2-(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetic acid → 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(7-chloro-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid

HRID 85590Notes

Reaction equation

N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC([C:28](OC)=[O:29])=CC=2)=CC3)CC1.CN(C)CCC([NH:47][C@:48]12[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]1[C@@H:50]1[C@@:63]([CH3:66])([CH2:64][CH2:65]2)[C@@:62]2([CH3:67])[C@@H:53]([C@:54]3([CH3:79])[C@@H:59]([CH2:60][CH2:61]2)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]2[CH:78]=[CH:77][C:73]([C:74]([OH:76])=[O:75])=[CH:72][CH:71]=2)=[CH:56][CH2:55]3)[CH2:52][CH2:51]1)=O.[Cl:87][C:88]1[CH:102]=[CH:101][C:91]2OC[C:94](=[O:100])[N:95]([CH2:96][C:97]([OH:99])=O)[C:90]=2[CH:89]=1>>[Cl:87][C:88]1[CH:102]=[CH:101][C:91]2[CH2:28][O:29][C:94](=[O:100])[N:95]([CH2:96][C:97]([NH:47][C@:48]34[CH2:82][CH2:81][C@@H:80]([C:83]([CH3:85])=[CH2:84])[C@@H:49]3[C@@H:50]3[C@@:63]([CH3:66])([CH2:64][CH2:65]4)[C@@:62]4([CH3:67])[C@@H:53]([C@:54]5([CH3:79])[C@@H:59]([CH2:60][CH2:61]4)[C:58]([CH3:69])([CH3:68])[C:57]([C:70]4[CH:71]=[CH:72][C:73]([C:74]([OH:76])=[O:75])=[CH:77][CH:78]=4)=[CH:56][CH2:55]5)[CH2:52][CH2:51]3)=[O:99])[C:90]=2[CH:89]=1

Participants

Reactant 3

HCID 27357062-(6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-4-yl)acetic acid

HCID 683578604-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid

HCID 68357865methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-1-isopropenyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate

Product 1

HCID 683578644-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(7-chloro-2-oxo-2,4-dihydro-1H-benzo[d][1,3]oxazin-1-yl)acetamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acidYield 36%

Procedure

The title compound was prepared in 36% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(6-chloro-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 653.5 (M+H)+, 2.29 min (method 6). 1H NMR (500 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.05-7.01 (m, 1H), 7.01-6.97 (m, 2H), 6.83 (s, 1H), 5.29 (dd, J=1.7, 6.3 Hz, 1H), 4.73 (d, J=1.8 Hz, 1H), 4.70 (d, J=1.2 Hz, 2H), 4.66 (br. s., 1H), 4.63 (s, 1H), 4.57-4.50 (m, 1H), 2.65-2.57 (m, 1H), 2.51-2.34 (m, 2H), 2.13 (dd, J=6.4, 17.1 Hz, 1H), 1.96-1.85 (m, 1H), 1.83-1.72 (m, 3H), 1.70 (s, 3H), 1.69-1.64 (m, 1H), 1.63-1.55 (m, 2H), 1.54-1.45 (m, 4H), 1.45-1.30 (m, 5H), 1.30-1.23 (m, 1H), 1.18-1.12 (m, 2H), 1.10 (s, 3H), 1.02 (s, 6H), 0.95 (s, 3H), 0.94 (s, 3H).

Workup

customm/e 653.5 (M+H)+, 2.29 min (method 6)

Sources & evidence

ORD record: ord-ebb0c3c732df4b05a53714f89e5cf870
Source dataset: uspto-grants-2014_09
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08846647B2

Reaction notes

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