Tadalafil spectral visit 1/4

 Tadalafil

INTRODUCTION Tadalafil is a potent and selective phosphodiesterase-5 (PDE-5) inhibitor, asecondary messenger for the smoothmuscle relaxing effects of nitric oxide,which plays an important role in thevasodilation of erectile tissues.1-3 OralPDE-5 inhibitors have become the preferredfirst-line treatment for erectile dysfunction worldwide.4    

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PREPARATION 

 Diastereoselective synthesis of (+)-tadalafil (1)describes a process for the synthesis of tadalafil (1) and itsintermediate of formula5which involves reactingD-tryptophan methylester 2 with a piperonal 3 in the presence of methanol and conc. HCl to

give compound 4 . The later compound is then reacted with chloroacetyl chloride in the presence of NaHCO 3

to afford the intermediate5, which is reacted with methylamine in chloroform to give tadalafil in 88% yield

   Stereoselective synthesis of (+)-tadalafil (1) and(+)-6-epi-tadalafil (8)[20]The target isomeric tadalafil molecule is shown . Thus,D-tryptophan methyl ester reacted with piperonal3under Pictet–Spen-gler reaction condition (TFA/CH2Cl2/MeOH) to furnish two diastereo-mers4and6in 25% and 24% yields, respectively. Condensation of4or6with chloroacetyl chloride provided acylated intermediate 5or7in almostquantitative yield. Subsequent cyclization of5withN-methyl amine inmethanol at 50C for 16 h provided diastereomers tadalafil (1) in 54%yield. Compound1is in full accordance with the literature data {[a]D20¼+71.4 (c 1.00, CHCl3); lit. [a]D20¼+71.2 (c 1.00, CHCl3)}[17,18]. Thus,under the elongated reaction time, 48 h, compound8was obtained fromprecursor7with decreased yield of 21% 

depicts an efficient and stereospecific synthesis of tadalafil (1)as well as 12a-epi-tadalafil (11). Pictet–Spengler reaction ofD-trypto-phan methyl ester hydrochloride9with equal molar piperonal byrefluxing for 4 h in nitromethane affordedcis-10-HCl in 98% ee and94% yield. The hydrochloride salt ofcistetrahydro-b-carboline deriva-tivecis-10-HCl was directly treated with 1.5 equiv of chloroacetyl chlo-ride in dichloromethane at 0o

C in the presence of 3 equiv oftriethylamine to formN-chloroacetyl tetrahydro-b-carboline derivative5

in 92% yield. Then compound5reacted with 5 equiv of methylamineovernight in DMF at room temperature to furnish tadalafil1in95% yields.

US PATENT

D. Ben-Zion, D. Dov, United States Patent, US 2006/0276652 A1, 2006.

B.D. Pandurang, B.B. Bharat, S.S. Sachin, P.S. Pranay, United States Patent, US 7, 223,

863 B2, 2007.

FROM L TRYPTOPHAN

X. Sen, S. Xiao-Xin, X. Jing, Y. Jing-Jing, L. Shi-Ling, L. Wei-Dong, Tetrahedron

Asymmetr. 20 (2009) 2090.

S. Xiao-Xin, L. Shi-Ling, X. Wei, X. Yu-Lan, Tetrahedron Asymmetr. 19 (2008) 435

S. Xiao, X. Lu, X.-X. Shi, Y. Sun, L.-L. Liang, X.-H. Yu, J. Dong, Tetrahedron Asymmetr.

20 (2009) 430.

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CILNIDIPINE

Cilnidipine

西尼地平

CAS 132203-70-4

• (E) – (±) 1 ,4 a dihydro-2 ,6 – dimethyl-4 – (3 – nitrophenyl) -3,5 – pyridinedicarboxylic acid, 2 – methoxy- ethyl butylester 3 – phenyl – 2 – propenyl ester FRC-8653 Cinalong
• More FRC 8653 1,4-Dihydro-2 ,6-dimethyl-4-(3-nitrophenyl) 3 ,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester
• Molecular formula:C 27 H 28 N 2 O 7
• Molecular Weight:492.52

CAS Name: 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 2-methoxyethyl (2E)-3-phenyl-2-propenyl ester

Additional Names: (±)-(E)-cinnamyl 2-methoxyethyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate

Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Manufacturers’ Codes: FRC-8653

Trademarks: Atelec (Morishita); Cinalong (Fujirebio); Siscard (Boehringer, Ing.)

