Methyl 2-chloro-6-methoxyisonicotinate → 2-Cyclopentyl-6-methoxy-isonicotinic acid methyl ester

HRID 2278768Notes

Reaction equation

HRID 2278768 reaction equation
[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6](Cl)[CH:5]=1.[Br-].[CH:15]1([Zn+])[CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1

Participants

4

Reactant 2

HCID 13339618Methyl 2-chloro-6-methoxyisonicotinateHCID 178419768HCID 178419768, compound

Product 1

HCID 674912832-Cyclopentyl-6-methoxy-isonicotinic acid methyl ester

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
85 °C

Procedure

Under argon, Pd(dppf) (2.00 g, 2.4 mmol) is added to a solution of 2-chloro-6-methoxy-isonicotinic acid methyl ester (32.0 g, 0.159 mol) in THF (100 mL). A 0.5 M solution of cyclopentylzincbromide in THF (330 mL) is added via dropping funnel. Upon complete addition, the mixture is heated to 85° C. for 3 h before it is cooled to rt. The reaction mixture is concentrated, diluted with 1 N aq. HCl (275 mL) and extracted with TBME (275 mL). The org. extract is washed with 1 N aq. HCl (275 mL), filtered over Celite and washed with water (275 mL). The org. extract is concentrated and dried to give crude 2-cyclopentyl-6-methoxy-isonicotinic acid methyl ester (34.8 g) as a brown oil. This material is dissolved in ethanol (180 mL), water (45 mL) and 32% aq. NaOH solution (45 mL). The mixture is stirred at 90° C. for 30 min before it is cooled to rt. The ethanol is evaporated and the remaining solution is diluted with water (150 mL) and extracted with DCM (200 mL). The aq. phase is acidified by adding 32% aq. HCl (45 mL) and then extracted twice with DCM (2×100 mL). The org. extracts are combined and concentrated. The crude product is purified by crystallisation from hot acetonitrile (174 mL). The crystalline material is collected and dried at 50° C. under HV. From the mother liquor a second crop of crystalline material can be obtained. The two crops are combined to give 2-cyclopentyl-6-methoxy-isonicotinic acid (24.1 g) as a pale grey crystalline powder; LC-MS: tR=0.93 min, [M+1]+=222.02; 1H NMR (CDCl3): δ1.68-1.77 (m, 2H), 1.81-1.90 (m, 4H), 2.03-2.12 (m, 2H), 3.15-3.25 (m, 1H), 3.99 (s, 3H), 7.18 (d, J=1.0 Hz, 1H), 7.35 (d, J=0.8 Hz, 1H).

Workup

  1. additionUpon complete addition
  2. temperatureis cooled to rt
  3. concentrationThe reaction mixture is concentrated
  4. additiondiluted with 1 N aq. HCl (275 mL)
  5. extractionextracted with TBME (275 mL)
  6. extractionextract
  7. washis washed with 1 N aq. HCl (275 mL)
  8. filtrationfiltered over Celite
  9. washwashed with water (275 mL)
  10. extractionextract
  11. concentrationis concentrated
  12. customdried

Sources & evidence

ORD record
ord-9ec2bf51e2b24ae7ae2ef7847d450c21
Source dataset
uspto-grants-2015_09
Patent number
US09133179B2

Reaction notes

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