CN102786444A - Preparation method for sulfonates of sibutramine analogues - Google Patents

Abstract

The invention discloses sulfonates of sibutramine analogues. The invention is characterized in that the sulfonates of sibutramine analogues have a general formula as described in the specification, wherein in the general formula, R1, R2 and R3 are different alkyl groups consisting of methyl groups, ethyl groups, propyl groups and isopropyl groups, R4 and R5 are same or different halogen elements consisting of fluorine, chlorine and bromine, and n is 0, 1, 2 or 3. A preparation method for the sulfonates of sibutramine analogues is described in the specification. According to the invention, the preparation method does not use tetrahydrofuran, which enables cost to be low, and is suitable for industrial production; the sulfonates of sibutramine analogues can be directly used as a bulk drug to replace sibutramine, have a fat-reducing effect as sibutramine does, but do not have side effects of sibutramine.

Description

A kind of preparation method of sulphonate of sibutramine analogue

Technical field

The present invention relates to a kind of preparation method of sulphonate of sibutramine analogue, belong to medical preparing technical field.

Background technology

Sibutramine

is a kind of depressor of nerve centre; Have excitement, press down effect such as food, it might cause elevation of the blood pressure, heart rate quickening, apocleisis, insomnia, dysfunction of liver etc. endanger severe side effect.China Bureau of Drugs Supervision halted the production and sales in the China's Mainland on October 30th, 2010, and U.S. fda and European Union have halted before and be used for fat-reducing effect, and reason just is that sibutramine causes the incidence of cardio-cerebrovascular disease.At present, the analogue through the preparation sibutramine solves this technical problem:

Route one:

Wherein: raw material one R4, R5 are different or halogen inequality, comprise fluorine, chlorine, bromine; Raw material two is 1, the 3-dihalopropane.X can be chlorine, bromine or iodine; The shortcoming of this route is to use ether, is unfavorable for amplifying generating.

Route two:

Raw material one R4 wherein, R5 is identical or different halogen, comprises fluorine, chlorine, bromine; Raw material two is 1, the 3-dihalopropane.X can be chlorine, bromine or iodine; The shortcoming of this route is to use THF, and cost is higher.

Therefore, find a kind ofly can replace sibutramine, can have the product of the similar medicinal effect of sibutramine again, and design a kind of suitability for industrialized production that both had been beneficial to, the preparation method of this medicine of the cost that economizes in raw materials again is that this area has technical problem to be solved.

Summary of the invention

The objective of the invention is sulphonate for a kind of sibutramine analogue is provided and preparation method thereof, to substitute sibutramine class medicine.

The object of the invention can be realized through following technical scheme.

A kind of sulphonate of sibutramine analogue, its general formula is:

Wherein, R1, R2, R3 is different alkyl, comprises methyl, ethyl, propyl group and sec.-propyl; R4, R5 is identical or different halogen, comprises fluorine, chlorine, bromine; N=0,1,2,3.

The preparation method of the sulphonate of above-mentioned sibutramine analogue is:

Wherein: the R4 in formula (1) compound, R5 is identical or different halogen, described halogen is selected from fluorine, chlorine and bromine; Formula (2) compound is 1, the 3-dihalopropane; Wherein, X can be chlorine, bromine or iodine.

Concrete steps are following:

1) in reaction kettle, add DMSO and grind to form short grained Pottasium Hydroxide, drip formula (1) compound and formula (2) compound gradually, controlled temperature is 20-25 ℃, drips off in 2 hours; Room temperature reaction 1 hour, the some plate, raw material reaction is complete, is cooled to 10 ℃; Drip 6 premium on currency gradually, keep temperature in the kettle to be no more than 20 ℃ in the dropping process; Add after-filtration, filter cake is washed with EA, the filtrating separatory, and water is washed (10L EA washes 3 times) with EA 10L * 3, merges organic phase and washes with saturated common salt, and drying is revolved dried, and getting oily compound is formula (3) compound;

2) (the self-control grignard reagent: the 1.8kg isobutane bromide slowly is added drop-wise in the isopropyl ether that is added with the 318g magnesium chips 2kg formula (3) compound and toluene wiring solution-forming to be added drop-wise to the 20L grignard reagent gradually; And stirring makes it to dissolve clear); 90 ℃ were reacted 3 hours; Reaction solution is joined in the Peng Qinghuana of 2kg and the solution that Virahol is made into, be warming up to 80 ℃ of back flow reaction 6 hours, room temperature reaction spends the night; The point board monitoring is until having reacted; Otherwise add Peng Qinghuana, add shrend and go out, the yellow oil that the EA extraction is revolved after doing is formula (a 4) compound;

3) modus ponens (4) compound is added to formalin and formic acid 1:2-1:3, spends the night 90 ℃ of reactions, boils off solvent, adds water, and sodium hydroxide (concentration does not influence reaction of the present invention) transfers to alkalescence, and the EA extraction is revolved dried;

4) formula (5) compound is added EA and dissolve clearly, drip the methylsulfonic acid of 1.05 equivalents (is 1 with formula (5) compound) gradually, stirred 2 hours under the room temperature, filter, solid adds sherwood oil and washes to such an extent that white solid is a final product of the present invention.

Preparing method of the present invention do not use THF, so cost is lower; And applicable to suitability for industrialized production; This compounds can be directly as bulk drug, and to replace the sibutramine medicine, this medicine has the fat-reducing effect the same with sibutramine, but does not have the spinoff of sibutramine.

