WO2010075887A1 - Methods and intermediates useful in the synthesis of hexahydrofuro[2,3-b]furan-3-ol - Google Patents
Methods and intermediates useful in the synthesis of hexahydrofuro[2,3-b]furan-3-ol Download PDFInfo
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- WO2010075887A1 WO2010075887A1 PCT/EP2008/068354 EP2008068354W WO2010075887A1 WO 2010075887 A1 WO2010075887 A1 WO 2010075887A1 EP 2008068354 W EP2008068354 W EP 2008068354W WO 2010075887 A1 WO2010075887 A1 WO 2010075887A1
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- 0 *C([C@@]([C@](C1)C(N(*)**I)=O)OC1O)=O Chemical compound *C([C@@]([C@](C1)C(N(*)**I)=O)OC1O)=O 0.000 description 6
- ZMERSNSGFWABIG-NJGYIYPDSA-N C=C([C@@H]([C@H](C1)C(O2)=O)OC1=O)C2=O Chemical compound C=C([C@@H]([C@H](C1)C(O2)=O)OC1=O)C2=O ZMERSNSGFWABIG-NJGYIYPDSA-N 0.000 description 1
- HLYSOMPKLRYLAE-UHFFFAOYSA-N CC(CN(CC(C(Cc(cc1)ccc1OCc1c[s]c(C)n1)NC(OC1C(CCO2)C2OC1)=O)O)S(c1c2)(=O)=O)c1cc1c2OCO1 Chemical compound CC(CN(CC(C(Cc(cc1)ccc1OCc1c[s]c(C)n1)NC(OC1C(CCO2)C2OC1)=O)O)S(c1c2)(=O)=O)c1cc1c2OCO1 HLYSOMPKLRYLAE-UHFFFAOYSA-N 0.000 description 1
- FVCMAICDZVMSCZ-UHFFFAOYSA-N O=C(CC1C(O2)=O)OC1C2=O Chemical compound O=C(CC1C(O2)=O)OC1C2=O FVCMAICDZVMSCZ-UHFFFAOYSA-N 0.000 description 1
- RCDXYCHYMULCDZ-UHFFFAOYSA-N OC1C(CCO2)C2OC1 Chemical compound OC1C(CCO2)C2OC1 RCDXYCHYMULCDZ-UHFFFAOYSA-N 0.000 description 1
- SEBNPZMOBUCYCA-UHFFFAOYSA-N OCN1CCOCC1 Chemical compound OCN1CCOCC1 SEBNPZMOBUCYCA-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/26—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D307/30—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Definitions
- TECHNICAL FIELD The present disclosure relates to methods for the synthesis of hexahydro-furo[2,3- b]furan-3-ol compounds and novel synthetic intermediates useful therein.
- Optically enriched hexahydro-furo[2,3-b]furan-3-ol e.g., the 3R, 3aS, 6aR isomer, can be prepared using the methods described herein.
- the compound (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol is a pharmacological moiety present in various protease inhibitors that have proven useful in the treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV).
- HIV human immunodeficiency virus
- HCV hepatitis C virus
- examples of such inhibitors include HIV protease inhibitors, darunavir, brecanavir, UIC- 94003, and GS-9005.
- Inhibition of the protease enzymes has proven to be an effective treatment against AIDS, and can be used in combination with reverse transcriptase inhibitors.
- In view of the importance of the above protease inhibitors and the consequent need to manufacture these compounds there exists a need to develop cost effective and efficient methods of preparing hexahydro-furo[2,3-b]furan-3-ol compounds.
- Certain embodiments relate to a process for preparing a compound of Formula 7:
- R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ; each of R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membere
- the reducing agent can be MBH 4 , MHB(R 3 ) 3 , MH 2 B(R 4 ) 2 , MH 3 BR 4 , MHB(OR 4 ) 3 , MH 2 B(OR 4 ) 2 , MH 3 BOR 4 , MAlH 4 , MHA1(OR 4 ) 3 , MH 2 A1(OR 4 ) 2 , MH 3 Al(OR 4 ), HB(R 4 ) 2 , H 2 BR 4 , BH 3 , H 2 A1(R 4 ) 2 , H 2 AlR 4 , or H 3 Al;
- M is Li, Na, K, R 3 4 N, 1/2Zn or 1/2Ca; and R 4 can be alkyl or aralkyl.
