JP2017128528A - Method for producing (s)-2-hydroxypropanoic acid derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing an (S)-2-hydroxypropanoic acid derivative and ambrisentan having high optical purity in an industrially advantageous manner.SOLUTION: There is provided a method for producing an (S)-2-hydroxypropanoic acid derivative represented by the formula (1a) by reacting an (RS)-2-hydroxypropanoic acid derivative represented by the formula (1) with (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine to form a diastereomer salt, followed by desalting.SELECTED DRAWING: None

Description

  The present invention relates to an industrially advantageous method for producing a (S) -2-hydroxypropanoic acid derivative having high optical purity and a method for producing ambrisentan using the same.

Pulmonary arterial pulmonary hypertension is a disease in which pulmonary vasoconstriction and cell proliferation are caused by an imbalance of various vasoactive substances, resulting in pulmonary vascular dysfunction. Symptoms such as shortness of breath, dyspnea, fatigue, and decreased ability of exercise that interfere with daily life due to worsening blood flow in the pulmonary artery. Progression also causes heart failure, reducing the patient's prognosis.
Endothelin is a peptide having strong vasoconstriction and cell growth promoting action, and a compound that inhibits binding to the endothelin receptor can be a therapeutic agent for pulmonary arterial hypertension. There are two subtypes of endothelin receptor, endothelin A receptor and endothelin B receptor. Of these, endothelin A receptor is considered to be deeply involved in the pathology of pulmonary arterial hypertension.

  Ambrisentan [(2S) -2-[(4,6-dimethylpyrimidin-2-yl) oxy] -3-methoxy-3,3-diphenylpropanoic acid] selectively inhibits endothelin A receptor pulmonary arterial Developed as a treatment for pulmonary hypertension. Exercise tolerance, which is considered to be an indicator of prognosis improvement in clinical trials, has been improved and results have been obtained. It is currently used for the treatment of pulmonary arterial hypertension.

Ambrisentan can be produced, for example, by the following method.
A (RS) -2,3-epoxypropenoic acid methyl derivative is synthesized from benzophenone and methyl chloroacetate. Thereafter, the epoxide is opened to synthesize a (RS) -2-hydroxypropanoic acid methyl derivative. Hydrolysis is performed to synthesize a (RS) -2-hydroxypropanoic acid derivative. Thereafter, optical resolution is performed to obtain an (S) -2-hydroxypropanoic acid derivative, which is then reacted with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine to obtain ambrisentan.

Since the pharmacological activity of ambrisentan is related to optical purity, it is important to obtain (S) -2-hydroxypropanoic acid derivatives with high optical purity in the optical resolution of (RS) -2-hydroxypropanoic acid derivatives. .
As a method for obtaining a (S) -2-hydroxypropanoic acid derivative having high optical purity in the optical resolution of the (RS) -2-hydroxypropanoic acid derivative, (S) -1- (4-chlorophenyl) ethylamine, (S)- Diastereomeric salts using optical resolution agents such as 1- (3-methoxyphenyl) ethylamine, (R) -1- (2,4-dichlorophenyl) ethylamine, (S) -1- (4-nitrophenyl) ethylamine The method is known (see Patent Documents 1 to 5). All of the above optical resolution agents are 1-phenylethylamine derivatives in which the benzene ring is 1 or 2 substituted, but the type, substitution position, and number of substitutions greatly affect optical purity and reaction yield. Is clear. In general, it is known that introduction of a substituent onto a benzene ring has different orientation and reactivity depending on the type of substituent and is difficult to control to a high degree (see Non-Patent Document 1). This optical resolution agent is also difficult to produce and obtain, which is a factor in increasing the cost in the industrial production of ambrisentan.

  By the way, in recent years, declining birthrate and aging are progressing globally, and the suppression of increasing medical costs and drug costs has become an issue. For this reason, provision of a cheap and stable pharmaceutical is demanded.

