2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol

2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol

 

2,2,2-trifluoro-1-(4-methoxyphenyl)-ethanol 2,2,2-trifluor-1-(4-methoxyphenyl)ethanol 2,2,2-trifluoro-1-(4-méthoxyphényl)éthanol 2,2,2-トリフルオロ-1-(4-メトキシフェニル)エタノール
Physical Properties
Melting Point: n/a Boiling Point: 87-88 ºC (1 mmHg) Density: n/a Refractive Index: n/a
H1 NMR Spectrum:	Predict NMR spectrum

 

Data

1H NMR (CDCl₃, 400 MHz) d ppm 3.24 - 3.37 (m, 1 H)
3.80 (s, 3 H) O-CH3
4.91 (q, J=6.85 Hz, 1 H) C-H
6.92 (d, J=8.80 Hz, 2 H) arom-H ortho to oxygen
7.37 (d, J=8.80 Hz, 2 H) arom-H

 13C NMR (CDCl₃, 101 MHz) d ppm
55.51 (CH₃) O-CH3
72.60 (q, J_C-C-F = 31.50 Hz, CH) CH-(OH)-CF3
114.28 (CH) AROM-C
120.44 – 128.84 (q, J_C-F = 281.70 Hz, CF₃)
126.54 (d, J_C-C-C-F = 1.47 Hz, CH) CARBON ATOM ON AROM RING ATTACHED TO -CH-(OH)-CF3
129.07 (C) AROM-C META TO OXYGEN ATOM
160.60 (C) AROM C-O-CH3

 19F NMR (CDCl₃, 377 MHz) d ppm -78.61 (d, J = 6.81 Hz) 

GC-MS (EI) 206 ([M]+, 37%), 137 (100%), 109 (27%), 94 (28%), 77 (25%), 69 (4%).

---

Kelly, C. B.; Colthart, A. M.; Constant, B.D.; Corning, S.R.; Dubois, L. N. E.;  Genovese, J. T.; Radziewicz, J. L.; Sletten, E. M.; Whitaker, K. R.; Tilley, J. J. Org. Lett.2011, 13, 1646.

Krishnamurti, R.; Bellew, D. R.; Prakash, G. K. S.  J.  Org. Chem. 1991, 56, 984.
DOI: 10.1021/jo00001a002

Elvitegravir dimer impurity spectral data

Elvitegravir dimer impurity, WO2011004389A2

Isolation of 1-[(2S)-1-({3-carboxy-6-(3-chloro-2-fluorobenzyl)-1 -[(2S)-I- hydroxy-3-methylbutan-2-yl]-4-oxo-1 , 4-dihydroquinolin-7-yl}oxy)-3- methylbutan-2-yl 6-(3-chloro-2-fluorobenzyl)-7-methoxy-4-oxo-1 , 4-dihydroquinoline-3-carboxylic acid (elvitegravir dimer impurity, 13)

After isolation of the elvitegravir from the mixture of ethyl acetate-hexane, solvent from the filtrate was removed under reduced pressure. The resultant residue purified by column chromatography using a mixture of ethyl acetate-hexane (gradient, 20-80% EtOAc in hexane) as an eluent. Upon concentration of the required fractions, a thick solid was obtained which was further purified on slurry washing with ethyl acetate to get pure elvitegravir dimer impurity (13). The 1H-NMR, 13C-NMR and mass spectral data complies with proposed structure.

1H-NMR (DMSO-Cf6, 300 MHz, ppm) – δ 0.79 (m, d=6.3 Hz, 6H, 20 & 2O’)\ 1.18 & 1.20 (d, J=6.3 Hz & J=6.2 Hz, 6H, 21 & 21′)1, 2.42-2.49 (m, 2H, 19 & 19′), 3.81-3.89 (m, 3H, T & 17′Ha), 3.94-4.01 (m, 1 H, 17′Hb), 4.01 (s, 3H, 23), 4.11 (s, 2H, 7), 4.83-4.85 (m, 3H, 17 & 18′), 5.22 (t, J=4.7 Hz, 1H, OH), 5.41-5.44 (m, 1 H, 18), 6.73-6.78 (t, J=7.1 Hz, 1 H, 11)1‘ 2, 6.92-6.98 (t, J=8.0 Hz, 1H, 3′) 1‘2, 7.12-7.22 (m, 2H, 1 & 3), 7.34-7.39 (m, 1H, 2′),

7.45-7.48 (m, 1 H, 2), 7.49, 7.56 (s, 2H, 15 & 15′), 7.99, 8.02 (s, 2H, 9 & 9′), 8.89, 9.01 (s, 2H, 13 & 13′), 15.30, 15.33 (s, 2H, COOH’ & COOH”).

