US2013172295A1PendingUtilityA1
Process for preparation of hiv protease inhibitors
Est. expiryMar 29, 2026(expired)· nominal 20-yr term from priority
A61P 31/18A61P 43/00A61P 31/12C07F 9/6561C07D 493/04C07C 51/412C07C 311/29C07C 253/30C07F 9/4084C07C 303/38C07F 9/4006C07C 303/40A61K 31/665C07F 9/4075C07F 9/02C07C 327/42
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Claims
Abstract
A process for the synthesis of bisfuran intermediates useful for preparing antiviral HIV protease inhibitor compounds is hereby disclosed
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A process for preparing a bisfuran alcohol of Formula 0:
3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol Formula 0,
comprising,
reacting 2,3-dihydrofuran and a glycoaldehyde or glycoaldehyde dimer in the presence of a lanthanide or transition metal catalyst to form the bisfuran alcohol of Formula 0.
2 . The process of claim 1 , where the catalyst comprises Yb, Pr, Cu, Eu or Sc complexed to a ligand selected from:
3 . The process of claim 2 , where the catalyst is Yb(hfc) 3 (+), Yb(hfc) 3 (−), Eu(hfc) 3 (+), Eu(hfc) 3 (−), Yb(fod) 3 (+) and S-Binaphthol, Yb(tfc) 3 (+), Sc(OTf) 3 and (S)-pybox, and Pr(tfc) 3 (+)
where
where, M represents Yb, Pr, Cu, Eu or Sc.
4 . The process of claim 1 , where the reaction is carried out at a temperature of between about 0° C. to about 100° C.
5 . The process of claim 1 , where the reaction is carried out in the presence of a catalyst comprising a lanthanide or transition metal complexed to a chiral ligand.
6 . The process of claim 5 , where the chiral ligand is
where,
Ph is phenyl.
7 . The process of claim 1 , which is carried out in the presence of a solvent.
8 . The process of claim 7 , where the solvent is a polar aprotic solvent.
9 . The process of claim 8 , where the solvent is methyl-t-butyl-ether, dichloromethane or a mixture thereof.
10 . The process of claim 1 , which is carried out in the presence of excess 2,3-dihydrofuran as a solvent.
11 . The process of claim 1 , where the catalyst comprises Sc.
12 . The process of claim 1 , where the catalyst comprises Yb.
13 . The process of claim 1 , further comprising,
(i) combining the bisfuran alcohol of Formula 0 with disuccinimidyl dicarbonate to form a compound of Formula L1:
(ii) combining the bisfuran alcohol of Formula 0 with bis(p-nitro)phenyl carbonate or p-nitrophenol chloroformate to form a compound of Formula L2:
or
(iii) combining the bisfuran alcohol of Formula 0 with dipyridyl carbonate to form a compound of Formula L3:
14 . The process of claim 13 , further comprising, combining the compound of Formula L1, L2 or L3 with a compound of Formula N,
to form a compound of Formula A,
where,
Me is methyl.
15 . The process of claim 14 , further comprising, combining the compound of Formula A with a compound of Formula J,
to form a compound of Formula I,
where,
Me is methyl;
Et is ethyl; and
Ph is phenyl.
16 . The process of claim 15 , further comprising, combining the compound of Formula I with adipic acid to form a salt of Formula IV,
where,
Me, Et and Ph are each independently defined the same as in claim 15 .
17 . The process of claim 14 , where the compound of Formula N is prepared by deprotecting a compound of Formula M:
18 . The process of claim 17 , where the deprotection is accomplished by combining the compound of Formula M with a deprotecting agent which is selected from trifluoroacetic acid, hydrochloric acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, or hydrobromic acid.
