CN103787881A

CN103787881A - Simvastatin ammonium salt

Info

Publication number: CN103787881A
Application number: CN201310597700.9A
Authority: CN
Inventors: 李伟
Original assignee: Chengdu Moer Biopharmaceutical Co Ltd
Current assignee: Chengdu Moer Biopharmaceutical Co Ltd
Priority date: 2013-11-22
Filing date: 2013-11-22
Publication date: 2014-05-14

Abstract

The invention discloses a simvastatin ammonium salt. A preparation method of the simvastatin ammonium salt comprises the following steps: (1) dissolving simvastatin acid in a good solvent, and stirring; (2) filling ammonia gas, stopping the filling of the ammonia gas when detecting that the pH value is 7, and stirring; (3) heating, concentrating, stopping heating when crystals are separated out, and stirring; (4) filtering, and washing the crystals by a good solvent the same as that in the step (1) to obtain a wet product; and (5) drying in vacuum to obtain the simvastatin ammonium salt. As the simvastatin acid is dissolved in the good solvent at first and then the ammonia gas is filled until the pH value is detected to be 7, the preparation method has the following advantages that 1, the reaction time is short and the operation is easy; 2, the reaction is complete and free from side reactions such as cyclization, few products are remained in the solvent through concentration and crystallization, and the reaction yield is high.

Description

Simvastatin ammonium salt

Technical field

The present invention relates to a kind of preparation method of statins ammonium salt, a kind of simvastatin ammonium salt of special design.

Background technology

Simvastatin is a kind of HMG-CoA reductase inhibitor of making as raw material is semi-synthetic take lovastatin of Merck company exploitation, this product was in listing in 1988, obtain U.S. FDA approval in December, 1991, be mainly used in clinically treating former generation hypercholesterolemia blood fat, hypertriglyceridemia and other hyperlipemias.Activity is four times of Pravastatin in vivo, and the development that effectively prevention of arterial is atherosis and heart trouble recurrence, reduce non-lethal myocardial infarction and myocardial vascular in the danger that forms art.International technique of producing Simvastatin mainly adopts following several routes at present:

1), Canadian Patent CA1199322 records: first lovastatin is hydrolyzed with lithium hydroxide; obtain triol acid; lactonize again and obtain interior alkylol cpd; then protected silane 4-position hydroxyl optionally; use again 2; 2-dimethyl-butyryl chloride and its reaction, finally slough protected silane base and obtain Simvastatin.

2), U.S. Pat 4582915 records: obtain the sylvite of lovastatin acid with lovastatin and potassium hydroxide reaction, then react with above-mentioned sylvite with n-Butyl Lithium and methyl iodide, on its side chain, methylate and obtain Simvastatin.

3) Canadian Patent CA1287063 records: lovastatin is reacted and obtains amine salt with normal-butyl ammonium, and recycle silicon alkane is protected the hydroxyl of 4-position, then uses methyl iodide and alkali to react with it, finally sloughs protected silane and lactonizes and obtain Simvastatin.

Above-mentioned three routes produce use in Shortcomings parts all, be mainly following some: 1. Article 1 route, because the first step pyrohydrolysis time is grown (approximately needing 56 hours), causes side reaction to increase, its total recovery lower (40% left and right).2. Article 2 route, owing to not being hydrolyzed the side chain that has larger space steric hindrance, only makes lactone open loop, therefore side reaction is less, but has the incomplete problem that methylates, and total recovery is also undesirable.3. Article 3 route, the incomplete problem that methylates existing in order to solve Article 2 route, this patent is carried out catalysis with tetramethyleneimine lithium as highly basic, the method yield that can make to methylate is greater than more than 99%, but there is the problem identical with Article 2 technique: a, with n-Butyl Lithium reaction, this compound is abnormally dangerous, makes to produce the potential safety hazard that existence is larger; , there is the multiple solvents such as THF, hexane, tetramethyleneimine in b, make solvent be difficult to reclaim in methylation reaction system, produces larger environmental hazard; C, from whole piece circuit, owing to having used much expensive reagent, makes total cost of production higher; D, final step cyclization has used toluene as solvent, makes the boundary of Residual Toluene much larger than ICH regulation, has also affected the promotion and application of this kind.

The synthesis route of Canadian Patent CA1287063 can adopt following procedural representation:

Then the ammonium salt that first utilizes simvastatin acid to prepare Simvastatin obtains Simvastatin through ring-closure reaction.Wherein, the detailed process of preparing amine salt is: in the ethyl acetate solution of simvastatin acid, add methyl alcohol, temperature control is at 25～30 ℃, press 1:3 and drip strong aqua methanol solution, after crystallize out, leave standstill 30 minutes, continue to drip strong aqua methanol solution, after strong aqua methanol solution adds, be cooled to-10 ℃ in 1 hour, at-10 ℃ of temperature, 100rpm stirs 2 hours, filter, wash crystalline substance with 3:5 ethyl acetate methanol solution, 40 ℃ of vacuum-drying 2 hours, obtains simvastatin ammonium salt.

