DE1057133B - Process for the production of new, pharmacologically active 1,1-diphenyl-2-aminoalkanols - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of new pharmaceutically valuable 1,1-diphenyl-2-aminoalkanols the general formula

CH ₅ H

C ₆ H ₅ -C-

-CR ₃

OH NR ₂

their acid addition and quaternary ammonium salts, in which R ₁ and R _{2 are} hydrogen or lower alkyl groups, for example methyl and ethyl groups, and R _{3 is} an aliphatic straight-chain hydrocarbon radical containing 4 to 6 carbon atoms. In particular, 1,1-diphenyl-2-dimethylaminohexanol, 1,1-diphenyl-2-ethylaminohexanol and 1,1-diphenyl-2-aminoheptanol are produced by the process according to the invention.

The compounds which can be prepared by the process according to the invention have an exciting effect on the central nervous system Nervous system. The compounds indicated above unfold in the central nervous system stimulating properties that are unexpectedly powerful and effective.

According to the present invention, the novel 1,1-diphenyl-2-aminoalkanols described above produced in a manner known per se by adding excess phenylmagnesium halide or phenyllithium reacted with the ester of a corresponding α-amino acid or with the salt of such an ester will. The implementation proceeds according to the following equation:

Method of manufacture

newer, more pharmacologically active

1,1-Diphenyl ^ aminoalkanols

Applicant:

Mead Johnson & Company,
Evansville, Ind. (V. St. A.)

Representative: Dr.-Ing. H. Ruschke, Berlin-Friedenau,

and Dipl.-Ing. K. Grentzenberg,

Munich 27, Pienzenauerstr. 2,

Patent attorneys

Claimed priority:
V. St. v. America January 25, 1956

Kenneth N. Campbell, Evansville, Ind. (V. St. A.),
has been named as the inventor

C ₂ H ₆ OC-CH-R ₃ + 2 C ₆ H ₅ MgBr
NR ₁

C _R H _S

, H ₅ -C-

-CH-R ₅

OH NR ₁

where R ₁ , R ₂ and R _{3 have} the above meanings.

The compounds thus obtained can optionally

with organic or inorganic acids or alkyl halides be reacted in a known manner to salts of these therapeutic compounds and, if here the starting amine is a tertiary amine to produce the quaternary ammonium compounds. Of course, it must be noted that the Preparation of these salts applied acids or alkyl halides either by themselves or after reaction are not toxic with the amine.

The process according to the invention is explained in more detail by the following examples. As far as new ones Starting materials are used, will also be theirs Production described in more detail.

example 1
1,1-Diphenyl-2-dimethylaminohexanol

The starting material, the ethyl a-dimethylammopentanecarboxylate, was made from commercially available α-bromopentanecarboxylic acid by the method of Leonard and Ruyle, J. Am. Chem. Soc. 71st, 3095, (1949), prepared and boiled at 92 to 96 ° C / 12 mm Hg. A solution of 9.35 g (0.05 mol) of ethyl a-dimethylaminopentanecarboxylate in 50 ecm anhydrous ethyl ether was added dropwise with stirring and cooling added in an ice bath to a solution of 0.15 mol of phenylmagnesium bromide in ethyl ether. The reaction mixture was then about 45 minutes at

909 510/453

Stirred room temperature and then heated to moderate boiling under reflux for 2 hours. The reaction mixture was poured onto crushed ice and with Ammonium chloride treated to dissolve precipitated magnesium hydroxide. The ethereal layer was separated and the aqueous layer extracted 3 times with ethyl ether. The combined layers of ether were over dried anhydrous magnesium sulfate and the ether removed by distillation at normal pressure. Of the oily residue was then distilled under reduced pressure; 11.8 g (80% of the Theory) of the desired!, L-Diphenyl ^ -dimethylaminohexanol (Bp 160 to 166 ° C / 0.6mm Hg) as the free base obtain. The hydrochloride was hygroscopic.