- the acid can be hydrochloric acid, hydrobromic acid sulfuric acid, phosphoric acid, nitric acid, metal hydrogen sulfate, metal dihydrogen phosphorate, trifluoroacetic acid, trichloroacetic acid, citric acid, oxalic acid, tartaric acid, oxalic acid, formic, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, 10-camphorsulfonic acid, 1,5-napthalene disulfonic acid, or 1,2-ethane disulfonic acid.
- Certain embodiments relate to any one of the aforementioned processes, where Y can be a bond; and each of R 1 and R 2 independently for each occurrence can be alkyl, cycloalkyl, aryl, or wherein independently for each occurrence R 10 can be hydrogen or alkyl, R 11 is alkoxy; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 5-8 membered optionally substituted heterocyclic ring.
- Certain embodiments relate to any one of the aforementioned processes, where Y is a bond; R is alkyl; and each of R 1 and R 2 independently for each occurrence is alkyl, cycloalkyl, aryl, or -[C(R 10 ) 2 ]m-R U , wherein independently for each occurrence R 10 is hydrogen or alkyl, R 11 is alkoxy; or R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 5-8 membered optionally substituted heterocyclic ring.
- Y can be a bond
- R can be methyl, ethyl, «-propyl, or /-propyl
- X is O
- R 1 and R 2 taken together with the nitrogen to which they are bonded can form a heterocyclic ring selected from piperidine, pyrrolidine, or morpholine.
- Certain embodiments relate to any one of the aforementioned processes, further comprising combining a compound of Formula 3:
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , - N(R 12 )COR 13 , -N(R 12 )
- R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R ⁇ ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give the compound of Formula 5.
- the coupling agent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N,N'- carbonyldiimidazole (CDI), 3 ⁇ (di ⁇ thoxyphosphorylcxy) ⁇ 1 ,2,3 ⁇ benzohiazin ⁇ 4GH) ⁇ cne
- DCC dicyclohexylcarbodiimide
- DIC diisopropylcarbodiimide
- CDI N,N'- carbonyldiimidazole
- R can he methyl, ethyl, / ⁇ -propyl, or 2 -propyl.
- X can be (J; and the compound of Formula 4 can be morpholine.
- Certain embodiments relate to any one of the aforementioned processes, further comprising combining a compound of Formula 1:
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , - N(R 12 )COR 13 , -N(R 12
- the compound of Formula 2 can be methanol, etbancl, w-propanol, or /-propanol.
- Certain embodiments relate to a process for preparing a compound of Formula 7a:
- H 7a comprising (a) combining methanol, ethanol, «-propanol, or z-propanol, and a compound of Formula Ia:
- Certain embodiments relate to a compound of Formula 5:
- X can be S or O
- Y can be O, -N(R 3 )-, or a bond
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2]m-R n ; each of R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R 10 independently for each
- Certain embodiments relate to the compound of Formula 5, where Y can be a bond; R can be alkyl; and R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3- 10 membered optionally substituted heterocyclic ring.
- Certain embodiments relate to the compound of Formula 5, where the compound can have the absolute stereochemistry shown below:
- Certain embodiments relate to the compound of Formula 5, where the compound of Formula 5 can be prepared by a process comprising: (a) combining a compound of Formula Ia:
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , - N(R 12 )COR 13 , -N(R 12 )
- R 1 , R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give the compound of Formula 5.
- Certain embodiments relate to a compound of Formula 3:
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , -N(R 12 )COR 13 , -N(R 12 )
- Certain embodiments relate to the compound of Formula 3 where R can be alkyl and X can be O.
- Certain embodiments relate to the compound of Formula 3 where the compound can have the absolute stereochemistry shown below:
- Certain embodiments relate to the compound of Formula 3 prepared by a process comprising (a) combining a compound of Formula Ia:
- X can be S or O;
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ⁇ ] nI -R 1 x ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , -N(R 12 )COR 13 , -N(R 12
- Certain embodiments relate to a compound of Formula 6:
- R 1 , R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
- each of R 12 and R 13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R 12 and R 13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8.
