CN102766147B

CN102766147B - Method for preparing fenspiride and halogen acid salt thereof

Info

Publication number: CN102766147B
Application number: CN201210274677.5A
Authority: CN
Inventors: 刘立刚; 严平; 刘雪
Original assignee: Wuxi Yaoxing Pharmaceutical Technology Co ltd
Current assignee: Jiangsu pharmaceutical Limited by Share Ltd
Priority date: 2012-08-03
Filing date: 2012-08-03
Publication date: 2015-07-15
Anticipated expiration: 2032-08-03
Also published as: CN102766147A

Abstract

The invention discloses a method for preparing fenspiride and halogen acid salt thereof. The method includes the following steps of subjecting 1-(2-phenethyl)-4-piperidone and nitromethane to reaction to obtain 1-phenethyl-4-hydroxy-4-nitryl methylene piperidine; subjecting the 1-phenethyl-4-hydroxy-4-hydroxy-4-nitryl methylene piperidine to reaction with halogenated formic acid ester to obtain 1-phenethyl-4-(2-alcoxyl carbonyl oxygen base)-4-nitryl methylene-piperidine halogen acid salt, and obtaining fenspiride halogen acid salt through catalytic hydrogenation, or subjecting the 1-phenethyl-4-(2-alcoxyl carbonyl oxygen base)-4-nitryl methylene-piperidine halogen acid salt to alkalization to obtain free alkali, and preparing fenspiride through catalytic hydrogenation. The method for preparing fenspiride and halogen acid salt thereof is simple and easy to operate and low in cost, raw materials are easy to obtain, and products high in purity are suitable for industrialized application.

Description

The preparation method of a kind of fenspiride and halogen acid salt thereof

Technical field

The present invention relates to the preparation method of a kind of fenspiride and halogen acid salt thereof.

Background technology

Fenspiride (Fenspiride) (I), chemistry 8-styroyl-1-oxa--3 by name, 8-diaza spiro [4.5] decane-2-ketone (8-Phenethyl-1-oxa-3,8-diazaspiro [4.5] decan-2-one), its hydrochloride (II) has been developed to the treatment of preparation for bronchial asthma, inflammation in respiratory system and the disease such as dysfunction, COPD.

About the synthesis of fenspiride and salt thereof, only there is a small amount of bibliographical information at present.US Patent No. 3399192 discloses prepares fenspiride (I) (route 1) via 1-styroyl-4-hydroxyl-4-aminomethylpiperidine (IV) with diethyl carbonate, as follows:

Route 1.

Wherein, 1-styroyl-4-hydroxyl-4-aminomethylpiperidine (IV) is obtained by the cyanalcohol reaction as shown in formula III, and the preparation of cyanalcohol needs the prussic acid using severe toxicity, and the yield of above-mentioned two-step reaction is all lower, be respectively 55% and 77%, be unfavorable for suitability for industrialized production.

Another section of US Patent No. 4028351 discloses a kind of with 1-(2-styroyl)-4-piperidone (V) prepares the method for fenspiride (I) for initiator, as shown in Scheme 2:

Route 2.

The method long reaction time, technology controlling and process point is many, complex operation, and product yield is not high.

In addition, document Synthetic Communications, 24 (10), 1483-1487 (1994), discloses by 1-(2-styroyl)-4-piperidone is the another kind of method that initiator prepares fenspiride, as shown in Scheme 3:

Route 3.

The people such as Wu Aiqun also disclose by 1-(2-styroyl)-4-piperidone is the method (study on the synthesis of fenspiride, Shanxi chemical industry, 27 (5), 19-20 (2007)) that initiator prepares fenspiride, as shown in Scheme 4:

Route 4.

In the method for above-mentioned two kinds of synthesis fenspirides, employ expensive reagent as (CH ₃) ₃siCN, LiAiH ₄, (CH ₃) ₂s (=O)=CH ₂, and violent in toxicity triphosgene, and yield is low, has that cost is high, operational danger large, be unsuitable for the shortcoming of industrial applications.

Summary of the invention

The invention provides a kind of method of synthesizing fenspiride halogen acid salt, route is as follows:

Wherein, R is alkyl, as methyl, ethyl, propyl group, and preferable methyl, ethyl; X is halogen, as chlorine atom, bromine atoms, and preferred chlorine atom.

Particularly, first by 1-(2-styroyl)-4-piperidone (V) and Nitromethane 99Min. be obtained by reacting 1-styroyl-4-hydroxyl-4-Nitromethylene-piperidines (VI) in the presence of a catalyst.

Reaction solvent can be selected from methyl alcohol, ethanol, Virahol etc., and catalyzer can be selected from sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide etc., and temperature of reaction is-20 ~ 50 DEG C, and preferably-10 ~ 10 DEG C, the reaction times is 1 ~ 20 hour, preferably 10 hours.

Then compound (VI) reacts with haloformate in aprotic polar solvent, and temperature of reaction is room temperature to 100 DEG C, obtains 1-styroyl-4-(2-alkyl oxy carbonyl oxygen)-4-Nitromethylene-piperidines halogen acid salt (VII).

Wherein, the preferred ethers of aprotic polar solvent, as ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF) etc.; Haloformate is preferably carbonochloridic acid ester, bromoformate, is more preferably methyl chlorocarbonate, chloro ethyl formate, bromo methyl-formiate, bromo ethyl formate; Reaction times is 4-20h, is preferably 6-10h.

