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

반응식

HRID 391942 반응식
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

참가 물질

7

반응물 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

생성물 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

시약·촉매·용매 1

HCID 6344Dichloromethane용매2회

실험 절차

(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.

후처리

  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)

출처 및 근거

ORD 기록
ord-9fc4856870bc4adf93b9ef6d2a097fba
출처 데이터셋
uspto-grants-2013_02
특허 번호
US08383644B2

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