WO2013135218A1

WO2013135218A1 - A method of preparing 3- ( ( (2r, 3s) -2- ( (r) -1- (3, 5 -bis (trifluoromethyl) phenyl) ethoxy) -3 - (4 - fluorophenyl) morpholino) methyl) - 1h- 1, 2, 4 -triazol- 5 (4h) -one (aprepitant) in polymorph form i or ii

Info

Publication number: WO2013135218A1
Application number: PCT/CZ2013/000037
Authority: WO
Inventors: Josef Zezula; Josef Hajicek
Original assignee: Zentiva, K.S.
Priority date: 2012-03-13
Filing date: 2013-03-13
Publication date: 2013-09-19
Also published as: CZ2012178A3; CZ304770B6

Abstract

The present solution relates to a method of preparing aprepitant of formula (1) in the desired crystalline form II or I, wherein the intermediate of formula (12) is extracted with a water immiscible high-boiling solvent selected from an alcohol, ester or ketone and, after washing with water and/or brine, the solution is heated up to the boiling point of the given solvent, which results in cyclization to aprepitant, and, after cooling, the produced aprepitant is isolated.

Description

A METHOD OF PREPARING

3 - ( ( (2R, 3S) -2 - ( (R) -1- (3 , 5 -BIS (TRIFLUOROMETHYL) PHENYL) ETHOXY) -3 - (4 - FLUOROPHENYL) MORPHOLINO) METHYL) - 1H- 1 , 2 , 4 -TRIAZOL- 5 (4H) -ONE (APREPITANT) IN POLYMORPH FORM I OR II

Technical Field

The invention relates to a method of preparing 3-(((2R,3S)-2-((R)- l -(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(4-fluorophenyl)morpholino)methyI)- l H- l ,2,4-triazol- 5(4H)-one of formula I in high purity in polymorph form I or II depending on the solvent used and crystallization conditions.

Background Art

Aprepitant 1 , chemically 3-(((2R,3S)-2-((R)-l -(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(4- fluorophenyl)morpholino)methyl)-l H- l ,2,4-triazol-5(4H)-one, is a selective antagonist of the human substance P/neurokinin 1 (NKl ) receptors with high affinity. It was developed by the company Merck as an antiemetic agent administered for mitigation of side effects of cancer chemotherapy.

The basic patent W09516679 describes the preparation of a high number of variously substituted morpholines, aprepitant itself is described in Example 75. The synthesis starts from iV-benzylated (5")-4-fluorophenylglycine 2, prepared in several stages from 4-fluoro- benzaldehyde. The amino acid 2 is cyclized by means of a reaction with 1 ,2-dibromoethane in the presence of a base to the morpholine 4. Reduction of the lactone by selectride at a low temperature leads to syn lactol, which was acylated in situ by the chloride 5, producing the substituted benzoate 6. Dimethyltitanocene, prepared by a reaction of titanocene dichloride with methyl magnesium bromide (or methyl lithium), was then added to a solution of the benzoate 6, which produced an enol ether 7. Enantioselective hydrogenation, stereochemically controlled by the configuration of the substrate, with simultaneous vV-debenzylation provided the N-nor morpholine 11, isolated as a salt. In the basic patent the free base 11 is then alkylated with chloromethyl acetamidrazone 10, prepared by addition of the methyl diazocarboxylate 8 to chloroacetonitrile in the presence of Hiinig's base and the intermediate 12 is subjected to cyclization in refluxing xylene.

MeOH/H₂0 purification

Reaction Conditions: a) 3/DIPEA/D F/100°C, (77%), b) l-selectride/THF/-75°C/15 min then 5/- 70 °C, (65%, soln), c) Cp₂TiCI₂/MeMgBr/THF, (94%), d) H₂/Pd-C/EtOAc-EtOH , (94%, *TsOH), e) DIPEA/CH₃CN, f) A/Xylenes

Examples of carrying out this basic synthesis in a large scale are only included in the patent covering polymorph forms of aprepitant, WO 1999/01444. The form, allegedly obtained using the procedure described in the basic patent, is referred to as II here and being heated or stirred in a suspension in solvents at the laboratory temperature it passes to the more stable form I. Another related process patent is WO2003/089429, claiming alkylation of the hydrochloride 11 with the amidrazone 10 in toluene in the presence of a excess of potassium carbonate and the addition of an aprotic solvent (e.g. DMSO); after completion of the alkylation the mixture is, washed with water, and the toluene extract containing the intermediate product 10 is heated up to boiling to initiate the cyclization producing aprepitant.