  As for ambrisentan, it is expected to provide an inexpensive drug. However, the known ambrisentan production method using the optical resolution agent of the 1-phenylethylamine derivative is difficult to adopt as a method for producing an inexpensive drug.

Japanese National Patent Publication No. 10-507190 Special table 2002-528524 gazette JP 2012-532863 A International Publication No. 2012/017441 International Publication No. 2011/114338

John McMurry, “Fundamentals of ORGANIC CHEMISTRY”, USA, Seventh Edition, Cengage Learning, 2010, p. 166-177

  An object of this invention is to provide the manufacturing method of ambrisentan which can be supplied stably at low cost.

  As a result of intensive studies on various optical resolving agents, the present inventors surprisingly used (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine, and thereby improved the optical purity. A high (S) -2-hydroxypropanoic acid derivative can be obtained, and if this is reacted with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine, ambrisentan with high optical purity can be produced industrially advantageously. I found out that I can do it.

  That is, the present invention provides the following [1] and [2].

[1] Formula (1)

(RS) -2-hydroxypropanoic acid derivative represented by the formula (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is reacted to form a diastereomeric salt, followed by desalting. Formula (1a) characterized by

The manufacturing method of the (S) -2-hydroxypropanoic acid derivative represented by these.

[2] Formula (1)

(RS) -2-hydroxypropanoic acid derivative represented by the formula (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is reacted to form a diastereomeric salt, followed by desalting. Formula (1a)

(S) -2-Hydroxypropanoic acid derivative represented by the following formula, and the resulting compound is reacted with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in the presence of a base: Manufacturing method.

  The present invention makes it possible to produce a (S) -2-hydroxypropanoic acid derivative at low cost and high optical purity, and is excellent as a means for supplying ambrisentan at a low cost and stably.

  The production method of the present invention can be represented by the reaction formula as follows.

  The (RS) -2-hydroxypropanoic acid derivative of formula (1) is reacted with (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine to give a diastereomeric salt, followed by desalting Thus, the (S) -2-hydroxypropanoic acid derivative of the formula (1a) is produced.

  That is, first, (RS) -2-hydroxypropanoic acid derivative (1) and (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine (optical resolution agent) were dissolved in a solvent. The solution is stirred and reacted for a certain time under heating or at room temperature to form a diastereomeric salt of (S) -2-hydroxypropanoic acid derivative (1a) and an optical resolution agent. Next, the precipitated crystals are obtained by solid-liquid separation, dissolved in water in a container, and then desalted by adding an organic solvent and an inorganic acid. The organic layer and the aqueous layer are separated by liquid-liquid separation, and the (S) -2-hydroxypropanoic acid derivative (1a) is obtained by evaporating the solvent from the obtained organic layer under reduced pressure. The obtained (S) -2-hydroxypropanoic acid derivative (1a) can be improved in optical purity by stirring in a suspended state under heating in an organic solvent for a certain period of time.

  In the step of forming a diastereomeric salt, (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is placed in a container together with (RS) -2-hydroxypropanoic acid derivative (1). A solvent may be added and dissolved in advance. Further, the (RS) -2-hydroxypropanoic acid derivative (1) may be added after being dissolved in a solvent. In the latter case, (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine may be added after being dissolved in a solvent, or may be added without being dissolved. The amount of the optical resolving agent is preferably 0.1 to 1 equivalent, more preferably 0.3 to 0.7 equivalent with respect to (RS) -2-hydroxypropanoic acid derivative (1), 0.4 to 0.6 equivalent is more preferred. As the solvent, methanol, ethanol, 2-propanol, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, tert-butyl methyl ether or a mixture thereof is preferable. 2-propanol, acetone, methyl isobutyl ketone, acetonitrile, ethyl acetate, tert- More preferred is butyl methyl ether or a mixture of acetone and tert-butyl methyl ether. The concentration of (RS) -2-hydroxypropanoic acid derivative (1) is preferably from 0.1 to 1 mol / L, more preferably from 0.1 to 0.5 mol / L. Crystals of the (S) -2-hydroxypropanoic acid derivative (1a) and the diastereomeric salt of the optical resolution agent are precipitated from the solvent during the reaction or from the solvent during the cooling after the reaction. The reaction temperature is preferably in the temperature range from room temperature to heating reflux. The reaction time is preferably 5 minutes to 5 hours. The cooling temperature is preferably 0 ° C. to room temperature. The cooling time is preferably 1 to 24 hours.

