JPS60115554A - Production of deacetylmoxisylyte - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a synthetic intermediate for sympatholytic agents and medicines for cardiovascular organs in high purity and yield, by hydrolyzing the acetyl group in an N,N-dimethylethylamine derivative, diazotizing the hydrolysis product, and distilling the diazotization product under reduced pressure. CONSTITUTION:The acetyl group in 2-(4-acetamino-2-isopropyl-5-methylphenoxy)- N.N-dimethylethylamine of formula I is hydrolyzed with an aqueous solution of hydrochloric acid or sulfuric acid, etc. and then diazotized with a nitrite, e.g. sodium nitrite. In the final stage, the diazotization product is then heated at <=180 deg.C under <=1mm.Hg reduced pressure to afford the aimed substance 2-(4-hydroxy-2-isopropyl-5-methylphenoxy)-N,N-dimethylamine (DAM) of formula II.

Description

Detailed Description of the Invention The present invention provides 2-(4-hydroxy-2-isopropyl-5
-methylphenoxy)-N,N-dimethylethylamine (also known as deacetylmoxysilito, hereinafter abbreviated as DAM)
The present invention relates to a method for producing the compound in high yield and with high purity.

DAM is commonly known as moxisilite hydrochloride (English name: Moxi
It has a sympathoblocking effect called sylyte hydrochloride (K. Greeff and
dH. J. Schumann, Arzneim-Fo.
rsch. , 3, 341 (1953)) and the British Pharmacopoeia (British Pharmacopoeia) as a cardiovascular drug.
-copoeia 1980, Vol I, p455) It is a valuable compound as a powerful intermediate in the production of useful compounds.

There are various methods for producing DAM, but generally, starting from thymol, an acetamino group is introduced at the rose position relative to the phenolic hydroxyl group of thymol, and then the phenolic hydroxyl group is etherified with a dimethylaminoethyl group to obtain formula (2). 2-(4-acetamino-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine, which has 5-
methylphenoxy)-N,N-dimethylethylamine (
Another name: aminothymol dimethyl aminoethyl ether (hereinafter abbreviated as ATE), which is then diazotized with a nitrite such as sodium nitrite, and the diazo is decomposed according to a conventional method to obtain DAM.

These methods are known in German Patent No. 905738, British Patent No. 745070, etc.
) without isolating JP-A-58-351
There is also a 49th mag. However, all of these methods involve a diazotization reaction, so the purity of the DAM obtained is not necessarily high. In fact, (1) the thin layer chromatogram shows at least five spots and Chromatography and high performance liquid chromatography analysis [manufactured by JASCO Corporation: TR
IROTARFAMILIC-300S (semi-micro)
, UV photometer wavelength 275 nm, column: Fine-Pa
k GEL110, methanol: water: strong ammonia water (
(2) For example, DA
There is also a description that in the reaction of M with acetyl chloride to form moxysilito hydrochloride, DAM that has undergone a diazotization reaction is unfavorable in terms of quality (Japanese Patent Application Laid-Open No. 58-121251, 3).
left side of the page).

German Patent No. 905738 and British Patent No. 745070
If the method in the above issue is used, DAM will be inferior in purity, and the process after DAM up to the production of moxisilite hydrochloride must be improved in purity with a significant drop in yield, making it industrially more expensive. It cannot be said that it is advantageous in terms of sacrificing other compounds. Moreover, the method of JP-A-58-35147 also has a lower purity because it skips the steps of isolation and purification prior to the diazonization reaction. As a general method to improve purity,
(1) When the recrystallization method is applied to DAM obtained after the diazonization reaction, the dark brown DAM has a slightly tar-like color and is usually treated with recrystallization solvents such as acetic acid ethyl ester, ethanol, acetone, toluene, dioxane, etc. A mixture of these and water in an appropriate amount cannot be easily recrystallized, and even when oily semicrystals are obtained, the purity and yield are not satisfactory. Furthermore, the decolorizing effect is also low, which is not preferable. (2) Normal vacuum distillation (several mmHg, heating temperature 170° to 190°C) can ensure a purity of 97% or more, but the fluidity of DAM is poor and it is difficult to achieve a distillation recovery rate of 80% or more. It is not possible to achieve a yield of 80% or more as the compound of formula (2) after distillation from the compound of formula (1).

The present inventors have learned that in order to satisfy the British Pharmacopoeia's purity standard for moxisilite hydrochloride of 99.0% or higher and to obtain it in high yield, DAM, the starting material, must be of high purity. As a result of intensive research to find a method to industrially produce DAM with high purity and high yield,
Vacuum distillation (5 mHg or less, heating temperature 160° to 190°C) is a good way to improve the purity of DAM, and in order to ensure the yield, it is especially preferable to use vacuum distillation conditions of 1 mmHg or less and heating temperature 180°C or less. Heading: The present invention has been completed.

That is, the present inventors studied the conditions for vacuum distillation, focusing on the fact that a sufficient amount of DAM remains in the residue after normal vacuum distillation, and found that the degree of vacuum was further increased to 1 mmHg.
Below, if you apply so-called molecular distillation (method of obtaining a large film heat transfer coefficient by forming a thin film, or centrifugal non-equilibrium distillation with thin film formation, etc.) in which the heating temperature is 180°C or less and the mass transfer during distillation is smooth, DAM is used. We discovered that DA significantly improves not only the purity but also the distillation recovery rate.
A purity of 97% or higher and a yield of 80% or higher for M were achieved.

Examples of industrial devices for molecular distillation include the WFE thin film distillation device manufactured by Shinko Powdler Co., Ltd. and the M manufactured by Nippon Car Seizo Co., Ltd.
A centrifugal molecular distillation apparatus of type S-380H or MS-1000 is sufficient.

