RU2471790C1 - Method of producing (3s,4s)-4-((r)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone and novel intermediate compound used in said method - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention relates to a method of producing highly pure (3S,4S)-4-((R)-2-(benzyloxy)tridecyl)-3-hexyl-2-oxetanone of formula 1:

,

with high output, using a metal salt of (2S,3S,5R)-2-hexyl-3,5-dihydroxyhexadecanoic acid of formula 111:

,

as an intermediate compound. The compound of formula 1 is an intermediate product for producing tetrahydrolipstatin.

EFFECT: method enables to obtain a compound of formula 1 with high output and high purity.

11 cl, 6 ex

Description

FIELD OF THE INVENTION

The present invention relates to a method for producing (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone and a new intermediate used for this.

PREVIOUS TECHNOLOGY

(3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of formula I is known for its usefulness as an intermediate for the preparation of tetrahydrolipstatin (orlistat) (US Pat. Nos. 5,245,056 and 5,399,720 , and Mark A. Schwindt et al., Org. Process Research, Dec. 2007, 524).

(2S, 3S, 5R) -3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one of formula IV was used as the main starting material in the preparation of optically pure (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of the formula I or its derivatives having an easily removable alkyl protecting group.

Such a production procedure, such as that described in US patent No. 5245056, involves several stages, as shown in scheme I:

<Scheme I>

That is, a compound of formula V is prepared by introducing a tetrahydropyranyl group to protect the hydroxyl group of the compound of formula IV. Then, the compound of formula V is hydrolyzed to obtain a compound of formula VI, which is treated with a benzylating reagent to obtain a compound of formula VII. The deprotection reaction is carried out by treating the compound of formula VII with acid, followed by the separation of the optical isomers of the resulting compound to obtain optically pure (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid of formula II. Finally, the cyclization reaction of the compound of formula II is carried out to obtain (3S, 4S) -4- (R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of the formula I.

However, the method has difficulties associated with the use of complicated reaction stages, which lead to a low overall yield.

As for an alternative method, Korean Patent No. 191365 discloses a procedure for preparing a compound of formula II based on a compound of formula IV, as shown in Scheme II:

<Formula II>

<Scheme II>

The above procedure involves protecting the hydroxyl group of a compound of formula IV by introducing a benzoyl group into it to obtain a compound of formula VIII, hydrolyzing a compound of formula VIII to obtain a compound of formula IX, which is subjected to benzylation to obtain a compound of formula X, and a compound of formula X is hydrolyzed to obtain a compound of formula II. The above method also gives a low yield.

However, this method has difficulties associated with the fact that it is necessary to carry out the introduction of a protective group and the subsequent deprotection of the hydroxyl group of the compounds of formula IV; due to the structure of the compound of formula VIII, which contains a sterically large benzoyl group adjacent to the hydroxyl group at the 5'-position, steric difficulties arise and severe reaction conditions are required for the benzylation reaction; and its total yield is only 41.2%.

US patent No. 5399720 discloses a method for producing the benzylamine salt of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-hydroxyhexadecanoic acid of formula IIa by using the compound of formula IV as a starting material, as shown in scheme III:

<Formula IIa>

<Scheme III>

However, this method also suffers from problems of low overall yield (43%) due to the need for stringent benzylation conditions and the need to carry out the deprotection and hydrolysis steps after benzylation.

The inventors of the present invention sought to solve the above problems by the methods of the prior art and found that the subject compound can be obtained in high yield and high purity by hydrolysis of the compound of formula IV without protecting its hydroxyl group and subjecting the resulting compound to selective benzylation and cyclization.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide an improved process for the preparation of (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of formula I using a new intermediate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a process for the production of high purity (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of formula I in high yield, comprising

1) treating the compound of formula IV with metal hydroxide in a solvent to obtain a compound of formula III;

2) treating the compound of formula III with a benzylating reagent in a solvent in the presence of a base to obtain a compound of formula II; and

3) subjecting the compound of formula II to a cyclization reaction to obtain a compound of formula I:

Where

M represents Na, K or Li.

According to another aspect of the present invention, there is provided a metal salt of (2S, 3S, 5R) -2-hexyl-3,5-dihydroxyhexadecanoic acid, which is useful as an intermediate for the above method.

