2-Nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-one → (1S,2S,3R,4R)-3-[5-Chloro-2-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide

HRID 1687530Notes

Reaction equation

HRID 1687530 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=2[CH:13]=1.ClC1N=C(NC2C=CC=CC=2C2N(C)C=CN=2)C(Cl)=CN=1.Cl[C:36]1[N:41]=[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])[C:39]([Cl:53])=[CH:38][N:37]=1.[N+](C1C=CC2CCC(=O)CCC=2C=1)([O-])=O>>[Cl:53][C:39]1[C:40]([NH:42][C@@H:43]2[C@@H:48]3[CH2:49][C@@H:45]([CH:46]=[CH:47]3)[C@@H:44]2[C:50]([NH2:52])=[O:51])=[N:41][C:36]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7][C:6]=3[CH:13]=2)=[N:37][CH:38]=1

Participants

5

Reactant 4

HCID 457903192-Nitro-8,9-dihydro-5H-benzo[7]annulen-7(6H)-oneHCID 57522618HCID 57522618, compoundHCID 672635032-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol2×HCID 86633891(2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine

Product 1

HCID 67264345(1S,2S,3R,4R)-3-[5-Chloro-2-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide

Procedure

Prepared analogously to Example 216d replacing 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine with 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol and (2,5-Dichloro-pyrimidin-4-yl)-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-amine was replaced with (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. 2-Amino-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ol is a byproduct from the reductive amination of 2-Nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one with various amines. The reaction was carried out in the presence of the desired reductive amination product to provide a crude mixture of amino and alcohol products. The crude mix was then reduced and a mixture of amino and alcohol products were used in the synthesis of target compounds. The mixture was then purified by prep HPLC to afford the desired amino compound as well as (1S,2S,3R,4R)-3-[5-Chloro-2-(7-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamino)-pyrimidin-4-ylamino]-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide. LC/MS (ESI): 440.22. 1H NMR (400 MHz, DMSO, d6) δ 9.12 (s, 1H), 7.93 (s, 1H), 7.78 (s, 1H), 7.69 (m, 1H), 7.46 (m, 2H), 7.26 (s, 1H), 6.97 (d, 1H, J=8.08 Hz), 6.35 (m, 1H), 6.27 (m, 1H), 4.58 (m, 1H), 4.15 (m, 1H), 3.72 (m, 1H), 3.31 (s, 2H), 2.88 (s, 1H), 2.78 (m, 3H), 2.11 (d, 1H, J=8.59 Hz), 1.89 (m, 2H), 1.41 (d, 1H, J=8.09 Hz), 1.33 (m, 2H).

Workup

  1. customPrepared analogously to Example 216d
  2. customto provide a crude
  3. additionThe crude mix
  4. customwere used in the synthesis of target compounds
  5. customThe mixture was then purified by prep HPLC

Sources & evidence

ORD record
ord-edf1df14719d41a080f295c24181bd1c
Source dataset
uspto-grants-2012_04
Patent number
US08148391B2

Reaction notes

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