1,2-Dichloroethane → (S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexylmethoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

HRID 391942

Reaction equation

HRID 391942 reaction equation
C(OC(N1[C@H](C(=O)N[C@H](C(O)=O)CC2C=CC(C3C=CN=C(C)C=3C)=CC=2)CC2C=C3OC[C@H](C4C=CC(O)=CC=4)OC3=CC=2C1)=O)(C)(C)C.FC(F)(F)C1CCC(CO)CC1.C[O:64][C:65](=[O:126])[C@@H:66]([NH:82][C:83]([C@@H:85]1[CH2:94][C:93]2[CH:92]=[C:91]3[O:95][CH2:96][C@H:97]([C:99]4[CH:104]=[CH:103][C:102]([O:105][CH2:106][CH:107]5[CH2:112][CH2:111][CH:110]([C:113]([F:116])([F:115])[F:114])[CH2:109][CH2:108]5)=[CH:101][CH:100]=4)[O:98][C:90]3=[CH:89][C:88]=2[CH2:87][N:86]1[C:117]([C:119]1[N:120]=[C:121]([CH3:125])[O:122][C:123]=1[CH3:124])=[O:118])=[O:84])[CH2:67][C:68]1[CH:73]=[CH:72][C:71]([C:74]2[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=2[CH3:81])=[CH:70][CH:69]=1.C(Cl)CCl.CC1OC(C)=C(C(O)=O)N=1>C(Cl)Cl>[CH3:125][C:121]1[O:122][C:123]([CH3:124])=[C:119]([C:117]([N:86]2[C@H:85]([C:83]([NH:82][C@@H:66]([CH2:67][C:68]3[CH:73]=[CH:72][C:71]([C:74]4[CH:79]=[CH:78][N:77]=[C:76]([CH3:80])[C:75]=4[CH3:81])=[CH:70][CH:69]=3)[C:65]([OH:126])=[O:64])=[O:84])[CH2:94][C:93]3[CH:92]=[C:91]4[O:95][CH2:96][C@H:97]([C:99]5[CH:100]=[CH:101][C:102]([O:105][CH2:106][CH:107]6[CH2:108][CH2:109][CH:110]([C:113]([F:114])([F:116])[F:115])[CH2:111][CH2:112]6)=[CH:103][CH:104]=5)[O:98][C:90]4=[CH:89][C:88]=3[CH2:87]2)=[O:118])[N:120]=1

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 27954652,5-Dimethyl-1,3-oxazole-4-carboxylic acidHCID 44228198[4-(Trifluoromethyl)cyclohexyl]methanolHCID 66719568(3s,8s)-8-{(s)-1-Carboxy-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6h-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl esterHCID 66719606(s)-2-({(3s,8s)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexyl-methoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester

Product 1

HCID 58327304(S)-2-({(3S,8S)-7-(2,5-Dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexylmethoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

(3S,8S)-8-{(S)-1-Carboxy-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-ethyl-carbamoyl}-3-(4-hydroxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester was coupled with (4-trifluoromethyl-cyclohexyl)-methanol according to the General Procedure K. The resulting product was converted to (S)-2-({(3S,8S)-7-(2,5-dimethyl-oxazole-4-carbonyl)-3-[4-(4-trifluoromethyl-cyclohexyl-methoxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester according to General Procedure C, then the residue was suspended in DCM. TEA (3 eq.) added and the mixture was concentrated. In a separate vial, EDC (3 eq.) and 2,5-dimethyl-oxazole-4-carboxylic acid (6 eq.) were dissolved in DCM and stirred for 40 minutes. This solution was added to the above mixture and stirred for 16 hours. The reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH). This ester was hydrolyzed according to General Procedure B to give the title compound. LCMS (m/z): 868.

Workup

  1. concentrationthe mixture was concentrated
  2. additionThis solution was added to the above mixture
  3. stirringstirred for 16 hours
  4. customThe reaction mixture was directly purified over silica (hexanes; 1:1 hexanes/EtOAc; 1:1 hexanes EtOAc+1% MeOH)

Sources & evidence

ORD record
ord-9fc4856870bc4adf93b9ef6d2a097fba
Source dataset
uspto-grants-2013_02
Patent number
US08383644B2

Linked notes

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