13C-NMR (DMSO-Cf6, 75 MHz, ppm)- δ 18.87, 19.03 (2OC, 20′C), 19.11 , 19.24 (21 C, 21 ‘C), 27.94 (7′C), 28.40 (7C), 28.91 , 30.08 (19C, 19′C), 56.80(23C), 60.11 (171C), 63.59 (18C), 66.52 (18′C), 68.53 (17C), 97.86, 98.97 (15, 15′), 107.43, 108.16 (12C, 12′C),

118.77, 119.38 (1OC, 10′C), 119.57 (d, J=17.6 Hz, 41C), 119.61 (d, J=17.9 Hz, 4C),

124.88 (d, J=4.3 Hz, 31C), 125.18 (d, J=4.2 Hz, 3C), 126.59, 126.96 (9C1 9′C), 127.14 (8′C), 127.62 (d, J=15.9 Hz, 61C), 127.73 (8C), 127.99 (d, J=15.2 Hz, 6C), 128.66 (2′C),

128.84 (11C), 128.84 (2C), 130.03 (d, J=3.4 Hz, 1C), 142.14, 142.44 (14C, 14′C), 144.37, 145.56 (13C, 131C), 155.24 (d, J=245.1 Hz, 5′C)1 155.61 (d, J=245.1 Hz, 5C),

160.17 (16′C), 162.04 (16C), 166.00, 166.14 (22C, 22′C), 176.17, 176.22 (11C, 111C).

DIP MS: m/z (%)- 863 [M+H]+, 885 [M+Na]+.

Elvitegravir 

European Commission Approves Gilead’s VitektaTM, an Integrase Inhibitor for the Treatment of HIV-1 Infection

NOVEMBER 24, 2013 3:27 AM

Elvitegravir

697761-98-1 CAS

FOSTER CITY, Calif.–(BUSINESS WIRE)–Nov. 18, 2013– Gilead Sciences, Inc. (Nasdaq: GILD) today announced that the European Commission has granted marketing authorization for VitektaTM (elvitegravir 85 mg and 150 mg) tablets, an integrase inhibitor for the treatment of HIV-1 infection in adults without known mutations associated with resistance to elvitegravir. Vitekta is indicated for use as part of HIV treatment regimens that include a ritonavir-boosted protease inhibitor.http://www.pharmalive.com/eu-oks-gileads-vitekta Vitekta interferes with HIV replication by blocking the virus from integrating into the genetic material of human cells. In clinical trials, Vitekta was effective in suppressing HIV among patients with drug-resistant strains of HIV.http://www.pharmalive.com/eu-oks-gileads-vitekta

Elvitegravir (EVG, formerly GS-9137) is a drug used for the treatment of HIV infection. It acts as an integrase inhibitor. It was developed[1] by the pharmaceutical company Gilead Sciences, which licensed EVG from Japan Tobacco in March 2008.[2][3][4] The drug gained approval by U.S. Food and Drug Administration on August 27, 2012 for use in adult patients starting HIV treatment for the first time as part of the fixed dose combination known as Stribild.[5]

According to the results of the phase II clinical trial, patients taking once-daily elvitegravir boosted by ritonavir had greater reductions in viral load after 24 weeks compared to individuals randomized to receive a ritonavir-boosted protease inhibitor.[6]

 Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency disease syndrome (AIDS).  After over 26 years of efforts, there is still not a therapeutic cure or an effective vaccine against HIV/AIDS.  The clinical management of HIV-1 infected people largely relies on antiretroviral therapy (ART).  Although highly active antiretroviral therapy (HAART) has provided an effective way to treat AIDS patients, the huge burden of ART in developing countries, together with the increasing incidence of drug resistant viruses among treated people, calls for continuous efforts for the development of anti-HIV-1 drugs.  Currently, four classes of over 30 licensed antiretrovirals (ARVs) and combination regimens of these ARVs are in use clinically including: reverse transcriptase inhibitors (RTIs) (e.g. nucleoside reverse transcriptase inhibitors, NRTIs; and non-nucleoside reverse transcriptase inhibitors, NNRTIs), protease inhibitors (PIs), integrase inhibitors and entry inhibitors (e.g. fusion inhibitors and CCR5 antagonists).