- Certain embodiments relate to any of the aforementioned compounds of Formula 6, where Y can be a bond and R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring.
- Certain embodiments relate to any one of the aforementioned compounds of Formula 6, where the compound of Formula 6 is prepared by a process comprising: (a) combining a compound of Formula Ia:
- R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ;
- R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , -
- R 12 and R 13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R and R 1 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give a compound
- R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give a compound of Formula 5a:
- Certain embodiments relate to a process for preparing a compound of Formula 7:
- R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R 10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroa
- R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; each of R 1 R 2 , and R 3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R 1
- amine containing protease inhibitor precursor can be: (i) a compound of Formula 13:
- protease inhibitor can be a compound of Formula 13a:
- protease inhibitor can be a compound of Formula 14a:
- protease inhibitor can be a compound of Formula 15a:
- protease inhibitor can be a compound of Formula 16a:
- Ar can be aryl
- A can be CH 2 , S, or O
- R ⁇ independently for each occurrence can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl
- the protease inhibitor can be a compound of Formula 18a:
- Af independently for each occurrence can be aryl optionally substituted with a water soluble oligomer and R ⁇ ⁇ can be alkyl or a water soluble oligomer, provided that at least one of Ar' or R ⁇ ⁇ comprises a water soluble oligomer; and the protease inhibitor can be a compound of Formula 19a:
- Ar can be aryl; each of R ⁇ ⁇ ' independently for each occurrence can be hydrogen, alkyl, heteroaryl, aralkyl, or heterocycloalkyl; and the protease inhibitor can be a compound of Formula 20a:
- carbamate coupling agent can be selected from the group consisting of phosgene, trichloromethyl chloroformate, bis(trichloromethyl) carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, N,N'-disuccinimidyl carbonate, 4-nitrophenyl chloroformate, 2,2'-dipyridyl carbonate, and N,N'-carbonyldiimidazole (CDI).
- R can be alkyl
- X can be O
- each of R 1 and R 2 independently for each occurrence can be alkyl, cycloalkyl, aryl, or -[C(R 10 ) 2 ]m-R n , wherein independently for each occurrence R 10 can be hydrogen or alkyl, R 11 is alkoxy; or R 1 and R 2 taken together with the nitrogen to which they are bonded can represent a 5-8 membered optionally substituted heterocyclic ring.
- Certain embodiments relate to a protease inhibitor prepared by any of the aforementioned processes.
- heteroatom refers to an atom of any element other than carbon or hydrogen.
- Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
- alkyl includes saturated aliphatic groups, including straight- chain alkyl groups and branched-chain alkyl groups.
- a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C 1 -C30 for straight chain, C1-C 30 for branched chain), and alternatively, about 20 or fewer.
- alkyl groups can be optionally substituted.
- cycloalkyl include saturated, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.
- Cycloalkyls include monocyclic and polycylic rings. Cycloalkyls can have from about 3 to about 15 carbon atoms in their ring structure, and alternatively about 5, 6, 7, or 10 carbons in the ring structure. In certain instances, cycloalkyl groups can be optionally substituted.
- aryl includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
- aryl heterocycles or
- heterocyclyl aromatic or heteroaromatic moieties
- the aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF 3 , -CN, or the like.
- substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxy
- aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
- heterocyclyl examples include 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be poly cycles.
- Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, o
- the heterocyclic ring may be substituted at one or more positions with such substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, or the like.
- substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl,
- optionally substituted refers to any chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogens may be replaced with a a substituent as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF3, -CN, or the like; or has the formula -[(CR5oR5i) n ]Rs2, wherein each of R50 and R51 independently for each occurrence is hydrogen, alkyl,
- salt includes any ionic form of a compound and one or more counter- ionic species (cations and/or anions). Salts also include zwitterionic compounds (i.e., a molecule containing one more cationic and anionic species, e.g., zwitterionic amino acids). Counter ions present in a salt can include any cationic, anionic, or zwitterionic species.
