1-(5-Cyano-2-pyridinyl)-4-piperidinecarboxylic acid → 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(SR)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile

HRID 2191147Notes

Reaction equation

HRID 2191147 reaction equation
ClC1C=CC(C2C(COC3C=CC(Cl)=CN=3)CCN(C(C3C=CC(C4ON=C(C)N=4)=CC=3)=O)C2)=CC=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][NH:46][CH2:45]2)=[CH:40][CH:39]=1.[C:61]([C:63]1[CH:64]=[CH:65][C:66]([N:69]2[CH2:74][CH2:73][CH:72]([C:75](O)=[O:76])[CH2:71][CH2:70]2)=[N:67][CH:68]=1)#[N:62]>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C@@H:44]2[C@@H:49]([CH:50]([NH:52][C:53]3[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][N:54]=3)[CH3:51])[CH2:48][CH2:47][N:46]([C:75]([CH:72]3[CH2:71][CH2:70][N:69]([C:66]4[CH:65]=[CH:64][C:63]([C:61]#[N:62])=[CH:68][N:67]=4)[CH2:74][CH2:73]3)=[O:76])[CH2:45]2)=[CH:40][CH:39]=1

Participants

4

Reactant 3

HCID 162274741-(5-Cyano-2-pyridinyl)-4-piperidinecarboxylic acidHCID 594381266-{1-[(3S,4S)-3-(4-Chloro-phenyl)-piperidin-4-yl]-ethylamino}-nicotinonitrileHCID 68473932[(3RS, 4RS)-3-(4-Chloro-phenyl)-4-(5-chloro-pyridin-2-yloxymethyl)-piperidin-1-yl]-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone

Product 1

HCID 594381214-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(SR)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2']bipyridinyl-5'-carbonitrile

Procedure

In analogy to the procedure described for the synthesis of [(3RS, 4RS)-3-(4-chloro-phenyl)-4-(5-chloro-pyridin-2-yloxymethyl)-piperidin-1-yl]-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone (example 1, step i) the title compounds were prepared from 6-{1-[(3S,4S)-3-(4-Chloro-phenyl)-piperidin-4-yl]-ethylamino}-nicotinonitrile and 5′-Cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid (commercially available) with subsequent separation via preparative HPLC on chiral pak AD eluting with heptane/ethanol to yield 4-{(3S,4S)-3-(4-Chloro-phenyl)-4-[(SR)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+] and 4-{(3S,45)-3-(4-Chloro-phenyl)-4-[(RS)-1-(5-cyano-pyridin-2-ylamino)-ethyl]-piperidine-1-carbonyl}-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile as off-white solid. MS (m/e): 554.4 [(M+H)+]

Workup

  1. customwith subsequent separation via preparative HPLC on chiral pak AD
  2. washeluting with heptane/ethanol

Sources & evidence

ORD record
ord-0fafad2d145048df951463ddb0d22c01
Source dataset
uspto-grants-2012_12
Patent number
US08324248B2

Reaction notes

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