1-Hydroxybenzotriazole → 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester

HRID 408625

Reaction equation

HRID 408625 reaction equation
[S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:24][O:25][C:26](=[O:46])[CH2:27][CH2:28][CH2:29][N:30]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1)[C:31]([C@@:33]1([CH3:37])[CH2:36][CH2:35][NH:34]1)=[O:32].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[CH3:24][O:25][C:26](=[O:46])[CH2:27][CH2:28][CH2:29][N:30]([C:31]([C@@:33]1([CH3:37])[CH2:36][CH2:35][N:34]1[C:6]([C:4]1[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=2[S:1][CH:5]=1)=[O:8])=[O:32])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[CH:40]=1

Participants

7

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 516892Sodium BicarbonateHCID 601280Benzo(b)thiophene-3-carboxylic acidHCID 705568104-[(3-chloro-benzyl)-((R)-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride

Product 1

HCID 705573284-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl esterYield 87%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolvent3×HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

To a suspension of benzo[b]thiophene-3-carboxylic acid (7.12 g, 1.2 eq.) in 210 mL of DCM and 210 mL of THF were added HOBt (5.4 g, 1.2 eq.) EDC.HCl (9.6 g, 1.5 eq.) and TEA (18.5 mL, 4 eq.). The reaction was stirred at 20° C. for 15 h, then a solution of 4-[(3-chloro-benzyl)-((R)-2-methyl-azetidine-2-carbonyl)-amino]-butyric acid methyl ester hydrochloride obtained in step i above (12.5 g, 1 eq.) in 105 mL of DCM and 105 mL of THF was added. The reaction was stirred at 20° C. for 4.5 h. The crude was diluted with DCM. A saturated aqueous solution of NaHCO3 was added. The aqueous layer was extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50) to afford 4-[[(R)-1-(benzo[b]thiophene-3-carbonyl)-2-methyl-azetidine-2-carbonyl]-(3-chloro-benzyl)-amino]-butyric acid methyl ester (14.53 g, yield=87%).

Workup

  1. stirringThe reaction was stirred at 20° C. for 4.5 h
  2. extractionThe aqueous layer was extracted three times with DCM
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 90/10 to 50/50)

Sources & evidence

ORD record
ord-c0471365e74041c686816c41d600d815
Source dataset
uspto-grants-2014_06
Patent number
US08759334B2

Linked notes

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