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Synthesis of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide and methyl-d3 deuterated form thereof

A methyl, V-2 technology, applied in the field of synthesis of compounds or their salts, can solve problems such as low overall yield of intermediates, adverse effects on drug product quality, raw material problems and the like

Pending Publication Date: 2021-12-07
奥格达股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] However, chlorocarbonylsulfinyl chloride and methyl cyanoformate are hazardous reagents that can cause raw material problems in large-scale production and should be avoided for large-scale production
Furthermore, this synthetic route generates sulfur impurities which adversely affect the quality of the final drug product
Furthermore, even after optimization, the overall yield of intermediate (I-1) was still less than 30%

Method used

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  • Synthesis of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide and methyl-d3 deuterated form thereof
  • Synthesis of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide and methyl-d3 deuterated form thereof
  • Synthesis of 3-methyl-1,2,4-thiadiazole-5-carbohydrazide and methyl-d3 deuterated form thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0336] Example 1A: Synthesis of deuterated d3-AMTD (IV-2) via the acetamidine route

[0337]

[0338] Pinner reaction via Pinner salt (VI-2) affords d3-acetamidine (V-2), followed by cyclization via the "bromine route" (step c1) or the "hypochlorite route" (step c2) to form compounds The thiadiazole ring of (IV-2).

[0339] Step a: Formation of Pinner salt (VI-2)

[0340] At 20-25°C, in a 750 mL three-necked glass flask equipped with two gas inlets, a thermometer and a magnetic stir bar, charged 74 mL of anhydrous diol and 51.2 g (1.161 mol, 1.0 eq) of d3-acetonitrile (VII -2) followed by cooling to 0-5°C (cooling by ice-salt mixture). Keeping the temperature below 10 °C, HCl gas was bubbled through the mixture for 6 hours. The reaction mixture was heated to 20-25°C and stirred for 16.5 hours (the mixture became a thick white suspension which was difficult to stir). 500 mL of TBME was added to the mixture, after which the mixture became an easily stirrable white suspe...

Embodiment 1B

[0348] Example 1B: Synthesis of deuterated d3-AMTD (IV-2) via the hydroxyacetamidine route

[0349]

[0350] d3-Hydroxyacetamidine (IX-2) is obtained from deuterated acetonitrile (VII-2). Afterwards, the corresponding tosyl intermediate (X-2) is cyclized in the presence of thiocyanate to form the thiadiazole ring of compound (IV-2).

[0351] Step a: Formation of d3-hydroxyacetamidine (IX-2)

[0352] Charge 5.5 mL (4.65 g, 105.4 mmol, 1.0 eq) of d3-acetonitrile (d: 0.844 g / mL) at 20-25 °C in a 100 mL glass container equipped with a reflux condenser, thermometer and magnetic stir bar , 33 mL EtOH and 25.1 mL (27.87 g, 422.3 mmol, 4.0 eq) of aqueous hydroxylamine solution (50 w / w%, MW: 33 g / mol, d: 1.11 g / mL). The mixture was heated to reflux temperature and stirred at reflux temperature for 5 hours. The solvent was evaporated from the reaction mixture under vacuum at 40°C. The product (IX-2) was obtained as a white solid. Yield: 84% (6.84 g). HPLC-MS (condition C) isoto...

Embodiment 2

[0357] Example 2: Synthesis of deuterated 3-(methyl-d3)-1,2,4-thiadiazole-5-carbohydrazide (I-2)

[0358]

[0359] Isotopic purity is preserved during all steps.

[0360] Step 1: Sandmeyer bromination formation (III-2-a)

[0361] At 20-25°C, put 2.7mL (4.61g Solution, containing 2.85g HBr, 35.2mmol, 3.0eq) 62w / w% HBr solution (d: 1.702g / mL), 2.1mL water and 1.39g (11.76mmol, 1eq) compound (IV-2) (isotopic purity: 93.4%, determined by titration: 85%). The mixture was heated to 40°C. Afterwards, 1.22 g (17.64 mmol, 1.5 eq) of NaNO dissolved in 2 mL of water was added through the dropping funnel 2 , the rate of addition was such that the temperature was maintained at 40-45° C. (within 5 minutes). During the addition, intense bubbling of brown gas was observed in the absorber and an oily phase separated out at the bottom of the flask. After the addition, the mixture was stirred for 1 h, monitored by TLC (Hex:EtOAc=1:1) and HPLC. The reaction mixture was cooled to 20-25...

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Abstract

The present invention relates to a method of synthesis of compound (I), wherein R1 represents methyl or methyl-d3, thus corresponding to 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or to the methyl-d3 deuterated form thereof. These compounds are useful as key intermediates in the synthesis of pharmaceutical compounds, especially fezolinetant and deuterated fezolinetant.

Description

[0001] field of invention [0002] The present invention relates to the field of chemical synthesis and provides a synthetic method of compound (I) or a salt thereof: [0003] [0004] where R 1 represents methyl or methyl-d3 and thus corresponds to 3-methyl-1,2,4-thiadiazole-5-carbohydrazide or its methyl-d3 deuterated form. These compounds are key intermediates for the synthesis of pharmaceutical compounds, especially fezolinetant and deuterated fezolinetant. [0005] Background of the invention [0006] Fezonitam was developed as a selective antagonist of the NK-3 receptor and is a useful therapeutic compound, especially in the treatment and / or prevention of sex hormone-dependent diseases. Fezolintan corresponds to (R)-(4-fluorophenyl)-(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6 - Dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone, described in WO2014 / 154895. [0007] Deuterium Fezolintan (R)-(4-fluorophenyl)-(8-methyl-3-(3-(methyl-d3)-1,2,4-thiadiazol-5-yl...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D285/08
CPCC07D285/08
Inventor H·哈维达G·杜塞尔
Owner 奥格达股份有限公司
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