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LEARN NMR ...Preparation of (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)

USING INFO FROM THE PATENT...--  EP2111401B1
Example 1HYDROXY METHYL PHENYL PYRAZOLYL UREA (4-{4-[({3-tert-Butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)
• [0124]
  
  

  


HYDROXY METHYL PHENYL PYRAZOLYL UREA
Step 1. Preparation of ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate
• [0125]
  
  

  
• [0126]
  Sulfuric acid (concentrated, 15.7 mL, 295.7 mmol) was carefully added drop-wise to cold EtOH (600 mL) with stirring. To this, 3-hydrazinobenzoic acid (45 g, 295.7 mmol) and 4,4-dimethyl-3-oxopentanenitrile (40.7 g, 325.3 mmol) were added and then the mixture was heated at 90°C for 48 h. Most of the solvent was evaporated at reduced pressure, and the residual mixture was diluted with ethyl acetate. The resulting mixture was washed with ice cold 2M NaOH followed by brine, and dried (Na₂SO₄). The solution was filtered through a bed of silica gel, washing with more ethyl acetate. Evaporation of ethyl acetate and treatment of the residue with dichloromethane/hexanes gave the product as an off-white crystalline solid (61 g, 71%). MS mlz 288.2 (M+H)⁺; calcd. mass 287. Retention time (LC-MS): 2.99 min.
•  ¹H-NMR (DMSO-d₆): 
• δ 8.16 (m 1H); sandwiched lone pron on benzene ring ortho to pyrazol ring and -C=0-0 substituent
• 7.88 (m, 2H); easy to know these arom protons  ie 2 
• 7.60 (t, 1H);   arom proton ortho to-C=0-0 and meta to pyrazol subs
• 5.40 (s, 1H);        Lone proton on pyrazole ring
• 5.32 (s, 2H);        NH2     2H
• 4.36 (q, 2H);      -O-CH2-CH3   2H   OF CH2
• 1.34 (t, 3H);       -O-CH2-CH3    METHYL GP
• 1.21 (s, 9H).      -C-(CH3)3  3X3=9H    3 METHYLS OR TERT BUTYL

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Step 2. Preparation of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}-benzoate
• [0127]
  
  

  
• [0128]
  To a mixture of ethyl 3-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)benzoate (60 g, 208.8 mmol) and K₂CO₃ (86.6 g, 626.4 mmol) in THF (1400 mL) was added phenyl chloroformate (98.1 g, 626.4 mmol). The reaction was stirred at room temperature overnight. The solid was removed by filtration and most of the solvent was evaporated under reduced pressure. The residual mixture was dissolved in EtOAc and washed with brine, then water. The organic layer was then dried and concentrated. The crude product was purified by recrystallization from CH₂Cl₂/hexanes to give the desired product as a white powder (78.5 g, 92%). 
• 
  
• MS m/z 408.1 (M+H)⁺; calcd. mass 407. Retention time (LC-MS): 3.92 min.
• 
  
• 
  
•  ¹H-NMR (DMSO-d₆):
• δ 10.19 (s, broad, 1H); NH PROTON
• 8.11 (m 1H);    sandwiched lone proton on benzene ring ortho to pyrazol ring and -C=0-0 substituent
• 7.97 (d, J = 7.6 Hz, 1H); Arom H on phenyl ring Ortho to pyrazole ring
• 7.86 (m, 1H);  Arom H on phenyl ring meta  to pyrazole ring but para to-C=0-0 gp
• 7.71 (t, 1H);   arom proton ortho to-C=0-0 and meta to pyrazol subs
• 7.38 (m, 2H);  META TO -O-PH GP, ON  NH-C=O-O -PH RING
• 7.24 (m, 1H);  PARA TO -O-PH GP, ON  NH-C=O-O -PH RING
• 7.08 (m, 1H);  1H AROM, ORTHO TO -O-PH RING
• 6.40 (s, 1H);   1H AROM  ORTHO TO -O-PH RING
• 5.40 (s, 1H);     Lone proton on pyrazole ring
• 4.38 (q, 2H);    -O-CH2-CH3   2H   OF CH2
• 1.32 (t, 3H);     -O-CH2-CH3    METHYL GP
• 1.29 (s, 9H).   -C-(CH3)3  3X3=9H    3 METHYLS OR TERT BUTYL