  Next, as the organic solvent used in the step of desalting the (S) -2-hydroxypropanoic acid derivative (1a) and the diastereomeric salt of the optical resolution agent, water and a general organic solvent capable of liquid-liquid separation are used. Can be used. Examples thereof include tert-butyl methyl ether, diethyl ether, methyl isobutyl ketone, ethyl acetate, toluene and the like and mixed liquids thereof. Examples of the inorganic acid used for desalting include hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrofluoric acid, hydroiodic acid and the like, and hydrochloric acid is more preferable.

  As an organic solvent used for suspension stirring of the (S) -2-hydroxypropanoic acid derivative (1a) after desalting, methanol, ethanol, 2-propanol, acetone, acetonitrile, tetrahydrofuran, tert-butyl methyl ether, diethyl ether, Examples thereof include ethyl acetate, toluene, heptane and the like, and a mixed solution thereof, and a mixed solution of tert-butyl methyl ether and heptane is more preferable. The heating temperature in suspension stirring is preferably in the range of room temperature to heating reflux, and the stirring time is preferably 30 minutes to 24 hours.

(S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine used in the method of the present invention is an optical resolution agent obtained by chemical synthesis, but has no substituent on the benzene ring. Therefore, it can be easily synthesized from a 1,2,3,4-tetrahydronaphthalene derivative.
(S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is inexpensive and can be stably obtained. For example, a general reagent sales company such as Sigma Aldrich (registered trademark) Can be purchased from.
(S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is a known optical resolution agent, but there is no example used for optical resolution of α-hydroxycarboxylic acid as in the present invention. .

  Ambrisentan can be obtained according to a known method using the obtained (S) -2-hydroxypropanoic acid derivative (1a). For example, based on the description in Patent Document 4, a method of reacting with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in the presence of a base can be mentioned.

  Examples of the base used in this reaction include sodium hydride, sodium amide, lithium diisopropylamide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide and the like. Of these, sodium hydride is preferred.

  This reaction is carried out in a solvent such as tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, etc. with respect to (S) -2-hydroxypropanoic acid derivative (1a). It is preferred to react ~ 2 equivalents, more preferably 1.3-1.5 equivalents of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine. The reaction temperature is preferably 0 ° C. to room temperature, and a reaction time of 1 to 24 hours is sufficient.

  Isolation of ambrisentan from the reaction mixture can be easily performed by liquid-liquid separation and crystallization.

  EXAMPLES The present invention will be specifically described below with reference to examples, but these examples do not limit the present invention.

Reference Example 1 (Synthesis of methyl (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoate)
Benzophenone 500 g (2.74 mol) was dissolved in 1200 mL of toluene. After replacing with nitrogen, 267 g (4.94 mol) of sodium methoxide was added, and the mixture was suspended and stirred. The suspension was cooled, and while maintaining -8-4 ° C, a solution of methyl chloroacetate 410 mL (4.68 mol) in toluene (300 mL) was slowly added dropwise over 90 minutes, and then at -3-4 ° C. Stir for 1 hour. After adding 1000 mL of water and stirring for 15 minutes, the organic layer obtained by liquid-liquid separation was washed with 1000 mL of water. The solvent was distilled off under reduced pressure, and the resulting residue (methyl (RS) -3,3-diphenyl-2,3-epoxypropenoate) was dissolved in 1200 mL of methanol, cooled at 0 ° C., and p-toluene. A solution of 15 g (0.08 mol) of sulfonic acid monohydrate in methanol (150 mL) was slowly added dropwise over 30 minutes. The mixture was stirred at 0 ° C. for 1.5 hours, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 2500 mL of ethyl acetate and washed twice with 1000 mL of 5% aqueous sodium carbonate solution. The solvent was distilled off under reduced pressure, 1000 mL of hexane was added to the resulting residue, and the mixture was suspended and stirred at room temperature for 1.5 hours and then stirred at 0 ° C. for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 60 ° C. for 5 hours to obtain 659 g (yield 84%) of methyl (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoate.
¹ H-NMR (CDCl ₃ ): 3.15 (3H, s), 3.62 (3H, s), 5.17 (1H, d, J = 8.5 Hz), 7.30 to 7.42 ( 10H, m).