Finally compound (VII) shortening in lower aliphatic alcohols can be obtained fenspiride halogen acid salt (VIII).

Wherein lower aliphatic alcohols particular methanol, ethanol, Virahols etc., the optional Pd/C of catalyzer, Raney's nickel etc., preferred Pd/C, wherein the content of Pd is 10% or 5%, H ₂pressure is 0.01MPa ~ 2.0MPa, is preferably 1.0MPa.

The present invention also provides a kind of preparation method of fenspiride, aforesaid method is adopted to prepare compound (VII), compound (VII) is converted into its free alkali form (Ⅸ) in the basic conditions, then shortening can obtain fenspiride under above-mentioned same condition, route is as follows:

The method of synthesis fenspiride provided by the invention and halogen acid salt thereof, simple to operation, starting material are easy to get, and cost is low, and product purity is high, and suitability for industrialized is applied.

Embodiment

Below in conjunction with embodiment, the present invention is further described, but content of the present invention is not limited to following embodiment.

The preparation of embodiment 1 1-styroyl-4-hydroxyl-4-Nitromethylene piperidines

Getting 1-(2-styroyl)-4-piperidone 203g is dissolved in the ethanolic soln of 2000ml sodium ethylate, drip 61g Nitromethane 99Min., drip and finish, at 0 ~ 10 DEG C, react 10h, the hydrochloric acid soln adding 10% regulates pH to 6 ~ 7, filters and obtains white needles 241g(yield 91.3%).

Embodiment 2 1-styroyl-4-(2-ethoxy carbonyl oxygen base) preparation of-4-Nitromethylene-piperidine hydrochlorate

Getting 264g1-styroyl-4-hydroxyl-4-Nitromethylene piperidines is dissolved in 2000ml tetrahydrofuran (THF), add 109g Vinyl chloroformate, back flow reaction 6h at 60 DEG C, cooling reaction solution to 0 ~ 10 DEG C, filtration obtains white crystals 331g, is 1-styroyl-4-(2-ethoxy carbonyl oxygen base)-4-Nitromethylene-piperidine hydrochlorate (yield 88.7%).

The preparation of embodiment 3 fenspiride hydrochloride

186g embodiment 2 product is dissolved in 2800ml ethanol, adds the Pd/C of 10g 10%, pass into hydrogen, pressure-controlling is at about 1.0MPa, and normal-temperature reaction 3h, filters, concentrated filtrate, after remnants add the dissolve with ethanol of 1500ml 95%, stirs 3h at 0 ~ 10 DEG C, separate out white crystal, filter, vacuum-drying 6h at 70 DEG C, obtains white crystals 138g, for fenspiride hydrochloride (yield 92.9%, HPLC:99.9%).

Embodiment 4 1-styroyl-4-(2-ethoxy carbonyl oxygen base) preparation of-4-Nitromethylene-piperidines

Get 37g embodiment 2 gained hydrochloride to be dissolved in 250ml methyl alcohol, add 25g K ₂cO ₃, stir 2 hours, filter and obtain 1-styroyl-4-(2-ethoxy carbonyl oxygen base) and the methanol solution of-4-Nitromethylene-piperidines.

The preparation of embodiment 5 fenspiride

In the methanol solution of embodiment 3 gained, add 3g 5%Pd/C, under hydrogen pressure 1.0MPa, in 30 DEG C of reaction 3h, filter, filtrate is concentrated into dry, and remnants add ethanol 100ml heating for dissolving, be cooled to 0 ~ 10 DEG C, stir 3h, filter to obtain white crystals, dry to obtain 23.8g white crystals for 65 DEG C, for fenspiride (yield 91%, HPLC:99.8%).

Claims

1. a preparation method for fenspiride halogen acid salt, route is as follows:

Wherein, R is methyl, ethyl or propyl group, and X is halogen atom;

Concrete steps are: (1) described compound (V) and Nitromethane 99Min. are obtained by reacting compound (VI), in this step, reaction solvent is methyl alcohol, ethanol or Virahol, catalyzer is sodium methylate, sodium ethylate, sodium hydroxide or potassium hydroxide, temperature of reaction is-20 ~ 50 DEG C, and the reaction times is 1 ~ 20 hour;

(2) described compound (VI) reacts with haloformate in ether, isopropyl ether, methyl tertiary butyl ether or tetrahydrofuran (THF), obtains compound (VII), and temperature of reaction is room temperature to 100 DEG C, and the reaction times is 4-20h;

(3) described compound (VII) shortening in methyl alcohol, ethanol or Virahol can obtain fenspiride halogen acid salt (VIII), and described catalyzer is Pd/C or Raney's nickel, H ₂pressure is 0.01MPa ~ 2.0MPa.

2. the preparation method of fenspiride halogen acid salt as claimed in claim 1, is characterized in that: described X is chlorine atom or bromine atoms.

3. the preparation method of a fenspiride, described compound (VII) is prepared for adopting the method described in claim 1, again described compound (VII) is prepared compound (Ⅸ) in the basic conditions, described compound (Ⅸ) shortening in methyl alcohol, ethanol or Virahol obtains fenspiride, described catalyzer is Pd/C or Raney's nickel, H ₂pressure is 0.01MPa ~ 2.0MPa: