Diisopropylethylamine → 4-(4-(1-(4-(2-(1-methylethylsulfonamido)-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)benzamide

HRID 1618342Notes

Reaction equation

HRID 1618342 reaction equation
[N:1]1([CH2:6][C:7]2([CH2:10][NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[N:26]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:24]=[C:23]([NH:33][C:34]5([C:37]6[CH:47]=[CH:46][C:40]([O:41][CH2:42][C:43](O)=[O:44])=[CH:39][CH:38]=6)[CH2:36][CH2:35]5)[N:22]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:48][CH:49]([S:51]([NH2:54])(=[O:53])=[O:52])[CH3:50].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:48][CH:49]([S:51]([NH:54][C:43](=[O:44])[CH2:42][O:41][C:40]1[CH:39]=[CH:38][C:37]([C:34]2([NH:33][C:23]3[N:24]=[C:25]([O:27][CH2:28][C:29]([F:32])([F:30])[F:31])[N:26]=[C:21]([NH:20][C:17]4[CH:16]=[CH:15][C:14]([C:12]([NH:11][CH2:10][C:7]5([CH2:6][N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)[CH2:9][CH2:8]5)=[O:13])=[CH:19][CH:18]=4)[N:22]=3)[CH2:35][CH2:36]2)=[CH:47][CH:46]=1)(=[O:53])=[O:52])[CH3:50]

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 3549191Propane-2-sulfonamideHCID 680331262-(4-(1-(4-(4-((1-(Pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid

Product 1

HCID 681827824-(4-(1-(4-(2-(1-methylethylsulfonamido)-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)benzamideYield 21.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

2-(4-(1-(4-(4-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methylcarbamoyl)phenylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)cyclopropyl)phenoxy)acetic acid (20 mg, 0.031 mmol), propane-2-sulfonamide (4.88 mg, 0.040 mmol), PyBOP (23.81 mg, 0.046 mmol), and Hunig's Base (0.027 mL, 0.153 mmol) were stirred in DCM (Volume: 3 mL) for 3 days. The solvent was removed and the crude material was purified by Prep-HPLC (Column: Sunfire prep C18 OBO 5 uM, 30×100 mm by Waters Corp) using a gradient of 10-60% ACN/water w/0.1% TFA modifier to give 4-(4-(1-(4-(2-(1-methylethylsulfonamido)-2-oxoethoxy)phenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)-N-((1-(pyrrolidin-1-ylmethyl)cyclopropyl)methyl)benzamide (5 mg). 1H NMR (500 MHz, MeOD) δ ppm 0.75 (s, 2H), 0.83 (s, 2H), 1.14-1.42 (m, 10H), 2.12-2.26 (m, 4H), 3.06-3.43 (m, 7H), 3.77-3.88 (m, 2H), 4.64 (s, 2H), 4.81-4.92 (m, 2H), 6.86-7.00 (m, 2H), 7.21-7.32 (m, 2H), 7.64-7.76 (m, 3H), 7.89 (s, 1H); LC-MS (Condition A), MS m/z (M++H) 761.2.

Workup

  1. customThe solvent was removed
  2. customthe crude material was purified by Prep-HPLC (Column: Sunfire prep C18 OBO 5 uM, 30×100 mm by Waters Corp)

Sources & evidence

ORD record
ord-f74a5a56cc414eb9aec332a00e445528
Source dataset
uspto-grants-2014_07
Patent number
US08765944B2

Reaction notes

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