2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → tert-Butyl trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]-3-hydroxypyrrolidin-4-carbamate

HRID 540130Notes

Reaction equation

HRID 540130 reaction equation
C(N(CC1C=CC=CC=1)[C:9]1([CH2:14][NH:15][C:16]2[C:25]3[C:20](=CC=C(C)[CH:24]=3)[N:19]=[C:18]([N:27]3[CH2:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[S:30](=[O:39])(=[O:38])[CH2:29][CH2:28]3)[CH:17]=2)CCOC1)C1C=CC=CC=1.[OH:47][C@@H:48]1[CH2:52][NH:51][CH2:50][C@H:49]1[NH:53][C:54](=[O:60])[O:55][C:56]([CH3:59])([CH3:58])[CH3:57].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1>[O:38]=[S:30]1(=[O:39])[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[CH2:33][N:27]([C:18]2[CH:17]=[C:24]([N:51]3[CH2:50][C@@H:49]([NH:53][C:54]([O:55][C:56]([CH3:57])([CH3:59])[CH3:58])=[O:60])[C@H:48]([OH:47])[CH2:52]3)[C:25]3[C:20](=[CH:9][CH:14]=[N:15][CH:16]=3)[N:19]=2)[CH2:28][CH2:29]1

Participants

6

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 59640689(3R,4R)-(4-Hydroxy-pyrrolidin-3-yl)-carbamic acid tert-butyl esterHCID 71262087N-{[3-(dibenzylamino)tetrahydrofuran-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-amine

Product 1

HCID 86691388tert-Butyl trans-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-1,6-naphthyridin-4-yl]-3-hydroxypyrrolidin-4-carbamateYield 10.2%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of -(4-chloro-1,6-naphthyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.84 mmol, prepared in analogy to 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide in Example 2-1 by using 2,3,4,5-tetrahydro-1,4-benzothiazepine and 2,4-dichloro-1,6-naphthyridine) in 1,4-dioxane (5 mL) was added tert-butyl (trans-4-hydroxypyrrolidin-3-yl)carbamate (204 mg, 1.02 mmol), tri(dibenzylideneacetone)dipalladium(0) (39 mg, 0.042 mmol), (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (24 mg, 0.063 mmol) and sodium tert-butoxide (114 mg, 1.17 mmol) under Ar protection. The reaction mixture was heated with stirring in a 10 mL of microwave process vial for 2 hours at 120° C. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give 45 mg of the desired product (yield was 10%).

Workup

  1. temperatureThe reaction mixture was heated
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. customThe residue was purified by preparative HPLC

Sources & evidence

ORD record
ord-d1ca4854005b4b328186beeaba364ee3
Source dataset
uspto-grants-2014_10
Patent number
US08871756B2

Reaction notes

Loading…