PL155849B1 - Method of obtaining 1-(p-chlorophenyl)-2-methyl-2-aminopropane salts in particular hydrochloride - Google Patents

Description

REPUBLIC PATENT DESCRIPTION 155 849 POLAND Additional Patent to Patent No. ---- Int. Cl. ⁵ C07C 211/29 Reported: 83 04 24 / P. 279109 / Precedence -— OFFICE PATENT Application announced: 89 12 ll Hua RP Patent description published: 1992 07 31

Creators of the invention: Jacek Jankowski, Eugeniusz Kaczur-Kaczyński, Kazimierz Witkowski, Jordan Zjawiony

Authorized by the patent: Research and Production Center

Of the Lodz University of Technology "ICHE / * Sp.z o.o., Łódź / Poland /

METHOD OF OBTAINING SALT l-pp ~ coro ro f βη _Υ 1ο / «- 2τΜΕΓϊΊ_Ο-2-ΑΜΙΡ0Ρ0ΡΡΑΝυ. ESPECIALLY l-Pp-chrcrophenylc / -ETHYETHYL0-2 // NMIPRPR0-ANU CHLORIDE

The subject of the invention is a method for the preparation of 1- (pcchlorophenyl) and 2 -methylamine aminopropane salts, in particular chloro-K wodor hydride 1- (ρ ^ΙΙ ^nyl) -2-methyl-2-methylphthylpropane, internationally known as Chloroentermine, used in the treatment of obesity. . ChlmOentermine suppresses appetite by selectively acting on the hypothalamus starvation center and stimulates the transformation of mtenia ..

There is known from the French patent specification No. 1,196,132, / 1299, a method for the preparation of 1-pochthylorophenyl / om -methyl-1-mmioppropane hydrochloride, consisting in the reaction of p-chlorobenzyl chloride with magnesium in anhydrous ethylene ether, and the product of this reaction treated with anhydrous acetone and then a mixture of acetic acid, a cyanide soda and concentrated ^k Vasu starting at 70 ° C, and the resulting (Środula ^ ^p by neutralization with sodium carbonate, is heated in concentrated hydrochloric acid. the process uses the expensive and hard available starting material, ie p-chlorobenzyl chloride, flammable and explosive ethylene ether and difficult to obtain anhydrous acetone. It is difficult to carry out this process, especially on an industrial scale, is the use of a mixture containing the toxic, releasing hydrogen cyanide, sodium cyanide.

Hungarian patents Nos. 155 783, 1 719 and 1 769 disclose a method of trimming 1- (O-chlorophenyl) -2-eethyl-2-mmio-propane hydrochloride, which consists in the reactivity of 3-jhloΓO-2-methylpropane πu with bromide - chlorophyll-olgiezlcw - in anhydrous ethyl ether at the boiling point of the solvent, and the product of this reaction is treated with potassium cyanide or acetonitrile in a mixture of acetic acid and sulfuric acid, and the product thus obtained is heated with sodium hydroxide. The disadvantage of this method is the use of anhydrous, flammable and explosive ethyl ether and the toxic potassium cyanide and acetonntril.

155 849

155 849

The method for the preparation of 1- (p-chlorophenyl) -2-methyl-2-8minopropane salt, especially 1- (p-chlorophenyl) -y-1-yl-2-yιiiropropane hydrochloride, according to the invention is characterized by the fact that benzyl chloride is subject to a netting reaction mixture of sulfuric and nitric acid at a temperature from - ⁵ to 10 ⁰ ° C and the product of n ^{and the (i?} 0oowan and treated with 2-nitro ^{p op in} an environment alkohotowego alkołiolanu solution of sodium at 30 - 100 ° ^C, and then reduction with iron in an aqueous solution of ethyl alcohol in the presence of a mineral acid, and the post-reaction mixture, after separation of iron sediment and its oxides from it, acidification and distillation of excess ethyl alcohol ₍ sodium nitrite solution is subjected to diazotization in water at a temperature from - ⁵ to * 1 ^{5 O} C, and a received ⁿ diazonium salt solution was heated in a solution of cupric chloride in concentrated hydrochloric acid at 30 - ⁹⁰ ° C and rc ^h Bovine ZLN ^{d and} u, and analyzing, extra ^ them to rozpuszczalniktom organi After which, the separated organic layer is subjected to vacuum distillation, and the 1- (p-chlorolnnyl) -2-l-ethyl-2-methyl-polyopoietic rthimanes are converted in a known manner to -Hlorohydride 1- / p-chloro-chlorinyl / -m-l-ethyl-2-methylpropane.

