DE202009009917U1 - Ambrisentan in specific crystalline form - Google Patents

Abstract

Ambrisentan in crystalline form characterized by a powder X-ray diffraction pattern with reflections at 2-theta values of approximately 8.9 °, 12.3 °, 17.9 ° and 26.9 °.

Description

Field of the invention

The The invention relates to ambrisentan in a specific crystalline Shape (hereinafter referred to as "Form R"), in particular Preparable from (2S) -2-hydroxy-3-methoxy-3,3-diphenyl-propanoic acid or (S) -2- (4,6-dimethyl-pyrimidin-2-yloxy) -3-methoxy-3,3-diphenyl-propanoic acid benzyl ester.

Background of the invention

ambrisentan 1 is a selective endothelin A receptor antagonist for treatment Pulmonary arterial hypertension (PAH) is approved. The Substance is crystalline, practically insoluble in water (0.06 mg / ml), and has a stereocenter. The chemical name is (S) -2- (4,6-dimethyl-pyrimidin-2-yl) oxy-3-methoxy-3,3-diphenylpropansäure.

In WO 96/11914 For the first time, the synthesis of an ambrisentan derivative was described. The Ambrisentan synthesis according to J. Med. Chem. 39, 2123-2128 (1996) leads to a racemate.

Preferred embodiments the invention

The The invention relates to ambrisentan in a specific crystalline Shape (hereinafter referred to as "Form R"). ambrisentan in crystalline form R is characterized by a powder X-ray diffraction pattern with Reflections at 2-theta (= 2Θ) values of approximately 8.9 °, 12.3 °, 17.9 ° and 26.9 °.

ambrisentan in crystalline form R may be advantageous in pharmaceutical formulations be used, in particular with regard to solubility behavior and storage stability.

Schema 1 Ambrisentan is preferably produced in the context of this invention by the process shown below in Scheme 1:

Scheme 1

The S-enantiomer 2 is obtained by reacting the racemic acid with a chiral base and then separating the salt. Suitable chiral bases are, for. L-proline methyl ester, (S) -1- (4-nitrophenyl) ethylamine and (S) -1- (4-chlorophenyl) -ethylamine (see WO 2000/26170 ).

Schema 2 In an alternative embodiment, ambrisentan can be prepared by a process according to Scheme 2:

Scheme 2

The S-enantiomer 3 can be prepared according to the instructions in WO 96/11914 be synthesized.

ambrisentan in form R is by crystallization of ambrisentan, preferably from Ambrisentan preparable according to Scheme 1 or 2, in an organic Solvent available.

In In a first preferred embodiment, the crystallization takes place of ambrisentan in the form R of organic ethers, in particular from diethyl ether. In this embodiment, it is preferable that ambrisentan is prepared according to Scheme 2.

In In a second preferred embodiment, the crystallization takes place of ambrisentan in the form R from a mixture containing organic Solvent and water, more preferably alcohol and water, especially isopropanol and water. The proportion of water in the mixture is usually from 10 to 90 wt .-%, preferably from 40 to 80% by weight.

The crystalline form R of ambrisentan was determined by powder X-ray diffractometry (abbreviated as XRPD = X-Ray Powder Diffraction) and if necessary Differential calorimetry (abbreviated as DSC = Differential Scanning Calorimetry).

The powder X-ray diffractometry was carried out as follows:
Samples were analyzed on a D8 Advance powder X-ray diffractometer (Bruker ^® -AXS, Karlsruhe, Germany). The measurement conditions were as follows: Radiation: Cu Ka, source 40 kV / 40 mA, divergence column 0.298 °, antiscattering column 3.872 °, detector column 10.28 mm, angular range 3 ° to 55 °, step 0.016 ° 2Θ, time per step 0.2 s.

The differential calorimetry was carried out as follows:
The measurements were performed on a Mettler Toledo DSC ^® 822E coupled to a Mettler Toledo ^® gas flow controller TS0800GC1 (Mettler ^® -Toledo GmbH, Giessen, Germany). A 40 μL perforated lid aluminum crucible was used. Measuring conditions: Temperature range 30 ° C to 300 ° C; Heating rate 10 ° C / min; Nitrogen flow: 50 ml / min. Software STARe Version. 8.10; Interpretation Endothermic.

1 shows a powder X-ray diffraction pattern of ambrisentan in crystalline form R with reflections at 8.9 °, 11.1 °, 12.3 °, 13.1 °, 17.9 °, 26.9 °, 14.1 °, 15 ° , 2 °, 18.2 ° and 20.6 ° 2Θ, obtainable by crystallization from isopropanol / water.

2 shows a powder X-ray diffraction pattern of ambrisentan in crystalline form R with reflections at substantially the same 2Θ values but with significantly lower peak intensities. Ambrisentan according to 2 is obtainable by crystallization from diethyl ether.

One Comparison of the XRPDs, the DSCs and the appearance of the two ambrisentan batches, which is recrystallized from isopropanol / water or diethyl ether were suggested that recrystallized from diethyl ether Material contains a higher amorphous content.

• a) 1 bis 99 Gew.-%, bevorzugt 20 bis 98 Gew.-%, insbesondere 60 bis 97 Gew.-%, kristallines Ambrisentan in Form R und
• b) 1 bis 99 Gew.-%, bevorzugt 2 bis 80 Gew.-%, insbesondere 3 bis 40 Gew.-%, amorphes Ambrisentan.

The invention therefore also mixtures with a different proportion of crystalline ambrisentan in the form R and amorphous ambrisentan. In a preferred embodiment, the invention relates to a mixture containing

• a) 1 to 99 wt .-%, preferably 20 to 98 wt .-%, in particular 60 to 97 wt .-%, crystalline ambrisentan in the form R and
• b) 1 to 99 wt .-%, preferably 2 to 80 wt .-%, in particular 3 to 40 wt .-%, amorphous ambrisentan.

Of the Term "amorphous" is used in the context of this invention used as a name for the state of solids, in which the building blocks (atoms, ions or molecules, i. in the case of amorphous ambrisentan the ambrisentan molecules) no periodic arrangement over a larger one Range (= remote order) have. In amorphous fabrics are the Building blocks usually not completely random and purely statistically arranged, but distributed so that one certain regularity and similarity with the crystalline state in terms of distance and orientation of the next neighbor are recognizable (= Nahordnung). amorphous Substances therefore preferably have close proximity but no long-range order on.

EXAMPLES

Example 1: Preparation of ambrisentan Form R according to Scheme 1

30.4 g (1.32 mol) of lithium amide were suspended in 200 ml of N, N-dimethylformamide and heated to 20 ° C. with a water bath. A solution of 120.0 g (0.44 mol) of (2S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid in 750 ml of N, N-dimethylformamide was added dropwise within 45 minutes and it was for a further 10 Stirred for minutes. Thereafter, a solution of 90.3 g (0.48 mol) of 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in 500 mL of N, N-dimethylformamide was added dropwise within 20 minutes and stirred for a further 17 hours. The mixture was added to 3000 ml of water and treated with 800 ml of 2M citric acid. The reaction mixture was extracted three times with 2000 ml of dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. The yellow oily residue thus obtained was recrystallized from 800 ml of isopropanol and 2000 ml of water. The crystals (103.2 g) were filtered off, washed with water and dried. The resulting crystals are needle-shaped.
Melting point (mp): 185.3 ° C (determined by DSC)
Powder X-ray diffraction pattern according to 1 ,

Example 2: Preparation of ambrisentan Form R according to Scheme 2

10 mg (0.1 mmol) of palladium on charcoal (10% w / w) were suspended in 8 ml of ethyl acetate and 3 ml of methanol. 0.55 g (1.2 mmol) of (S) -2- (4,6-dimethyl-pyrimidin-2-yloxy) -3-methoxy-3,3-diphenyl-propanoic acid benzyl ester 3 was added and the mixture became saturated with hydrogen. The reaction mixture was hydrogenated for 12 hours. Thereafter, the catalyst was filtered off. The filtrate was concentrated in vacuo and the resulting crude product was recrystallized from diethyl ether. A flaky material (0.25 g) was obtained.
Melting point (mp): 179.5 ° C (DSC)
Powder X-ray diffraction pattern according to 2 ,

QUOTES INCLUDE IN THE DESCRIPTION

This list The documents listed by the applicant have been automated generated and is solely for better information recorded by the reader. The list is not part of the German Patent or utility model application. The DPMA takes over no liability for any errors or omissions.

Cited patent literature

• WO 96/11914 [0003, 0009]
• WO 2000/26170 [0007]

Cited non-patent literature

• Ambrisentan Synthesis according to J. Med. Chem. 39, 2123-2128 (1996) [0003]

Claims (6)

Ambrisentan in crystalline form, characterized through a powder X-ray diffraction pattern with reflections at 2-theta values of about 8.9 °, 12.3 °, 17.9 ° and 26.9 °. Ambrisentan according to claim 1, wherein the powder X-ray diffraction pattern further reflections at 2-theta values of about 11.1 °, 13.1 °, 14.1 °, 15.2 °, 18.2 ° and / or 20.6 ° shows. Ambrisentan according to claim 1 or 2, preparable by Crystallization from an organic solvent or a mixture of organic solvent and water. Ambrisentan according to claim 3, wherein the crystallization from ether or a mixture of isopropanol and water. Ambrisentan according to any one of the preceding claims 1 to 4, preparable by reaction of (2S) -2-hydroxy-3-methoxy-3,3-diphenylpropanoic acid with 4,6-dimethyl-2- (methylsulfonyl) pyrimidine in the presence of lithium amide. Mixture containing: a) 1 to 99 wt .-%, preferably 20 to 98 wt .-% crystalline ambrisentan according to claim 1 or 2; and b) 1 to 99% by weight, preferably 2 to 80% by weight, amorphous ambrisentan.