Title compd pregabalin or compd 1
Pregabalin ((S)-3-(aminomethyl)-5-methylhexanoic acid) as a white solid .
The obtained solid 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:
δ 2.95 (1H, dd, J=12.84 Hz and 3.54 Hz),
2.82 (1H, dd, J=12.82 Hz and 7.94 Hz),
2.44 (1H, dd, J=15.73 Hz and 3.37 Hz),
2.25 (1H, dd, J=15.70 Hz and 8.76 Hz),
2.06 (1H, m),
1.69 (1H, m),
1.23 (2H, m),
0.92 (6H, t, J=6.42 Hz), two CH3 groups at the end
shown in FIG. 16.
δ 2.95 (1H, dd, J=12.84 Hz and 3.54 Hz),
2.82 (1H, dd, J=12.82 Hz and 7.94 Hz),
2.44 (1H, dd, J=15.73 Hz and 3.37 Hz),
2.25 (1H, dd, J=15.70 Hz and 8.76 Hz),
2.06 (1H, m),
1.69 (1H, m),
1.23 (2H, m),
0.92 (6H, t, J=6.42 Hz), two CH3 groups at the end
shown in FIG. 16.
The result of 13C NMR (100 MHz, CD3OD) of Compound 1 was as follows: 180.6(COOH Carbon), 45.9(CH2-NH2), 43.4, 43.1, 33.2(LONE CH2-H), 26.2( CH2-(CH3)2), 23.2, 22.6, shown in FIG. 17.
The result of HRMS (EI) (C8H17NO2) was as follows: calculated value=159.1259, measured value=159.1259.
Novel method for preparing pregabalin
US 20100286442 A1
US 20100286442 A1
(S)-(+)-3-(aminomethyl)-5-methylhexanoic acid is generally known as (S)-pregabalin, and also called (S)-(+)-β-isobutyl-γ-aminobutyric acid, (S)-3-isobutyl-GABA, or CI-1008. (S)-Pregabalin, marketed under the trade name LYRICA, is a neurotransmitter modulator that is effective for the treatment of neuropathic pain, seizure and generalized anxiety disorder, and is known to have a more rapid onset of action and be convenient to use. Thus, it is known to significantly alleviate a patient's symptoms, compared with other therapeutic agents for each disease (U.S. Pat. No. 5,563,175).
It was reported that chronic pain syndrome is associated with excessive neuronal activity and can be treated by reducing the concentration of neurotransmitters. Pregabalin, gabapentinoid drug, has a unique mechanism of action which allows treatment of certain neurologic and psychiatric disorders. Pregabalin modulates the voltage-dependent calcium channel in the central nervous system to increase the concentration of an endogenous inhibitory neurotransmitter, γ-aminobutyric acid or GABA (gamma-aminobutyric acid), resulting in the treatment of certain neurologic disorders, pains, and psychiatric disorders (Nature Reviews Drug Discovery 2005, 4, 455).
The anticonvulsant effect of racemic isobutyl-GABA is primarily attributable to the (S)-enantiomer, pregabalin (Bioorg. Med. Chem. Lett., 1994, 4, 823). Thus, the commercial utility of pregabalin requires an efficient method for preparing the (S)-enantiomer with a high enantiomeric excess (hereinafter, referred to as “ee”).
Typically, a racemic mixture of 3-(aminomethyl)-5-methyl-hexanoic acid is synthesized and subsequently resolved into its (R)- and (S)-enantiomers. Such methods may employ an azide intermediate (Richard Silverman et al., Synthesis, 1989, 953., U.S. Pat. No. 5,563,175), a malonate intermediate (Grote et al., U.S. Pat. Nos. 6,046,353, 5,840,956, and 5,637,767), or Hofmann synthesis (Huckabee and Sobieray, U.S. Pat. Nos. 5,629,447 and 5,616,793). In these methods, the classical method of resolving a racemate is used to separate and purify the desired (S)-enantiomer. Classical resolution involves preparation of a salt with a chiral resolving agent to separate and purify the desired (S)-enantiomer, and also substantial additional cost associated with the resolving agent. Partial recycling of the resolving agent is feasible, but this is associated with waste generation. Moreover, the maximum theoretical yield of pregabalin is 50%, since only half of the racemate is the desired product and the undesired (R)-enantiomer is ultimately discarded as waste. This reduces the effective throughput of the process (the amount that can be made in a given reactor volume) by 50% or less.
Pregabalin has been also synthesized by stereoselective synthesis using chiral auxiliary, (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone (Richard Silverman et al., U.S. Pat. Nos. 6,359,169, 6,028,214, 5,847,151, 5,710,304, 5,684,189, 5,608,090 and 5,599,973). Although these methods provide pregabalin in high enantiomeric purity, they are not practical for large-scale synthesis because they employ costly reagents which are difficult to handle, as well as special cryogenic equipment to reach the required operating temperatures.
Pregabalin can be also synthesized by asymmetric reaction using a catalyst. In this regard, US Patent Application No. 2003/0212290 describes a method of making pregabalin using a chiral rhodium catalyst via asymmetric hydrogenation of a cyano-substituted olefin to produce a chiral cyano precursor of (S)-3-(aminomethyl)-5-methylhexanoic acid. The cyano precursor is subsequently reduced to yield pregabalin. However, the method may create serious safety problems in large scale synthesis, because of using high levels of carbon monoxide gas in the preparation of the starting material, cyano-substituted olefin. In addition, pregabalin can be also synthesized by asymmetric cyanation using an Al-(Salen) catalyst (Jacobsen et al., J. Am. Chem. Soc. 2003, 125, 4442). However, the method is also not practical for large-scale synthesis, since its enantiomeric excess is as low as 96% ee and toxic reagents such as HCN and high-pressure hydrogen (500 psi) treatment are needed.
