CN103319478A

CN103319478A - Synthesis process of important medicinal chemical raw material bromomethyl scopolamine

Info

Publication number: CN103319478A
Application number: CN2013101759541A
Authority: CN
Inventors: 彭学东; 张梅; 赵金召; 陈晓龙
Original assignee: ZHANGJIAGANG WEISHENG BIOLOGICAL PHARMACEUTICAL CO Ltd
Current assignee: ZHANGJIAGANG WEISHENG BIOLOGICAL PHARMACEUTICAL CO Ltd
Priority date: 2013-05-14
Filing date: 2013-05-14
Publication date: 2013-09-25

Abstract

The invention relates to a synthesis process of an important medicinal chemical raw material bromomethyl scopolamine. NaBr and CH3OH are mixed, a mixed liquid of H2SO4 and the CH3OH is slowly added drop by drop to the mixture, the mixture reacts at 50 DEG C-60 DEG C, a gas is obtained and is washed by alkali water. The gas is dried and finally is introduced into a test tube in the salt ice bath environment for reaction, and then a liquid, namely bromomethane (CH3Br) in the test tube is collected after the reaction is completed. The CH3Br is added into an alcohol solution of the scopolamine, a reaction is carried out in the organic alkali environment at room temperature, pumping filtration is carried out after the reaction, a filter cake is taken for drying, an organic solvent is added for washing, and then the bromomethyl scopolamine is obtained through pumping filtration, drying and purifying, with the yield of about 60% and the purity of about 98%.

Description

A kind of synthesis technique of important medicine chemical material pamine bromide

Technical field

The invention belongs to technical field of organic synthesis, be specifically related to a kind of synthetic method of pamine bromide.

Background technology

Pamine bromide is a kind of muscarinic receptor antagonist of similar neurotransmitter acetylcholine.Its mechanism of action is the blocking-up mAChR.Pamine bromide is a kind of oral pharmaceutical that use with other drug, and by reducing gastric acid secretion treatment peptide ulceration, it also can be used to stomach or enterospasm, reduce salivation, treatment is carsick etc., also is commonly used for flu, irritable bowel syndrome and irritated medicine.The anticholinergic of the quaternary ammonium of the liver toxicity problem that pamine bromide also is considered to basically to avoid potential has certain potential market.

There are many deficiencies in the synthesis technique of pamine bromide at present, as: Atom economy is low, cost is high, yield is low etc., there is no the relevant report of large-scale production both at home and abroad.We have designed take Scopolamine as raw material on the basis with reference to existing document, and the route of two step synthetic bromide epoxytropine tropates has carried out in depth studying and improving to its synthesis condition, greatly reduces cost consumption, has improved processing condition.

Summary of the invention

The object of the invention is to overcome the above-mentioned shortcoming of prior art, a kind of synthesis technique of pamine bromide of easy to operate, yield is high, purity good, energy consumption is low suitable suitability for industrialized production is provided.

Concrete, a kind of synthesis technique of pamine bromide, it comprises following a few step:

The first step, the preparation of monobromethane: with NaBr and CH ₃OH mixes, and slowly drips by H ₂SO ₄With CH ₃The liquid that OH mixes, 50 ℃～60 ℃ reactions, gas is washed by buck, and drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid in the test tube, is monobromethane; Wherein NaBr, CH ₃OH, H ₂SO ₄Weight ratio is 1: 1～1.5: 1.8～2;

Second step, pamine bromide synthetic: with the CH of the first step gained ₃Br adds in the Rhizome of Japanese Scopolia alkali alcosol, adds organic bases, room temperature reaction, and suction filtration after the reaction end is got the filter cake oven dry, adds organic solvent washing, suction filtration, oven dry, purifying had both got target product; CH wherein ₃Br and Scopolamine mol ratio are 1: 1.1～1.2, and the organic bases consumption is 0.6～0.9 times of Scopolamine weight.

Preferably, buck described in the first step is 3%～8% the inorganic strong alkali aqueous solution such as NaOH, KOH, alcohol described in second one is one or more in methyl alcohol, ethanol, the propyl alcohol etc., organic bases is the organic alkalis such as sodium methylate, sodium ethylate, and washing used organic solvent is methylene dichloride, trichloromethane etc.

Step involved in the present invention is easy to operate, and mild condition is by using methyl alcohol, the vitriol oil etc. be simple and easy to reagent react, greatly reduced operation easier, all right recycle of methyl alcohol has reduced production cost, reduced environmental pollution, operation steps is simple, can realize large-scale industrial production, and product production is high, purity is high, and energy consumption is low.