Example 2
1,1-Diphenyl-2-ethylaminohexanol

The starting material, ethyl α-ethylaminopentanecarboxylate, was prepared as follows: A solution of 30 g of ct-bromopentanecarboxylic acid in 300 ecm of 70% aqueous ethylamine was left to stand for 3 days at room temperature and then concentrated by heating under vacuum in a steam bath to a solid residue. The solid residue was dissolved in 600 ecm of 5.9% strength alcoholic hydrochloric acid and the solution was refluxed for 4 hours. The solution was then concentrated in a steam bath under vacuum to a syrupy residue, which was cooled in an ice bath and covered with ethyl ether. 150 ecm of 15% strength aqueous potassium carbonate were added to the reaction mixture, the flask was shaken and the two liquid layers were allowed to separate. The ether layer was decanted and the aqueous layer was further extracted 3 times with 100 ecm of ethyl ether each time. The ether fractions were combined and washed successively with aqueous potassium carbonate solution, water and saturated aqueous sodium chloride solution. The ethereal solution was then dried over anhydrous magnesium sulfate, concentrated by evaporation in a steam bath and the resulting liquid residue was distilled to give a clear, colorless liquid which boiled at 96 ° C./15 mmHg. The refractive index of the product was nf 1.4348.

The ethyl a-ethylaminopentanecarboxylate thus prepared was reacted with phenyl magnesium bromide according to Example I above to give the desired 1,1 - Diphenyl - 2 - ethylaminohexanol, the melting point of which is 72 to 73 ° C, to be prepared. It a hydrogen chloride salt exhibiting hygroscopic properties was prepared.

Example 3
1,1-Diphenyl-2-aminoheptanol

The starting material for this compound was prepared as follows: '

The α-aminohexanecarboxylic acid with a melting point of 284 to 285 ° C. was determined by the method of J. Parrod, Bull. Soc. Chim., France (1951) pp. 420 to 423; Approx. 46, 2049 d (1952). The a-aminohexanecarboxylic acid ethyl ester, whose refractive index n'S 1.4320 and whose boiling point was 106 ° C / 15mmHg, was by the method of S. Akabori and S. Numano, Ber. 66B, 159 (1933). The ethyl α-aminohexanecarboxylate obtained was reacted with phenylmagnesium bromide according to the procedure given in Example I in order to produce a crude product which melted at 55 to 65.degree. The purified hydrogen chloride had a melting point of 223 to 224 ° C.

Arrives at the quaternary ammonium compounds of the products prepared in the preceding examples one by mixing the amines with alkyl halides

ίο implemented in a known manner. The salts of the present Amine compounds are obtained by using the amine with organic or inorganic acids usual laboratory methods. Such salts are water-soluble and have the advantage that they are quickly absorbed.

Claims (2)

Patent claims: 1. Process for the preparation of new, pharmacologically active l, l-diphenyl-2-aminoalkanols of the general formula C «H _K H C ₆ H ₅ C - R ₃ OH NR ₂ their acid addition salts and quaternary ammonium salts, in which R ₁ and R _{2 are} hydrogen or lower alkyl radicals and R _{3 is} an aliphatic straight-chain hydrocarbon radical having 4 to 6 carbon atoms, characterized in that a phenylmagnesium halide or phenyllithium is in a manner known per se with an ester of an α- Amino acid of the general formula HO-C-CH-R ₃
NR ₁ or a salt thereof, where R ₁ , R ₂ and R _{3 have} the above meanings, and the products separated off as free bases are optionally converted in a manner known per se into salts with organic or inorganic acids or into quaternary ammonium compounds with alkyl halides. 2. The method according to claim 1, 'characterized in, that a-Dimethylaminopentancarbonsäureäthylester, a-Äthylaminopentancarbonsäureäthylester or ethyl a-aminohexanecarboxylate can be used as starting materials. Considered publications:
German Patent No. 682 876;
British Patent No. 491,951.