ChemicalBook CAS DataBase List Pregabalin

Pregabalin synthesis

10synthesis methods

Product Name:Pregabalin
CAS Number:148553-50-8
Molecular formula:C8H17NO2
Molecular Weight:159.23

Several syntheses of pregabalin (X) have been disclosed in the literature, including process scale-up comparison of several different routes. The most cost efficient route as described in the publication is shown in the Scheme. Condensation of diethyl malonate 69 in the presense of diisopropyl amine in acetic acid gave a,b-unsaturated diester 70 in high yield. Reaction of the enone diester with potassium cyanide gave cyano diester 71 in 95% yield. In a remarkable three step, one pot process, the nitrile in 71 was hydrolyzed followed by decarboxylation of one of the esters to provide 72 in 73% yield. Resolution of the two enantiomers was achieved using (S)-(+)-mandellic acid, one of the best acid found after many salt screening, to give, after two recrystallization, a 99:1 ratio of the desired diastereomer.Removal of the acid was done with wet THF instead of base separation, to avoid salt impurities, and one recrystallization in ethanol gave 100% ee diastereomer in 25 – 29% overall yield.
It’s worth noting that the Pfizer group have come up with a new process of preparing pregabalin (X) via enantioselective reduction, that promises to further reduce cost and waste associated with the manufacture of this drug.

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Yield:148553-50-8 99%

Reaction Conditions:

with hydrogen;palladium 10% on activated carbon in methanol; for 3 h;

Steps:

7

Example 7: Preparation of pregabalin (Compound 1); Compound 4 (569.7 mg, 3.08 mmol) prepared in Example 5 and 10% Pd/C (90 mg) were added to methanol (30 mL) , and then stirred under a hydrogen balloon for 3 hrs. 10% Pd/C was removed by filtering with cellite, and the solvent was evaporated under reduced pressure to obtain Compound 1, pregabalin( (S) -3- (aminomethyl) -5-methylhexanoic acid) as a white solid (485 mg, 99.0%) .The obtained solid (Compound 1) had a melting point of 182 to 183^°C and [α]²⁰_D was + 6.0 (c 0.54, H₂O) .The result of H¹ NMR (400 MHz, CD₃OD) of Compound 1 obtained in this Example was as follows: 52.95 (IH, dd, J = 12.84 Hz and 3.54 Hz), 2.82 (IH, dd, J = 12.82 Hz and 7.94 Hz), 2.44 (IH, dd, J = 15.73 Hz and 3.37 Hz), 2.25 (IH, dd, J = 15.70Hz and 8.76 Hz), 2.06(1H, m) , 1.69 (IH, m) , 1.23 (2H, m) , 0.92 (6H, t, J= 6.42 Hz), shown in FIG. 16.The result of ¹³C NMR (100 MHz, CD₃OD) of Compound 1 was as follows: 5180.6, 45.9, 43.4, 43.1, 33.2, 26.2, 23.2, 22.6, shown in FIG. 17.The result of HRMS (EI) (C₈Hi₇NO₂) was as follows: calculated value = 159.1259, measured value = 159.1259.