Diisopropylethylamine → N-tert-butoxycarbonyl O-allyl L-seryl alpha,alpha-dimethylglycyl L-valyl O-allyl L-seryl glycine methyl ester

HRID 2370904Notes

Reaction equation

HRID 2370904 reaction equation
FC(F)(F)C(O)=O.[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH2:15].[C:23]([O:27][C:28]([NH:30][C@H:31]([C:37]([NH:39][C:40]([CH3:52])([CH3:51])[C:41]([NH:43][C@H:44]([C:48](O)=[O:49])[CH:45]([CH3:47])[CH3:46])=[O:42])=[O:38])[CH2:32][O:33][CH2:34][CH:35]=[CH2:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)C(C)C)(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:8][O:9][C:10](=[O:22])[CH2:11][NH:12][C:13](=[O:21])[C@H:14]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH:15][C:48](=[O:49])[C@H:44]([CH:45]([CH3:46])[CH3:47])[NH:43][C:41](=[O:42])[C:40]([CH3:52])([CH3:51])[NH:39][C:37](=[O:38])[C@H:31]([CH2:32][O:33][CH2:34][CH:35]=[CH2:36])[NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29]

Participants

7

Reactant 5

HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 86671353N-tert-butoxycarbonyl O-allyl L-seryl alpha,alpha-dimethylglycyl L-valineHCID 86671357O-allyl L-seryl glycine methyl ester trifluoroacetate

Product 1

HCID 86762377N-tert-butoxycarbonyl O-allyl L-seryl alpha,alpha-dimethylglycyl L-valyl O-allyl L-seryl glycine methyl esterYield 73%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

O-allyl L-seryl glycine methyl ester trifluoroacetate 20 (4.42 g, 13.4 mmol) was dissolved in CH2Cl2 (40 mL) and N-tert-butoxycarbonyl O-allyl L-seryl α,α-dimethylglycyl L-valine 16 (5.75 g, 13.4 mmol) added. N,N-diisopropylethyl amine (1.73 g, 13.4 mmol) and HOBt hydrate (2.05 g, 13.4 mmol) were added and the solution cooled to 0° C. EDC hydrochloride (2.82 g, 14.7 mmol) was added in small portions together with 10 mL CH2Cl2. The reaction mixture was stirred for 1 h 30 min at 0° C. after which the icebath was removed and the mixture stirred for an additional 26 hours. The solution was diluted by addition of CH2Cl2 (60 mL) and washed with 2 M aqueous H2SO4 (3×90 mL), 7.5% (w/w) aqueous K2CO3 (3×90 mL) and saturated brine (90 mL). The volume was increased by addition of CH2Cl2, the solution dried with anhydrous MgSO4 and the solvent evaporated affording a slightly orange solid (6.14 g, 73%); δH (300 MHz; d6-DMSO) 8.25 (1H, t, J 6, NH(Gly)), 8.14 (1H, s, NH(Aib)), 7.88 (1H, d, J 8, NH(Ser(All))), 7.14 (1H, d, J 8, NH(Val)), 6.84 (1H, d, J 7, NH (Ser(All)1)), 5.92-5.74 (2H, m, CH═CH2), 5.28-5.11 (4H, m, CH═CH2), 4.50 (1H, m, CαH(Ser(All)2)), 4.17-4.09 (2H, m, CαH(Ser(All)1)/CαH(Val)), 3.95 (4H, m, CH2CH═CH2), 3.85 (2H, d, J 6, CαH2(Gly)), 3.61 (3H, s, OCH3), 3.58-3.46 (4H, m, CH2), 2.06-1.95 (1H, m, CH(CH3)2), 1.38 (9H, s, (CH3)3), 1.35 (3H, s, CH3(Aib)), 1.34 (3H, s, CH3(Aib)), 0.83 (3H, d, J 7, CH3(Val)), 0.78 (3H, d, J 7, CH3(Val)); δC (75 MHz; d6-DMSO) 173.9, 170.7, 169.9, 169.8, 169.7, 155.3, 134.8, 116.4, 116.3, 78.4, 71.0, 69.4, 58.2, 56.2, 54.8, 54.5, 52.5, 51.6, 40.6, 30.0, 28.0, 24.9, 24.7, 19.0, 17.8; m/z 650.3366 ([M+Na]+; C29H49N5O10Na requires 650.3377)

Workup

  1. customwas removed
  2. stirringthe mixture stirred for an additional 26 hours
  3. additionThe solution was diluted by addition of CH2Cl2 (60 mL)
  4. washwashed with 2 M aqueous H2SO4 (3×90 mL), 7.5% (w/w) aqueous K2CO3 (3×90 mL) and saturated brine (90 mL)
  5. temperatureThe volume was increased by addition of CH2Cl2
  6. dry with materialthe solution dried with anhydrous MgSO4
  7. customthe solvent evaporated

Sources & evidence

ORD record
ord-7de31ebd30464dcbba82c554062bf832
Source dataset
uspto-grants-2014_04
Patent number
US08710008B2

Reaction notes

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