Glutaric anhydride → HCID 44539368, compound

HRID 1668307Notes

Reaction equation

HRID 1668307 reaction equation
[C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:22](=[O:25])[N:21]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@@H:34]([CH:36]5[CH2:38][CH2:37]5)[OH:35])=[C:28]([O:39][CH3:40])[CH:27]=4)[CH:20]=[N:19][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:22](=[O:25])[N:21]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C@@H:34]([CH:36]5[CH2:37][CH2:38]5)[O:35][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8])=[C:28]([O:39][CH3:40])[CH:27]=4)[CH:20]=[N:19][C:18]=3[CH:17]=2)=[CH:12][CH:11]=1

Participants

5

Reactant 3

HCID 7940Glutaric anhydride2×HCID 755674-Pyrrolidinopyridine2×HCID 444764516-(4-Chlorophenyl)-3-{4-[(2R)-2-cyclopropyl-2-hydroxyethoxy]-3-methoxyphenyl}thieno[3,2-d]pyrimidin-4(3H)-one

Product 1

HCID 44539368HCID 44539368, compoundYield 78%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
40 °C

Procedure

A mixture of glutaric anhydride (73.0 mg, 0.640 mmol), (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (60 mg, 0.128 mmol) prepared in Example 1 and 4-pyrrolidinopyridine (18.96 mg, 0.128 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. for 25 hours. LC-MS indicated about 35% conversion. Additional portions of glutaric anhydride (130 mg) and 4-pyrrolidinopyridine (20 mg) were added. After stirring at 40° C. for another 16h, conversion was complete according to HP LC. The mixture was cooled to RT, diluted with CH2Cl2 (10 mL), washed with 1N HCl, brine-, died (Na2SO4), filtered, and evaporated to yield a white solid, which was purified by Preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A:100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 inn) to yield impure title compound (58 mg, 78%) as a white solid. The product was further purified by Preparative HPLC using CH3CN-system (PHENOMENEX® Luna Axia 5® C18 30×100 mm; 10 min gradient from 40% A: 60% B to 0% A: 100% B (A 90% H2O/10% CH3CN+0.1% TFA); (B=90% CH3CN/10% H2O+0.1% TFA); detection at 220 nm) to yield the title compound (40 mg, 0.069 mmol, 53.6% yield) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 0.33-0.43 (m, 1H), 0.45-0.55 (m, 1H), 0.55-0.68 (m, 2H), 1.06-1.18 (m, 1H), 1.85-1.95 (m, 2H), 2.30-2.45 (m, 4H), 3.86 (s, 3H), 4.23-4.35 (m, 2H), 4.64-4.73 (m, 1H), 6.87-6.96 (m, 2H), 7.03 (d, J=7.9 Hz, 2H), 7.44 (d, J=8.35 Hz, 2H), 7.53 (s, 1H), 7.65 (d, J=8.35 Hz, 2H), 8.24 (s, 1H). LC-MS, [M+H]-4=583.5. HPLC Method: Gradient solvent system from 100% A:0% B to 0% A:100% B (A=90% H2O/10% MeOH+0.2% H3PO4; B=90% MeOH/10% H2O+0.2% H3PO4) for 4 min; detection at 220 nm. YMC S3 ODS 4.6×50 mm Ballistic column; Retention time=4.35 min.

Workup

  1. temperatureThe mixture was cooled to RT
  2. washwashed with 1N HCl, brine-
  3. filtrationfiltered
  4. customevaporated
  5. customto yield a white solid, which
  6. customwas purified by Preparative HPLC (PHENOMENEX® Luna Axia 5μ C18 30×100 mm
  7. custom10 min gradient

Sources & evidence

ORD record
ord-f0f2b1f6dfab45fd9886ffe6598c3422
Source dataset
uspto-grants-2011_08
Patent number
US07989433B2

Reaction notes

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