Embodiment

Further set forth technical characterstic of the present invention below in conjunction with specific embodiment:

Embodiment 1: preparation 1-(1-(3, the 4-dichlorophenyl) cyclobutyl)-N, N, 3-trimethylammonium butyl-1-amine sulphonate

The first step, reaction detailed process:

Add the DMSO12 liter in 50 liters of reaction kettles, adding grinds to form short grained Pottasium Hydroxide, drips 1 gradually, 3-dibromopropane and 3,4-dichloro benzyl cyanide; Controlled temperature 20-25 degree dripped off in 2 hours, room temperature reaction 1 hour, and the some plate, raw material reaction is complete; Be chilled to 10 degree, drip 6 premium on currency gradually, temperature is no more than 20 degree, filters, and filter cake is washed with EA; The filtrating separatory, water is washed with EA10L*3, merges the washing of organic phase saturated common salt, and drying is revolved and was done post, gets oily solid mixture

Second step, reaction detailed process:

1.8 kilogram isobutyl bromide and 318 gram magnesium chips add 8 liters of isopropyl ethers and make grignard reagent, 2 kilograms of int-1 are added 8 liters of toluene wiring solution-formings be added drop-wise to gradually in the grignard reagent, 90 degree reactions 3 hours; Reaction solution is added in the solution that 1 kilogram of Peng Qinghuana and 40 liters of Virahols be made into, and 6 hours room temperature reactions of back flow reaction spend the night, and the some board monitoring is until having reacted; Otherwise add Peng Qinghuana; Add shrend and go out, the yellow oil after doing, 2.3 kilograms are revolved in the EA extraction;

The 3rd step, reaction detailed process:

3 kilograms of int3 add 10 liters in formic acid with formalin 2 liter of 90 degree reaction spend the night, boil off solvent, add water, transfer to alkalescence, the EA extraction is revolved dried;

The 4th step, reaction detailed process:

4 kilograms of DCS add EA and dissolve clearly, drip 1.05 normal methylsulfonic acids gradually, stir 2 hours under the room temperature, filter, solid add sherwood oil wash white solid.

The NMR spectrum of the H of the product for preparing is: 1H NMR (CDCl3,400MHz) δ 7.5 (s, 1H), δ 7.461-7.478 (d; 1H), and δ 7.252-7.269 (d, 1H), δ 2.814-2.831 (d; 2H), and δ 2.555-2.613 (m, 2H), δ 2.415-2.490 (m; 1H), and δ 2.043-2.120 (m, 1H)

Keep other parameter conditions constant, embodiment 1-6 yield is as shown in the table:

Can find out that from last table the total recovery of reaction can reach 60%, is applicable to suitability for industrialized production.Product of the present invention can replace the sibutramine medicine, and this medicine has the fat-reducing effect the same with sibutramine, but does not have the spinoff of sibutramine.

Claims (2)

1. the sulphonate of a sibutramine analogue, it is characterized in that: its general formula is:

Wherein, R1, R2, R3 is different alkyl, comprises methyl, ethyl, propyl group and sec.-propyl; R4, R5 is identical or different halogen, comprises fluorine, chlorine, bromine; N=0,1,2,3.

2. one kind prepares the method for the sulphonate of sibutramine analogue according to claim 1, and it is characterized in that: reaction equation is following:

Wherein: the R4 in formula (1) compound, R5 is identical or different halogen, described halogen is selected from fluorine, chlorine and bromine; Formula (2) compound is 1, the 3-dihalopropane; Wherein, X can be chlorine, bromine or iodine;

Concrete steps are following:

1) in reaction kettle, add DMSO and grind to form short grained Pottasium Hydroxide, drip formula (1) compound and formula (2) compound gradually, controlled temperature is 20-25 ℃, drips off in 2 hours; Room temperature reaction 1 hour, the some plate, raw material reaction is complete, is cooled to 10 ℃; Drip 6 premium on currency gradually, keep temperature in the kettle to be no more than 20 ℃ in the dropping process; Add after-filtration, filter cake is washed with EA, the filtrating separatory, and water is washed (10L EA washes 3 times) with EA 10L * 3, merges organic phase and washes with saturated common salt, and drying is revolved dried, and getting oily compound is formula (3) compound;

2) (the self-control grignard reagent: the 1.8kg isobutane bromide slowly is added drop-wise in the isopropyl ether that is added with the 318g magnesium chips 2kg formula (3) compound and toluene wiring solution-forming to be added drop-wise to the 20L grignard reagent gradually; And stirring makes it to dissolve clear); 90 ℃ were reacted 3 hours; Reaction solution is joined in the Peng Qinghuana of 2kg and the solution that Virahol is made into, be warming up to 80 ℃ of back flow reaction 6 hours, room temperature reaction spends the night; The point board monitoring is until having reacted; Otherwise add Peng Qinghuana, add shrend and go out, the yellow oil that the EA extraction is revolved after doing is formula (a 4) compound;

3) modus ponens (4) compound is added to formalin and formic acid 1:2-1:3, spends the night 90 ℃ of reactions, boils off solvent, adds water, and sodium hydroxide (concentration does not influence reaction of the present invention) transfers to alkalescence, and the EA extraction is revolved dried;

4) formula (5) compound is added EA and dissolve clearly, drip the methylsulfonic acid of 1.05 equivalents (is 1 with formula (5) compound) gradually, stirred 2 hours under the room temperature, filter, solid adds sherwood oil and washes to such an extent that white solid is a final product of the present invention.