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Modified method for preparing (1,4,5,6-tetrahydro-2-pyrimidyl)thiourea or salts thereof

A technology for thiourea and pyrimidine amine, which is applied in the improved field of preparing thiourea or its salt, can solve the problems of long reaction time, high requirements on equipment and safeguard measures, etc., achieves good product quality, improves the preparation method, and is beneficial to industrialized production Effect

Inactive Publication Date: 2011-05-04
CHONGQING PHARMA RES INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is obvious that the existing technology for preparing (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II) uses highly toxic and malodorous hydrogen sulfide, the reaction time is longer, and the equipment and guarantee during industrialization Measures require higher deficiencies

Method used

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  • Modified method for preparing (1,4,5,6-tetrahydro-2-pyrimidyl)thiourea or salts thereof
  • Modified method for preparing (1,4,5,6-tetrahydro-2-pyrimidyl)thiourea or salts thereof
  • Modified method for preparing (1,4,5,6-tetrahydro-2-pyrimidyl)thiourea or salts thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Preparation of (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II) hydrochloride

[0040] In a 3L three-necked flask, add (1,4,5,6-tetrahydro-2-pyrimidinyl)aminonitrile (III) 124.0g (1.0mol), thioacetamide (IV) 113.0g (1.5mol) and about 10% (g / g) hydrogen chloride / N, N-dimethylformamide solution 1000ml, react at 80-85°C to the raw material (1,4,5,6-tetrahydro-2-pyrimidinyl)aminonitrile (III) disappeared (reaction progress monitored by TLC, developer: ethyl acetate: methanol = 10:1), it took about 2 hours. After the reaction solution was cooled, it was filtered, and the filter cake was dried to obtain 182.6 g of the title compound as a white solid.

[0041] HPLC: 98.66%;

[0042] Mp: 183~185℃;

[0043] IR (KBr): 3140, 3022, 1687, 1637, 1603, 1573, 1402, 1333, 1304, 1055, 986, 961, 686cm -1 ;

Embodiment 2

[0045] Preparation of (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II)

[0046] In a 2L three-necked flask, add (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II) hydrochloride 100.0 g obtained in Example 1, 10% (g / g) of carbonic acid 750ml of sodium solution was stirred at 40-45°C for 0.5h, cooled, filtered, and the filter cake was dried to obtain 76.5g of the title compound (II) as a white solid.

[0047] HPLC: 99.25%;

[0048] Mp: 173~175℃;

[0049] IR (KBr): 3424, 3301, 3104, 3028, 2967, 2870, 1615, 1590, 1457, 1420, 1374, 1324, 1171, 1079, 905, 736, 656cm -1 ;

[0050] (+) ESI-MS: 159 (M+1).

Embodiment 3

[0052] Preparation of (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II)

[0053] In a 2L three-necked flask, add (1,4,5,6-tetrahydro-2-pyrimidinyl)aminonitrile (III) 124.0g (1.0mol), thioacetamide (IV) 90.0g (1.2mol) and Saturated hydrogen chloride / tetrahydrofuran solution 1000ml, react at 45-50°C until the raw material (1,4,5,6-tetrahydro-2-pyrimidinyl)aminonitrile (III) disappears (TLC monitors the reaction progress, developer: acetic acid Ethyl ester: methanol = 10: 1), it takes about 4h. Add about 20% (g / g) sodium hydroxide aqueous solution to adjust the pH of the reaction solution to about 8, filter, and dry the filter cake to obtain 143.5 g of the title compound (II) as a white solid.

[0054] HPLC: 98.30%;

[0055] Mp: 172~174℃;

[0056] IR (KBr): 3425, 3301, 3105, 3028, 2967, 2870, 1618, 1591, 1458, 1422, 1374, 1323, 1172, 1078, 905, 735, 657cm -1 ;

[0057] 1 H NMR (400MHz, CDCl 3 ) δ (ppm): 1.97 ~ 2.03 (2H, quintet), 3.43 ~ 3.46 (4H, t);

[0058] (+) ESI-MS: 15...

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Abstract

The invention relates to a modified preparation method of (1, 4, 5, 6-tetrahydrochysene-2-pyrimidinyl) sulfourea or a corresponding salt as the important intermediate of antifungal Abafungin, belonging to organic chemistry and drug synthesis technical field. The preparation method comprises reacting (1, 4, 5, 6-tetrahydrochysene-2-pyrimidinyl) aminonitrile or a corresponding salt with thioacetamide in suitable acid medium to prepare (1, 4, 5, 6-tetrahydrochysene-2-pyrimidinyl) sulfourea or relative salt. The modified preparation method of (1, 4, 5, 6-tetrahydrochysene-2-pyrimidinyl) sulfoureaor a corresponding salt eliminates the toxic hydrogen sulfide of prior art, shortens reaction and improves production efficiency, with simple operation in general reactors, high product quality and yield, thus is beneficial to industrial production. Further, the invention applies the method for the preparation of Abafungin to improve the preparation method of Abafungin.

Description

technical field [0001] The invention relates to the fields of synthetic organic chemistry and pharmacy, in particular to an improved method for preparing (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea or a salt thereof, using (1,4,5, 6-tetrahydro-2-pyrimidinyl)aminonitrile or its salt is prepared by reacting with thioacetamide in a suitable acidic medium; (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea is A key intermediate for the preparation of the antifungal drug abafungin. Background technique [0002] Abafungin (Abafungin), the chemical name is N-[4-[2-(2,4-dimethylphenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetra Hydrogen-2-pyrimidinamine, whose structure is shown in formula I, is the first thiazole ring antifungal drug, has a novel dual mechanism of action, has a killing effect on fungal cells in growth and rest, and has the ability to inhibit fungi The drug is the first drug with this mechanism of action and is expected to become the first-line antifungal product. The drug has a ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/12C07D417/12
CPCC07D417/12
Inventor 罗杰林波叶文润
Owner CHONGQING PHARMA RES INST