(3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of formula I according to the present invention can be obtained synthetically, as shown in scheme IV:

<Scheme IV>

Where

M represents Na, K or Li,

A detailed description regarding the method of the present invention shown in Scheme IV is as follows.

Stage 1

(3S, 4S, 6R) -3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one of formula IV can be obtained by the method disclosed in Korean Patent Application Laid-Open Publication No. 2009-0044817. In step 1 of Scheme IV, a metal salt of (2S, 3S, 5R) -2-hexyl-3,5-dihydroxyhexadecanoic acid (Formula III) can be obtained by hydrolysis of a compound of formula IV with a metal hydroxide such as sodium hydroxide, potassium hydroxide and lithium hydroxide in solvent.

The solvent as used herein may be an aprotic solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, methyl acetate, ethyl acetate, toluene and mixtures thereof, or mixtures of an aprotic solvent and water.

Metal hydroxide, such as sodium hydroxide, potassium hydroxide and lithium hydroxide, can be converted to the salt form of calcium or magnesium. The amount of metal hydroxide to be used is in the range of 1 to 50 mol equivalents, preferably 1 to 3 mol equivalents, more preferably 1.05 to 1.2 mol equivalents, based on the compound of formula IV.

The reaction in step 1 can be carried out at a temperature ranging from 0 ° C to the boiling point of the solvent, preferably from 30 ° C to 80 ° C.

The compound of formula III thus obtained can be used in step 2 without further purification, and it is useful as an intermediate for the preparation of (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2 -oxetanone of the formula I.

Stage 2

In stage 2, the compound of formula III obtained in the above stage 1, is subjected to benzylation without introducing a protective group in a solvent in the presence of a base to obtain (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid formula II, in which the benzyl group is selectively introduced into the 5'-position.

The solvent as used herein may be an aprotic solvent selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4-dioxane, dichloromethane, dichloroethane, acetonitrile, methyl acetate, ethyl acetate, toluene, N, N-dimethylformamide, dimethyl sulfoxide and mixtures thereof, or a mixture of an aprotic solvent and water. A preferred solvent as used herein is tetrahydrofuran, methyl tert-butyl ether or 1,2-dimethoxyethane.

Meanwhile, the base as used here may be lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide or potassium tert-butoxide, and the amount of base to be used is in the range of 1 to 5 mol equivalents, preferably 1 to 3 mol equivalents, more preferably 1.05 to 2.0 mol equivalents based on the compound of formula III.

The benzylation reagent, as used herein, for benzylation may be an optionally substituted benzyl halide such as benzyl chloride, benzyl bromide and benzyl iodide, and taking into account the reactivity, benzyl bromide is preferred. The amount of benzylation reagent to be used is in the range of 1 to 5 mol equivalents, preferably 1 to 3 mol equivalents, more preferably 1.05 to 2.0 mol equivalents based on the compound of formula III.

The reaction in step 2 can be carried out at a temperature ranging from 0 ° C to the boiling point of the solvent, preferably from 10 ° C to 100 ° C. Additives such as tetrabutylammonium iodide can be used to increase the reaction rate.

In addition, in order to easily obtain (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid of formula II as crystals during the purification process, an amine base can be added to the reaction to convert (2S, 3S , 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid to its amine salt.

Stage 3

In step 3, (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of formula I can be obtained by cyclization of (2S, 3S, 5R) -5-benzyloxy-2 hexyl-3-hydroxyhexadecanoic acid of formula II with a cyclization reagent. The aforementioned 3-hydroxyhexadecanoic acid containing a protecting group at the 5'-position can be converted to oxetanone using benzenesulfonyl chloride in pyridine, as described in US Pat. Nos. 4,998,746 and 5,245,056.

(3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of the formula I obtained in the above 3 steps can be further debenzylated to obtain (3S, 4S) - 3-hexyl-4 - ((R) -2-hydroxytridecyl) -2-oxetanone, which can be used to produce orlistat.

The present invention will be described in further detail with reference to the following examples. However, it should be understood that the present invention is not limited to specific examples.