Patent applications have also been filed for the following variations of this basic synthesis:

-with isolation of 8 as an oxalate (MSN, WO2009/116081)

-with the use of 1 ,2-dibromoethane as a solvent in the first step and isolation of 8 as camphor sulfonate (Orchid, WO 2009/001203) The key intermediate 11 in the hydrochloride or tosylate form can be conveniently prepared in accordance with WO 01/94323 and WO 01/94324 using an efficient process developed by Merck.

Preparation of polymorph II by transformation of a mixture of I and II of ca. 40:60 by crystallization with the use of an antisolvent or by heating of form III in decalin is described by the patent WO2009/106486 of Sandoz.

Glenmark's patent WO2007088483 describes preparation of a mixture of polymorphs I and II in various crystallization ratios, again with the use of addition of an antisolvent.

Preparation of pure form II is very difficult as its physical properties (melting point, DSC) are very similar to form I and form II passes into form I in suspension in an organic solvent

(WO1999/01444).

Disclosure of Invention

The invention provides a method of preparing aprepitant of formula 1, 3-(((2R,3S)-2-((R)- l - (3 ,5-bis(trifluoromethyl)phenyl)ethoxy)-3 -(4-fluorophenyl)morpholino)methyl)- 1 H- 1 ,2,4- triazol-5(4H)-one

in the desired crystalline form II or I, wherein the intermediate 12, prepared by alkylation of the amine 11 with chloroacetamidrazone 10 in N.N-dimethylformamide (DMF) in the presence of potash,

¹ (12) is extracted with a water-immiscible high-boiling solvent selected from an alcohol, ester or ketone, and after washing with water and/or brine the solution is heated up to the boiling point of the given solvent, which results in cyclization to aprepitant, and after cooling the produced aprepitant is isolated; Scheme 2.

A suitable selection of the solvent for the extraction, its quantity and cooling mode during the crystallization can be used to control the production of the desired polymorph.

Polymorph form II of aprepitant is preferably obtained if the immiscible high-boiling solvent is n-pentanol, preferably in a ratio of 10 to 25 ml per 1 g of the intermediate 12.

It is convenient to boil the obtained solution with active carbon before the start of cooling and to filter it when hot then. The solution is then gradually cooled from the boiling point of the solvent to a temperature in the range of -20 to -30°C.

Polymorph form II can also be prepared by re-crystallization of polymorph I or a mixture of polymorph I and II, or other forms of aprepitant, from «-pentanol.

Polymorph form I of aprepitant is obtained if the water-immiscible high-boiling solvent is methyl isobutyl ketone (MIBK), preferably in a ratio of 10 to 50 ml per 1 g of the intermediate 12, or ft-butyl acetate (n-BuOAc), preferably in a ratio of 30 to 70 ml per 1 g of the intermediate 12. It is convenient to boil the obtained solution with active carbon before the start of cooling and filter it when hot then. The solution is then gradually cooled from the boiling point of the solvent to a temperature in the range of -20 to -30°C.

Compared to xylene, which is used in the basic patent, the crude crystalline product is surprisingly obtained with a much higher chemical purity (99.00-99.80 compared to 97.3 1 % using crystallization from xylene) and in better or comparable yields in the process with n- pentanol, methyl isobutyl ketone or n-butyl acetate. Moreover, the solvents used are not as toxic as xylene.

Comparisons of the yields and purities of crude products are summarized in Table 1 .