The process according to the invention eliminates the use of toxic and flammable reagents, which is of particular importance for the implementation of this process. this method under industrial conditions. In the process according to the invention, commercially available and cheap starting materials and nuts are used.

The method according to the invention is illustrated by the following example.

Example. In a four-necked flask with a capacity of 6 1 equipped with a stirrer, these ^^ EER and dropping funnel uylsiczoio 1375 ml of concentrated siadowego and 1375 ml of concentrated nitric acid and after cooling the flask zawaarości to 0 ° C ^with stirring was added dropwise 490 mL of benzyl at a rate such as to maintain the temperature of the olution in the range of 0-5 ° C. After the dropwise addition of benzyl chloride, the stirring was continued until the temperature of 15 ⁰ C, then stirred for ^p ^ fionakrjną Water ^quench poured onto ice. W'to ^± coi osati ^{y, p} and to destroy wodjj washing, recrystallized from ethanol and then added to a mixture of 184 ml of 2-iitropropaiu, yeteiolaiu 84.2 g of sodium in 1560 ml meeanolu. The reaction mixture was refluxed for 1 hour, then cooled and poured into ice water. The precipitate formed is filtered off, washed with water and reduced with 374.4 g of iron in a medium of 1870 ml of 50% aqueous ethanol in the presence of a catalyst in the form of a solution of 47 ml of concentrated hydrochloric acid in 375 ml of 50% aqueous ethanol at reflux. After the reduction was complete, the reaction mixture was cooled down, the precipitate of iron and iron was filtered off, acidified with 160 ml of concentrated hydrochloric acid and ethanol was distilled off. The remaining aqueous solution was cooled to 5 ° C and diazotized with a solution of 78 g of sodium nitrite in 95 ml of water. Diazotization ^/ oowediril reaction ^{at 5} - 10 ° C until a stable color reaction is obtained on the sperm iodine paper. The resulting solution was poured diazozwiązku powooi to a solution of 106.4 g of copper in 515 ml of concentrated Itwasu nlgr tr ^l, oc ^h łodzone ^g to temperatures of 3 ° C and ^p for the solutions are mixed temperature mieszanir ^/ rdwyżsirnr powoH to 60 ⁰ C, then for ^p it was opened until nitrogen evolution ceased. The solution was then cooled to room temperature, quenched with water, alcohol, and quenched with 1500 ml of ethyl acetate. The separated organic layer was washed with water, and from / Arro of the ethyl acetate, the residue was subjected to distillation (vacuum ,;] collecting toakcję in jzedziato temperature 1 ^{32 -} 1 ³⁶ ° C ^p y ^y Cl ^S iililu 22.7 26.6 hPa.

92.3 g of 1β-β-chtolOlinyl (-2-methyl-2-yropyropyne) are obtained, which are dissolved in 1600 ml of ethyl acetate. Through the solution prepared in this way, hydrogen chloride gas is obtained until a stable color is obtained on Congo paper. The 1- (p-chloroennlo (2-methyl-2-ymmol) chlorohydride precipitated was filtered, washed with ethyl acetate and dried. Received

106.4 g of 1 - / - cchlololinyl / -2-yl-ethyl-a-ymirporppan hydrochloride, m.p.

233.5 - 234 ° C.

155 849

Claims (1)

Patent claim Method for the preparation of 1- (p-chtotophenyl) -2-methyl-2-aminopropane salt, especially 1-pp hydrochloride, chlorophenyl / -2-methyl-2-aminopropane, characterized in that benzyl chloride is subjected to eitoouania reaction meszaeinę siakkowego acid and nitric acid at a temperature of -5 to 10 ° ^C, the product nitoowaeia treated with 2-nlonppnopanu ^acid in an alcoholic alkoxy-an ^ l sodium at ³⁰ - 1 ° C ° C, and then ^re-d AHS and iron in an aqueous solution of ethyol alcohol in the presence of a mineral acid, and the post-reaction mixture, after separating the iron sludge and its oxides from it, acidifying and distilling off the excess ethanol, is subjected to diazotization with an aqueous sodium nitrite solution ^{at a} temperature of ^d - ⁵ to + -15 ^{0 °,} and the received ^y ^ azoniowej salt solution is heated to ^Un t ^WNr of Tarku ^l ^ I ^ ^ ziawe in concentrated hydrochloric ^k mustache at 30 - ⁹ 0 ° C and ^p o n ^c łndzeniu ralkalroowaeiu and extracted with an organic rnrpuszczalniklem immiscible with water, then take off The resulting organic layer is subjected to vacuum distillation and the 1- (p-cClnrofβnyl) -2-amino-2-aminopropane hydrochloride is converted into 1- (p-cClnrofβnyl) -2-amino-2-aminopropane hydrochloride in a known manner.