Example 1. Obtaining sodium (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoate (compound of formula III) - (1)

25.5 g of (2S, 3S, 5R) -3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one was dissolved in 178.5 ml of methyl tert-butyl ether, 90 ml of 2N was added. NaOH solution and the resulting solution was stirred for 3 hours, while the temperature of the mixed solution was maintained at 50 ° C. Then, the reaction mixture was kept until phase separation occurred, the aqueous layer was removed, and the remaining organic phase was washed twice with 100 ml of salt water each time. The organic solution thus obtained was dried over anhydrous sodium sulfate, and filtered, and distilled to remove the solvent under reduced pressure to obtain 28.4 g of the title compound (yield: 100%) as an oil.

¹ H-NMR, 300 MHz (CD ₃ OD, ppm): δ 0.89 (dd, 6H, J = 5.8, 1.2 Hz), 1.24-1.80 (m, 32H ), 2.10-2.49 (m, 2H), 3.72-3.87 (m, 1H).

Example 2. Obtaining methylbenzylamine salt of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (compound of formula IIa) - (1)

98 ml of sodium (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoate obtained in the above Example 1 was dissolved in a mixed solvent of 98 ml of tetrahydrofuran and 328 ml of methyl tert-butyl ether. The reaction mixture was cooled to 0 ° C. and 7.19 g of sodium hydride and 30.7 g of benzyl bromide were successively added to the mixed solution. Then, the temperature of the reaction mixture was raised to 60 ° C., and the reaction mixture was refluxed for 5 days (step (a)). After the reaction mixture was cooled to room temperature, its pH was adjusted to 1, and the solution was stirred at room temperature for 3 hours. Then the pH of the reaction mixture was adjusted to 4 and the mixed solution was kept until phase separation occurred. The aqueous layer was removed and the remaining organic phase was washed twice with 120 ml of salt water each time. The resulting above-mentioned organic solution was dried over anhydrous magnesium sulfate, filtered and distilled to remove the solvent under reduced pressure. While stirring the reaction mixture, 438 ml of methyl acetate and 8.7 g of (S) -α-methylbenzylamine were added. After stirring for 3 hours, the mixture was cooled to 5 ° C and further stirred for 1 hour (step (b)). The mixture was dried and filtered to obtain 31.1 g of the title compound (yield: 74%) as a white solid.

Melting point 104-106 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ): 0.85-0.91 (m, 6H), 1.24 (m, 26H), 1.54 (d, 3H), 1.71-1.39 (m, 6H), 2.09-2.16 (m, 1H), 3.70-3.72 (m, 1H), 3.85-3.90 (m, 1H), 4.18 (q , 1H), 4.52 (d, 2H), 6.10 (br s, 5.0), 7.36-7.22 (m, 10H).

Example 3: Preparation of Sodium (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoate (compounds of formula III) - (2)

300 g of (2S, 3S, 5R) -3-hexyl-4-hydroxy-6-undecyltetrahydropyran-2-one was dissolved in 1.8 L of methyl tert-butyl ether. To the reaction mixture was added 9 L of 2 N NaOH solution, the temperature of the reaction mixture was slowly raised, and the aqueous layer was separated and removed from the reaction mixture. The organic layer was separated from the residual reaction mixture and washed with 450 ml portions of saturated salt water each, and the solvent was removed under reduced pressure. 900 ml of toluene was added to the residue and the solvent was removed and moisture was removed by azeotropic distillation under reduced pressure. 1.8 L of heptane and 1.8 L of methyl tert-butyl ether were added to the residue, and the temperature of the reaction mixture was raised to 40 ° C. Then the reaction mixture was cooled to room temperature and 50 ml of methanol was added. When the formation of crystals began, the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then cooled to 10 ° C. and stirred for 30 minutes. Then the reaction mixture was filtered and dried in warm air to obtain 534 g of the title compound (yield: 96%).

Differential Scanning Calorimetry (DSC): 109.29-117.30 ° C.

¹ H-NMR, 300 MHz (CD ₃ OD, ppm): δ 0.89 (dd, 6H, J = 5.8, 1.2 Hz), 1.24-1.80 (m, 32H ), 2.10-2.49 (m, 2H), 3.72-3.87 (m, 1H).

