Hydrochloric Acid → (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)acrylic acid

HRID 1008975Notes

Reaction equation

HRID 1008975 reaction equation
[CH:1]1([C:7]2[C:8]3[S:25][C:24]([C:26](O)=[O:27])=[CH:23][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]4[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].C([O:32][C:33](=[O:51])/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:43]([C:45]2([NH3+:50])[CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:44])=[CH:38][CH:37]=1)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O[Li].O.Cl>CN(C=O)C.CCOC(C)=O.C1COCC1.CO.O>[CH:1]1([C:7]2[C:8]3[S:25][C:24]([C:26]([NH:50][C:45]4([C:43]([NH:42][C:39]5[CH:38]=[CH:37][C:36](/[CH:35]=[CH:34]/[C:33]([OH:51])=[O:32])=[CH:41][CH:40]=5)=[O:44])[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:27])=[CH:23][C:9]=3[N:10]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:13]4[CH:19]=[CH:20][CH:21]=[CH:22][C:12]=4[C:11]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 168937Lithium hydroxide, monohydrateHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 1594889713-Cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[2,1-a][2,5] benzodiazocine-11-carboxylic acidHCID 866297801-[({4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]phenyl}amino)carbonyl]cyclopentanaminium chloride

Product 1

HCID 15947224(2E)-3-(4-{[(1-{[(13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2',3':4,5]pyrrolo[2,1-a][2,5]benzodiazocin-11-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)acrylic acid

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 21892291Methanol tetrahydrofuran waterSolvent

Conditions

Temperature
40 °C

Procedure

A solution of 13-cyclohexyl-6-methyl-5,6,7,8-tetrahydrothieno[2′,3′:4,5]pyrrolo[2,1-a][2,5]benzodiazocine-11-carboxylic acid (1 eq, from Example 3), 1-[({4-[(1E)-3-ethoxy-3-oxoprop-1-en-1-yl]phenyl}amino)carbonyl]cyclopentanaminium chloride (1.3 eq.) and DIPEA (4 eq) in anhydrous DMF (0.025 M) was treated with HATU (1.3 eq.) and stirred overnight at 40° C. The reaction mixture was then diluted with EtOAc, washed with aqueous HCl (1M solution), aqueous NaHCO3 (saturated solution) and brine. The foregoing compound (1 eq.) was dissolved in THF/MeOH/H2O (4:1:1, 0.025 M) and treated with LiOH.H2O (2 eq) at RT for 3 h. The acidified (1N HCl) reaction mixture was purified by RP-HPLC (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min) to afford, after freeze-drying, the title compound (0.16 eq) as a colourless powder. 1H NMR (400 MHz, DMSO, 300 K, δ) 12.36 (bs, 1H), 10.02 (bs, 1H), 9.68 (s, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.92-7.47 (m, 9H), 6.40 (d, J 15.8, 1H), 4.47-4.39 (m, 2H), 4.02-3.15 (m, 4H, partially hidden by H2O signal), 3.07 (s, 3H), 2.50 (m, 1H, hidden by the DMSO signal), 2.38-1.05 (m, 18H); MS (ES+) m/z 651 (M)+.

Workup

  1. washwashed with aqueous HCl (1M solution), aqueous NaHCO3 (saturated solution) and brine
  2. customwas purified by RP-HPLC (Conditions
  3. wait75% A isocratic for 3 min
  4. customlinear to 20% A in 12 min) to afford
  5. customafter freeze-drying

Sources & evidence

ORD record
ord-d34b2d077cbe4139bac91040cb854b64
Source dataset
uspto-grants-2011_07
Patent number
US07973026B2

Reaction notes

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