Table 1 :

Brief Description of Drawings:

Figure 1 : Powder XRPD of Form I (at the top) and Form II (at the bottom)

Figure 2: Powder XRPD record - superposition of Forms I and II

Working Examples of Invention:

In the following examples the samples were characterized using the X-Ray Powder Diffraction Method (XRPD) and the purity was measured with HPLC.

XRPD measurement parameters: The diffraction patterns were measured using an X'PERT PRO MPD PANalytical diffractometer with a graphite monochromator, radiation Cu a (λ= 1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01 ° 2Θ. The measurement was carried out using a flat powder sample that was placed on a Si plate. For the primary optic setting programmable divergence diaphragms with the irradiated sample area of 10 mm, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm ¼ were used. For the secondary optic setting an X'Celerator detector with the maximum opening of the detection slot, Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used. High-Performance Liquid Chromatography (HPLC):

Chemical purity of the samples was determined on a Gemini NX C I 8 column, 3.0 um or equivalent (Phenomenex);

- dimensions: 1 = 0.10 m, 0 = 4.6 mm

- temperature: 30°C.

Mobile phase:

- A : ammonium dihydrogen phosphate 0.02 M, pH adapted with ammonium hydroxide to 9.8 ± 0.05

B: acetonitrile R

Gradient elution:

Detection: spectrophotometer at 220 nm

Example 1 :

Potash (5. 10g, 36.90 mmol, 1.75 equiv.) was added to a suspension of the hydrochloride 11 ( 10 g, 21 . 10 mmol) in DMF (20 ml) at the laboratory temperature and the suspension was stirred for 30 mins and then addition of a suspension of amidrazone (3.83 g, 23.19 mmol, 1 .1 equiv.) in DMF (10 mL) was started within ca. 10 min. Stirring at the laboratory temperature followed for 4 h. The reaction was monitored with HPLC. The reaction mixture was then diluted with MIBK ( 100 ml) and water ( 100 ml) and brine (20 ml) were added under intensive stirring; the phases were thoroughly mixed and then separated. The aqueous phase was still washed with MIBK (50 ml). The combined organic phase was washed with water (50 ml) and brine (20 ml). The solution of the intermediate obtained this way was heated up to boil and the residual water was removed by azeotropic distillation. Reflux for 17 h, the mixture was concentrated by distillation, ca. 85 mL of MIBK removed. The solution was slowly cooled to the laboratory temperature while being stirred and then cooled to 5 °C; crystals were removed by filtration and washed with cold MIBK (3 x 10 ml) and air-dried. 8. 15 g (72%) of crystals were obtained, purity 99.80 %, polymorph form I.

Example 2:

A reaction mixture containing the crude intermediate 12 (ca. 1 .4 g), prepared in accordance with Example 1 , was extracted with o-butyl acetate ( 10 ml) and the solution was heated up to reflux in Ar atmosphere for 6 h; the crystalline product starts to get separated during the reaction already. After cooling to the laboratory temperature and then to 4 °C the crystals were filtered off and washed with heptane (2 2 ml) and dried overnight in a vacuum drier (18 kPa/50°C). 0.84 g (64%) of crystals were obtained, HPLC 99.12%, polymorph form I.

Example 3:

