US Patent 2728779
Esters of Substituted Aminobutanes
This invention relates to substituted 1,2-diphenylbutanes and more particularly to esters of 1,2-diphenyl-2-hydroxy-3-methyl-4-(substituted amino)-butanes and their acid addition salts.
R1 = Me, Et ; R2 = dimethylamino and pyrrolidino radicals.
These bases are generally low melting and soluble in common organic solvents and water insoluble. The acid addition salts are generally water soluble.
The new substituted diphenylbutanes and their acid salts are analgesics, and are characterized by their ability to produce analgesia without toxic side effects such as respiratory depression. The compounds can be utilized for therapeutic use by parenteral injection in aq. Solution or other pharmaceutical extending media, or they may be administered orally in pharmaceutical preparations suitable for that purpose, such as tablets, capsules, elixirs, suspensions and the like.
Alpha-methyl-beta-pyrrolidinopropiophenone is reacted with benzylmagnesium chloride to form 1,2-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane hydrochloride, which is esterified with propionic anhydride to form 1,2-diphenyl-2-propionoxy-3-methyl-4-pyrrolidinobutane hydrochloride.
The esterified substituted diphenylbutanes each possess two centers of asymmetry, and therefore occur in diastereoisomeric forms. In accordance with the usual practice, the less soluble diastereoisomer is designated as the alpha-dl-isomer, and the more soluble as the beta-dl-isomer; and that terminology is used herein to designate the substituted diphenylbutanes of this invention. The alpha-dl-isomers are the preferred compounds of the invention since they possess marked analgesic activity in contrast to the beta-dl-isomers, which are substancially inactive.
Example 1: 1,2-Diphenyl-2-Propionoxy-3-Methyl-4-Dimethylaminobutane Hydrochloride
A sol. of benzylmagnesium chloride prep’d from 63.3g (0.5mol) of benzyl chloride, 30.5g (1.25mol) of Mg metal and 750cc of ether was added dropwise with stirring to a sol. of 61.9g (0.35mol) of alpha-methyl-beta-dimethylaminopropiophenone (prep’d by the method of Burchalter et al., JACS 70, 4186, Post 1948 (not existing)), in 150ml of ether. When all of the Grignard reagent had been added, the sol. was refluxed for one hour. The reaction mix was then quenched with sat. aq. ammonium chloride. The ether sol. containing the 1,2-diphenyl-2-hydroxy-3-methyl-4-dimethylaminobutane formed in the reaction was decanted from the granular precipitate and dried over anhydrous Mg sulfate. Dry HCl gas was passed into the ether solution until precipitation was completed. The solid was removed by filtration and was recrystallized from methanol and ethyl acetate. The HCl salt had a MP: 231-232*C
A mix of 50g of the HCl salt formed above, 50g of propionic anhydride and 50cc of pyridine was refluxed for about 5 hours. The reaction mix was cooled to 50*C and ethyl ether was added to the point of incipient precipitation. The HCl salt of the 2-propionoxy ester precipitated upon cooling and was removed by filtration and washed with anhydrous ether. On recrystallization from a mix of methanol and ethyl acetate, alpha-dl-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminobutane hydrochloride melted at 170-171*C.
Example 2: 1,2-diphenyl-2-acetoxy-3-methyl-4-dimethylaminobutane hydrochloride
Rxn mix containing 5g of alpha-dl-1,2-diphenyl-2-hydroxy-3-methyl-4dimethylaminobutane hydrochloride (as in Example 1), 5ml of acetic anhydride and 25ml of pyridine was heated on a steam bath for sixteen hours. The rxn mix was cooled and ether added to the point of incipient precipitation, and the mix was cooled in the refrigerator. The resulting crystalline precipitate of alpha-2-acetoxy ester was recryst. From methanol and ethyl acetate, MP: 177-178*C
Example 3: 1,2-diphenyl-2-propionoxy-3-methyl-4-pyrrolidinobutane hydrochloride
A rxn mix of 108g pyrrolidine, 134g propiophenone, 39.4g p-formaldehyde, 200ml ethanol and 1.7ml conc. HCl (aq.) was refluxed overnight. The ethanol was removed in vacuo, the residue dissolved in about 100ml water, washed with about 100ml of ether and the aq. solution was made alkaline with ammonium hydroxide. An oil consisting of beta-pyrrolidinoisobutyrophenone formed and was extracted with three 50ml portions of ether, dried with Mg sulfate and frac. dist. in vacuo. BP: 117-118*C/0.3mmHg, Ref. Index @ 26*C = 1.5302.
A sol. of 54.2g of the product above in 100ml of ether was added dropwise to a grignard reagent prep’d from 24.3g of Mg metal, 63.3g of benzyl chloride, and 600ml of ether. The rxn mix was refluxed for an hour and then quenched with sat. aq. ammonium chloride. The ether layer with 1,2-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane was removed and dried over anhydrous Mg sulfate. Dry HCl was bubbled through the ether solution and the salt was filtered off and recryst. from methanol/ethyl acetate with the addition of ether. The alpha-dl-1,2,-diphenyl-2-hydroxy-3-methyl-4-pyrrolidinobutane hydrochloride had MP: 188-189*C. Evap. Of the mother liquors from recrystallization yields the Beta isomer that has MP: 202-203*C.
A rxn mix with 10g of the alpha product above, 10ml pyridine, 10ml of propionic anhydride was refluxed 2 hours. The mix was cooled and ether added to cloudiness whereupon the product precipitated. Recryst. from methanol/ethyl acetate, the material had MP: 196-197*C w/decomp.
Several other examples were present. All followed similar synthetic pathways and methods. The valuable statistics are listed below.
alpha-dl-1,2-diphenyl-2-acetoxy-3-methyl-4-pyrrolidinobutane hydrochloride: recryst. methanol/ethyl acetate w/added ether. MP: 202-203*C.
alpha-dl-1,2-diphenyl-2-propionoxy-3-methyl-4-dimethylaminopropane: recryst. pet. Ether. MP: 70-71*C.
Most of the freebases obtained were oils that only crystallized after standing several weeks.