1.  Gilead Press Release Phase III Clinical Trial of Elvitegravir July 22, 2008
2.  Gilead Press Release Gilead and Japan Tobacco Sign Licensing Agreement for Novel HIV Integrase Inhibitor March 22, 2008
3.  Shimura K, Kodama E, Sakagami Y, et al. (2007). “Broad Anti-Retroviral Activity and Resistance Profile of a Novel Human Immunodeficiency Virus Integrase Inhibitor, Elvitegravir (JTK-303/GS-9137)”. J Virol 82 (2): 764. doi:10.1128/JVI.01534-07. PMC 2224569. PMID 17977962.
4.  Stellbrink HJ (2007). “Antiviral drugs in the treatment of AIDS: what is in the pipeline ?”. Eur. J. Med. Res. 12 (9): 483–95. PMID 17933730.
5.  Sax, P. E.; Dejesus, E.; Mills, A.; Zolopa, A.; Cohen, C.; Wohl, D.; Gallant, J. E.; Liu, H. C.; Zhong, L.; Yale, K.; White, K.; Kearney, B. P.; Szwarcberg, J.; Quirk, E.; Cheng, A. K.; Gs-Us-236-0102 Study, T. (2012). “Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: A randomised, double-blind, phase 3 trial, analysis of results after 48 weeks”.The Lancet 379 (9835): 2439–2448. doi:10.1016/S0140-6736(12)60917-9. PMID 22748591. edit
6.  Thaczuk, Derek and Carter, Michael. ICAAC: Best response to elvitegravir seen when used with T-20 and other active agents Aidsmap.com. 19 Sept. 2007.

 

 The life cycle of HIV-1.  1. HIV-1 gp120 binds to CD4 and co-receptor CCR5/CXCR4 on target cell; 2. HIV-1 gp41 mediates fusion with target cell; 3. Nucleocapsid containing viral genome and enzymes enters cells; 4. Viral genome and enzymes are released; 5. Viral reverse transcriptase catalyzes reverse transcription of ssRNA, forming RNA-DNA hybrids; 6. RNA template is degraded by ribonuclease H followed by the synthesis of HIV dsDNA; 7. Viral dsDNA is transported into the nucleus and integrated into the host chromosomal DNA by the viral integrase enzyme; 8. Transcription of proviral DNA into genomic ssRNA and mRNAs formation after processing; 9. Viral RNA is exported to cytoplasm; 10. Synthesis of viral precursor proteins under the catalysis of host-cell ribosomes; 11. Viral protease cleaves the precursors into viral proteins; 12. HIV ssRNA and proteins assemble under host cell membrane, into which gp120 and gp41 are inserted; 13. Membrane of host-cell buds out, forming the viral envelope; 14. Matured viral particle is released

Elvitegravir, also known as GS 9137 or JTK 303, is an investigational new drug and a novel oral integrase inhibitor that is being evaluated for the treatment of HIV-1 infection. After HIVs genetic material is deposited inside a cell, its RNA must be converted (reverse transcribed) into DNA. A viral enzyme called integrase then helps to hide HIVs DNA inside the cell’s DNA. Once this happens, the cell can begin producing genetic material for new viruses. Integrase inhibitors, such as elvitegravir, are designed to block the activity of the integrase enzyme and to prevent HIV DNA from entering healthy cell DNA. Elvitegravir has the chemical name: 6-(3-chloro-2-fluorobenzyl)-1-[(S)-1 -hydroxy -methyl-2- methylpropyl]-7-methoxy-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid and has the following structural formula:

WO 2000040561 , WO 2000040563 and WO 2001098275 disclose 4-oxo-1 , 4-dihydro-3- quinoline which is useful as antiviral agents. WO2004046115 provides certain 4- oxoquinoline compounds that are useful as HIV Integrase inhibitors.

US 7176220 patent discloses elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and their method of treatment. The chemistry involved in the above said patent is depicted below in the Scheme A. Scheme-A

Toluene, DIPEA

SOCl2 ,COCl (S)-(+)-Valinol

Toluene

,4-Difluoro-5-iodo- benzoic acid

THF

dichlorobis(triphenylphosphine)

palladium argon stream,

Elvitegravir Form ] Elvitegravir (residue) US 7635704 patent discloses certain specific crystalline forms of elvitegravir. The specific crystalline forms are reported to have superior physical and chemical stability compared to other physical forms of the compound. Further, process for the preparation of elvitegravir also disclosed and is depicted below in the Scheme B. The given processes involve the isolation of the intermediates at almost all the stages.

