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A kind of levomaprotamol phenylcarbamate-l-(+)-tartrate and its preparation method

A technology of meprotamol phenylcarbamate and phenol phenylcarbamate, applied in the field of levomaprotamol phenylcarbamate-L--tartrate and its preparation, can solve the difficulty of industrial production and control, HCl-anhydrous ether is difficult to prepare and store, and is not suitable for industrial production, etc., to achieve the effects of low cost, shortened reaction time, and improved work efficiency

Inactive Publication Date: 2016-06-08
DISHA PHARMA GRP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The above three steps all use flammable and explosive ether as a solvent or extraction agent, which is not suitable for industrial production
And the used HCl-anhydrous ether in the third step is difficult to prepare and store, and industrialized production is difficult to implement and control

Method used

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  • A kind of levomaprotamol phenylcarbamate-l-(+)-tartrate and its preparation method
  • A kind of levomaprotamol phenylcarbamate-l-(+)-tartrate and its preparation method
  • A kind of levomaprotamol phenylcarbamate-l-(+)-tartrate and its preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] The preparation of embodiment 1 levomabutamol

[0032] 2.0Kg (8.58mol) racemic mebutamol and 3.07Kg (8.58mol) L-(-)-dibenzoyl tartaric acid (L-(-)-DBTA) were placed in a 100.0L reactor, and no Water ethanol 47.3L (37.4Kg), after heating and reflux for 3.0 hours, stop heating, turn on condensed water to cool, wait until the temperature drops to 8.8°C, release the white solid suspension from the bottom of the kettle, suction filter, and wash with 1.1kg of ethanol Filter cake to obtain white powder levomaprotamol-L-(-)-dibenzoyl tartrate, wet weight 3.70Kg, dry in an infrared drying oven at 40-42°C overnight, dry weight 2.30Kg, yield: 90.6 %.

[0033] Add 2.30Kg of levomaprotamol-L-(-)-dibenzoyl tartrate into the reaction kettle, add 25.6L (20.3Kg) of methanol, and keep the temperature at 60°C for 2.0 hours. Stop heating, turn on the condensate water, and when the temperature drops to 8.8°C, release the white solid suspension from the bottom of the kettle, filter it with...

Embodiment 2

[0035] The synthesis of embodiment 2 levomaprotamol phenylcarbamate

[0036] Levomaprotamol (100 g, 0.429 mol) was dissolved in 3000 mL of ethyl acetate, phenyl isocyanate (61.26 g, 0.514 mol) was added, and stirred overnight at room temperature. TLC detects that the starting material disappears.

[0037] Add 1000mL of water to destroy the remaining unreacted phenyl isocyanate, adjust the pH to 3 with 1N hydrochloric acid, separate the layers, and extract the aqueous phase with 500mL×2 ethyl acetate. Add 1500 mL ethyl acetate to the water phase, then add ammonia water dropwise to adjust the pH to 9, separate the layers, and extract the water phase with 500 mL×2 ethyl acetate. Combined organic phases, anhydrous Na 2 SO 4 dry. Filtrate and concentrate to obtain levomaprotamol phenylcarbamate, 141.0 g of off-white solid (crude product).

[0038] Put the obtained 141.0g crude product in a 3000mL beaker, add 700mL acetonitrile, heat it in a water bath to 50°C under stirring to...

Embodiment 3

[0039] Example 3 Preparation of Levomaprotamol phenylcarbamate-L-(+)-tartrate

[0040] The L-(+)-tartaric acid of 45.0g levomaprotamol phenyl carbamate and 19.2g is placed in the 1.0L single-necked bottle, add 400mL acetone, heat reflux under stirring and make solid dissolve completely, after 1.0 hour, Heating was stopped, the acetone was spin-dried under reduced pressure, and then the temperature of the water bath was kept at 50° C. for 1.0 hour under reduced pressure, and the obtained light yellow foamy solid was placed in a vacuum drying oven at room temperature and dried under reduced pressure with an oil pump overnight (P 2 o 5 is a desiccant), and finally the solid obtained is placed in a vacuum oven at 50° C. and dried under reduced pressure by an oil pump (P 2 o 5 be the desiccant) in 4.0 hours to obtain 62.1 g of levomaprotamol phenylcarbamate-L-(+)-tartrate light yellow foamy solid, [α] 25 D -11.61 (c1.013, EtOH); 1HNMR (600MHz, DMSO-d 6 )δ10.19(s, 1H, CONH), 7...

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Abstract

The invention relates to a levo-meptazinol phenylamino carbamate-L-(+)-tartrate type-I crystal and a preparation method thereof. The levo-meptazinol phenylamino carbamate-L-(+)-tartrate type-I crystal provided by the invention is stable and is characterized in that the degrees of angles 2[theta] of characteristic peaks shown in an X-ray powder diffractogram are respectively 10.1, 11.9, 13.4, 14.9, 15.4, 17.5, 17.9, 18.7, 19.6, 20.5, 21.7, 22.1, 22.6, 23.3, 24.4, 25.4, 26.9, 27.2, 27.6, 29.0, 29.8, 30.0 and 30.3, and corresponding relative intensities are respectively 42, 14, 26, 43, 66, 28, 14, 20, 33, 100, 25, 31, 51, 14, 15, 10, 10, 12, 16, 10, 12, 11 and 10. The melting point of the levo-meptazinol phenylamino carbamate-L-(+)-tartrate type-I crystal provided by the invention is 101.6-103.8 DEG C.

Description

[0001] Technical field The present invention relates to a levomaprotamol phenylcarbamate-L-(+)-tartrate for treating senile dementia and a preparation method thereof. Background technique [0002] Alzheimer's disease, the so-called senile dementia, is a progressive and fatal neurodegenerative disease. Symptoms and behavioral disturbances. Prevalence research shows that the number of Alzheimer's cases in the United States in 2000 was 4.5 million, and the percentage of Alzheimer's disease patients will increase by 2 times for every 5 years of age increase. The prevalence rate is 1%, compared with 30% in the 85-year-old population. [0003] Alzheimer's disease has seriously affected the quality of life of the elderly and threatened their life safety. The curative effect of the medicine for treating or preventing senile dementia sold in the market is not exact enough, and a kind of medicament with definite curative effect for treating or preventing senile dementia is urgently ne...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D223/04C07C59/255C07C51/41A61K31/55A61P25/28
Inventor 丛日刚彭亮蔡亚辉孙大伟于忠文张永霞肖川
Owner DISHA PHARMA GRP
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