Hydrochloric Acid → ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

HRID 882143Notes

Reaction equation

HRID 882143 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([O-])=[O:28])[CH3:24].[Na+].Cl.O1CCOCC1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CN(C=O)C>[CH3:22][N:23]([CH2:25][C:26](=[CH2:30])[C:27]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:28])[CH3:24]

Participants

7

Reactant 5

HCID 313Hydrochloric AcidHCID 312751,4-DioxaneHCID 111923Propylphosphonic anhydrideHCID 71598790ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylateHCID 89613520Sodium 2-[(dimethylamino)methyl]prop-2-enoate

Product 1

HCID 89630135ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To methyl 2-[(dimethylamino)methyl]prop-2-enoate (314 mg, 2.19 mmol) in tetrahydrofuran (1.4 mL) and water (1.4 mL) was added LiOH (52.5 mg, 2.19 mmol). The solution was stirred at 40° C. for 4 hours, before being frozen and lyophilized to afford sodium 2-[(dimethylamino)methyl]prop-2-enoate which was used as is in the next step as is. To a solution of ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (100 mg, 0.354 mmol) in DMF (886 μL) was added sequentially sodium 2-[(dimethylamino)methyl]prop-2-enoate (96 mg, 0.71 mmol), 4 M solution of HCl in dioxane (177 μL, 0.708 mmol), TEA (197 μL, 1.42 mmol), and 1-propanephosphonic acid cyclic anhydride (422 μL, 0.708 mmol) at room temperature. The reaction was stirred overnight before being purified by reverse phase HPLC using an acetonitrile gradient in water with 0.1% TFA modifier. The combined fractions with the desired product were concentrated until only the water layer remained and the water layer was neutralized with saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate (×5). The combined organic fractions were dried with sodium sulfate, filtered and concentrated under reduced pressure to give ethyl 4-[3-({2-[(dimethylamino)methyl]acryloyl}amino)phenyl]-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate. LRMS (ESI) calc'd for C21H24N5O3 [M+H]+: 394, found 394. 1H NMR (600 MHz, DMSO-D6) δ 12.9 (s, 1H), 11.1 (s, 1H), 8.90 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.77 (d, 1H, J=8.21 Hz), 7.42 (t, 1H, J=8.21 Hz), 7.35 (d, 1H, J=7.63 Hz), 6.01 (s, 1H), 5.58 (s, 1H), 3.87 (q, 2H, J=7.04 Hz), 3.23 (s, 2H), 2.24 (s, 6H), 0.86 (t, 3H, J=7.04 Hz).

Workup

  1. custombefore being purified by reverse phase HPLC
  2. concentrationThe combined fractions with the desired product were concentrated until only the water layer
  3. extractionthe mixture was extracted with ethyl acetate (×5)
  4. dry with materialThe combined organic fractions were dried with sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-7921c582128c41dfa6ffe4ce2df584ba
Source dataset
uspto-grants-2015_03
Patent number
US08993756B2

Reaction notes

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