Reference Example 2 Synthesis of (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid 500 g (1.75 mol) of methyl (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoate Was suspended in 1000 mL of water, 950 mL (1.90 mol) of 2 mol / L sodium hydroxide was added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was cooled to room temperature, 1500 mL of tert-butyl methyl ether was added, 700 mL of 10% hydrochloric acid was added, and the mixture was stirred for 20 minutes to dissolve the precipitated solid. After liquid-liquid separation, the organic layer was washed with 1000 mL of water. 1,200 mL of heptane was added, and the solvent was distilled off under reduced pressure (200 mmHg) at 40 ° C. to precipitate crystals. Heptane 1000mL was added and it stirred at 0 degreeC for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 7 hours to obtain 431 g (yield 91%) of (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid.
¹ H-NMR (CDCl ₃ ): 3.16 (3H, s), 5.08 (1H, d, J = 4.0 Hz), 7.36-7.45 (10H, m).

Example 1
(RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid 500 mg (1.84 mmol) was dissolved in 2-propanol 8 mL, and (S)-(+)-1,2,3,4- Tetrahydro-1-naphthylamine 135 mg (0.92 mmol) was added. After stirring for 1 hour under heating and refluxing, the mixture was cooled to room temperature and stirred for 2 hours. The precipitated crystals were collected by filtration, washed with 2-propanol, and dried under reduced pressure.

Examples 2-7
The same operation as in Example 1 was performed using the solvents in Table 1.

Comparative Examples 1-10
(RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid 0.5 or 1 g (1.84 or 3.68 mmol) was added to an organic solvent (Table 1) 0.2 to 0.3 mol / L (Table 1). 12-16 mL / g) and 0.5 equivalent (0.92 or 1.84 mmol) of optical resolution agent (Table 1) was added. After stirring for 1 hour under heating to reflux, the mixture was cooled to room temperature and stirred for 2 to 5 hours. The precipitated crystals were collected by filtration, washed with an organic solvent (Table 1), and then dried under reduced pressure.

Test Example 1 (Optical purity measurement)
HPLC analysis conditions HPLC: D-7000 type HPLC system (manufactured by Hitachi High-Tech)
Detector: Ultraviolet absorptiometer Detection wavelength: 220 nm
Column: CHIRALPAK (registered trademark) AD-H (inner diameter 4.6 mm, length 250 mm, particle diameter 5 μm), manufactured by Daicel Corporation Column temperature: 35 ° C.
Mobile phase: 0.1% trifluoroacetic acid hexane solution / 0.1% trifluoroacetic acid 2-propanol solution = 95/5
Degasser: Off

