Ethanone, 1-(4-chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]- → (S)-N-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide

HRID 2279458Notes

Reaction equation

HRID 2279458 reaction equation
FC1C=C([C@H](N[C:26]([N:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[N:33][C:32]([NH:38][CH:39]([CH3:41])[CH3:40])=[N:31][C:30]=3[CH2:29]2)=[O:27])[C@H]2CCCN2C(OC(C)(C)C)=O)C=CC=1C(F)(F)F.[Si]([O:49][CH2:50][C@H:51]([C:53]1[CH:58]=[CH:57][C:56]([Cl:59])=[C:55](F)[CH:54]=1)[NH2:52])(C(C)(C)C)(C)C.[Si](OCC(C1C=CC([Cl:78])=C(F)C=1)=O)(C(C)(C)C)(C)C.O1CCC(NC2N=CC3CCN(C(OC(C)(C)C)=O)CC=3N=2)CC1>>[Cl:78][C:55]1[CH:54]=[C:53]([C@H:51]([NH:52][C:26]([N:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[N:33][C:32]([NH:38][CH:39]([CH3:41])[CH3:40])=[N:31][C:30]=3[CH2:29]2)=[O:27])[CH2:50][OH:49])[CH:58]=[CH:57][C:56]=1[Cl:59]

Participants

5

Reactant 4

HCID 68294408Ethanone, 1-(4-chloro-3-fluorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-HCID 68295332tert-butyl 2-(tetrahydro-2H-pyran-4-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxylateHCID 86705474(S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine2×HCID 131733484(R)-tert-butyl 2-((S)-(3-fluoro-4-(trifluoromethyl)phenyl)(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)methyl)pyrrolidine-1-carboxylate

Product 1

HCID 60198327(S)-N-(1-(3,4-dichlorophenyl)-2-hydroxyethyl)-2-(isopropylamino)-5,6-dihydropyrido[3,4-d]pyrimidine-7(8H)-carboxamide

Procedure

To a solution of 1-(3,4-dichlorophenyl)-2-hydroxyethanone (11.86 g, 57.843 mmol, CASRN 113337-38-5), imidazole (5.91 g, 86.764 mmol), and DMAP (0.71 g, 5.7843 mmol) in DMF (100 mL) cooled to 0° C. was added slowly tert-butylchlorodimethylsilane (10.898 g, 72.304 mmol) and the reaction was stirred at RT for 18 h. Water was added and the mixture was extracted with ether. The organic layer was dried, filtered, and concentrated. The crude residue was purified by passage through a SiO2 plug eluting with an EtOAc/hexane gradient (10 to 50% EtOAc) to afford 12.15 g (82.0%) of 2-(tert-butyldimethylsilyloxy)-1-(3,4-dichlorophenyl)ethanone (84). Conversion of 84 to (S)-2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanamine (85) was carried out in accord with the procedure in steps 3 to 5 of example 10 except in step 3,2-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethanone (62) was replaced with 84. The title compound was prepared from 85 in accord with the procedure in steps 6 and 7 of example 10 except in step 6, 72 was used in place of 26 and 85 was used in place of 68 to afford 136 mg (56%) of I-16: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.42 (m, 2H), 7.18 (d, 1H), 5.32 (m, 1H), 4.95 (m, 1H), 4.81 (d, 1H), 4.38 (s, 2H), 4.10 (m, 1H), 3.92 (m, 1H), 3.83 (m, 1H), 3.75-3.60 (m, 2H), 2.67 (t, 2H), 2.55 (bs, 1H), 1.22 (d, 6H); LCMS (ACPI-pos) m/z 426.4 (M+H)+.

Workup

  1. customto afford 136 mg (56%) of I-16

Sources & evidence

ORD record
ord-fe0a2b49dd8041faae936cdc07c28e1c
Source dataset
uspto-grants-2015_09
Patent number
US09133187B2

Reaction notes

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