Potash ( 19.43g, 140.56 mmol, 2.0 equiv.) was added to a suspension of the hydrochloride 11 (33.3 g, 70.28 mmol) in DMF (35 ml) at the laboratory temperature under Ar atmosphere and the suspension was stirred for 25 min.; then, addition of a suspension of amidrazone ( 13.35g, 80.82 mmol, 1. 15 equiv.) in DMF ( 15 ml) was started within ca. 20 min. Under stirring it was slowly heated up to ca. 35°C (ca. 4 h). The reaction was monitored with HPLC. The reaction mixture was then diluted with «-pentanol (370 ml) and water ( 100 ml) was added under intensive stirring, the mixture was intensively stirred for ca. 10 min, separated and the organic phase was then washed with water (100 ml) and brine (100 ml). The aqueous phase was washed with «-pentanol (50 ml), separated and the organic phase was washed with brine (50 ml) and combined with the first extract. The mixture was heated up to boiling ( 160°C bath), ca. 50 ml of H2O-DMF/ pentanol were removed by distillation and the mixture refluxed overnight ( 1 7 h). The mixture was slightly cooled, active carbon (6.66 g) carefully added, reflux in Ar atmosphere for 1 h, hot filtration through a cellulose filter, the orange-coloured filtrate being then mechanically stirred (cooled to ca. 55°C), a seed of form ΪΙ (77 mg) added and, when the temperature of the mixture dropped to 40°C, another seed of II (77 mg) was added, ice bath was applied and the mixture was quickly cooled to 10 °C, then to -20 °C and in a cooling bath with thermostatic control and stirred for 5 h. Crystals were removed by filtration, washed with cooled heptane (- 20°C, 3 x 50 mL), dried by suctioned air on frit overnight. 21 .1 g of crystals were obtained (56%, HPLC 99.0%, polymorph II), mother liquors were concentrated in a vacuum evaporator at 50°C (ca. 325 mL removed by distillation), cooled to the laboratory temperature and seeded with crystals of II, stirred in a cooling bath at ca. 10°C, then to RT overnight. Stored in a freezer (-20°C for 20 h), filtration of the second fraction, washed with iced heptane (50 ml), dried by suctioned air; 6. 1 g of .crystals were obtained ( 16%, HPLC 98.90%, polymorph II).

Example 4:

Aprepitant (4.32 g) as a mixture of polymorphs I and II was dissolved in «-pentanol (70 ml) under stirring and heating ( 105°C). Being continuously stirred the solution was slowly cooled down to the laboratory temperature (crystallization starts at 55-50 °C) and further to 5°C for 1 h. The crystals were removed by filtration, washed with cold heptane ( 10 ml) and dried by suctioned air at the laboratory temperature. 3.76 g (87%) of aprepitant of form II were obtained, HPLC 99.97%.

Claims

C L A I M S

1 ) A method for the preparation of a repitant 1

in the desired crystalline form II or I, characterized in that the intermediate 12

(12) is extracted with a water immiscible high-boiling solvent selected from an alcohol, ester or ketone and, after washing with water and/or brine, the solution is heated up to the boiling point of the given solvent, which results in cyclization to aprepitant, and, after cooling, the produced aprepitant is isolated.

2) A method for the preparation of polymorph form II of aprepitant according to claim 1 , wherein said water immiscible high-boiling solvent is /7-pentanol.

3) The method according to claim 2, characterized in that «-pentanol is used in the ratio of 10 to 25 ml/g of the intermediate 12.

4) The method according to claims 1 to 3, characterized in that, before cooling, said

solution is boiled with active carbon and filtered when hot.

5) The method according to claims 2 to 4, characterized in that said solution is gradually cooled down to a temperature in the range of -20 to -30°C. 6) The method according to claims 2 to 5, characterized in that, after cooling to less than 55°C, said solution is seeded with crystals of aprepitant form II.

7) A method for the preparation of polymorph form I of aprepitant according to claim 1 , characterized in that said water immiscible high-boiling solvent is methyl isobutyl ketone.

8) The method according to claim 7, characterized in that methyl isobutyl ketone is used in the ratio of 10 to 50 ml/g of the intermediate 12.

9) A method for the preparation of polymorph form I of aprepitant according to claim 1 , wherein said water immiscible high-boiling solvent is «-butyl acetate.

10) The method according to claim 9, characterized in that /i-butyl acetate is used in the ratio of 30 to 70 ml/g of the intermediate 12.

1 1 ) The method according to any one of claims 7 to 10, characterized in that the resulting solution is cooled down to a temperature in the range of -20 to -30°C.

12) The method according to claim 1 , characterized in that the obtained aprepitant in the polymorph form II, optionally in a mixture with aprepitant in the polymorph form I, is further re-crystallized from «-pentanol.

13) The method according to claim 12, characterized in that the amount of w-pentanol is in the range of 10-20 ml/g of crude aprepitant.

14) The method according to claims 13 or 13, characterized in that aprepitant is dissolved in «-pentanol at the boiling temperature and then gradually cooled to a temperature in the range of -20 to -30°C.