Method for synthesizing 2-acetyl-4-chlorothiophene

Abstract

The invention provides a method for synthesizing 2-acetyl-4-chlorothiophene, which comprises the following steps: dissolving 2-acetylthiophene in a solvent, adding a chlorinating agent and a Lewis acid, and reacting to obtain the 2-acetyl-4-chlorothiophene, wherein the chlorinating agent is N-chlorosuccinimide. The method is simple to operate, the synthesized 2-acetyl-4-chlorothiophene is high inyield and purity which can reach 99.66%, the raw material conversion rate is high, and few byproducts are produced. Meanwhile, the solid N-chlorosuccinimide is used as the chlorinating agent in the synthesis process of the method, and the chlorinating agent is low in cost, environmentally friendly, convenient to use and easy to control in dosage. Therefore, the method for synthesizing the 2-acetyl-4-chlorothiophene also has the advantages of low cost and environmental friendliness, is suitable for industrial large-scale production, and has a good market prospect.

Description

technical field

[0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a method for synthesizing 2-acetyl-4-chlorothiophene. Background technique

[0002] 2-Acetyl-4-chlorothiophene is an important intermediate of Avatrombopag (Avatrombopag). Avatrombopag is an oral thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes in myeloid progenitor cells, thereby increasing platelet production. Avatrombopag was first developed by Japan's Astellas Pharmaceutical Group, after several authorizations, the new drug development was finally completed by AkaRx Pharmaceuticals, a subsidiary of Dova Pharmaceuticals in the United States. It was approved by the US FDA on May 23, 2018. The product name is Doptelet, which is used for adults with chronic liver disease (CLD) who suffer from thrombocytopenia and plan to undergo medical or dental surgery. Doptelet has been shown to safely increase pl...

Examples

Embodiment 1

[0028] Embodiment 1, the method for synthesizing 2-acetyl-4-chlorothiophene of the present invention

[0029] Add 2-acetylthiophene (1kg, 7.925mol) and dichloromethane (10L) into the reaction flask, then add aluminum trichloride (3.17kg, 23.775mol) in batches, stir for 30min after the addition, and then Add N-chlorosuccinimide (NCS, 2.12kg, 15.85mol), and react at room temperature for 6 hours after the addition, and the reaction is complete as detected by TLC. Pour the reaction solution into 2L of cold water, separate the layers, extract the organic phase with water twice (500ml each time), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain a crude product. Distillation under reduced pressure gave 914.0 g of 2-acetyl-4-chlorothiophene with a yield of 71.8%.

[0030] The HNMR spectrum of the 2-acetyl-4-chlorothiophene prepared by the present invention is as follows figure 1 shown. The HPLC collection of illustrative p...

Embodiment 2

[0031] Embodiment 2, the method for synthesizing 2-acetyl-4-chlorothiophene of the present invention

[0032] Add 2-acetylthiophene (1 kg, 7.925 mol) and dichloromethane (10 L) into the reaction flask, and then add zinc chloride (3.24 kg, 23.775 mol) in batches, and stir for 30 min after the addition is complete. Then N-chlorosuccinimide (NCS, 2.12 kg, 15.85 mol) was added in batches, and after the addition was completed, it was reacted at room temperature for 7 hours, and the reaction was complete as detected by TLC. Pour the reaction solution into 2L of cold water, separate the layers, extract the organic phase with water twice (500ml each time), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain a crude product. Through distillation under reduced pressure, 869.4 g of 2-acetyl-4-chlorothiophene was obtained, with a yield of 68.3% and a purity of 99.58% upon detection.

technical field

[0001] The invention belongs to the field of chemical drug synthesis, and in particular relates to a method for synthesizing 2-acetyl-4-chlorothiophene. Background technique

[0002] 2-Acetyl-4-chlorothiophene is an important intermediate of Avatrombopag (Avatrombopag). Avatrombopag is an oral thrombopoietin (TPO) receptor agonist that stimulates the proliferation and differentiation of megakaryocytes in myeloid progenitor cells, thereby increasing platelet production. Avatrombopag was first developed by Japan's Astellas Pharmaceutical Group, after several authorizations, the new drug development was finally completed by AkaRx Pharmaceuticals, a subsidiary of Dova Pharmaceuticals in the United States. It was approved by the US FDA on May 23, 2018. The product name is Doptelet, which is used for adults with chronic liver disease (CLD) who suffer from thrombocytopenia and plan to undergo medical or dental surgery. Doptelet has been shown to safely increase pl...

Examples

Embodiment 1

[0028] Embodiment 1, the method for synthesizing 2-acetyl-4-chlorothiophene of the present invention

[0029] Add 2-acetylthiophene (1kg, 7.925mol) and dichloromethane (10L) into the reaction flask, then add aluminum trichloride (3.17kg, 23.775mol) in batches, stir for 30min after the addition, and then Add N-chlorosuccinimide (NCS, 2.12kg, 15.85mol), and react at room temperature for 6 hours after the addition, and the reaction is complete as detected by TLC. Pour the reaction solution into 2L of cold water, separate the layers, extract the organic phase with water twice (500ml each time), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain a crude product. Distillation under reduced pressure gave 914.0 g of 2-acetyl-4-chlorothiophene with a yield of 71.8%.

[0030] The HNMR spectrum of the 2-acetyl-4-chlorothiophene prepared by the present invention is as follows figure 1 shown. The HPLC collection of illustrative p...

Embodiment 2

[0031] Embodiment 2, the method for synthesizing 2-acetyl-4-chlorothiophene of the present invention

[0032] Add 2-acetylthiophene (1 kg, 7.925 mol) and dichloromethane (10 L) into the reaction flask, and then add zinc chloride (3.24 kg, 23.775 mol) in batches, and stir for 30 min after the addition is complete. Then N-chlorosuccinimide (NCS, 2.12 kg, 15.85 mol) was added in batches, and after the addition was completed, it was reacted at room temperature for 7 hours, and the reaction was complete as detected by TLC. Pour the reaction solution into 2L of cold water, separate the layers, extract the organic phase with water twice (500ml each time), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness to obtain a crude product. Through distillation under reduced pressure, 869.4 g of 2-acetyl-4-chlorothiophene was obtained, with a yield of 68.3% and a purity of 99.58% upon detection.

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