Hydrochloric Acid → 1-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride

HRID 1040334Notes

Reaction equation

HRID 1040334 reaction equation
C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[C:43]([C:45]([OH:47])=O)[CH:42]=[CH:41][C:40]=2[C:48]2[C:53]([O:54][CH3:55])=[CH:52][CH:51]=[CH:50][C:49]=2[O:56][CH3:57])=[CH:35][C:34]=1[O:58][CH2:59][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63].[NH2:65][C:66]1([C:72]([OH:74])=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl>CN(C=O)C.C(#N)C.CCOC(C)=O.CCOCC.O>[ClH:32].[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:44]=[C:43]([C:45]([NH:65][C:66]3([C:72]([OH:74])=[O:73])[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]3)=[O:47])[CH:42]=[CH:41][C:40]=2[C:48]2[C:49]([O:56][CH3:57])=[CH:50][CH:51]=[CH:52][C:53]=2[O:54][CH3:55])=[CH:35][C:34]=1[O:58][CH2:59][CH2:60][CH2:61][N:62]([CH3:64])[CH3:63]

Participants

11

Reactant 6

HCID 313Hydrochloric AcidHCID 13661-Aminocyclohexanecarboxylic acidHCID 81531DiisopropylethylamineHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate2×HCID 6913588N,O-bis(trimethylsilyl)acetamideHCID 667208756-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid2×

Product 1

HCID 667208541-({[6-{4-Chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochlorideYield 79.8%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6342AcetonitrileSolventHCID 21584169Diethylether ethylacetateSolvent

Procedure

Add, under argon, 0.74 mL (0.41 mmol) of diisopropylethylamine and 409 mg (1.28 mmol) of TBTU to a solution of 200 mg (0.42 mmol) of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2-carboxylic acid in 50 mL of anhydrous DMF. In parallel, heat, while stirring under argon, a mixture of 84 mg (0.59 mmol) of 2-aminocyclohexane-2-carboxylic acid and 0.18 mL (0.76 mmol) of N,O-bis(trimethylsilyl)acetamide (BSA) in 5 mL of anhydrous acetonitrile to 90° C. After 2 h, the mixture has dissolved completely. Cool the solution to RT, then add it to the solution of 6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridine-2 carboxylic acid activated with TBTU. After stirring for 18 h at RT, add 10 mL of 0.5N HCl aqueous solution and continue stirring for 3 h. Then distribute the reaction mixture in a mixture of 20 mL of EtOAc/ether 1:1 and 10 mL of water. After extraction, extract the aqueous phase again with 10 mL of 1:1 ether/EtOAc mixture. Combine the organic phases, wash with 2×10 mL of water, dry over Na2SO4 and concentrate under reduced pressure. Then purify the residue by reverse-phase HPLC(RP18) eluting with a 0.01N HCl/acetonitrile gradient from 5% to 100% of acetonitrile. After concentration under reduced pressure and lyophilization, we obtain 106 mg of 1-({[6-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-5-(2,6-dimethoxyphenyl)pyridin-2-yl]carbonyl}amino)cyclohexanecarboxylic acid hydrochloride in the form of white powder.

Workup

  1. additionAdd, under argon
  2. temperatureIn parallel, heat
  3. dissolutionthe mixture has dissolved completely
  4. stirringAfter stirring for 18 h at RT
  5. stirringcontinue stirring for 3 h
  6. extractionAfter extraction
  7. extractionextract the aqueous phase again with 10 mL of 1:1 ether/EtOAc mixture
  8. washwash with 2×10 mL of water
  9. dry with materialdry over Na2SO4
  10. concentrationconcentrate under reduced pressure
  11. customThen purify the residue by reverse-phase
  12. washHPLC(RP18) eluting with a 0.01N HCl/acetonitrile gradient from 5% to 100% of acetonitrile
  13. concentrationAfter concentration under reduced pressure and lyophilization, we

Sources & evidence

ORD record
ord-19764d8e2aec49e6a57a2bd01a8c23d7
Source dataset
uspto-grants-2013_10
Patent number
US08552201B2

Reaction notes

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