1,2-Dichloroethane → 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine

HRID 2091729Notes

Reaction equation

HRID 2091729 reaction equation
Cl.[CH2:2]([C:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[N:6][N:5]=1)[CH3:3].[CH3:13][C:14]([CH3:34])([O:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:21][C:22](O)=[O:23])=[O:18])[CH3:15].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH3:15][C:14]([CH3:34])([O:16][C:17]([NH:19][C@H:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:21][C:22]([N:11]1[CH2:10][CH2:9][N:8]2[C:4]([CH2:2][CH3:3])=[N:5][N:6]=[C:7]2[CH2:12]1)=[O:23])=[O:18])[CH3:13]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 7009791(R)-3-((tert-butoxycarbonyl)amino)-4-(3,4-difluorophenyl)butanoic acidHCID 670584843-Ethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride

Product 1

HCID 112362567-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazineYield 38.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

The title compound was prepared from 3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (400 mg, 2.12 mmol, from Step B), (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoic acid (668 mg, 2.12 mmol), DIPEA (1.1 mL, 4.24 mmol), HOBT (343.8 mg, 2.54 mmol) and EDC (609.6 mg, 3.18 mmol) in 20 mL of dichloromethane, using a procedure analogous to that described in Example 1, Step C. The crude product was purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.% trifluoroacetic acid) to give 366.3 mg of the title compound as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 1.31-1.34 (m, 12H), 2.67-2.92 (m, 6H), 4.03-4.12 (m, 4H), 5.03-5.31 (m, 3H), 6.93 (s, 1H), 7.05 (m, 2H). ESI-MS 450 (M+1).

Workup

  1. customThe crude product was purified by HPLC (Gilson; YMC-Pack Pro C18 column, 100×20 mm I.D.; solvent gradient from 10% acetonitrile, 90% water, and 0.1% trifluoroacetic acid to 90% acetonitrile, 10% water, and 0.% trifluoroacetic acid)

Sources & evidence

ORD record
ord-7962fa2570054c9e824daee9b1349cf5
Source dataset
uspto-grants-2013_05
Patent number
US08440668B2

Reaction notes

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