Vorbipiprant,
CR6086
1417742-86-9
4-[1-[[[(5R)-6-[[4-(Trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]benzoic acid
Benzoic acid, 4-[1-[[[(5R)-6-[[4-(trifluoromethyl)phenyl]methyl]-6-azaspiro[2.5]oct-5-yl]carbonyl]amino]cyclopropyl]-
| Molecular Weight | 472.50 |
|---|---|
| Formula | C26H27F3N2O3 |
Vorbipiprant (CR6086) is an EP4 receptor antagonist, serving as a targeted immunomodulator. Thus, Vorbipiprant is also a potential immune checkpoint inhibitor, to turn cold tumors into hot tumors. Vorbipiprant also antagonizes PGE2-stimulated cAMP production (IC50=22 nM). Vorbipiprant exhibit striking DMARD effects in rodents, and anti-inflammatory activity to inhibt immune-mediated inflammatory diseases.
SCHEME
PATENT
Rottapharm S.p.A.
World Intellectual Property Organization, WO2013004290
https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2013004290&_cid=P10-M25P3U-15334-1
Example 7: 4-(1-(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoic acid (single unknown enantiomer) (E7)
Procedure A:
The title compound (E7) (54 mg) was prepared according to the general procedure for esters hydrolysis (Method B) starting from methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D122b) (100mg). (LiOH: 4 eq; Reaction time: 18 hrs; RT)
MS: (ES/+) m/z: 473.4 [MH+] C26H27F3N2O3 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 18.97 min.
1 H NMR (400 MHz, CHCI3-d) δ (ppm): 7.97 (d, J = 8.0 Hz, 2 H), 7.74 – 7.35 (m, 5 H), 7.26 (br. s., 1 H), 3.86 (d, J = 14.1 Hz, 1 H), 3.38 (d, J = 14.1 Hz, 1 H), 3.08 (d, J = 7.8 Hz, 1 H), 2.91 (d, J = 9.8 Hz, 1 H), 2.27 (br. s., 1 H), 2.05 (t, J = 1 1 .2 Hz, 1 H), 1 .84 (br. s., 1 H), 1 .50 – 1 .24 (m, 4 H), 1 .14 (br. s., 1 H), 0.98 (d, J = 12.7 Hz, 1 H), 0.53 – 0.23 (m, 4 H)
Procedure B:
methyl 4-(1 -(6-(4-(trifluoromethyl)benzyl)-6-azaspiro[2.5]octane-5-carboxamido)cyclopropyl)benzoate (D123)) (17.7 g, 36.38 mmol) was partitioned between dioxane (485 ml) and water (242 ml) prior addition of LiOH H2O (6.1 g,
145.5 mmol). The mixture was stirred at RT for 10 hrs. Water (200 ml) was added followed by addition of acetic acid (5.27 ml). Dioxane was evaporated off and acetic acid was added until the pH of the aqueous solution reached the value of ~ 4. The white solid was filtered from the reaction and dried under vacuum overnight then 24 hrs under vacuum at 40 °C affording the title compound (E7) (16.7g).
MS: (ES/+) m/z: 473.3 [MH+] C26H27F3N203 requires 472.20
Chiral HPLC: [DAICEL AD-H; Mobile phase A: 90% n-heptane (+0.2% TFA), B: 10% EtOH; DAD: 245 nm]: Peak retention time: 19.07 min.
1 H NMR (400 MHz, DMSO-d6) δ (ppm): 12.92 – 12.51 (m, 1 H), 8.83 – 8.62 (m, 1 H), 7.85 – 7.75 (m, 2 H), 7.74 – 7.57 (m, 4 H), 7.26 – 7.14 (m, 2 H), 3.87 – 3.72 (m, 1 H), 3.27 – 3.20 (m, 1 H), 2.99 – 2.86 (m, 1 H), 2.79 – 2.69 (m, 1 H), 2.19 – 1 .98 (m, 2 H), 1 .86 – 1 .70 (m, 1 H), 1 .32 – 1 .07 (m, 5 H), 0.94 – 0.82 (m, 1 H), 0.46 -0.17 (m, 4 H).
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