SYNTHESIS OF 1-(3-ISOBUTOXY-2-(PHENYLBENZYL)-AMINO)-PROPYL-PYRROLIDINO HYDROCHLORIDE

Abstract: A process for the synthesis of 1-(3-isobutoxy-2-(phenylbenzyl)-amino)-propyl-pyrrolidino hydrochloride by preparation of 1-(3-isobutoxy-2-chloro) propyl pyrrolidine followed by condensation thereof with N-benzylaniline in the presence of an equimolecular amount of sodium hydride condensing agent.

Description: SYNTHESIS OF 1-(3-ISOBUTOXY-2-(PHENYLBENZYL) AMIN θ }-PROPYL-PYRROLIDINO HYDROCHLORIDE This invention relates to the preparation of ethers of formula: in which A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, R is a straight or branched chain lower alk l group or an aralkyl group, Ar is an aromatic group and Ar is an aromatic or heterocyclic group, and addition salts thereof with pharmacologically acceptable acids. When Ar and Ar are both aromatic groups, they may be the same or different. Ar and Ar may both be monocyclic aromatic groups and Ar may be a hetero- monocyclic group which may contain a nuclear nitrogen atom with or without an additional nuclear hetero atom. The ethers prepared in accordance with the pre¬ sent invention have found utility in the treatment of various cardiovascular conditions. Earlier United States Patents, i.e., U.S. 3,962,238 and Re. 30,577, disclose the preparation of ethers of n-propanoldiamine such as g-[ (2-me h lpropoxy) methyl]-N-phenyl-N- (phenylmethyl)-1-pyrrolidineethanamine commonly called bepridil, wherein amino alcohols having the general formula: OMPI in which R is a straight or branched chain lower alkyl group or an aralkyl group and A is a tertiary aliphatic, cycloaliphatic or heterocyclic amino group, are reacted with thionyl chloride dissolved in a suitable solvent such as chloroform in order to obtain the corresponding chloro compounds having the general formula: in which R and A are as defined above. The compounds thus obtained are then condensed with amines having the general formula: Ar-CH 2 -N-AR 1 I H wherein Ar is an aromatic group and Ar is an aromatic or heterocyclic group, which have previously been convert¬ ed to their sodium derivatives by reaction with sodium amide, to obtain the ethers of n-propanoldiamine. The multi-step synthesis described in the prior art referred to above produces an overall yield of approximately 20%. I have now found a more efficient and economical process for the manufacture of ethers of n-propanoldiamine which produces an overall yield of approximately 50%. Essentially the present invention eliminates several steps of the prior art process thereby avoiding the handling and isolation of intermediates as well as a distillation step. In addition, the condensing step is carried out utilizing sodium hydride dispersed in mineral oil, a much safer and more reactive condensing agent. Further, the use of sodium hydride as a con¬ densing agent in lieu of sodium amide of the prior art eliminates the occurance of a significant number of reaction by-products, i.e., ammonia. Moreover, the final product is isolated as a solid in accordance with the precedures of the present invention thereby doing away with the difficul and expensive distillation pro- cess of the prior art which yields the final product as a viscous liquid. In accordance with the present invention ethers of n-propanoldiamine are prepared by first reacting at elevated temperatures lower alkyl alcohols, i.e., 3 to 6 carbon atoms, with epichlorohydrin in the presence of a Lewis Acid. The resulting product is reacted with pyrrolidine and the mixture rendered alkaline, upon com¬ pletion of the reaction, the mixture is extracted with a petroleum solvent and combined with thionyl chloride and the reaction mixture heated to reflux. The reaction mix¬ ture is decomposed by the addition of water, rendered alkaline and the oil layer and petroleum solvent extract of the aqueous layer are recovered and concentrated. The concentrate is condensed with sodium hydride in the pre- sence of N-benzylaniline. The reaction mixture is cooled and the desired n-propanoldiamine ether as the hydro- chloride is recovered. As an example of the preferred embodiment of the present, invention following is the synthesis of bepridil: 275 g. Of isobutanol (3.676 moles) is placed in a one liter three neck round bottom flask equipped with a stirrer and condenser. 225 g. Of epichlorohydrin (2.45 moles) and 5 g. of powdered anhydrous zinc chloride are added with stirring. The reaction mixture is heated on a steam bath at 95°C. for approximately twenty-four hours. The mixture is cooled to 40°C. and 213 g. of pyrrolidine (3.0 moles) is added. Cooling is continued to approximately 15°C. and 196 g. (2.45 moles) of a 50% sodium hydroxide solution diluted with 250 ml. of water is dripped into the mixture. After all the alkali has been added, remove the cooling bath and continue stirring. The temperature slowly rises to 70-80°C. Stirring is continued for one- half hour and then the mixture is heated to 95°C. on a steam bath for half an hour. 250 ml. Of water is added and the mixture let cool to room temperature. The mix¬ ture is extracted with 300 ml. of toluene and the extract is washed with 250 ml. of water. The extract is concen¬ trated and distilled to obtain 364 g. of product B .P . 146-9 °C . § 25 mm. n 27 d = 1.4565 having the following structure: 166 g. (1.39 moles) Of thionyl chloride are dissolved in 110 ml. of toluene in a 1 liter three neck round bottom flask equipped with a dropping funnel, thermometer, stirrer and condenser. A solution of 166 gm. of Compound I dissolved in 110 ml. of toluene is dripped in. The temperature rises to 90°C. during the addition and the thionyl chloride refluxes. Reflux is continued for two hours after addition is completed and then the solution is concentrated in vacuo on a steam bath. The concentrate is decomposed by the careful addition of 200 ml. of water and made alkaline with 200 g. of 50% NaOH in 400 ml. of water. The oily layer is separated and the aqueous layer is extracted with 200 ml. of toluene. The oil layer and extract are combined and washed with 200 ml. of water. The product is con¬ centrated in vacuo on a steam bath and may be used directly. However, distillation of the chloroamine can be done but with much foaming. The bpiling point of the 20 product is 136-139°C. @ 17 mm. n * - *u d = 1.4606 and the yield is 85%. The structure of the compound is: Compound II 15 g. Of 50% sodium hydride dispersed in mineral oil (0.21 moles) is placed in a 500 ml. round bottom flask equipped with a dropping funnel, stirrer and condenser whose exit port is connected to a bubbler containing toluene. 150 ml. Of toluene is added to the sodium hydride, and stirred while heating to 70°C. A solution of 50 g. of Compound II (0.23 moles) and 33 g. of N-benzylaniline (0.21 moles), dissolved in 150 ml. of 5 toluene is dripped in and the temperature is allowed to rise to reflux the toluene. A steady stream of hydrogen bubbles will appear. The addition is adjusted to pro¬ duce an even flow of hydrogen. After all the material is added heating at reflux with stirring is continued for 10 two hours. The reaction mixture is cooled to 25°C. and decomposed slowly with 40 ml. of methanol and then 200 ml. of water. The toluene is concentrated in vacuo and 150 ml. of 10% hydrochloric acid is added and stirring continued for 10 minutes. The reaction is diluted with 15 400 ml. of water, cooled to room temperature, and seeded. The product is filtered and washed with water and a small amount of cold toluene to remove oil. Air dry overnight and then in vacuo at 60°C. 70 g. Of Compound III M.P. 88-90°C. having the following structure is Compound III The foregoing Compound III is useful in the form of its addition salts with pharmaceutically accept¬ able organic and inorganic salts such as hydrochloric acid 5 and fumaric acid, which can be prepared by conventional and well known methods. While the preferred embodiment of the present in¬ vention has beeif'described in connection with the prepara¬ tion of bepridil it will be readily apparent to those skill- 0 ed in the art that the method described is applicable to a series of n-propanoldiamine ethers by substituting the appropriate intermediates containing the required reactive sites.