Scheme B

2,

-

Zn THF,

CK Br THF CU “ZnBr dιchlorobis(trιphenylphos

phine)palladium

Elvitegravir WO 2007102499 discloses a compound which is useful as an intermediate for the synthesis of an anti-HIV agent having an integrase-inhibiting activity; a process for production of the compound; and a process for production of an anti-HIV agent using the intermediate.

WO 2009036161 also discloses synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

The said processes are tedious in making and the purity of the final compound is affected because of the number of steps, their isolation, purification etc., thus, there is a need for new synthetic methods for producing elvitegravir which process is cost effective, easy to practice, increase the yield and purity of the final compound, or that eliminate the use of toxic or costly reagents.

US Patent No 7176220 discloses Elvitegravir, solvate, stereoisomer, tautomer, pharmaceutically acceptable salt thereof or pharmaceutical composition containing them and ■ their method of treatment. US Patent No 7635704 discloses Elvitegravir Form II, Form III and processes for their preparation. The process for the preparation of Form Il disclosed in the said patent is mainly by three methods – a) dissolution of Elvitegravir followed by seeding with Form II, b) recrystallisation of Elvitegravir, and c) anti-solvent method.

The process for the preparation of Form III in the said patent is mainly by three methods – a) dissolution of Form Il in isobutyl acetate by heating followed by cooling the reaction mass, b) dissolution of Form Il in isobutyl acetate by heating followed by seeding with Form III, and c) dissolving Form Il in 2-propanol followed by seeding with Form III.

Amorphous materials are becoming more prevalent in the pharmaceutical industry. In order to overcome the solubility and potential bioavailability issues, amorphous solid forms are becoming front-runners. Of special importance is the distinction between amorphous and crystalline forms, as they have differing implications on drug substance stability, as well as drug product stability and efficacy.

An estimated 50% of all drug molecules used in medicinal therapy are administered as salts. A drug substance often has certain suboptimal physicochemical or biopharmaceutical properties that can be overcome by pairing a basic or acidic drug molecule with a counter- ion to create a salt version of the drug. The process is a simple way to modify the properties of a drug with ionizable functional groups to overcome undesirable features of the parent drug. Salt forms of drugs have a large effect on the drugs’ quality, safety, and performance. The properties of salt-forming species significantly affect the pharmaceutical properties of a drug and can greatly benefit chemists and formulators in various facets of drug discovery and development.

chemical synthesis from a carboxylic acid 1 starts after conversion to the acid chloride iodide NIS 2 , and with three condensation 4 . 4 and the amino alcohol 5 addition-elimination reaction occurs 6 , 6 off under alkaline conditions with TBS protected hydroxy get the ring 7 , 7 and zinc reagent 8 Negishi coupling occurs to get 9 , the last 9 hydrolysis and methoxylated

Elvitegravir

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PREGABALIN 普瑞巴林 SPECTRAL DATA

 
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.

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

https://www.google.co.in/patents/US20100286442?pg=PA15&dq=us+2010286442&hl=en&sa=X&ei=K7ONUrmjBovSrQef54GAAg&ved=0CDcQ6AEwAA

(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

 

............................................................................

http://www.faqs.org/patents/app/20100292506

[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=Shah

The 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

..........................................

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)

..............................................................

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).

LINOXEPIN SPECTRAL DATA

Weinstabl, H., Suhartono, M., Qureshi, Z. and Lautens, M. (2013), Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction . Angew. Chem. Int. Ed., 52: 5305–5308. doi: 10.1002/anie.201302327

1. ^†
   We gratefully thank the NSERC, Merck Frosst, and Merck for an Industrial Research Chair. We also thank the University of Toronto for support of our program, Dr. Alan Lough (Chemistry Department, University of Toronto) for single-crystal X-ray structure analysis. H.W. thanks the Austrian Science Fund (FWF): J3250-N19 for an Erwin Schroedinger postdoctoral fellowship and M.S. thanks the DFG for a postdoctoral fellowship. We would like to thank Pierre Thesmar and Patrick Lui for their contributions.

Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction^†

1. Dr. Harald Weinstabl, 
2. Dr. Marcel Suhartono, 
3. Zafar Qureshi, 
4. Prof. Dr. Mark Lautens^*

Article first published online: 16 APR 2013

DOI: 10.1002/anie.201302327

http://onlinelibrary.wiley.com/doi/10.1002/anie.201302327/full

Lignans are a diverse class of plant-derived natural products belonging to the phytooestrogen family. They have long been used as herbal remedies for pain, rheumatoid arthritis, and warts. However, more recently, lignans exhibiting immunosuppressive activity, tumor growth inhibition, and anti-fungal properties have been used in disease therapy, such as the anticancer agent etoposide.2

In 2007, Schmidt and co-workers isolated a lignan from the aerial parts of Linum perenne L. (Linaceae) with a previously undescribed carbon skeleton, which they named linoxepin (1). This caffeic acid dimer exhibits an oxidation-prone dihydronaphthalene core, a tetrasubstituted double bond embedded within a highly strained ring system, and a dibenzo–dihydrooxepine moiety, which is unique within this class of molecules. These interesting structural characteristics and their associated challenges make (+)-linoxepin (1) an interesting synthetic target.