- Exemplary ions include, but are not limited to chloride, bromide, iodide, nitrate, sulfate, bisulfate, sulfite, phosphate, acid phosphate, chlorate, perchorate, hypochlorite, iodate, periodate, hypoiodite, carbonate, bicarbonate, isonicotinate, acetate, trichloroacetate, trifluroacetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, trifluormethansulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, p-trifluormethylbenzenesulfonate, hydroxide
- each expression e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
- chemical structures which contain one or more stereocenters depicted with wedged shaped bonds i.e., f ' are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure.
- chemical structures which contain one or more stereocenters depicted with non-wedge shaped bonds, i.e., > * I or - M ' are meant to indicate relative stereochemistry of the stereocenter(s) present in the chemical structure.
- Compound 1 can be prepared according to the procedure described in DE226473, from isocitric acid (e.g., (2R,3S), (2S, 3R), racemic isocitric acid), which is readily produced on large scale by fermentation (DE2065207, JP35014494, JP50155683).
- the anhydride lactone 1 can be reacted with a nucleophile, e.g., an alcohol, to yield carboxylic acid 3.
- Carboxylic acid 3 can be coupled with, e.g., an amine to yield compound 5, which can then be reacted with a reducing agent, such as LiAlH 4 , and subjected to acid catalyzed cyclization to yield the desired compound 7.
- a nucleophile e.g., an alcohol
- Carboxylic acid 3 can be coupled with, e.g., an amine to yield compound 5, which can then be reacted with a reducing agent, such as LiAlH 4 , and subjected to
- Optically enriched hexahydro-furo[2,3-b]furan-3-ol is readily available by starting from optically enriched lactone anhydride 1, or by separating the desired enantiomer at any step in the synthesis starting from racemic compound 1.
- nucleophile 2 such as an alcohol or thiol
- anhydride ring opening in a regioselective fashion to afford compound 3.
- nucleophile is an alcohol, thiol, or salts thereof.
- nucleophiles useful for reaction with the anhydride include, but are not limited to methanol, ethanol, «-propanol, sec-propanol, «-butanol, seobutanol, tert- butanol, benzyl alcohol, methylthiol, «-propanthiol, seopropanthiol, «-butanthiol, sec- butanthiol, tert-butanthiol, and benzylthiol.
- the nucleophile 2 is a compound of formula RXH, where X is S or O; R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n , where R 10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and R 11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , -N(R 12 )
- R 12 and R 13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R 12 and R 13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8.
- RXH is methanol.
- a salt of nucleophile 2 can be used for the anhydride ring opening.
- Such salts include alkali metal, alkaline earth metal, and ammonium salts of the nucleophile.
- the anhydride ring opening can be accomplished using a number of well known procedures. For example, an alcohol or thiol can be reacted with compound 1 to afford compound 3. In certain instances, the alcohol or thiol can serve as the solvent for the reaction.
- solvents may be used in this reaction, such as tetrahydrofuran, tetrahydropyran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane, ethylacetate, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, acetone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, alcohols, water, and mixtures thereof.
- solvents such as tetrahydrofuran, tetrahydropyran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane, ethylacetate, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, acetone,
- the reaction can be run at a temperature from about -10 0 C to about 120 0 C, from about -10 0 C to about 100 0 C, from about -10 0 C to about 80 0 C, from about -10 0 C to about 60 0 C, form about -10 0 C to about 40 0 C, from about 0 0 C to about 40 0 C, or from about 20 0 C to about 30 0 C.
- the reaction can be run from about -30 0 C to about 0 0 C,. from about -10 0 C to about 30 0 C, from about 30 0 C to about 70 0 C, from about 70 0 C to about 120 0 C.
- nucleophiles such salts of alcohols and tniols
- methanol is used as the nucleophile and the reaction is run at room temperature.
- An organic or inorganic base can optionally be used in the reaction of the nucleophile 2 (e.g., alcohol or thiol) with compound 1.
- Inorganic bases such as alkali and alkali earth, oxides, hydroxides, carbonates, bicarbonates, and hydrides; and ammonium hydroxide can be used in the anhydride ring opening.
- Organic bases useful in the anhydride ring opening include but are not limited to tertiary amines, such as triethylamine N, N-diisopropylethyl amine (H ⁇ nig's base), N-methyl morpholine, and 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, imidazole, and alkali and alkaline earth metal alkoxides, such as sodium tert-butoxide.