19 . The process of claim 17 , where the compound of Formula M is prepared by reducing a compound of Formula C:
20 . The process of claim 19 , where the reduction is accomplished by contacting the compound of Formula C with a reducing agent which is lithium aluminum hydride, sodium borohydride, lithium borohydride, sodium trisacetoxyborohydride, sodium cyanoborohydride, potassium triisopropoxy borohydride or diisobutyl aluminum hydride
21 . The process of claim 19 , where the compound of Formula C is prepared by combining a compound of Formula F with a compound of Formula G:
22 . The process of claim 21 , where the compound of Formula F is prepared by combining a compound of Formula E with an amine:
23 . The process of claim 22 , where the amine is
24 . A compound having the formula C:
or a pharmaceutically acceptable salt thereof.
25 . A compound having the formula M:
or a pharmaceutically acceptable salt thereof.
26 . A compound having the formula N:
or a pharmaceutically acceptable salt thereof.
27 . A salt having the formula IV:
28 . A pharmaceutical composition comprising the salt of claim 27 and an excipient, diluent or carrier.
29 . A method for the treatment or prophylaxis of a retrovirus infection in a patient, comprising administering to the patient a therapeutically effective amount of the salt of claim 27 .
30 . The method of claim 29 , where the retrovirus is human immunodeficiency virus (HIV).
31 . The method of claim 29 , where the therapeutically effective amount is about 10 mg to about 2000 mg.
32 . The method of claim 29 , where the salt is administered in a pharmaceutical composition.
33 . The method of claim 32 , where the pharmaceutical composition is in a unit dosage form of a tablet.
34 . The method of claim 29 , where the salt is administered orally.
35 . A kit comprising: (1) the pharmaceutical composition of claim 28 ; (2) prescribing information; and (3) a container.
36 . The kit of claim 35 , where the pharmaceutical composition is in a unit dosage form of a tablet.
37 . A compound, composition or method as disclosed herein.
38 . The use of the salt of claim 27 for the manufacture of a medicament for inhibiting activity of a retrovirus protease in a patient, comprising administering to the patient a therapeutically effective amount of the salt.
39 . The use of the salt of claim 27 for the manufacture of a medicament for the treatment or prophylaxis of a retrovirus infection in a patient, comprising administering to the patient a therapeutically effective amount of the salt.
40 . The use of claim 38 or 39 , where the retrovirus is human immunodeficiency virus (HIV).
41 . The use of the salt of claim 38 or 39 , where the salt is administered to the patient as a single composition.
42 . The use of the salt of claim 38 or 39 , where the salt is administered to the patient orally.
43 . The use of claim 42 , where the oral administration is once a day.
44 . The use of claim 38 or 39 , where the patient is also receiving one or more agents selected the group consisting of stavudine, emtricitabine, tenofovir, emtricitabine, abacavir, lamivudine, zidovudine, didanosine, zalcitabine, phosphazide, efavirenz, nevirapine, delavirdine, tipranavir, saquinavir, indinavir, atazanavir, nelfinavir, amprenavir, samprenavir, lopinavir, ritonavir, enfuvirtide, Fozivudine tidoxil, Alovudine, Dexelvucitabine, Apricitabine, Amdoxovir, Elvucitabine (ACH126443), Racivir (racemic FTC, PSI-5004), MIV-210, KP-1461, fosalvudine tidoxil (HDP 99.0003), AVX756, Dioxolane Thymine (DOT), TMC-254072, INK-20, 4′-Ed4T, TMC-125 (etravirine), Capravirine, TMC-278 (rilpivirine), GW-695634, Calanolide A, BILR 355 BS, and VRX 840773, and pharmaceutically acceptable salts thereof.
45 . The use of claim 38 or 39 , where the therapeutically effective amount is about 10 mg to about 2000 mg.
46 . The use of claim 38 or 39 , where the salt is administered in a pharmaceutical composition.
47 . The use of claim 46 , where the pharmaceutical composition is in a unit dosage form of a tablet.
48 . The use of claim 47 , where the salt is administered orally.Join the waitlist — get patent alerts
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