3 -Phenylpropylamine

FIGURE 4.24 Adsorption chromatography of small molecules with a TSK-GEL G2500PWxl column. Column TSK-GEL G2500PWxl, 6 /tm, 7.8 mm X 30 cm. Sample (I) phenylacetic acid. (2) 3-phenylpropionic acid, (3) 4-phenylbutyric acid, (4) benzylamine, (5) 2-phenylethylamine, (6) 3-phenylpropylamine, (7) benzyl alcohol, (8) 2-phenylethanol, and (9) 3-phenyl-1 -propanol. Elution 0.1 M NaCIO, in water. Flow rate 2.0 ml/min. Temperature 65 C. Detection UV at 215 nm. 

Fuller, R.W. Perry, K.W. and Molloy. B.B. Effeet of 3-(p-trifluoromethyl-phenoxy)-N-methyl-3-phenylpropylamine on the depletion of brain serotonin by 4-chloroamphetamine. J Pharmacol Exp Ther 193 796-803, 1975b. 

The (2S,4S)-MCCPM-Rh(I) complex was found previously by Achiwa and colleagues to be an efficient catalyst for the enantioselective hydrogenation of /9-amino ketone derivatives, leading to a practical enantioselective synthesis of (F)-fluoxetine [N-methyl-3-(4-trifluoromethylphenoxy)-3-phenylpropylamine] hydrochloride [22 b]. Moreover, the use of AMPP ligands again proved to be efficient for these substrates, as exemplified in Table 33.6 [15 i],... 

Procedure 3 Dynamic Kinetic Resolution of l-Methyl-3-phenylpropylamine... 

Dried and degassed toluene (3 mL) l-methyl-3-phenylpropylamine (90 mg, 0.60 mmol)... 

Fluoxetine Fluoxetine, 3-[p-(trifluoromethyl)-phenoxy]-N-methyl-3-phenylpropylamine (7.3.6), is synthesized by reaction of p-trifluoromethylphenol with 3-(chloro)-N-methyl-3-phenylpropylamine in the presence of potassium carbonate [59,60]. 

PREPARATION OF SECONDARY AMINES FROM PRIMARY AMINES VIA 2-NITROBENZENESULFONAMIDES N-(4-METHOXYBENZYL)-3-PHENYLPROPYLAMINE [Benzenepropanamine, N-[(4-methoxyphenyl)methyl]-]... 

In this paper we will report on using a series of modifiers to enhance selectivity during 1-phenyl-1-propyne over a Pd/alumina catalyst. The modifiers, trans-cinnamaldehyde, trans-cinnamonitrile, 3-phenylpropionitrile, and 3-phenylpropylamine, were chosen to have a functionality that potentially could adsorb more strongly than an alkene and to be unreactive under the reaction conditions. 

The reaction of 1-phenyl-l-propyne (IPP) was then studied after modilying the catalyst with trans-cinnamaldehyde (TCA), trans-cinnamonitrile (TCN), 3-phenylpropionitrile (3PPN), and 3-phenylpropylamine (3PPA). The first-order rate constant calculated for the loss of 1-phenyl-l-propyne in each of the systems is reported in Table 1. All the modifiers were unreactive under the conditions used. 

Bischler-Napieralski cyclization of N- formyl-3-phenylpropylamine yields not the desired 4,5-dihydro-3f/-2-benzazepine, but its dimer, 3,4,10,ll-dibenz-l,8-diazacyclotetradeca-1,3,8,10-tetraene (78) (73AP271). 

As shown in Scheme 1 (17,19,21), rapid catalytic addition of to I produces Ilia and Illb. The presence of Ilia and the absence of Illb in the products is at least qualitatively consistent with the fact that the former is kinetically favored while the latter is thermodynamically favored (17,19,21). Structure-reactivity relationships provide a preference for hy-drogenolysis of the N-C(2) bond rather than the C(8a)-N bond in Ilia producing V rather than 3-phenylpropylamine. Both Ilia and Illb are converted to decahydroquinoline (VI), mass 139 the rate constant for the latter conversion is significantly greater than the one for the former (17,19,21). The absence of significant amounts of VI in the products is consistent with its facile conversion to hydrocarbons and NH (17,19,21,35). 

A solution of 100 g potassium hydroxide, 85 ml water, 400 ml ethylene glycol and 9.50 g of N-methyl-N-cyano-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine was prepared in a 1 L three-neck, round-bottom flask equipped with magnetic stirrer and condenser. The reaction mixture was heated to refluxing temperature (130°C) for 20 h, and was then cooled. 500 ml of water were added. The reaction mixture was extracted with three 500 ml portions of ether. The ether extracts were combined, and the combined extracts washed with water. The water wash was discarded. The ether solution was next contacted with 2 N aqueous hydrochloric acid. The acidic aqueous layer was separated. A second aqueous acidic extract with 2 N hydrochloric acid was made followed by three aqueous extracts and an extract with saturated aqueous sodium chloride. The aqueous layers were all combined and made basic with 5 N aqueous sodium hydroxide. N-Methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, formed in the above reaction, was insoluble in the basic solution and separated. The amine was extracted into ether. Two further ether extractions were carried out. The ether extracts were combined, and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the ether in vacuo yielded about 6.3 g of N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine. 

A solution of 50 g p-trifluoromethylphenol, 12 g of solid sodium hydroxide and 400 mL of methanol were added 29.8 g of N,N-dimethyl 3-phenyl-3-chloropropylamine hydrochloride. The resulting reaction mixture was refluxed for about 5 days and then cooled. The methanol was removed by evaporation, and the resulting residue taken up in a mixture of ether and 5 N aqueous sodium hydroxide. The ether layer was separated and washed twice with 5 N aqueous sodium hydroxide and three times with water. The ether layer was dried, and the ether removed by evaporation in vacuo to yield as a residue N,N-dimethyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine. 

Could R-l-methyl-3-phenylpropylamine (R-amine, VIII) be sourced at low enough cost ... 

Raw Materials Sourcing. There was relatively little problem in sourcing 5-bromoacetylsalicylamide (in-house) or dibenzoyl-(+)-tartaric acid (large tonnage Italian source). Although RS-l-methyl-3-phenylpropylamine was available at low cost ( 10-12/kg) in tonnage quantities (Germany and Holland) no supplier of the R-amine VIII was known. 

R-l -Methyl-3-phenylpropylamine. Many chiral acids were evaluated, with water as the solvent, before AMormyl-L-phenylalanine (FPA) was selected as the best acid for resolving RS-l-methyl-3-phenylpropylamine. The resolving acid and process were patented.8 An outline of the commercial process implemented in Germany is given in Scheme 6. 

The l-methyl-3-phenylpropylamine containing fractions of largely S conformation were found to be readily racemized without degradation by heating at 150°C and 150 psi hydrogen in the presence of Raney nickel.9 Thus the manufacturers of... 

RS-l-methyl-3-phenylpropylamine, who produced this compound by the reductive animation of benzylacetone, were well able to racemize the byproduct S-containing fractions, thereby providing some additional cost reduction and also avoiding a waste disposal problem. 

Although the above commercial process succeeded in providing R-l-methyl-3-phenylpropylamine (VIII) for significantly less than 100/kg several other companies carried out research to find even lower cost processes based on the RS raw material. A few of these processes will be described later. 

Cost reduction efforts were undertaken both inside and outside the company. They covered the preparation of the raw materials, particularly R-l-methyl-3-phenylpropylamine and derivatives, and also several exciting programs for the direct preparation of dilevalol from chiral intermediates. 

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