Formaldehyde → HCID 66588051, compound

HRID 625373Notes

Reaction equation

HRID 625373 reaction equation
[CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.CN(CC1N=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=CC=1)CCN1CCNCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>O1CCCC1>[CH3:1][N:2]([CH2:18][C:19]1[N:20]=[C:21]([C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)=[O:59])[CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1

Participants

7

Reactant 5

HCID 712FormaldehydeHCID 5049666Sodium triacetoxyborohydrideHCID 21863450Trifluoroacetic acid methylene chlorideHCID 66586745HCID 66586745, compoundHCID 66586859HCID 66586859, compound

Product 1

HCID 66588051HCID 66588051, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 8-mL sealed tube, was placed a solution of 6-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (100 mg, 0.14 mmol, 1.00 equiv) in tetrahydrofuran (3 mL), NaBH(OAc)3 (90 mg, 0.42 mmol, 3.00 equiv), and formaldehyde (2 mL). The resulting solution was stirred for overnight at 40° C. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 53.7 mg (27%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.44 (s, 1H), 9.82 (s, 1H), 9.58 (t, J=5.4 Hz, 1H), 9.06 (d, J=5.1 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.26 (s, 1H), 8.21-8.15 (m, 2H), 7.90-7.84 (m, 2H), 7.71-7.55 (m, 4H), 7.47 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 4.64-4.58 (m, 4H), 3.36-3.29 (m, 8H), 2.97 (s, 4H), 2.86 (s, 3H), 2.76 (s, 5H), 2.33-2.27 (m, 2H), 1.71-1.58 (m, 6H). MS (ES, m/z): 729 [M+H]+.

Workup

  1. customby partitioning between ethyl acetate and aqueous sodium bicarbonate solution
  2. customInto a 8-mL sealed tube
  3. concentrationThe resulting mixture was concentrated under vacuum
  4. customThe crude product (100 mg) was purified by reverse phase HPLC
  5. washeluting with a water/CH3CN gradient
  6. additioncontaining 0.05% TFA
  7. customThe product was obtained as 53.7 mg (27%) of as a yellow solid

Sources & evidence

ORD record
ord-8ee93ddebe824a0f901495a043c9da00
Source dataset
uspto-grants-2016_04
Patent number
US09301951B2

Reaction notes

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