (340 mmol) of triethylamine were added thereto. 26.2 g (120 mmol) of di-t-butyl dicarbonate was dissolved in 50 ml of methylene chloride, slowly added dropwise, and stirred for 3 hours. When TLC confirmed that the amino group was protected, 50 g of methanesulfonyl chloride was slowly added dropwise and stirred for 2 hours. Add 100 ml of purified water and separate the layers. Dry the organic layer, add 22.8 g (200 mmol) of trifluoroacetic acid and stir for 30 minutes. 34 g of sodium bicarbonate was dissolved in 200 ml of water, and the reaction temperature was raised to 50 ° C. and stirred for 5 hours. The layers were separated and the organic layer was washed several times with water and recrystallized to obtain 23 g of an oily labeling compound.

Example 2 Preparation of (3R, 4R, 5R) -4,5- (N-acetyl) imino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester

250 ml of methylene chloride (2R, 4R, 5R) -4,5- (N-triphenylmethyl) imino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester The solution dissolved in was added 250 ml of 0.5 N hydrochloric acid solution and stirred vigorously for 30 minutes. The layers were separated and the organic layer was dried. 6 g (60 mmol) of triethylamine and 6.5 g (60 mmol) of acetic anhydride were added and stirred for 2 hours. 500 ml of purified water was added, the layers were separated, and the organic layer was dried and concentrated to give 15 g (yield 98%) of the labeled compound.

Example 3 Preparation of (3R, 4R, 5S) -4- (N-acetyl) amino-5-azido-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester

150 ml of (3R, 4R, 5R) -4,5- (N-acetyl) imino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester 12.5 g (42.5 mmol) in dimethylformamide To the solution dissolved in 5 g (75 mmol) of sodium azide and 6 g (110 mmol) of ammonium chloride were added. Stir at 80 ° C. for 5 hours and add 250 ml of purified water. Extracted with 150 ml of ethyl acetate, dried and concentrated the organic layer. 150 ml of cyclohexane was added to the residue and recrystallized at 5 ° C. to obtain 13.8 g of a white solid labeled compound (yield 96%).

Example 4 (3R, 4R, 5S) -4- (N-acetyl) amino-5-amino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1: 1) Manufacture

(3R, 4R, 5S) -4- (N-acetyl) amino-5-azido-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester 3.3 g (9.8 mmol) in 20 ml of ethanol Lanni nickel (1.1 g) was added to the dissolved solution, and hydrogen gas was passed through for 16 hours. After the reaction was completed, the solid was removed by filtration, and a solution in which 1.1 g of 85% phosphoric acid was dissolved in 30 ml of ethanol was added. The solution was left for 24 hours and then filtered to obtain 3.0 g (yield 73%) of the labeled compound.

mp 203-204 ° C

The method for preparing oseltamivir phosphate or intermediate of the present invention provides a novel process for preparing 1,2-diamino compounds using a process that removes the explosiveness of azide compounds in a dangerous process of concentrating an azide compound in anhydrous conditions. Compared with the preparation method of the present invention, it is very stable to provide a process for preparing oseltamivir phosphate or intermediate.

Claims (4)

(a) reacting 1,2-epoxide of compound 6 of Scheme 4 with an azide reagent to synthesize compound 12 , which is an intermediate, in the presence of water, and then to form compound 17 via intermediate, compound 16 ; (b) converting compound 17 to compound 18 using dilute acid; (c) reacting compound 18 with an azide reagent to form compound 10 in the presence of water, wherein the 1,2-diamino compound or addition salt thereof is prepared. Scheme 4

R ₁ in Scheme 4 is a tert-butyloxycarbonyl group, triphenyl methyl group, or triphenyl methyl derivative group of the following formula (3). [Formula 3]

In the general formula _{3 R 2, R 3, R} 4 each independently is hydrogen, an alkoxy group of C ₁ ~ C ₁₀ alkyl group or a C ₁ ~ C ₁₀ of. According to claim 1, wherein the step (a) is reacted with compound 6 and azide reagent, 12 is not a separate process of concentration by extraction with an organic solvent, by directly reducing the azide synthesis of compound 12, and an amino alcohol compound And then react with a compound having an R ₁ substituent to form compound 17 , aziridine, via intermediate compound 16 , to prepare a 1,2-diamino compound or an addition salt thereof. 2. The method of claim 1, wherein step (b) converts compound 17 to compound 18 by removing and acetylating R ₁ using dilute acid. The diluted acid used here is an organic acid of an inorganic acid and trifluoroacetic acid, and the concentration of the diluted acid is 0.5 mol to 2 mol. The method of claim 1, wherein step (c) reacts the acetylated aziridine compound 18 with an azide reagent, extracts the azide with an organic solvent, omits a separate concentration step, and immediately reduces the azide compound 10. A method for producing a 1,2-diamino compound or an addition salt thereof which synthesizes the same.