Piperidine → SHP-627

HRID 2175678Notes

Reaction equation

HRID 2175678 reaction equation
N1CCCCC1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20])[CH:12]=O.C([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:10]=[C:11](/[CH:12]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][CH2:18][C:19]#[CH:20]

Participants

5

Reactant 3

HCID 8082PiperidineHCID 4399222-(2-Carboxyacetamido)benzoic acidHCID 31440663-Methoxy-4-prop-2-ynyloxy-benzaldehyde

Product 1

HCID 23648966SHP-627Yield 61.1%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

Piperidine (158 mL, 1.59 mol) was added to a suspension of 3-methoxy-4-propargyloxybenzaldehyde (302 g, 1.59 mol) and 2-[(carboxyacetyl)amino]benzoic acid (322 g, 1.44 mol) in toluene (1.5 L). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 L) and water (1 L) at 50° C. and the solution was acidified with 50% aqueous AcOH. The precipitate was filtered and the crude product was recrystallised from EtOH (35 mL/g), filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-propargyloxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (309 g, 61%) as a yellow crystalline solid; mp 201-203° C.; δH (400 MHz, DMSO-d6) 3.59 (t, J=2.4 Hz, 1H, C≡CH), 3.84 (s, 3H, OCH3), 4.84 (d, J=2.4 Hz, 2H, OCH2), 6.81 (d, J=15.6 Hz, 1H, CH═CHCO), 7.05 (d, J5,6=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.25 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.41 (s, 1H, H2′), 7.56 (d, J=15.6 Hz, 1H, CH═CHCO), 7.61 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.62 (d, J5,6=8.0 Hz, 1H, H6), 11.31 (s, 1H, NH), 13.57 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 55.9, 78.6, 79.1, 110.8, 113.5, 116.6, 120.4, 120.4, 122.2, 122.7, 128.2, 131.2, 134.0, 141.0, 141.5, 148.3, 149.3, 164.1, 169.5; HRMS (ESI) calculated for C20H17NO5 [M+H]+ 352.1179, found 352.1187; νmax 755, 1010, 1140, 1253, 1502, 1582, 1657, 3278, 3522 cm−1.

Workup

  1. customThe reaction flask was fitted with a Dean-Stark apparatus
  2. temperatureheated
  3. temperatureto reflux for 30 min
  4. filtrationthe resulting suspension was filtered
  5. washwashed with toluene
  6. dissolutionThe piperidinium salt was dissolved in MeOH (4 L)
  7. customat 50° C.
  8. filtrationThe precipitate was filtered
  9. customthe crude product was recrystallised from EtOH (35 mL/g)
  10. filtrationfiltered
  11. washwashed with cooled EtOH

Sources & evidence

ORD record
ord-6b523ced8e5b448fb226ab5ab4270c80
Source dataset
uspto-grants-2015_06
Patent number
US09062076B2

Reaction notes

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