Claims: C L A I M S 1. A process for preparing 0- [ (2-methylpropoxy) methyl]-N-phenyl-N-(phenylmethyl)-1-pyrrolidineethanamine hydrochloride hydrate comprising: (a) reacting isobutanol with epichlorohydrin in the presence of a Lewis Acid; (b) combining the product of step (a) with pyrrolidine and a base, extracting the reaction mixture with a petroleum solvent; (σ) combining the extractant of step (b) with thionyl chloride and heating the mixture to reflux; (d) decomposing the reaction mixture of step (c) with water, rendering the decomposed mixture alkaline and recovering and combining the oil layer and petroleum solvent extract of the aqueous layer and concentrating; (e) condensing the concentrate of step (d) with n-benzylaniline and recovering the desired n- propanoldiamine ether as its hydrochloride salt. 2. A process according to claim 1, wherein said Lewis Acid is anhydrous zinc chloride. 3. A method according to claim 1, wherein said base is sodium hydroxide. 4. A method according to claim 1, wherein said con¬ densing step is carried out utilizing sodium hydride dis¬ persed in mineral oil as a condensing agent.

Inventors: STIEFEL FRANK J, STIEFEL, FRANK, J.
Applicants: CARTER WALLACE, CARTER-WALLACE, INC.
Application year: 1982
Main classification: C07D207
IPC codes: A61K31, A61P9, C07D295