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 708731Notes

Reaction equation

HRID 708731 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-ac07ac822de844b782460636b57da321
Source dataset
uspto-grants-2015_11
Patent number
US09175003B2

Reaction notes

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