CN108863929A - A kind of deuterated pleasure cuts down the refining methd for Buddhist nun - Google Patents

Abstract

The refining methd for Buddhist nun is cut down the invention discloses a kind of deuterated pleasure.Purification operations step is：Deuterated pleasure is cut down to the in the mixed solvent for being added to methanol, water, sodium hydroxide, active carbon for the crude product of Buddhist nun, is heated to 64~68 DEG C of micro- reflux states, is continued return stirring 2~6 hours, it filters while hot, filtrate stirs cooling crystallization to 2~6 DEG C, keeps the temperature 6~8 hours, then filters, vacuum drying, it obtains deuterated pleasure and cuts down sterling for Buddhist nun, purity is greater than 99.5%, and single miscellaneous content is less than 0.1%, total miscellaneous content meets the requirement of general medicament contg less than 0.5%.

Description

A kind of deuterated pleasure cuts down the refining methd for Buddhist nun

Technical field

The invention belongs to field of medicinal chemistry, in particular to a kind of deuterated pleasure cuts down the refining methd for Buddhist nun.

Background technique

Chinese patent CN2018105615621 reports a kind of deuterated pleasure and cuts down for Buddhist nun's

Preparation method, as follows,

Third step reacts the impurity compound I shown in following formula being primarily present,

Its structure is confirmed by nuclear magnetic resonance spectroscopy and mass spectrum：¹H-NMR(400MHz,DMSO-d₆)δppm11.84(brs, 1H), 7.47 (d, J=3.95Hz, 1H), 6.79 (s, 1H), 6.63 (d, J=3.95Hz, 1H), 4.95 (brs, 1H), 3.42 (s, 1H), 0.61~0.47 (m, 4H)；ESI/MS：M/z=431 (M+H)+.According to the post-processing approach reported in patent, gained is produced Product purity is 98.4%, and the content of impurity I is 0.15%~0.32%.It does not meet in general drug standard and contains in relation to singly miscellaneous Amount is lower than 0.1% requirement.Moreover, because impurity content is excessively high, during the quality research of drug, it is necessary to impurity I into Row correlation toxicological experiment research, so that the cost and risk of medicament research and development can be greatly increased.

Summary of the invention

The refining methd for Buddhist nun is cut down the present invention provides a kind of deuterated pleasure, it is therefore an objective to which product purity is low for solution, major impurity I The problem of too high levels.

The purpose of the present invention is what is be achieved by the steps of：

Deuterated pleasure is cut down the in the mixed solvent that methanol, water, sodium hydroxide, active carbon are added to for the crude product of Buddhist nun by step 1), Deuterated pleasure, which is cut down, is equal to 1 for Buddhist nun's crude product and the mass ratio of in the mixed solvent methanol, water, sodium hydroxide, active carbon:10~25:15~ 25:1~5:0.5~2.5, it is heated to micro- reflux state, system temperature is 64~68 DEG C, is continued return stirring 2~6 hours；

Step 2) filters while hot, and the system temperature filtered while hot is not less than 35 DEG C；

Step 3) filtrate stirs cooling crystallization to 2~6 DEG C, keeps the temperature 6~8 hours；

Step 4) then filters, and washs filter cake with 50% methanol aqueous solution；

Filter cake is dried in vacuo 15 by step 5) at 45~55 DEG C~for 24 hours, obtain purity and qualified deuterated of single miscellaneous content Pleasure is cut down for Buddhist nun's sterling.

It is second that preferred deuterated pleasure, which is cut down for Buddhist nun's crude product and the mass ratio of in the mixed solvent methanol, water, sodium hydroxide, active carbon, Alcohol：Water：Sodium hydroxide：Active carbon=1:1:13~20:15~20:2~4:0.5~2.

The system temperature preferably filtered while hot is not less than 40 DEG C.

The preferred vacuum drying time is 15~20h.

Operation of the present invention is simple, the period is short, product purity is high, single miscellaneous content is controllable.