Example 4. Obtaining methylbenzamine salt of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (compound of formula IIa) - (2)

300 g of sodium (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoate obtained in the above Example 3 were dissolved in a mixed solvent of 405 ml of toluene and 45 ml of dimethyl sulfoxide. The reaction mixture was cooled to 5 ° C. and 49.8 g (1.5 equivalents) of 55% sodium hydride were added and stirred at the same temperature for 30 minutes. Then 325 g of benzyl bromide was added. The temperature of the reaction mixture was maintained at 15 ° C and the reaction mixture was stirred for 18 hours. Then, the same reaction was carried out as described in step (b) of Example 2, and the solid obtained from the above reaction was filtered and dried to obtain 332.9 g of the title compound (yield: 75%) as a white solid colors.

The same analysis results were obtained as in Example 2.

Example 5. Obtaining methylbenzamine salt of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid (compound of formula IIa) - (3)

100 g of sodium (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoate obtained in the above Example 3 was dissolved in 1.5 L of toluene. 108.4 g of benzyl bromide and 48.3 g of potassium tert-butoxide were successively added to the reaction mixture. Then its temperature was slowly raised to 60-75 ° C and the reaction mixture was heated for 12 hours. Then, the same reaction was carried out as described in step (b) of Example 2, and the solid obtained from the above reaction was filtered and dried to obtain 106 g of the title compound (yield: 72%) as a white solid.

The same analysis results were obtained as in example 2.

Example 6. Obtaining (3S, 4S) -4 - ((R) -2 (benzyloxy) tridecyl) -3-hexyl-2-oxetanone (compound of formula I)

330 g of the (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid methylbenzylamine salt obtained in the above Example 4 was dissolved in a mixed solvent of 1.65 L of hexane and 1.65 L of 2N. aqueous hydrochloride solution. After stirring for 2 hours, the aqueous layer was removed and the remaining organic phase was washed twice with 1.65 L of distilled water each. The organic solution obtained above was dried over anhydrous magnesium sulfate, filtered and distilled under reduced pressure. Then, 2.61 L of pyridine was added and the reaction mixture was cooled to 0 ° C and stirred. Then, 1.44 L of benzenesulfonyl chloride was added slowly over 2 hours, and the reaction mixture was stirred for an additional 20 hours at the same temperature. After adding 2.61 L of distilled water and 2.61 L of hexane, the reaction mixture was vigorously stirred. Then, the reaction mixture was kept until phase separation occurred, and the aqueous layer was removed from the reaction mixture. The organic solution obtained above was washed twice with 2N. hydrochloride, in portions of 2.61 l, and additionally washed twice with distilled water, in portions of 2.61 l. The organic solution obtained above was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under reduced pressure. Accordingly, 270.1 g of the title compound was obtained (yield: 101.2%) as a white solid.

¹ H-NMR (300 MHz, CDCl ₃ ): 0.80-0.95 (m, 6H), 1.15-1.85 (m, 30H), 1.94 (t, 2H, J = Hz) , 3.15-3.26 (m, 1H), 3.55-3.65 (m, 1H), 4.35-4.63 (m, 3H), 7.25-7.40 (m, 5H).

Reference Example 1. Preparation of (3S, 4S) -3-hexyl-4 - ((R) -2-hydroxytridecyl) -2-oxetanone

270 g of (3S, 4S) -4 - ((R) -2 (benzyloxy) tridecyl) -3-hexyl-2-oxetanone obtained in the above Example 6 was dissolved in 1.89 L of ethyl acetate. 19 g of 5% Pd / c (palladium / on carbon) was added and the reaction mixture was stirred for 3 hours while the hydrogen pressure was 6 bar. Pd was removed by filtration through Celite® and the solvent was removed under reduced pressure. 2.15 L of hexane was added and the temperature of the reaction mixture was raised to 40 ° C. to melt the solid obtained above. Then the reaction mixture was cooled to room temperature, and crystals formed in the reaction mixture at 20 ° C. After stirring for 8 hours, the reaction mixture was cooled to 5 ° C, stirred for 2 hours and filtered to obtain 166.3 g of the title compound (yield: 83%) as a white solid. Melting point 60-61 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ): 4.54-4, 44 (m, 1H), 3.87-3.74 (m, 1H), 3.3-3.16 (m, 1H) 1.95-1.12 (m, 32H); 0.88 (t-shaped, 6H).