Embodiment

Embodiment 1: the preparation of pamine bromide

The first step, the preparation of monobromethane: with 40gNaBr and 20mlCH ₃OH mixes, and slowly drips by 38mlH ₂SO ₄With 25mlCH ₃The liquid that OH mixes, 55 ℃ of reactions, gas is washed by 3%NaOH, anhydrous CaCl ₂Drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid, approximately 20ml in the test tube;

Second step, pamine bromide synthetic: with the 20mlCH of the first step gained ₃Br adds 500ml and is dissolved with in the methanol solution of 120g Scopolamine, adds the 95g sodium methylate, room temperature reaction, suction filtration after reaction finishes, get the filter cake oven dry, add the washing of 100ml trichloromethane, suction filtration is dried to get the 73.1g white powder, the dehydrated alcohol recrystallization gets 72.8g, purity 98.7%.

Embodiment 2: the preparation of pamine bromide

The first step, the preparation of monobromethane: with 20gNaBr and 10mlCH ₃OH mixes, and slowly drips by 19mlH ₂SO ₄With 15mlCH ₃The liquid that OH mixes, 60 ℃ of reactions, gas is washed by 5%NaOH, anhydrous CaCl ₂Drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid, approximately 11ml in the test tube;

Second step, pamine bromide synthetic: with the 11mlCH of the first step gained ₃Br adds 240ml and is dissolved with in the methanol solution of 60g Scopolamine, adds the 45g sodium methylate, room temperature reaction, suction filtration after reaction finishes, get the filter cake oven dry, add the washing of 50ml trichloromethane, suction filtration, dry to get the 36.5g white powder, the dehydrated alcohol recrystallization gets 35.6g purity 99.2%.

Embodiment 3: the preparation of pamine bromide

The first step, the preparation of monobromethane: with 10gNaBr and 5mlCH ₃OH mixes, and slowly drips by 9mlH ₂SO ₄With 6mlCH ₃The liquid that OH mixes, 50 ℃ of reactions, gas is washed by 8%NaOH, anhydrous CaCl ₂Drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid, approximately 5ml in the test tube;

Second step, pamine bromide synthetic: with the 5mlCH of the first step gained ₃Br adds 150ml and is dissolved with in the methanol solution of 30g Scopolamine, adds the 24g sodium methylate, room temperature reaction, suction filtration after reaction finishes, get the filter cake oven dry, add the washing of 30ml trichloromethane, suction filtration, dry to get the 6.2g white powder, the dehydrated alcohol recrystallization gets 5.7g purity 98.5%.

Embodiment 4: the preparation of pamine bromide

The first step, the preparation of monobromethane: with 120gNaBr and 60mlCH ₃OH mixes, and slowly drips by 115mlH ₂SO ₄With 75mlCH ₃The liquid that OH mixes, 55 ℃ of reactions, gas is washed by 5%NaOH, anhydrous CaCl ₂Drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid, approximately 58ml in the test tube;

Second step, pamine bromide synthetic: with the 58mlCH of the first step gained ₃Br adds 1500ml and is dissolved with in the methanol solution of 360g Scopolamine, adds the 280g sodium methylate, room temperature reaction, suction filtration after reaction finishes, get the filter cake oven dry, add the washing of 300ml trichloromethane, suction filtration, dry to get the 215.8g white powder, the dehydrated alcohol recrystallization gets 215.3g purity 98.2%.

Claims

1. an important medicine chemical material pamine bromide is synthetic, it is characterized in that NaBr and CH ₃OH mixes, and slowly drips by H ₂SO ₄With CH ₃The liquid that OH mixes, 50 ℃～60 ℃ reactions, gas is washed by buck, and drying passes in the test tube of salt ice bath environment at last, reacts complete, collects liquid in the test tube, is monobromethane, with CH ₃Br adds in the Rhizome of Japanese Scopolia alkali alcosol, adds organic bases, room temperature reaction, and suction filtration after reaction finishes is got the filter cake oven dry, adds organic solvent washing, suction filtration, oven dry, purifying namely gets target product.

2. wherein NaBr according to claim 1, CH ₃OH, H ₂SO ₄Weight ratio is 1: 1～1.5: 1.8～2, CH ₃Br and Scopolamine mol ratio are 1: 1.1～1.2, and the organic bases consumption is 0.6～0.9 times of Scopolamine weight.

3. CH according to claim 1 ₃The temperature of reaction of Br is 50 ℃～60 ℃, and collecting envrionment temperature is-5 ℃～0 ℃, and the temperature of reaction of Scopolamine is room temperature.

4. the organic bases that adds in the reaction according to claim 1 is a series of organic alkalis such as sodium methylate, sodium ethylate.

5. the organic solvent of articles for washing according to claim 1 is trichloromethane, methylene dichloride equal solvent.