Oxolane--water (1/1) → HCID 76283033, compound

HRID 2199782Notes

Reaction equation

HRID 2199782 reaction equation
[C:1]([C:3]1[N:4]=[C:5]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]([N:24]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:25]3)=[O:23])[CH2:16]2)[S:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)#[N:2].[O:33]1CCCC1.O>>[C:1]([C:3]1[N:4]=[C:5]([N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([NH:21][C:22]([N:24]3[CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:32]3)=[O:23])[CH2:16]2)[S:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)(=[O:33])[NH2:2]

Participants

3

Reactant 2

HCID 21881883Oxolane--water (1/1)HCID 90220161HCID 90220161, compound

Product 1

HCID 76283033HCID 76283033, compound

Procedure

To a solution of give 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-cyano-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide (11.3 mg, 25.4 μmol) in 10:1 v/v tetrahydrofuran/water (2.75 mL total volume) was added hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (CAS number 173416-05-2) (1.1 mg, 2.5 μmol) and the mixture was heated to reflux under argon. After 8 hours LC/MS indicated approximately ˜30% conversion to a single main product which exhibited the molecular ion for the expected product. The reaction mixture was transferred to a resealable tube, an additional aliquot of hydrido(dimethylphosphinous acid-kP)[hydrogen bis-(dimethylphosphnito-kP]platinum (II) (1 mg, 2.3 μmol) was added and the tube heated to 80° C. overnight. LC-MS indicated the expected product as the major component present in the reaction mixture but with some starting material still present. An additional aliquot of hydrido(dimethylphosphinous acid-kP)[hydrogen bis(dimethylphosphnito-kP]platinum (II) (1 mg, 2.3 μmol) was added and the reaction vessel heated at 100° C. for 3.5 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by reverse phase chromatography using a C-18 column gradient eluted from 10% up to 100% acetonitrile in water. The product containing fractions were combined and concentrated in vacuo to give partially purified 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a yellow solid. Purified further by reverse phase HPLC using a C-18 column gradient eluted from 30% to 100% acetonitrile in water to remove a close running impurity. The product containing fractions were combined and concentrated in vacuo and the residue lyophilized from acetonitrile/water to obtain 1,3-dihydro-isoindole-2-carboxylic acid {(R)-1-[4-carbamoyl-5-(pyridin-2-ylamino)-thiazol-2-yl]-piperidin-3-yl}-amide as a pale yellow solid (2.1 mg, 18%).

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux under argon

Sources & evidence

ORD record
ord-dc7ba718fba041eaa42bbdf0231e3212
Source dataset
uspto-grants-2016_06
Patent number
US09359345B2

Reaction notes

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