SI8610655A8 - Process for preparation of 1-phenyl-1-diethylaminocarbonyl-2- aminomethyl-cyclopropanhydrochloride - Google Patents

Description

PROCEDURE FOR OBTAINING 1-PHENYL 1-DIETHYLAMINOCARBONYL 2-AMINOMETHYL

CYCLOPROPANHLORHYDRATE (Z)

Technical field

The invention is in the field of organic synthesis. In the narrower sense, it relates to the preparation of cycloaliphatic carboxylic acid amide derivatives, as well as to medical preparations in which this acid constitutes the active substance.

IPC: C 07 C 103/737; A 61 K 31/16

Technical problem

A technical problem to be solved by the invention is to find a new process for the preparation of 1-phenyl 1-diethylaminocarbonyl 2-aminomethyl cyclopropane hydrochloride (Z) known under the general name MIDALCIPRAN and corresponding to formula I

CD i has the effect of an antidepressant.

Unlike the known solutions, the process according to the invention is carried out without side reactions, with a smaller number of steps and without the need for additional purification so that the desired product is obtained in a higher yield and in a cost-effective manner.

.The state of the art

In the prior art illustrated by FR-A-2.508.035, this compound is prepared by a 5-step process starting from 1-phenyl 2-oxo 3-oxabicyclo (3: 1: 0) hexane, and this last derivative is described in FR-A-2,302,994 ·.

According to this earlier technique, the limiting step of the preparation process is the reaction step of 1-phenyl 2-aminomethylcyclopropane chloride hydrochloride with diethylamine. In the course of this reaction, a secondary reaction occurs, namely intramolecular cyclization, which leads to the formation of lactams: l-phenyl 2-oxo 3-azabicyclo (1: 1: 0) hexane

SECONDARY PARASITIC RBAKOIJB STAFF

> H

Slimming the elbow requires an additional yield of MIDALCIPRAN.

A description with an example embodiment

The object of the present invention is novel to obtain MIDALCIPRAN in 3 steps, characterized in that, in the first stage, a purification occurs which is a serious industrial synthesis process. The process is an amine function in a protected form, thus allowing the activation of the carboxyl function in the form of condensation to diethylamine without creating a secondary product.

The process of the invention can be shown schematically as follows;

- .....:

reaction shbu

The first stage

Second stage

/ v

N

(XII)

Gossip Stage (IV)

1) R-NH

2) HCI

® © NH ^ Cl

O = C (IV)

Et

Et (I)

The first step in the process consists in the condensation of lactones of formula II with salts of phthalimide, preferably potassium phthalimidone, in an organic solvent, preferably selected from the group consisting of dimethylformamide, dimethylacetamide and methylpyrrolidone. The reaction temperature is preferably between 150 ° and 200 ° C and the reaction time varied from 5 to 15 hours.

During the second reaction step, the acid of formula III is treated with an acid chloride, in particular thionyl chloride, used primarily in stoichiometric excess. It is advantageous for the reaction to be carried out by heating with τ · ° ωuxation for a period between 0.5 and 2 hours. After removal of the thionyl chloride, the resulting acid chloride is condensed to diethylamine in an organic solvent, preferably selected from the group consisting of methylene chloride, chloroform, tetrahydrofuran and dioxane. It is good that the temperature at this amidification is between 5 and 3θ ° 0 ·

During the third reaction step, the function of the primary amine is released by treating the amide of formula IV with an alkylamine or hydroxyalkylamine of low molecular weight, in particular ethanolamine, used alone or in the presence of a solvent, such as water or low molecular weight alcohol (methanol, ethanol, propanol, isopropanol). This reaction is performed at a temperature between the ambient temperature and the boiling point of the reaction medium.

After extraction of the reaction medium ^with a solvent such as methylene chloride, chloroform or ethyl acetate, the residual oil obtained after removal of the solvent is chlorinated ^with a, for example, an ethanolic hydrochloric acid solution, and the compound of formula I is crystallized by addition of ether, isopropyl ether or methyl.

MODE OF WORK

Step 1 1-Phenyl 2-f thalimidomethylcyclopropane-1-carboxylic acid (compound III)

Suspension of 52.56 g (0.3 mol) of 1-phenyl 2-oxo 3-oxabicyclo (3 * 1: 0) hexane (compound II) and 61 g (0.33 mol) of potassium

X phthalimide in 270 cm of dimethylformamide was maintained for 12 hours at 150 ° C with stirring.

The solution obtained after returning to ambient temperature is poured into 1000 cnr 'of water. After extraction with ethyl acetate, the aqueous phase is acidified with excess acetic acid and then frozen. The crystallizing acid was washed, washed with water and crystallized in ethanol to give 62.6 g of compound III (yield: 65%).