Example 8: (Synthesis of (S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid)
200 g (734 mmol) of (RS) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid is dissolved in 1500 mL of acetone, 1500 mL of tert-butyl methyl ether is added, and (S)-(+)-1, 2,4.1-tetrahydro-1-naphthylamine (54.1 g, 367 mmol) was added. The mixture was stirred for 1 hour under reflux with heating, and then stirred at room temperature for 16 hours. The precipitated crystals were collected by filtration and washed twice with 45 mL of tert-butyl methyl ether. To the obtained crystals, 360 mL of water and 500 mL of tert-butyl methyl ether were added, and 140 mL of 10% hydrochloric acid was added dropwise with suspension stirring. After stirring at room temperature for 1 hour to dissolve the crystals, liquid-liquid separation was performed, and the aqueous layer was extracted with 500 mL of tert-butyl methyl ether. After the organic layer was washed with 500 mL of water, 500 mL of heptane was added, and the solvent was distilled off under reduced pressure (200 mmHg) at 40 ° C. to precipitate crystals. Heptane (500 mL) was added, and the mixture was stirred at room temperature for 45 minutes and at 0 ° C. for 1.5 hours. After the crystals were collected by filtration, tert-butyl methyl ether (138 mL) and heptane (322 mL) were added, and the mixture was stirred at 40 ° C. for 1 hour. Then, after stirring at room temperature for 1 hour, it stirred at 0 degreeC for 1 hour. The crystals were collected by filtration and dried under reduced pressure at 40 ° C. for 4 hours, and (S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid 65.9 g (yield 66%, optical purity 99.9%). )
Melting point: 124-126 ° C
¹ H-NMR (CDCl ₃ ): 3.16 (3H, s), 5.08 (1H, d, J = 4.0 Hz), 7.36-7.45 (10H, m).

Example 9 (synthesis of ambrisentan)
(S) -2-Hydroxy-3-methoxy-3,3-diphenylpropanoic acid 10 g (36.7 mmol) was dissolved in N, N-dimethylformamide 80 mL. After purging with nitrogen, 6.3 g (157 mmol) of 60% sodium hydride was slowly added over 1 hour 30 minutes at room temperature. After stirring for 1 hour, a solution of 9.56 g (51.3 mmol) of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in N, N-dimethylformamide (20 mL) was slowly added dropwise over 1 hour at room temperature. And stirred for 15 hours. After cooling to 0 ° C. and slowly dropping 10 mL of methanol over 20 minutes, 100 mL of cold water was added. After adding 75 mL of 10% hydrochloric acid, the mixture was extracted twice with 100 mL of ethyl acetate. The organic layer was extracted 3 times with 50 mL of 1N sodium hydroxide. Further, 60 mL of 10% hydrochloric acid was slowly added to the aqueous layer and stirred for 1 hour. The precipitated crystals were collected by filtration and washed twice with 25 mL of water. The obtained crystals were dried under reduced pressure at 60 ° C. for 5 hours to obtain 13.1 g of ambrisentan (yield 95%, optical purity 98.6%).
Melting point: 175 ° C
¹ H-NMR (DMSO-d6): 2.33 (6H, s), 3.36 (3H, s), 6.12 (1H, s), 6.94 (1H, s), 7.19- 7.33 (10H, m).
IR (νmax) (KBr): 2965, 1752, 1597, 1560, 1446, 1406, 1380, 1194, 1175, 1116, 749, 701 cm ⁻¹

  Unlike (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine, unlike the optical resolution agent of the prior art, it is not necessary to introduce regioselective substituents into the benzene ring by chemical synthesis. Therefore, it is an optical resolution agent with high availability, and is excellent in cost reduction and stable supply of ambrisentan.

Claims (2)

Formula (1)

(RS) -2-hydroxypropanoic acid derivative represented by the formula (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is reacted to form a diastereomeric salt, followed by desalting. Formula (1a) characterized by

The manufacturing method of the (S) -2-hydroxypropanoic acid derivative represented by these. Formula (1)

(RS) -2-hydroxypropanoic acid derivative represented by the formula (S)-(+)-1,2,3,4-tetrahydro-1-naphthylamine is reacted to form a diastereomeric salt, followed by desalting. Formula (1a)

(S) -2-Hydroxypropanoic acid derivative represented by the following formula, and the resulting compound is reacted with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in the presence of a base: Manufacturing method.