- tertiary amines such as triethylamine N, N-diisopropylethyl amine (H ⁇ nig's base), N-methyl morpholine, and 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8
- Lewis acids can also be utilized to catalyze the addition of the nuecleophile 2 to the anhydride.
- Lewis acids useful in the reaction include, but are not limited to rare earth salts, such as scandium, ytterbium, and lanthanum, magnesium, zinc salts, manganese, cobalt, copper, and silver salts.
- the crude carboxylic acid 3 can either be used directly in the next reaction, without purification, or purified prior to the acylation reaction.
- the crude lactone can be purified by any number of techniques, including Ii quid- Ii quid extraction, solid- Ii quid extraction, chromatography, distillation and crystallization.
- the carboxylic acid 3 can be reacted directly or indirectly with nucleophile 4 under conditions suitable to form compound 5. Indirect methods for forming compound 5 include first preparing an activated carboxyl intermediate, which is then reacted with nucleophile 4.
- reagents useful for preparing activated carboxyl intermediates include, halogenating agents, such as SOCl 2 , SO 2 Cl 2 , PCI3, PBr 3 , POCI3, POBr 3 , oxalyl chloride, dichlorotriphenylphosphorane, and N,N- dimethylchloromethylenammonium chloride, 1,1-carbonyldiimidazole (CDI), and reagents which generate mixed anhydrides, such as pivaloyl chloride and isobutyl chloroformate (IBCF).
- halogenating agents such as SOCl 2 , SO 2 Cl 2 , PCI3, PBr 3 , POCI3, POBr 3
- oxalyl chloride dichlorotriphenylphosphorane
- N,N- dimethylchloromethylenammonium chloride 1,1-carbonyldiimidazole (CDI)
- CDI 1,1-carbonyldiimidazole
- the amine to be coupled acts as the base.
- the carboxylic acid 3 is activated in situ and the resulting activated carboxyl containing compound is reacted with the nucleophile 4 to afford compound 5. In situ generation of the activated carboxyl compounds can provide synthetic efficiencies and lower material costs.
- Reagents useful for generating the activated carboxyl include, but are not limited to carboiimides, such as ⁇ -tert-hvXy ⁇ -1- ethylcarbodiimide, N,7V-di-fert-butylcarbodiimide, 7V,7V-dicyclohexylcarbodiimide, N,N- diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, 1 -[3- (dimethylamino)propyl]-3-ethylcarbodiimide methiodide, and l,3-di-/>tolylcarbodiimide, phosphonium reagents, such as (7-azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (benzotriazol- 1 -yloxy)tripyrrol
- Suitable organic bases include tertiary amines, such as Hunig's base, triethylamine, TV- methyl morpholine, piperidine and pyridine.
- Inorganic bases including alkali and alkali earth carbonates, bicarbonates, hydroxide, and alkoxides can be used in the coupling reaction.
- Various nucleophiles can be used in the acylation reaction.
- the nucleophile 4 can be a primary or secondary amine, a hydrazine, or alkoxyamine.
- Suitable amines include, but are not limited to pyrrolidine, piperidine, and morpholine, or can be represented by the formula R 1 YNR 2 , where Y can be a bond (i.e., a single bond) between N and R 1 or oxygen; each of R 1 and R 2 independently for each occurrence can be C1-C8- alkyl, C5-C8-cycloalkyl, optionally substituted phenyl or benzyl; or R 1 is a Cl-C8-alkyl, C5-C8-cycloalkyl, optionally substituted phenyl or benzyl, and R 2 is a Cl-C8-alkyloxy, C5-C8-cycloalkyloxy; or R 1 and R 2 together with the N atom form a five- to eight- membered optionally substituted ring.
- R 1 and R 2 are identical radicals, e.g., each Cl-C4-alkyl, such as methyl, ethyl, n- or /-propyl or n-, i- or ⁇ -butyl; or R 1 is a Cl-C4-alkyl, such as methyl, ethyl, «-propyl, /-propyl or n- or /-butyl, and R 2 is a Cl-C4-alkyloxy, such as methoxy, ethoxy, n- or /-propyloxy, n- or i- or t-butyloxy; or Y is oxygen, R 1 is methyl and R 2 is methoxy.
