PL158223B1 - Method for mnufacturing 4-(1-methyl-4-pirperidilidene)-9,10-dihydro--benso(4,5) cyclohepta (1,2) thiophen-10-on - Google Patents

Abstract

1. A method of producing 4-/1- methyl-4- piperidylidene/-9,10-dihydro-4 H-benzo [4,5] cyclohepta [1,2] thiophene-10-on with the formula presented in 1, characterized in that diketone with the formula presented in 3 is reacted with Grignard compound with the formula presented in 4, which is used in the amount of at least 2 moles per 1 mole of diketone with the formula presented in 3.2. A method of producing 4-/1- methyl-4- piperidylidene/-9,10-dihydro-4 H-benzo [4,5] cyclohepta [1,2] thiophene-10-on with the formula presented in 1, characterized in that diketone with the formula presented in 3 is respectively treated with Grignard compound with the formula presented in 6, where R<2> stands for the lower alkyl group and X stands for halogen atom, used in the amount not larger than 1 mole per 1 mole of diketone with the formula presented in 3, and then with Grignard compound with the formula presented in 4, used in the amount not smaller than 1 mole per 1 mole of diketone with the formula presented in 3.<IMAGE>

Description

© PATENT DESCRIPTION® EN © 158223 © BI

REPUBLIC

POLAND

^Filing number: 279865

Patent Office of the Republic of Poland ( ³³ ) Date of filing: 09.06. ¹⁹⁸⁹ © IntCl ⁵ :

C07D 409/04

CZIiTElBlA0 Gó Lim

Method for the preparation of 4- (1-methyl-4-piperidylidene) -9.10-dihydro-4H-benzo [4.5] cyclohepta [1,2] thiophen-10-one

Application announced:

10/12/1990 BUP 25/90

The grant of the patent was announced on: August 31, 1992, WUP 08/92

The holder of the patent:

Warsaw Pharmaceutical Works "Polfa", Warsaw, PL

Warsaw University of Technology, Warsaw, PL

Inventors:

Andrzej Jończyk, Warsaw, PL Zbigniew Wróbel, Warsaw, PL Michał Fedoryński, Warsaw, PL Irena Kmiotek-Skarżyriska, Warsaw, PL Wiesława Kiełbasińska, Milanówek, PL Marek Gnyś, Warsaw, PL Andrzej Tyrał, Warsaw, PL

PL 158223 BI

1. A process for the preparation of 4- (1-methyl-4-piperidylidene) -9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2] thiophen-10-one of formula 1, characterized in that the diketone 3 is reacted with a Grignard compound of formula 4 used in an amount of at least 2 moles per mole of the diketone of formula 3.

2. A process for the preparation of 4- (1-methyl-4-piperidylidene) -9,10-dihydro-4H-benzo [4,5] cyclohepta [1,2] thiophen-10-one of formula 1, characterized in that the diketone of formula 3 is treated sequentially with a Grignard compound of formula 6, where R, is lower alkyl, X is halogen, used in an amount not greater than 1 mole per 1 mole of the diketone of formula

3, followed by a Grignard compound of formula

4, used in an amount not less than 1 mole per mole of the diketone of formula 3.

/\.M ₉ CL

WZdR 4 r ² h ₉ x

UZdA and

METHOD OF MAKING 4- (1-METHYL-4-PIPERIDYLIDENO) -9.10-DIHYDRO-4H-BENZO / 4.5 / CYCLHEPTA [1.2] THIOPHEN-IOoON

Claims (2)

