Diisopropylcarbodiimide → (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)-propanoate

HRID 1668309Notes

Reaction equation

HRID 1668309 reaction equation
[C:1]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:29][C:28]3[C:27](=[O:30])[N:26]([C:31]4[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]5(O)[CH2:42][C:41]([F:44])([F:43])[CH2:40]5)=[C:33]([O:46][CH3:47])[CH:32]=4)[CH:25]=[N:24][C:23]=3[CH:22]=2)=[CH:17][CH:16]=1.C(N=C=NC(C)C)(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([O:13][C:39]1([CH2:38][O:37][C:34]2[CH:35]=[CH:36][C:31]([N:26]3[C:27](=[O:30])[C:28]4[S:29][C:21]([C:18]5[CH:17]=[CH:16][C:15]([Cl:14])=[CH:20][CH:19]=5)=[CH:22][C:23]=4[N:24]=[CH:25]3)=[CH:32][C:33]=2[O:46][CH3:47])[CH2:40][C:41]([F:44])([F:43])[CH2:42]1)=[O:12])=[O:2])([CH3:7])([CH3:5])[CH3:6]

Participants

5

Reactant 3

HCID 12734DiisopropylcarbodiimideHCID 85082Tert-butoxycarbonylalanineHCID 57988809HCID 57988809, compound

Product 1

HCID 57988835(S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)-propanoateYield 88%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of Boc-alanine (94 mg, 0.495 mmol), 6-(4-chlorophenyl)-3-(4-((3,3-difluoro-1-hydroxycyclobutyl)methoxy)-3-methoxyphenyl)thieno[3,2-d]pyrimidin-4(3H)-one (50 mg, 0.099 mmol) from Example 2,4-pyrrolidinopyridene (14.68 mg, 0.099 mmol) and N,N′-diisopropylcarbodiimide (0.077 mL, 0.495 mmol) in CH2Cl2 (4 mL) was stirred at 40° C. in a sealed tube for 18 hours. After cooling to RT and removal of the volatiles under vacuum, the crude product was subjected to gradient chromatography (silica gel/EtOAc/hexane 0 to 30%) to afford (S)-1-((4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutyl 2-(tert-butoxycarbonylamino)propanoate (59 mg, 0.087 mmol, 88% yield) as off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.13 (1 H, s), 7.66 (2 H, d), 7.54 (1 H, s), 7.46 (2 H, d), 6.87-7.06 (3 H, m), 4.96 (1 H, br. s.), 4.34-4.48 (2H, m), 4.20-4.34 (1 H, m), 3.87 (3 H, s), 3.09-3.24 (2 H, m), 2.97 (2 H, broad s.), 1.45 (9 H, s), 1.38 (3 H, d, J=7.30 Hz). LC-MS: 2.72 min 677 (M+H). Luna 5 u C18 30×4.6 mm ID, flow rate=4 ml/min., gradient=0% A to 100% B in 2 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA).

Workup

  1. temperatureAfter cooling to RT
  2. customremoval of the volatiles under vacuum

Sources & evidence

ORD record
ord-dd5ca769139a4eaea71830c8c557c936
Source dataset
uspto-grants-2011_08
Patent number
US07989433B2

Reaction notes

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