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Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound

A compound and chemical formula technology, applied in the field of preparation of 1,3-thiazole derivatives, can solve problems such as not suitable for oral administration

Inactive Publication Date: 2016-10-05
SHIONOGI & CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Low-molecular-weight peptides having affinity for the thrombopoietin receptor are also known in Patent Document 1 and Patent Document 2, but these peptide derivatives are generally not suitable for oral administration

Method used

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  • Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound
  • Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound
  • Methods respectively for producing optically active compound having agonistic activity on thrombopoietin receptors and intermediate of said compound

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0380] In terms of the crystals of compound (II'), crystals of compound (XI') and crystals of compound (VIII') or adducts thereof produced in the above-mentioned production method, stable, in performing the above-mentioned production steps or It is easy to handle in the preparation of a pharmaceutical composition containing compound (XI') as an active ingredient, and has high purity, so it is a useful crystal for the preparation of a pharmaceutical composition.

[0381] The crystals of the present invention can also be determined by thermal analysis.

[0382] Here, TG / DTA (simultaneous determination of differential calorimetry and thermogravimetry) is one of the main measurement methods of thermal analysis, and is a method of measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules.

[0383] TG / DTA is a method of determining the temperature or time-dependent weight and heat changes of pharmaceutical active ingredients, by plotting the o...

Embodiment 1

[0448] [chemical formula 46]

[0449]

[0450] (Step 1) Synthesis of compound (VII')

[0451] Compound 1 (2.00 kg) was dissolved in 1,2-dimethoxyethane (28.0 kg) under nitrogen atmosphere. Thereto, a 25% LDA tetrahydrofuran-heptane-ethylbenzene solution (13.20 kg) was added dropwise at -55°C over 1 hour, followed by stirring for 30 minutes. A solution of N-formylmorpholine (3.74 kg) in 1,2-dimethoxyethane (3.0 kg) was added dropwise at -55°C over 40 minutes, followed by stirring for 1 hour. A 1,2-dimethoxyethane (3.0 kg) solution of triethyl 2-phosphonopropionate (3.74 kg) was dropped there over 45 minutes at 0° C., and stirred for 2 hours. A 35% sulfuric acid aqueous solution (15.8 kg) was added dropwise to the reaction liquid over 40 minutes. Water (16.0 kg) was added and extracted. The obtained organic layer was washed with water (8.0 kg), and the solvent was distilled off under reduced pressure. Acetonitrile (16.0 kg) was added, stirred at 25°C for 1 hour, cooled t...

Embodiment 2

[0460] (Synthesis of compound (XI'))

[0461]

[0462] (Step 2) Synthesis of compound 4

[0463] Compound 3 (3.00 kg) was added dropwise to a tetrahydrofuran solution (11.40 kg) of 1 mol / L isopropylmagnesium chloride over 1 hour at 25° C. under a nitrogen atmosphere, followed by stirring for 2 hours. At 25°C, a tetrahydrofuran solution (0.56 kg) of 1 mol / L isopropylmagnesium chloride was added, followed by stirring for 2 hours. At 25°C, N-methoxy-N-methylacetamide (1.45 kg) was added dropwise to the reaction liquid over 40 minutes, followed by stirring for 80 minutes. 7% hydrochloric acid (9.7 kg) was added to the reaction liquid, and extraction was performed with toluene (11.0 kg). The obtained organic layer was washed twice with water (7.5 kg each), and the solvent was distilled off under reduced pressure to obtain Compound 4 (2.63 kg).

[0464]

[0465] (Step 3) Synthesis of Compound 5

[0466] To compound 4 (2.63 kg) was added [(1S,2S)-N-(p-toluenesulfonyl)-1,2-d...

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Abstract

The present invention relates to: a method for producing an intermediate having high chemical purity and / or high optical purity; a crystal of an intermediate having high chemical purity and / or optical purity; a method for producing an intermediate, in which two reactions can be carried out sequentially substantially in a single step; and a method for producing an optically active 1,3-thiazole derivative having an agonistic activity on thrombopoietin receptors.

Description

technical field [0001] The present invention relates to a preparation method of optically active 1,3-thiazole derivatives with thrombopoietin receptor agonism. More specifically, it relates to compounds useful as production intermediates, crystals of the production intermediate compounds, methods for their production, and the like. Background technique [0002] Thrombopoietin is a polypeptide cytokine composed of 332 amino acids. It stimulates the differentiation and proliferation of megakaryocytes through the receptor to promote the production of platelets. Therefore, it is expected to be used as a pathological treatment for blood diseases accompanied by abnormal platelet counts such as thrombocytopenia. medicine. The nucleotide sequence of the gene encoding the thrombopoietin receptor is described in Non-Patent Document 1. Low-molecular-weight peptides having affinity for the thrombopoietin receptor are also known in Patent Document 1 and Patent Document 2, but these pep...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/20C07C67/333C07C69/65C07D277/40C07D277/46
CPCA61P43/00C07C45/45C07C67/343C07D277/40C07D277/46C07C69/65
Inventor 福井雄树前川雄亮松浦孝治栗田贵教
Owner SHIONOGI & CO LTD
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