The present invention will be specifically explained below using Examples, Comparative Examples, and Reference Examples, but these are not intended to limit the present invention.

Example 1 2-(4-acetamino-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine 376
256.0 ml of 5N-H2SO4 solution was added to the solution, the mixture was refluxed for 2 hours, and then cooled.

While cooling with ice water, a solution prepared by dissolving 105 g of NaNO2 in 275 ml of water was added dropwise with stirring over 1.5 hours. It is then stirred for 2 hours and 170 g of urea is added over about 1 hour. Next, 97 g of Glauber's salt (anhydrous) was added, heated under reflux for 2 hours, and then cooled. A 6N-NaOH solution was added dropwise to this until the pH reached 10. This was extracted with ethyl acetate, further washed with water, and then dried with sodium sulfate and filtered to remove the sodium sulfate.
Ethyl acetate is removed under reduced pressure to obtain the desired DAM2.
95.0 g (high performance liquid chromatography analysis (hereinafter abbreviated as HPLC) purity 92%, yield 92%) was obtained.

32 g of the DAM obtained above was heated using a 2-03 experimental thin film distillation apparatus (manufactured by Shinko Powdler Co., Ltd.) at a vacuum level of 0.3 to 0.4 mmHg and a heating temperature of 160° to 19°C.
30.08 g of DAM distilled at 0°C (HPLC purity 98.2
%, recovery rate 94%).

Example 2 2-(4-acetamino-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine 77.
04g was stirred and dissolved in a solution of 360ml of water and 210ml of concentrated hydrochloric acid, and the mixture was refluxed at 100°C for 2 hours. Then, 220ml of 6N-NaOH was added dropwise under cooling with ice water to adjust the pH to 12.
The extract was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered to remove ethyl acetate, and ethyl acetate was removed under reduced pressure to obtain 65.04 g of ATE (HPLC purity 98%, yield 99.5%). .

65.04 g of ATE obtained above was stirred and dissolved in a solution of 72 ml of water and 49.5 ml of concentrated sulfuric acid, and NaN
A solution of 13.5 g of O2 and 75 ml of water is added dropwise. After that, stir for 30 minutes, add 3g of anhydrous sodium sulfate, and heat at 100℃ for 2 hours.
Reflux for an hour. Thereafter, a 6N-NaOH solution was added dropwise to the solution under ice water cooling until the pH reached 10. This was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered off the sodium sulfate, and the ethyl acetate was removed under reduced pressure to obtain the desired DAM62.
72 g (HPLC purity 93%, yield 96%) was obtained.

2-03 type thin film distillation apparatus (described above)
vacuum degree 0.3~0.4mmHg, heating temperature 160°~
57.0 g of DAM distilled at 190°C (HPLC purity 98.
5%, recovery rate 95%).

Comparative Example 1 2-(4-acetamino-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine 37.
Add and dissolve 256 ml of 5N-H2SO4 solution to 6 g,
Hereinafter, the same reaction operation was carried out using one-tenth the amount of Example 1, and DA
M29.17g (HPLC purity 92% as described in text, yield 9
1%).

The entire amount was put into a distillation flask and distilled at a vacuum degree of 3 mmHg and a heating temperature of 170° to 190°C. Distillate DAM showed a tendency to clog in the distillate outlet and condenser, indicating difficulty in distillation. Distilled DAM was 22.46 g (HPLC purity 98.3%, recovery rate 77%).

That is, if the degree of vacuum is relatively high or vacuum distillation is used, the recovery rate is low and the process is unstable.

Reference Example 1 DAM 20g (0.084mol, HPLC purity 98.
3%) was added with 12.6 g (0.123 mol) of acetic anhydride, stirred and dissolved, and heated and stirred at 95° C. for 2 hours.

The above reaction solution was heated in an oil bath at 120°C and a reduced pressure of 11 mmHg for 30 minutes.
Concentrate for minutes to 1 hour. After concentration, add 165 ml of 1,1,1-trichloroethane to dissolve and cool to around 0°C.
While stirring, add 4.18g (0.115mol) of hydrogen chloride gas.
1) is introduced, and excess hydrogen chloride gas is expelled by heating while introducing nitrogen gas. After removing the hydrogen chloride gas, it was left to cool, and then further cooled on ice to precipitate crystals, which were collected by filtration and 2-
(4-acetoxy-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine hydrochloride (m.
p. 211-212℃) 25.3g (HPLC purity 99
．． 3%, yield 95.4%).

The elemental analysis values of this hydrochloride were as follows.

Calculated values as C15H26NO3Cl: C%60.84%, H%8.30%, N%4.
43% actual measured value 〃60.75%, 〃8.25%, 〃
4.40%, that is, it shows that if high purity DAM is used, a useful pharmaceutical (moxisilite hydrochloride) can be obtained in high yield and high purity.

Patent applicant: Kojin Co., Ltd.

Claims (1)

[Claims] 2-(4-acetamino-2-isopropyl-) having formula (1)
After hydrolyzing the acetyl group from 5-methylphenoxy)-N,N-dimethylethylamine, diazotization with nitrous acid yields 2-(4-hydroxy-2-isopropyl-5 having the formula (2))
-Methylphenoxy)-N,N-dimethylethylamine is produced by vacuum distillation at a temperature of 1 mmHg or less and a heating temperature of 180°C or less in the final step. ) with 2-(
A method for producing 4-hydroxy-2-isopropyl-5-methylphenoxy)-N,N-dimethylethylamine.