Ambrisentan degradation product and preparation method thereof

Abstract

The invention discloses an ambrisentan degradation product and a preparation method thereof. The ambrisentan degradation product is represented by formula I, is one of main impurities of ambrisentan raw materials or preparations thereof and the formula I can be used for analyzing the purity of ambrisentan, and can also be used for controlling the quality of ambrisentan. The preparation method of the product of the formula I is characterized in that a substitution reaction of 2,2-diphenyl acetaldehyde and a compound represented by formula II is carried out under the action of sodium hydride and other alkaline compounds.

Description

technical field

[0001] The invention belongs to the field of biomedicine, and in particular relates to a degradation product of ambrisentan and a preparation method thereof. Background technique

[0002] Ambrisentan is an endothelin receptor antagonist (ERA) originally developed by Abbott of the United States, and Myogen Corporation of the United States has acquired its global development and marketing rights. Subsequently, GlaxoSmithKline (Glaxosmithkline) of the United States signed an agreement with Myogen to obtain the production rights of this product outside the United States. On November 17, 2006, Gilead Science of the United States acquired Myogen as a subsidiary company and obtained the ownership of Ambrisentan. The drug was approved by the US FDA on June 15, 2007. The trade name is Letairis. It is used orally for the treatment of pulmonary arterial hypertension (PAH). The chemical name is (+)-(2S)-2-[(4,6-two Methylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropan...

Examples

Embodiment 1

[0012] Example 1 Preparation of ambrisentan degradation product I

[0013]

[0014] Sodium hydride (3.5 g, 0.08 mol) was added to 50 mL of DMF solution, under nitrogen protection, cooled to 0~5 degrees, and then 2,2-diphenylacetaldehyde (5 g, 0.026 mol ) in DMF was added dropwise (50 mL) solution, maintain the temperature at 0~5 degrees, continue to stir the reaction for 0.5 h after the drop, and then add dropwise 4,6-dimethyl-2-methylsulfonylpyrimidine (5.2 g, 0.028 mol ) in DMF (50 mL) solution, continue to stir for 2 h after dripping, TLC detects that the reaction is complete, pour the reaction solution into 200 mL of ice-water mixture, filter, wash the filter cake with water (30 ml x 3) for 3 times, and then vacuum-dry to obtain a 8 g of white solid is the degradation product I of ambrisentan.

[0015] Mass Spectrum (ESI): m / z 303.1 (M+H) + .

[0016] 1 H NMR (400 MHz, CDCl 3 ) δ: 7.91 (s, 1H), 7.43 (d, J = 8 Hz, 2H), 7.35 ~ 7.25 (m, 8H), 6.78 (s, 1H), 2.44 (s, 6...

Embodiment 2

[0018] Example 2 Separation and detection of ambrisentan degradation product I

[0019] HPLC conditions:

[0020] Octadecylsilane-bonded silica gel was used as filler, mobile phase A was 0.01 mol / L dipotassium hydrogen phosphate buffer (phosphoric acid adjusted to pH 4.5), mobile phase B was acetonitrile, and the gradient elution was as follows Table 1 For elution, the detection wavelength is 210 nm, and the column temperature is 30 °C. The theoretical plate number should not be less than 5000 based on the calculation of Anlishengtan peak.

[0021] Gradient elution table 1

[0022] time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 3 90 10 13 35 65 40 35 65

[0023] Take an appropriate amount of impurity I and ambrisentan respectively, dilute with acetonitrile to prepare 0.5 mg / mL, inject 20 μL each into the sample, and separate and detect under the above HPLC conditions.

[0024] Analysis results: The HPLC chart of Ambrisent...

technical field

[0001] The invention belongs to the field of biomedicine, and in particular relates to a degradation product of ambrisentan and a preparation method thereof. Background technique

[0002] Ambrisentan is an endothelin receptor antagonist (ERA) originally developed by Abbott of the United States, and Myogen Corporation of the United States has acquired its global development and marketing rights. Subsequently, GlaxoSmithKline (Glaxosmithkline) of the United States signed an agreement with Myogen to obtain the production rights of this product outside the United States. On November 17, 2006, Gilead Science of the United States acquired Myogen as a subsidiary company and obtained the ownership of Ambrisentan. The drug was approved by the US FDA on June 15, 2007. The trade name is Letairis. It is used orally for the treatment of pulmonary arterial hypertension (PAH). The chemical name is (+)-(2S)-2-[(4,6-two Methylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropan...

Examples

Embodiment 1

[0012] Example 1 Preparation of ambrisentan degradation product I

[0013]

[0014] Sodium hydride (3.5 g, 0.08 mol) was added to 50 mL of DMF solution, under nitrogen protection, cooled to 0~5 degrees, and then 2,2-diphenylacetaldehyde (5 g, 0.026 mol ) in DMF was added dropwise (50 mL) solution, maintain the temperature at 0~5 degrees, continue to stir the reaction for 0.5 h after the drop, and then add dropwise 4,6-dimethyl-2-methylsulfonylpyrimidine (5.2 g, 0.028 mol ) in DMF (50 mL) solution, continue to stir for 2 h after dripping, TLC detects that the reaction is complete, pour the reaction solution into 200 mL of ice-water mixture, filter, wash the filter cake with water (30 ml x 3) for 3 times, and then vacuum-dry to obtain a 8 g of white solid is the degradation product I of ambrisentan.

[0015] Mass Spectrum (ESI): m / z 303.1 (M+H) + .

[0016] 1 H NMR (400 MHz, CDCl 3 ) δ: 7.91 (s, 1H), 7.43 (d, J = 8 Hz, 2H), 7.35 ~ 7.25 (m, 8H), 6.78 (s, 1H), 2.44 (s, 6...

Embodiment 2

[0018] Example 2 Separation and detection of ambrisentan degradation product I

[0019] HPLC conditions:

[0020] Octadecylsilane-bonded silica gel was used as filler, mobile phase A was 0.01 mol / L dipotassium hydrogen phosphate buffer (phosphoric acid adjusted to pH 4.5), mobile phase B was acetonitrile, and the gradient elution was as follows Table 1 For elution, the detection wavelength is 210 nm, and the column temperature is 30 °C. The theoretical plate number should not be less than 5000 based on the calculation of Anlishengtan peak.

[0021] Gradient elution table 1

[0022] time (min) Mobile phase A (%) Mobile phase B (%) 0 90 10 3 90 10 13 35 65 40 35 65

[0023] Take an appropriate amount of impurity I and ambrisentan respectively, dilute with acetonitrile to prepare 0.5 mg / mL, inject 20 μL each into the sample, and separate and detect under the above HPLC conditions.

[0024] Analysis results: The HPLC chart of Ambrisent...

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