Patent claims 1. Process for the preparation of 4- (1-methylt-4-piperidylident) -9.10-di-hydro-4H-benzth [4.5 J cyclohepta [1,2] ttophen-10-one according to formula 1, characterized by the diketone t of the formula 3 p is reacted with the Grignerd compound t of the formula 4, used in an amount of ct of the least 2 moles per 1 mole of diketone t Formula 3. 2. Preparation method of 4- (1-methylt-4-piperidylident) -9,10-di-hydro-4H-benzt / 4.57 cyclohepta [1,2] thioeen-10-one of formula 1, characterized in that diketone t formula. 2 3 is treated sequentially with a Gngnard compound t of formula 6, where R is a lower alkite group, X is a halogen atom, used in an amount not greater than 1 mole per 1 mole of diketone t of formula 3, and then a Grignard compound t of formula 4, used in an amount not less than 1 mole per 1 mole of diketone t formula 3. *** The title compound T, Formula I, is used in the form of a salt with fumaric acid pdd by the name Zaditen, a modern and effective drug in the chronic primary treatment of asthma. Known sptstby preparation of this compound consists in reacting ketones t Formula 2 wherein ^R1 tznacza ^g u ^p e ^ alkiloairdtow ^ halogen lu ^bg ru ^u re alkmsylową, ^k t ^about Re s ^N momyrni diketone t formula 3 wherein one of the groups karbtnylowych is secured ^that the above-mentioned three ptdany sptsób with idc7yinikfem Grignard of formula 4 obtained in this connection sptsób of formula 5 ^g day ^r1 is wżej podaif important operations are carried out: i.em acid ^of the mineral tytutowy compound of formula 1. In the known methods for preparing a compound of formula 1 is used a compound of formula 2, kluczowm step of the synthesis uses a large excess of the second Grignard reagent background Formula 4 and the carrying out of the reaction product p Formula 5 in the final product of formula ¹ requires dehydration and removal ^g roup protecting ^r1 . In the method according to the invention, all these disadvantages and difficulties are eliminated. According to the invention, 4- (methyl-4-piperidylidene) -9.10-dihydro-4H-benzt / 4.57 cyclohepta [1,2] ttoeen-10-one of formula 1 is prepared by reacting a diketone of formula 3 with the compound The grignard of formula 4 used in an amount of at least 2 moles per mole of the diketone of formula 3. Alternatively, the product of formula 1 is prepared by treating the diketone of formula 2 3 successively with a Grignard compound of formula 6, where R is a lower alkyl group, X is a halogen atom, in an amount not greater than 1 mole per 1 mole of diketone t of formula 3, and then a Grignard compound of formula 4, used for no more than than 1 mole of the diketone of formula 3. In the process own preferences ^g wnalazku no potrzet> ^y removal ^g ru ^dust protective ^R1 in the intermediate of formula 5, and using the piewwszym reaction step cheap and readily available Grignard reagents of formula 6 wherein R and X are as defined above, saves expensive Grignard reagent of formula 4. According to the invention, compound t of formula 1 is obtained in high yields with a high degree of purity. The following examples illustrate the method of the invention without limiting its scope. EXAMPLE Grignard compound prepared from a 26,7g (0.20 m) of l-methyl - chltropiperydyny, 5.28 g (0.22 species.), Magnesium turnings ^ch "to the kryształku iodine in 30 ml tetrahydrofuran. To a solution of the Grignard reagent was added ^ mL of tetrahydrofuran, cooled dt 0 ° C and ^p for ^the mixing ^{and d} of ^d await portionwise 3.7 g ^{1 (0,} 0 <> m) 10-oxo-9,10-dihyiro-4H-bfnzo / -, 5] cyclohepta [1,2-b] thiophen-4-one, keeping temperature 158 223 0 ° C (addition Tiwa 30-40. After the addition the reaction temperature was raised reakcjynej to 20-25 ° ^C and stirring was continued at this temperature for ⁴ -5 hours. The reaction was poured into a solution of 20 g ammonium chloride in 400 ml of water and extracted with methylene chloride . The organic extracts were combined, washed with water, dried with magnesium sulfate, and the solvent was evaporated. The residue was taken up in 200 ml of 3N hydrochloric acid, heated to reflux for 3 hours, cooled, basified with 10% aqueous sodium hydroxide solution and extracted with methylene chloride. The organic extracts were dried with magnesium sulfate, the solvent was evaporated, and the crude product was crystallized from ethyl acetate to give 14.9 g (80% yield) of 4- (1-imeyl-4-piperidylidene) -9.10-dihydro-4H-benzo / 4.5 / cyclohepta f 1.2 / tg / een-10-one, mp 150-153 ° C. With the product of the ottoman and fumaric acid fumarate, m.p. 186-199 ° C rozktadem (tt own preferences ^g liiezatury is ¹⁸⁴ ~ ²⁰⁰ ° ^C dec). Example II. From 3.38 g (0.031 m) of ethyl bromide and 0.79 g (0.033 grade) of magnesium turnings in 10 ml of tetaahydrofuran, a solution was prepared containing 0.0295 m of Grignard compound. Separately, a solution of the Grignard compound was prepared from 6.0 g (0.045) 1-methyl-4-chloropiperidine, 1.1 g (0.046 grade) magnesium turnings and iodine crystal in 20 ml of tetrahydrofuran. While stirring, 6.84 g (0.03 m) of 10-poxo-9,10-dihyZro-4H-benio / 4.5 / cyclohepta-b / to / een4-one in 20 ml of tetrahydrofuran was added dropwise at a temperature of p5 ° - 0 ° C roztwiir reagent Gri ^g nar ^d and certainly wipe the iany ^ ^b Romek acetate. ^{P d} odaniu, stirring was continued for 1 hour at this temperature and then at a temperature of about 0 ° C was added ^p owooi roztwcir of factor Grięrna ^d ^ and, ^ Otry any of l-methyl ^ ^ -chlorp erydyny. Next, ^ę then stirring was continued at ² 0- ²⁵ ° C for about ^{4 g} odziny, ^th whole was poured into aqueous ammonium chloride solution and chlorine ekstahhowano ^ em methylene chloride. The organic extracts were washed with water, dried with magnesium sulfate and the solvent was evaporated. The residue was taken up in 3N hydrochloric acid, heated to reflux for 3 hours, cooled, and basified with 10% sodium hydroxide solution and extracted with methylene chloride. The combined organic extracts were dried, the solvent was evaporated and the residue was crystallized from ethyl acetate. There was obtained 6.6 g (71% yield) of 4- (1-methyl- ^{4β-piperidylidene) -9.} IO-dithiydro-1H-benzo (4.5) -cyclohexf2 / t-10-one with mp. ¹⁵ 2-1.5 ^4θ Ο (literature mp ¹ 51 ^ ¹⁵ 3 ° C).