N

COOH

II —1—.,. 1

Melting point: 186 °

Formula: 521.22

CGM (silica - GF 254 Merck)

Rf: 0.6 (chloroform 85 - methanol 15)

IR: (KBr) C = 0: 1775, 1710 and 1650 cm ^-1

RMN (CDCl3) ppm (TMS): 1.1 to 2 (m, 5H, cyclopropane);

5.9 (d, 2H, GH ₂ N); 7.15 (s, 5H, aromatic); 7.75 (s, 4H, aromatic)

Step 2 l-Phenyl l-diethylaminocarbonyl 2-phthalimidomethylcyclopropane (Z) (compound IV) x

In 50 cm thionyl chloride, while stirring at ambient temperature, 16.2 g (0.05 mol) of 1-phenyl 2-phthalimidomethylcyclopropane carboxylic acid (compound III) was added in portions. After two hours at ambient temperature, a solution is obtained.

The solution was then refluxed for 2 hours. After removal of the excess thionyl chloride, the crude acid chloride was dissolved

X in 5θ cm of methylene chloride is introduced drop by drop while stirring in an ice bath. After stirring overnight at ambient temperature, the resulting solution was washed with water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Addition of isopropyl ether afforded 15 "4 g of compound IV (yield: 82 /").

--- 8-4: ......

Oh

Oh

Melting point: 131 °

Formula θ23 ^ 24 ^ 2θ3 ^: 376.46

G CM (GF 234 Merck silica)

Rf: 0.66 (chloroform 95 - methanol 5)

IR (KBr) Sl 0 = 0 1630, 10 05 and 1770 cm @ ^{-1 X} H RMN (CDCl3) J ppm (TMS): 0.65 (t, 3H, CH2); 1.15 (t, 3H, GH 4) 1.25 (m, 1H, cyclopropane); 1.5-2.5 (m, 2H, cyclopropane);

3-3.7 (m, 5H, CH ₂ N, cyclo-CH-N); 4.15 (dd, 1H, cyclo-CH-N);

7.1 (s, 5H, aromatic); 7.6 (m, 4H, aromatic).

Third stage

1- Phenyl 1-diethylaminocarbonyl 2-aminomethylcyclopropane (Z) chlorhydrate (compound I). MIDALCIPRAN

a) A suspension of 18.82 g (0.05 mol) of 1-phenyl 1-diethylaminocarbonyl 5

2- Phthalimidomethyl cyclopropane (compound IV) in 95 ^cm 40/6 aqueous methylamine was maintained under stirring for 5 hours at ambient temperature.

Dissolution occurs and the Ν, Ν-dimethylphthalimide is crystallized. The suspension was extracted 3 times with ethyl acetate. The organic phase was washed with water, dried with anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. Addition of ethanolic hydrochloric acid solution followed by ether gave 10 g of crystals of compound I (yield: 71%) ·

Cl

CONEt

Melting point: 180 °

Formula C- ^ H ^ Cl ^ O: 282.82

CCM (GF 245 Merck silica)

Rf: 0.43 (chloroform 84 - methanol 14 - NH ^ OH)

IR (KBr): J 0 = 0 1610 cm ^{1 1} H RMN (D ₂ O) / ppm (T.8.P.) 0.8 (t, 3H, CH 2); 1.15 t, 3H, CH 2);

1.5-2.1 (m, 3H, cyclopropane) j 3-3.7 (m, CH2 N); 7.3 (s, aromatic).

b) A suspension of 60 g (0.159 mol) of 1-phenyl 1-diethylamino carbonyl.

After addition of 300 ml of ice water, it is extracted 3 times with ethyl acetate.

,: -ΙΌ- The organic phase is washed with ice water, dried with anhydrous sodium sulfate, filtered and the solvent removed under reduced pressure.

Adding 3N ethanol solution of hydrochloric acid followed by ether gave 39.7 g of crystals of compound I (Prinor 88%).

Melting point: 178 - 180 ° C.

Claims (1)

A process for the preparation of 1-phenyl 1-diethylaminocarbonyl 2-aminomethyl cyclopropane hydrochloride (Z) of formula I, wherein the hexane of formula II e (I) n a z n (3: 1: 0) 1-Phenyl 2-oxo bicyclo (II) first opens the lactone ring with the help of a phthalimide salt, preferably potassium phthalimide, in an organic solvent from the group consisting of dimethylformamide, dimethylacetamide and methylpyrrolidone, at a temperature of between 150 ° and 200 ° C, and thus obtained 1-Phenyl 2-phthalimidomethyl-cyclopropane (Z) of Formula III (III) is treated in the second stage with acid chloride, preferably thionyl chloride, after reflux, after which the resulting acid chloride is amidified by condensation with diethylamine in an organic solvent of the methylene chloride group, chloroform. , tetrahydrofuran and dioxane at a temperature between 5 ° and 30 ° C, i - 12 - which is then treated in the third stage by the thus obtained 1-phenyl 1-diethylaminocarbonyl 2-phthalimidomethylcyclopropane (Z) of formula IV (IV) with a primary amine, preferably ethanolamine at a temperature between 60 ° and 100 ° C, and finally using ethanol of hydrochloric acid solution is achieved by hydrochloride to give the desired compound of formula I 11023 PROCEDURE FOR THE PREPARATION OF 1-PHENYL i-diethylaminocarbonyl 2-AMIN0METYL0IKL0PR0PANHL0RHydrate (Z)