Angewandte Chemie International Edition

Volume 52, Issue 20, pages 5305–5308, May 10, 201
3

IR spectra were obtained using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as neat films or as solutions (CHCl3 or CH2Cl2) on a NaCl plate. Data is presented as frequency of absorption (cm–1).  1H and 13C NMR spectra were recorded at 23 °C in CDCl3 or DMSO-d6 with a Bruker Avance 400 spectrometer or a Varian Mercury 400 spectrometer. Recorded shifts for protons are reported in parts per million (δ scale) and are referenced to residual proton signals in the NMR solvent (CHCl3: δ = 7.26, DMSO-d6: δ = 2.50). Chemical shifts for carbon resonances are reported in parts per million (δ scale) and are referenced to the carbon resonances of the solvent (CDCl3: δ = 77.0, DMSO-d6:  39.43). Data are represented as follows: chemical shift, multiplicity (s=singlet, d=doublet, t=triplet,

(+)-linoxepin (1) or (R)-6-methoxy-9a,10-dihydro-4H-[1,3]dioxolo[4',5':3,4]benzo[1,2-e]furo[3',4':6,7]naphtho[1,8-bc]oxepin-12(9H)-one 

1H NMR (500 MHz, CDCl3): δ = 6.87 (d, J = 8.0 Hz, 1H), 6.84 (dd, J = 8.2, 1.2 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.04 – 6.02 (m, 2H), 5.39 (dd, J = 12.6, 1 Hz, 1H), 5.14 (d, J = 12.5 Hz, 1H), 4.68 (t, J = 8.9 Hz, 1H), 4.03 (t, J = 8.7 Hz, 1H), 3.85 (s, 3H), 3.36 – 3.16 (m, 1H), 2.99 (dd, J = 14.7, 5.7 Hz, 1H), 2.66 (td, J = 14.8, 1.3 Hz, 1H);  

13C NMR (125 MHz, CDCl3): δ = 168.83, 149.43, 149.04, 148.52, 145.68, 144.79, 129.43, 128.15, 124.35, 124.14, 122.22, 119.82, 116.50, 111.83, 108.12, 101.85, 70.00, 64.66, 56.18, 36.84, 34.46;  

IR (neat) νmax = 2900, 1748, 1661, 1572, 1481, 1464, 1436, 1300, 1277, 1264, 1244, 1199, 1183, 1102, 1032, 1013, 913, 760  

HRMS (DART) [M+H]+ m/z = 365.10195 calcd. for C21H17O6: 365.10251.  

Melting point: decomp. 228 °C  

Optical rotation: [α]D20: + 90.0 (c = 0.25, CHCl3). 

Weinstabl H, Suhartono M, Qureshi Z, Lautens M * University of Toronto, Canada 

Total Synthesis of (+)-Linoxepin by Utilizing the Catellani Reaction.

Angew. Chem. Int. Ed. 2013;
52: 5305-5308

Lautens and co-workers report the synthesis of linoxepin, a lignin isolated from Linum perennne L.(Linaceae). The elegant strategy relies on the Catellani reaction, in which a strained olefin (norbornene) is used to couple an iodoarene, an alkyl halide, and a terminal olefin using palladium catalysis. This is the first application of the Catellani reaction in the synthesis of a natural product and underscores the power of processes that form multiple bonds in a single step. In this context, it is worth highlighting the recent synthesis of linoxepin by Tietze and co-workers (Angew. Chem. Int. Ed. 2013, 52, 3191), which relies on a different palladium-catalyzed domino reaction.

Alkylation of phenol A with benzyl iodide B gave Catellani precursor C in 94% yield. The norbornene-mediated domino process involving aryl iodide C, enantiopure alkyl iodide D and acrylate E delivered key intermediate F in 89% yield. Oxidative cleavage of the olefin followed by TiCl4-promoted aldol condensation furnished G, which in the presence of catalytic amounts of a palladium catalyst underwent a Mizoroki–Heck reaction to give (+)-linoxepin in 76% yield.