Trifluoroacetic acid → 1-[4-[2-(Azetidin-1-yl)-ethoxy]-4-pyridin-3-yl-piperidin-1-yl]-2-[[(2S)-1-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-piperidin-2-yl]-methoxy]-ethanone

HRID 1881700Notes

Reaction equation

HRID 1881700 reaction equation
[N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.[CH3:34][O:35][C:36]1[CH:41]=[C:40]([CH3:42])[C:39]([S:43]([N:46]2[CH2:51][CH2:50][CH2:49][CH2:48][C@H:47]2[CH2:52][O:53][CH2:54]C(O)=O)(=[O:45])=[O:44])=[C:38]([CH3:58])[CH:37]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]1([CH2:5][CH2:6][O:7][C:8]2([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:15])[CH2:54][O:53][CH2:52][C@@H:47]3[CH2:48][CH2:49][CH2:50][CH2:51][N:46]3[S:43]([C:39]3[C:40]([CH3:42])=[CH:41][C:36]([O:35][CH3:34])=[CH:37][C:38]=3[CH3:58])(=[O:45])=[O:44])[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4]1

Participants

8

Reactant 6

HCID 6422Trifluoroacetic acidHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57819715(S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acidHCID 57916280Tert-butyl 4-(2-(azetidin-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate

Product 1

HCID 444661441-[4-[2-(Azetidin-1-yl)-ethoxy]-4-pyridin-3-yl-piperidin-1-yl]-2-[[(2S)-1-[(4-methoxy-2,6-dimethyl-phenyl)sulfonyl]-piperidin-2-yl]-methoxy]-ethanoneYield 39%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent3×

Conditions

Temperature
0 °C

Procedure

After the BOC deprotection of tert-butyl 4-(2-(azetidin-1-yl)ethoxy)-4-(pyridin-3-yl)piperidine-1-carboxylate [amine E] (0.15 g, 1.2 eq.) in the presence of TFA (10-13 eq.) in methylene chloride (see e.g. stage (iii)/amine H), the amine was added to a cooled (0° C.) solution comprising (S)-2-((1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methoxy)acetic acid [acid D] (1 eq.), EDCl (1.5 eq.), HOBT (1 eq.) and DIPEA (3 eq.) in methylene chloride (10 ml). When the addition was complete, the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was diluted with methylene chloride and washed with aqueous ammonium chloride solution and aqueous sodium bicarbonate solution. After concentration, the crude product was purified by means of column chromatography (Alox). Yield: 39%. MS, Rt=2.7 min, m/z=615.4 [MH]+

Workup

  1. additionWhen the addition
  2. temperaturethe reaction mixture was warmed to room temperature
  3. washwashed with aqueous ammonium chloride solution and aqueous sodium bicarbonate solution
  4. concentrationAfter concentration
  5. customthe crude product was purified by means of column chromatography (Alox)

Sources & evidence

ORD record
ord-654a91a68a0444e883a2102ef1ffad61
Source dataset
uspto-grants-2012_11
Patent number
US08318769B2

Reaction notes

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