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Trifluoroacetic acid → cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-ylmethyl]-amine

HRID 2078710
Notes
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Reaction equation

HRID 2078710 reaction equation
C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:19]1[C:20]2[S:33][CH:32]=[CH:31][C:21]=2[N:22](C(OC(C)(C)C)=O)[N:23]=1)=O)(C)(C)C.[NH2:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1.C([BH3-])#N.C(OC(N1C2C(=CC(CNCC3CCCCC3)=CC=2)C=C1C1C2SC=CC=2N(C(OC(C)(C)C)=O)N=1)=O)(C)(C)C.C(OC(N1C2C(=CC(CNCC3CCCCC3)=CC=2)C=C1C1C2SC=CC=2NN=1)=O)(C)(C)C.C(OC(N1C2C=CSC=2C(C2NC3C(C=2)=CC(CNCC2CCCCC2)=CC=3)=N1)=O)(C)(C)C.FC(F)(F)C(O)=O>CN(C)C=O.ClCCl.C(O)(=O)C>[CH:36]1([CH2:35][NH:34][CH2:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][C:9]([C:19]2[C:20]4[S:33][CH:32]=[CH:31][C:21]=4[NH:22][N:23]=2)=[CH:10]3)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

11

Reactant 7

HCID 6422Trifluoroacetic acidHCID 76688CyclohexanemethylamineHCID 498716Cyano-borohydrideHCID 576373352-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester2×HCID 670974995-[(cyclohexylmethyl-amino)-methyl]-2-(1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester
HCID 67098454
2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-[(cyclohexylmethyl-amino)-methyl]-indole-1-carboxylic acid tert-butyl ester
HCID 1363667803-{5-[(cyclohexylmethyl-amino)-methyl]-1H-indol-2-yl}-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 135431571cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-ylmethyl]-amine

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

A mixture of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-formyl-indole-1-carboxylic acid tert-butyl ester [200 mg, 1 eq, Intermediate (11) prepared as described in Step 1 of Example 24], aminomethylcyclohexane (1.1 eq), MP-cyanoborohydride (macroporous triethylammonium methylpolystyrene cyanoborohydride, 1.5 eq), and acetic acid (0.5 ml) in dimethyl formamide (10 ml) at room temperature was shaken overnight. The resin was filtered and the filtrate was poured into water. The mixture was extracted twice with ethyl acetate; the extract was dried over magnesium sulfate and concentrated. The residue was purified by silica gel column (eluted by 20% methanol in ethyl acetate) to yield a mixture of 2-(1-tert-butoxycarbonyl-1H-thieno[3,2-c]pyrazol-3-yl)-5-[(cyclohexylmethyl-amino)-methyl]-indole-1-carboxylic acid tert-butyl ester [major product, LC/MS: 565 (M+H), RT=3.5 minutes], 5-[(cyclohexylmethyl-amino)-methyl]-2-(1H-thieno[3,2-c]pyrazol-3-yl)-indole-1-carboxylic acid tert-butyl ester and 3-{5-[(cyclohexylmethyl-amino)-methyl]-1H-indol-2-yl}-thieno[3,2-c]pyrazole-1-carboxylic acid tert-butyl ester. This mixture was treated with trifluoroacetic acid in dichloromethane (10 ml, 1:1) at room temperature for 2 hours and the reaction mixture was passed through SCX column eluting with 7N ammonia in methanol affording cyclohexylmethyl-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-ylmethyl]-amine [Example 52]. LC/MS: 365 (M+H), RT=2.5 minutes; 1H NMR [(CD3)2SO)]: δ 11.4 (1H, s), 7.8 (d, 2H), 7.5 (1H, s), 7.4 (1H, d), 7.2 (1H, d), 7.0 (1H, d), 6.6 (1H, s), 3.8 (2H, s) 2.2 (2H, d), 1.8-2.0 (4H, m), 1.0-1.2 (4H, m), 0.8-1.0 (3H, m).

Workup

  1. filtrationThe resin was filtered
  2. additionthe filtrate was poured into water
  3. extractionThe mixture was extracted twice with ethyl acetate
  4. dry with materialthe extract was dried over magnesium sulfate
  5. concentrationconcentrated
  6. customThe residue was purified by silica gel column (eluted by 20% methanol in ethyl acetate)
  7. customto yield
  8. washeluting with 7N ammonia in methanol

Sources & evidence

ORD record
ord-34185efa9d0f4feb9899cd6094c5dce2
Source dataset
uspto-grants-2011_04
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07928231B2

Reaction notes

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