Reference Example 2: Orlistat Synthesis

166 g of (3S, 4S) -3-hexyl-4 - ((R) -2-hydroxytridecyl) -2-oxetanone obtained according to Reference Example 1 was dissolved in 830 ml of tetrahydrofuran. After adding 160 g of triphenylphosphine (PPh ₃ ) and 86 g of N-formyl-L-leucine, the reaction mixture was cooled to 0 ° C. A mixed solution was continuously added over 1.5 hours in which 120 ml of diisopropylazodicarboxylate (DIAD) was diluted in 332 ml of tetrahydrofuran. After stirring for an additional 30 minutes, the reaction mixture was stirred for 4 hours, while the temperature was slowly raised. After removing the solvent, 832 ml of hexane was added and the reaction mixture was stirred for 5 hours. The resulting solid was removed by filtration, and the hexane layer was washed three times with 499 ml of a 55% methanol / distilled water mixture. The remaining organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was removed under reduced pressure. Then 2.5 L of hexane was added, and the reaction mixture was cooled to 10 ° C. and stirred for 1 hour, followed by the addition of the orlistat seed crystal. The reaction mixture was again slowly cooled to 0 ° C. and stirred overnight. The resulting solid was filtered, washed with 500 ml of cold hexane and dried to give 192.5 g of the title compound (yield: 83%) as a white solid.

Melting point 42.4-44.5 ° C.

¹ H-NMR (300 MHz, CDCl ₃ ): 8.22 (s, 1H), 5.99 (d, 1H), 5.06-4.98 (m, 1H), 4.77-4.60 (m, 1H), 4.32-4.22 (m, 1H), 3.27-3.16 (m, 1H), 2.28-1.98 (m, 2H), 1.90-1 15 (m, 30H); 1.03-0.82 (m, 12H).

Although the invention has been described in relation to the above specific embodiments, it should be appreciated that those skilled in the art can make various modifications and changes that also fall within the scope of the invention as defined by the appended claims.

Claims (11)

1. The method of obtaining (3S, 4S) -4 - ((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone of the formula I, including
1) treating the compound of formula IV with metal hydroxide in a solvent to obtain a compound of formula III;
2) treating the compound of formula III with a benzylating reagent in a solvent in the presence of a base to obtain a compound of formula II; and
3) subjecting a compound of formula II to a cyclization reaction to obtain a compound of formula I:

where M represents Na, K or Li. 2. The method according to claim 1, where the solvent used in stage 1) is an aprotic solvent selected from the group consisting of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, 1,2 -dimethoxyethane, acetonitrile, methyl acetate, ethyl acetate, toluene and mixtures thereof, or a mixture of an aprotic solvent with water. 3. The method according to claim 1, where the metal hydroxide in stage 1) is used in an amount of from 1 to 50 mol equivalents based on the compound of formula IV. 4. The method according to claim 1, where the solvent used in stage 2) is an aprotic solvent selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, 1,4 dioxane, dichloromethane, dichloroethane, acetonitrile, methyl acetate, ethyl acetate, toluene, N, N-dimethylformamide, dimethyl sulfoxide and a mixture thereof, or a mixture of an aprotic solvent with water. 5. The method according to claim 1, where the base used in stage 2) is selected from the group consisting of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium tert-butoxide, sodium tert-butoxide and potassium tert-butoxide. 6. The method according to claim 5, where the base is used in an amount of from 1 to 5 mol equivalents based on the compound of formula III. 7. The method according to claim 1, where the benzylating reagent used in stage 2) is a benzyl halide selected from the group consisting of benzyl chloride, benzyl bromide and benzyl iodide. 8. The method according to claim 1, where the benzylating reagent in stage 2) is used in an amount of from 1 to 5 mol equivalents based on the compound of formula III. 9. The compound of formula III;

where M represents Na, K or Li. 10. A method of obtaining a compound of formula III, comprising the stage of processing (3S, 4S, 6R) -3-hexyl-4-hydroxy-6-undecyl tetrahydropyran-2-one of formula IV with metal hydroxide in a solvent:

where M represents Na, K or Li. 11. A method of obtaining a compound of formula II, comprising the step of treating a metal salt of (2S, 3S, 5R) -3,5-dihydroxy-2-hexylhexadecanoic acid of formula III with a benzylating reagent in a solvent in the presence of a base:

where M represents Na, K or Li.