Specific embodiment

Embodiment 1

The deuterated pleasure that 2.7g content is 98.4% is added in 500ml three-necked flask to cut down for Buddhist nun's crude product, sequentially adds 33g Methanol, 38g water, 5g sodium hydroxide, 1.25g active carbon open stirring, are heated to micro- reflux state, and system temperature is 64~68 DEG C, continue return stirring 2 hours, filter while hot, keeps when filtering system temperature to be not less than 40 DEG C, filtrate stirs cooling crystallization extremely It 2 DEG C, insulated and stirred 6 hours, then filters, washs filter cake with 50% methanol aqueous solution, filter cake is dried in vacuo, vacuum oven Temperature setting is 50 DEG C, and the dry time is 15h, obtains light yellow deuterated pleasure and cuts down crystallization 2.24g for Buddhist nun, content 99.75%, Impurity I content 0.07%, other single miscellaneous respectively less than 0.1%.

Embodiment 2

The deuterated pleasure that 2.7g content is 98.4% is added in 500ml three-necked flask to cut down for Buddhist nun's crude product, sequentially adds 40g Methanol, 40g water, 5.5g sodium hydroxide, 1.3g active carbon open stirring, are heated to micro- reflux state, and system temperature is 64~68 DEG C, continue return stirring 4 hours, filter while hot, keeps when filtering system temperature to be not less than 45 DEG C, filtrate stirs cooling crystallization extremely It 5 DEG C, insulated and stirred 10 hours, then filters, washs filter cake with 50% methanol aqueous solution, filter cake is dried in vacuo, be dried in vacuo Box temperature degree is set as 50 DEG C, and the dry time is 15h, obtains light yellow deuterated pleasure and cuts down crystallization 2.33g for Buddhist nun, content 99.59%, impurity I content 0.04%, other single miscellaneous respectively less than 0.1%.

Embodiment 3

The deuterated pleasure that 2.7g content is 98.4% is added in 500ml three-necked flask to cut down for Buddhist nun's crude product, sequentially adds 45g Methanol, 43g water, 6.2g sodium hydroxide, 1.8g active carbon open stirring, are heated to micro- reflux state, and system temperature is 64~68 DEG C, continue return stirring 3 hours, filter while hot, keeps when filtering system temperature to be not less than 45 DEG C, filtrate stirs cooling crystallization extremely It 5 DEG C, insulated and stirred 11 hours, then filters, washs filter cake with 60% methanol aqueous solution, filter cake is dried in vacuo, be dried in vacuo Box temperature degree is set as 50 DEG C, and the dry time is 16h, obtains light yellow deuterated pleasure and cuts down crystallization 2.19g for Buddhist nun, content 99.72%, impurity I content 0.05%, other single miscellaneous respectively less than 0.1%.

Embodiment 4

The deuterated pleasure that 2.7g content is 98.4% is added in 500ml three-necked flask to cut down for Buddhist nun's crude product, sequentially adds 47g Methanol, 50g water, 7g sodium hydroxide, 2.0g active carbon open stirring, are heated to micro- reflux state, and system temperature is 64~68 DEG C, continue return stirring 6 hours, filter while hot, keeps when filtering system temperature to be not less than 40 DEG C, filtrate stirs cooling crystallization extremely It 3 DEG C, insulated and stirred 14 hours, then filters, with 50% methanol aqueous solution filter cake, filter cake is dried in vacuo, be dried in vacuo box temperature Degree is set as 50 DEG C, and the dry time is 20h, obtains light yellow deuterated pleasure and cuts down crystallization 1.93g for Buddhist nun, content 99.81% is miscellaneous Matter I content 0.03%, other single miscellaneous respectively less than 0.1%.

Claims (1)

1. a kind of deuterated pleasure cuts down the refining methd for Buddhist nun, reduce has Formulas I structure as follows

Impurity content, purification step is：

Deuterated pleasure is cut down the in the mixed solvent that methanol, water, sodium hydroxide, active carbon are added to for the crude product of Buddhist nun by step 1), deuterated Happy cut down is equal to 1 for Buddhist nun's crude product and the mass ratio of in the mixed solvent methanol, water, sodium hydroxide, active carbon:10~25:15~25:1 ~5:0.5~2.5, it is heated to micro- reflux state, system temperature is 64~68 DEG C, is continued return stirring 2~6 hours；

Step 2) filters while hot, and the system temperature filtered while hot is not less than 35 DEG C；

Step 3) filtrate stirs cooling crystallization to 2~6 DEG C, keeps the temperature 6~8 hours；

Step 4) then filters, and washs filter cake with 50% methanol aqueous solution；

Filter cake is dried in vacuo 15 by step 5) at 45~55 DEG C~for 24 hours, the deuterated pleasure for obtaining purity and single miscellaneous content qualification is cut down For Buddhist nun's sterling.