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• will be updated soon
• 
  
• 
  
• 
Step 3. Preparation of ethyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]-oxy}phenyl)carbamoyl]amino}-1H-pyrazol-1-yl)benzoate
• [0129]
  
  

  
• [0130]
  A solution of ethyl 3-{3-tert-butyl-5-[(phenoxycarbonyl)amino]-1H-pyrazol-1-yl}benzoate (9.36 g, 22.0 mmol), 4-(4-amino-3-fluorophenoxy)-N-methylpyridine-2-carboxamide (5.0 g, 19.1 mmol; prepared as described in Dumas et al., PCT Int. Appl. WO 2004078748 (2004 )) and triethyl amine (3.87 g, 38.3 mmol) in anhydrous THF (100 mL) was stirred at room temperature overnight. The crude product was purified by column chromatography (CH₂Cl₂ plus 1% to 3% of 2M NH₃ in MeOH), followed by recrystallization from EtOAc/hexanes to give the desired product as an off-white crystalline solid (6.32 g, 57%). MS m/z 575.1 (M+H)⁺; calcd. mass 574. Retention time (LC-MS): 3.75 min.
• 
  
• ¹H-NMR (DMSO-d₆): δ 8.97 (m, 1H);
• 8.89 (m, 1H); 8.80 (m, 1H); 
• 8.52 (d, J = 5.6 Hz, 1H); 
• 8.16 (t, 1H); 
• 8.06 (m, 1H); 
• 7.99 (m, 1H); 
• 7.85 (m, 1H); 
• 7.71 (t, 1H);
• 7.39 (m, 1H);
• 7.33 (m, 1H);
• 7.17 (m, 1H); 
• 7.06 (m, 1H); 
• 6.42 (s, 1H);
• 4.36 (q, 2H);
• 2.78 (d, J = 5.2 Hz, 3H); NEW SIGNAL FROM NHCH3 GP, 3H OF CH3
• 1.31 (m, 12H). TERT BUTYL METHYLS AND CH3 OF 0-CH2CH3 MIXED
• will be updated...............................
• 
  
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• 
  

Step 4. Preparation of (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide)
• [0131]
  
  

  
• [0132]
  To a well-stirred cooled solution of 4-(4-{3-[5-tert-butyl-2-(3-ethoxycarbonyl-phenyl)-2H-pyrazol-3-yl]-ureido}-3-fluoro-phenoxy)-pyridine-2-carboxylic acid methylamide (56 mg, 0.1 mmol) in ethanol (10 mL), NaBH₄ (50 mg) was added in portions. After 14 h, ice water (10 mL) was carefully added to the reaction mixture. Then, most of the ethanol was evaporated under reduced pressure. The residual mixture was treated with saturated aqueous ammonium chloride solution (10 mL) and extracted three times with dichloromethane (50, 25, and 25 mL). The combined dichloromethane extract was dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by preparative thin layer chromatography on silica gel using 3-5% 2M ammonia in methanol in dichloromethane as the eluent to yield the desired product as a white powder (31 mg, 58%).
  For a larger scale synthesis, the following similar procedure was followed: To a solution of ethyl 3-(3-tert-butyl-5-{[(2-fluoro-4-{[2-(methylcarbamoyl)pyridin-4-yl]oxy}phenyl)carbamoyl]-amino}-1H-pyrazol-1-yl)benzoate (11.2 g, 19.5 mmol) in EtOH was added NaBH₄ stepwise as a solid. The reaction was then stirred at room temperature overnight, and then quenched by gradual addition of aqueous NH₄Cl. The mixture was diluted with EtOAc, washed with aq. NH₄Cl, followed by brine. The organic layer was then dried and concentrated. The crude product was then purified by column chromatography on silica gel (CH₂Cl₂ plus 1 to 5% of 2M NH₃ in MeOH), followed by recrystallization from dichloromethane/hexanes to give the desired product as a white crystalline solid (8.0 g, 77%). Mp 160 ºC; after further recrystallization, desired product was obtained with mp 196 ºC.
• 
  