IR, CADILA HEALTHCARE LIMITED
WO 200862460
IR (KBr, v cm"1) : sp3 C-H stretch : 2960, 2935, 2902; N-H stretch : 2818, 2872; C-H bend : 1388 and C-O stretch : 1163.08.
SEE
Bioorganic and Medicinal Chemistry, 2013 , vol. 21, 8, pg. 2305 - 2313
European Journal of Organic Chemistry, 2013 , 21, pg. 4495 - 4498
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[0007]FIGURE: XRPD spectrum of crystalline pregabalin.
Chromatography and Tandem Mass Spectrometry
http://www.japtr.org/article.asp?issn=2231-4040;year=2010;volume=1;issue=3;spage=354;epage=357;aulast=ShahThe liquid chromatography system consists of the LC pump and autosampler from theAgilent 1100 series SPLC system (India). The detector was the API-2000 (Applied Biosystem / MDS Sciex, Toronto, Canada) mass spectrometer. Hypurity advance column (50 mm × 4.6 mm, 5 μm Thermo Electron Corporation, USA) was used as a stationary phase. The isocratic mobile phase consisting of Mehanol: 0.1% acetic acid (80:20, v / v) was used throughout the analysis. The flow rate of the mobile phase was 0.250 mL / minute with a splitter. The column oven temperature was kept at 40°C and the sample injection volume was 10 μL.
The Mass Spectrometer was operated in the multiple reaction monitoring (MRM) mode. The sample introduction and ionization technique was electrospray with positive polarity. The ion spray voltage was 4500 KV and the source temperature was 450 o C. Nitrogen sheath gas (GAS1) and auxiliary gas (GAS2) were 25 psi and 30 psi, respectively. The mass parameter and multiple reaction monitoring (MRM) condition of each individual analyte is summarized in [Table 1]. The retention times of PB and GB were observed at 1.27 and 1.40 minutes, respectively, as shown in [Figure 2]a and b. Quantification was performed with the MRM of the transitions of m / z 160.2→55.1 for PB and m / z 172.2→95.0 for GB, with a scan time of 0.2 seconds per transition.
 | Table 1: Intra- and inter-day precision and accuracy of the measurement of PB when used for positive ion detection Click here to view |
 | Figure 2: (a) Chromatogram of PB R.T - 1.27 (b) Chromatogram of GB R.T - 1.40 Click here to view |
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Crystalline forms of pregabalin and co-formers in the treatment of pain
http://www.google.com/patents/EP2527319A1?cl=en
Crystalline forms of pregabalin and co-formers in the treatment of pain
http://www.google.com/patents/EP2527319A1?cl=en
Figure 1 : Differential scanning calorimetry (DSC) analysis of (S)-pregabalin - L-(+)-tartaric acid (1:1)(EXAMPLE 1)Figure 2 : Thermogravimetric analysis (TGA) of (S)-pregabalin - L-(+)-tartaric acid (1:1) (EXAMPLE 1)Figure 3 : X-ray powder diffraction (XRPD) pattern of (S)-pregabalin - L-(+)-tartaric acid (1:1) (EXAMPLE 1)
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CAS 148553-50-8
CAS Name: (3S)-3-(Aminomethyl)-5-methylhexanoic acid
(S)-(+)-4-amino-3-(2-methylpropyl)butanoic acid; (S)-(+)-3-isobutyl-g-aminobutyric acid
Manufacturers' Codes: CI-1008; PD-144723
: Lyrica (Pfizer)
MF C8H17NO2
MW 159.23
Percent Composition: C 60.34%, H 10.76%, N 8.80%, O 20.10%
Literature References: Structural analog of g-aminobutyric acid, q.v.; ligand at a2d subunit of voltage-gated calcium channels. Prepn of racemate: R. Andruszkiewicz, R. B. Silverman, Synthesis 1989, 953.
Enantioselective synthesis: P. Yuen et al., Bioorg. Med. Chem. Lett. 4, 823 (1994).
Manufacturing process: M. S. Hoekstra et al., Org. Process Res. Dev. 1, 26 (1997).
HPLC determn in biological fluids: B. L. Windsor, L. L. Radulovic, J. Chromatogr. B 674, 143 (1995).
Clinical trial in post-herpetic neuralgia: R. Sabatowski et al., Pain 109, 26 (2004).
Overview of mechanism and pharmacology: S. M. Stahl, J. Clin. Psychiatry65, 596, 1033 (2004).
Review of pharmacology and clinical experience: B. A. Lauria-Horner, R. B. Pohl, Expert Opin. Invest. Drugs12, 663-672 (2003); R. Huckle, Curr. Opin. Invest. Drugs 5, 82-89 (2004).
Properties: White crystalline solid, mp 186-188°. [a]D23 +10.52° (c = 1.06 in water).
Melting point: mp 186-188°
Optical Rotation: [a]D23 +10.52° (c = 1.06 in water)
Therap-Cat: Anticonvulsant; anxiolytic; analgesic in treatment of peripheral neuropathic pain.
Keywords: Anticonvulsant; Anxiolytic; Analgesic (Non-Narcotic).