It is partly the synthetic route that adopts this patent that the technique of producing at home Simvastatin has, but time prepared by above-mentioned ammonium salt, the yield of this step is very low, and complicated operation, major cause is that simvastatin acid has part cyclization in the time dripping ammoniacal liquor, can not all become ammonium salt; Be crystallization in alcohol water, ammonium salt is separated out not exclusively simultaneously; This step reaction adopts the mixed solvent of ethyl acetate, second alcohol and water in addition, and solvent cannot reclaim, and there is no cost advantage and is unfavorable for environment protection.

Summary of the invention

Order of the present invention is, a kind of simvastatin ammonium salt is provided, and solves ammonium salt in prior art and prepares the low problem of link productive rate.

Simvastatin ammonium salt of the present invention, its preparation method comprises the steps:

1), simvastatin acid is dissolved in optimum solvent to stirring;

2), pass into ammonia, detecting pH value is to stop logical ammonia at 7 o'clock, stirs;

3), heating is concentrated, stops heating in the time having crystal to separate out, stir;

4), filter, and use with optimum solvent identical in step 1) and wash crystalline substance, obtain wet product;

5), vacuum drying simvastatin ammonium salt;

In above-mentioned steps 1), 4) in optimum solvent be that carbochain is 1---the one in 5 alcoholic solvent, DMF, ethyl acetate, methylene dichloride, chloroform, acetone.

In above-mentioned steps 1), 2), 3) in stirring be all to carry out at 16 ℃-20 ℃.

In above-mentioned steps 3) in simmer down to concentrating under reduced pressure.

In above-mentioned steps 5) in dry temperature be 55 ℃-60 ℃.

In sum, simvastatin ammonium salt provided by the present invention, owing to first simvastatin acid being dissolved in optimum solvent, then passes into ammonia, and detecting pH value is 7, so tool has the following advantages:

1, the reaction times is short, simple to operate;

2, react completely, and reaction is without side reactions such as cyclizations, by condensing crystal, remains in product in solvent few, reaction yield is high.

Embodiment

Embodiment mono-

Simvastatin acid (compound shown in formula 1) 8g is dissolved in 120ml methanol solution, at 20 ℃, 200rpm stirs, and passes into ammonia approximately 5 minutes, and detecting pH value is 7 o'clock, stop logical ammonia, stir 10min, after stable, stir half an hour, 35 ℃ of concentrating under reduced pressure, after having crystal sucking-off, stop concentrating, at 20 ℃, stir 2 hours, filter, wash crystalline substance with methanol solution.Obtain white wet product 10.6g, 55 ℃ of vacuum drying simvastatin ammonium salts (compound shown in formula 2) 8.02g, yield 96.4%.

Present method can be utilized following procedural representation.

Embodiment bis-

By compound 1(simvastatin acid) 8g is dissolved in 100ml ethanolic soln, 16 ℃ of stirrings, pass into ammonia approximately 5 minutes, and detecting pH value is 7 o'clock, stop logical ammonia, 16 ℃ are stirred 5～10 minutes, after stable, stir half an hour, then concentrating under reduced pressure below 50 degree, after having crystal to separate out, stop concentrating, 16 ℃ are stirred one hour, filter, and wash crystalline substance with 10ml ethanolic soln.Obtain white wet product 12.4g, 15 ℃ of vacuum-dryings obtain simvastatin ammonium salt 8.05g, yield 97.2%.

Embodiment tri-

By compound 1(simvastatin acid) 10g is dissolved in 120ml chloroformic solution, 17 ℃ of stirrings, pass into ammonia approximately 10 minutes, and detecting pH value is 7 o'clock, stop logical ammonia, 17 ℃ are stirred 5～10 minutes, stir half an hour, then at 60 degree left and right concentrating under reduced pressure after stable, after having crystal to separate out, stop concentrating, 17 ℃ are stirred two hours, filter, and wash crystalline substance with the chloroformic solution of 10ml ice.Obtain white wet product 14.2g, 60 ℃ of vacuum-dryings obtain simvastatin ammonium salt 9.88g, yield 95.1%.

Although the specific embodiment of the present invention is described in detail, should not be construed as the restriction of the protection domain to this patent.In the described scope of claims, the various modifications that those skilled in the art can make without creative work and distortion still belong to the protection domain of this patent.

Claims

1. a simvastatin ammonium salt, its preparation method comprises the steps:

1), simvastatin acid is dissolved in optimum solvent to stirring;

5), vacuum drying simvastatin ammonium salt;

2. simvastatin ammonium salt according to claim 1, is characterized in that: in above-mentioned steps 1), 2), 3) in stirring be all to carry out at 16 ℃-20 ℃.

3. simvastatin ammonium salt according to claim 1, is characterized in that: in above-mentioned steps 3) in simmer down to concentrating under reduced pressure.

4. simvastatin ammonium salt according to claim 1, is characterized in that: in above-mentioned steps 5) in dry temperature be 55 ℃-60 ℃.