Percent Composition: C 65.84%, H 5.73%, N 5.69%, O 22.74%

Properties: Crystals from methanol, mp 115.5-116.6°. LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally;³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada).

Melting point: mp 115.5-116.6°

Toxicity data: LD50 in male, female mice, rats (mg/kg): ³5000, ³5000, ³5000, 4412 orally; ³5000 all species s.c.; 1845, 2353, 441, 426 i.p. (Wada)

Ajinomoto (INNOVATOR)

NMR………http://file.selleckchem.com/downloads/nmr/S129301-Cilnidipine-NMR-Selleck.pdf

HPLC……..http://file.selleckchem.com/downloads/hplc/S129301-Cilnidipine-HPLC-Selleck.pdf

 Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

Cilnidipine

………………..

http://www.google.com/patents/EP0161877A2?cl=en

AN EXAMPLE

Example 1

• 3.51 g (10 mM) of 2-(3-nitrobenzylidene) acetoacetic acid cinnamyl ester were mixed with 1.38 g (12 mM) of 3-aminocrotonic acid methyl ester, and heated at 120°C for 3 hours. The reaction mixture was separated by silica gel column chromatography, and 3.00 g of cinnamyl methyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (trans) were obtained (yield 67%). This derivative was recrystallized once from methanol.
• Elemental Analysis; C 25 H 24 N 2 0 6
  

  • Calcd. (%) C: 66.95, H: 5.39, N: 6.25
  • Found (%) C: 67.03, H: 5.31, N: 6.20

(trans)

• • m.p.; 143.5-144.5°C
  • IR (cm-1); vNH 3370, νCO 1700, νNO2 1530, 1350
  • NMR δCDCl3; 2.34(s,6H), 3.60(s,3H), 4.69(d,2H), 5.13(s,lH), 6.14(tt,lH), 6.55(d,lH), 7.1-8.1(m,9H)

(cis)

• • m.p.; 136-137°C
  • IR (cm-1); vNH 3360, νCO 1700, 1650, νNO2 1530, 1350
  • NMR δCDCl3; 2.30(s,6H), 3,60(s,3H), 4.80(d,lH), 5.10(s,1H), 5.77(tt,lH), 6.56(d,1H), 6.64(bs,1H), 7.1-8.1(m,9H)

  
  

 EXAMPLE 13

• Example 13 Cinnamyl 2-methoxyethyl 4-(3-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate
• Elemental Analysis; C27H28N2O7
  

  • Calcd. (%) C: 65.84, H: 5.73, N: 5.69
  • Found (%) C: 65.88, H: 5.70, N: 5.66
  • m.p.; 115.5-116.5°C
  • IR (cm-1); vNH 3380, νCO 1710, 1680, νNO2 1530, 1350
  • NMR δCDCl3; 2.34(s,6H), 3.25(s,3H), 3.50(t,2H), 4.15(t,2H), 4.68(d,2H), 5.15(s,lH), 5.9-6.9(m,3H), 7.1-8.2(m,9H)

cyclization of 2-(3-nitrobenzylidene)acetocetic acid cinnamyl ester (I) with 2-aminocrotonic acid 2-methoxyethyl ester (II) by heating at 120 C.

MORE

NMR

CARBOHYDRATE POLYMERS 90 PG 1719-1724 , YR2012

Numerous peaks were found in the spectrum of cilnidipine: 2.3555 (3H, s, CH3), 2.3886(3H, s, CH3), 3.2843(CD3OD), 3.3292(3H, s, OCH3), 3.5255–3.5623(2H, m, CH3OCH2CH2 ), 4.1224–4.1597(2H, m, CH3OCH2CH2 ), 4.6695–4.7293(2H, m, CH2 CH CH ), 4.8844(D2O), 5.1576(1H, s, CH), 6.2609(1H, dt, CH2 CH CH ), 6.5518(1H, d, CH2 CH CH ), 7.2488–7.3657(6H, m, ArH), 7.7002(1H, dd, ArH), 7.9805(1H, dd, ArH), 8.1548(1H, s, ArH)

COCK WILL TEACH YOU NMR

COCK SAYS MOM CAN TEACH YOU NMR

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