•  MS m/z 533.3 (M+H)⁺; calcd. mass 532. Retention time (LC-MS): 3.13 min.
• 
  
•  ¹H-NMR (DMSO-d₆): δ 9.02 (s, broad, 1H); 8.87 (s, 1H); 8.81 (m, 1H); 8.52 (d, J= 5.2 Hz, 1H); 8.21 (t, 1H); 7.51 (m, 2H); 7.39 (m, 3H); 7.32 (m, 1H); 7.17 (m, 1H); 7.06 (m, 1H); 6.40 (s, 1H); 5.36 (t, 1H); 4.59 (d, J = 5.6 Hz, 2H); 2.78 (d, J = 4.8 Hz, 3H); 1.27 (s, 9H). 
• 
  
• Elemental Analysis: C 62.92%; H 5.43%; N 15.70%; calcd. C 63.15%; H 5.49%; N 15.78%.

Nitrilotriacetic Acid Anhydride,1H NMR AND 13C NMR

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PROTON NMR

1H(d6-acetone, 400 MHz): 

3.920(s, 4H), 
The two PLUS two  NCH2 protons of -NCH2-C=O-O on the ring

3.620(s, 2H); 

The two   NCH2 protons of -NCH2-C=O-OH on side chain


CARBON 13 NMR


13C(d6-acetone, 100 MHz): 

171.18, The single carbonyl carbon  of -NCH2-C=O-OH on side chain

165.51(2C),  The two  carbonyl carbons  of -NCH2-C=O- on the ring

54.79, The single N attached carbon  of -NCH2-C=O-OH on side chain

52.54(2C), The two N attached Carbons at   -NCH2-C=O-O on the ring




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MIDOSTAURIN MP

MIDOSTAURIN
https://www.google.co.in/patents/US5093330
EXAMPLE 18 N-benzoyl-staurosporine

0.035 ml (0.3 mmol) of benzoyl chloride is added at room temperature to a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N,N-diisopropylethylamine in 2 ml of chloroform and the whole is stirred for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated by evaporation. The crude product is chromatographed on silica gel (eluant:methylene chloride/ethanol 30:1); m.p. 235


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IDELALISIB NMR

Idelalisib

An antineoplastic agent and p110delta inhibitor

(S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one

Icos (Originator)

• CAL-101
• GS-1101
• Idelalisib
• UNII-YG57I8T5M0

M.Wt: 415.43
Formula: C22H18FN7O

CAS No.: 870281-82-6
CAL-101 Solubility: DMSO ≥80mg/mL Water <1.2mg/mL Ethanol ≥33mg/mL

5-Fluoro-3-phenyl-2-[(1S)-1-(7H-purin-6-ylamino)propyl]-4(3H)-quinazolinone

 WO2005113556A1
compound 107 idelalisib as a light yellow solid (7.2 g, 50%).

1H NMR (300 MHz, 80 0C, DMSO-d5) δ 12.66 (broad s, IH), 8.11 (s, IH), 8.02 (broad s, IH), 7.81-7.73 (m, IH),7.60-7.42 (m, 6H), 7.25-7.15 (m, 2H), 4.97 (broad s, IH), 2.02-1.73 (m, 2H), 0.79 (t, J= 7.3 Hz, 3H).

ESI-MS m/z 416.2 (MH+).

C, H, N elemental analysis (C22Hi8N7OF-EtOH- 0.4 H2O).

Chiral purity 99.8:0.2 (S:R) using chiral HPLC (4.6 x 250 mm Chiralpak ODH column, 20 °C, 85:15 hexanes : EtOH, 1 rnL/min, sample loaded at a concentration of 1 mg/mL in EtOH) . The reaction described above and compound 107 idelalisib are shown below.

WO2005113556A1

The synthesis of a compound in accordance with formula I is first exemplified using steps A-E below, which provide a synthetic procedure for compound 107, the structure of which is shown below.

(107) is idelalisib

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