- the nucleophile 4 used in the acylation reaction is represented by R 1 YNR 2 , where Y is a bond (i.e., a single bond between R 1 and N) between N and R 1 , oxygen, or -N(R 3 )-; each of R 1 , R 2 , and R 3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl (i.e., alkyl radicals having one or more halogens), or -[C(R 10 )2] m - R 11 ; or R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 3- 10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring; or
- R 12 and R 13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R 12 and R 13 taken together form a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8.
- EDCI and HOBT are used to couple morpholine to carboxylic acid 3 in acetonitrile.
- solvents useful in the reaction include, but are not limited to propionitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1 ,2-dimethoxy ethane, dimethylformamide, dimethylsulfoxide, methylacetate, ethylacetate, «-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, and hexamethylphosphoramide.
- the acylation reaction can be run at any temperature from about -40 to about 100 0 C ⁇ e.g., about -40 0 C to about 0 0 C, about -20 0 C to about 20 0 C, about 20 0 C to about 60 0 C, or about 60 0 C to about 100 0 C). In certain instances the acylation reaction is run at about room temperature or about 0 0 C.
- Crude compound 5 can be purified prior to reduction or can be reduced without purification. Any number of methods can be used to purify compound 5, including liquid-liquid extraction, solid-liquid extraction, chromatography, and crystallization.
- Compound 5 can then be reacted with a reducing agent.
- the reducing agent is any reagent capable of reducing the lactone and ester or thioester functional groups to primary alcohols and the amide to an N, O- aminal or aldehyde.
- Reducing agents useful for reducing compound 5 include but are not limited to zinc, N(R 4 K alkali (e.g., Li, Na, and K), and alkali earth salts (e.g., Ca)of ⁇ BH 4 , ⁇ HBR 4 3 , ⁇ H 2 BR 4 2 , S H 3 BR 4 , ⁇ HB(OR 4 ) 3 , ⁇ H 2 B(OR 4 ) 2 , and ⁇ H 3 BOR 4 , boranes, such as HBR 4 2, H 2 BR 4 , and BH 3 , including borane amine complexes, and aluminum reducing agents, such as ⁇ A1H 4 , ⁇ HA1R 4 3 , ⁇ H 2 A1R 4 2 , ⁇ H 3 A1R 4 , ⁇ HA1(OR 4 ) 3 , ⁇ H 2 A1(OR 4 ) 2 , and ⁇ H 3 AlOR 4 , and organo-aluminum reagents such as HA
- M can be a cation, e.g., zinc(I), ⁇ N(R 4 ) 4 , alkali(I) (e.g., Li, Na, and K), and alkali earth(II) salts (e.g., Ca and Mg) ,where R 4 is as defined above.
- alkali(I) e.g., Li, Na, and K
- alkali earth(II) salts e.g., Ca and Mg
- Suitable solvents for the reduction include diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, or alcohols, such as methanol, ethanol, n-propanol, ⁇ o-propanol, «-butanol, s-butanol, tert-butanol, and mixtures thereof.
- the reduction can be run at temperatures of from about -100 0 C to about 80 0 C (e.g., about -100 0 C to about -40 0 C, about -40 0 C to about 20 0 C, about 20 0 C to about
- Protic solvents such as water and alcohols, can be used to increase the reactivity of the reducing agent employed.
- reaction of a reducing agent with compound 5 yields a salt of compound 6.
- Salts of compound 6 include alkali, alkali earth, boron (e.g., borate ester, boronic ester, borinic ester), aluminum (e.g., aluminates, aluminum alkoxides, and organo-aluminum alkoxides), and ammonium salts, mixtures thereof, and/or polymeric complexes thereof.
- boron e.g., borate ester, boronic ester, borinic ester
- aluminum e.g., aluminates, aluminum alkoxides, and organo-aluminum alkoxides
- ammonium salts mixtures thereof, and/or polymeric complexes thereof.
- Compound 6 and salts thereof can be subjected directly to acid catalyzed cyclization to afford the desired product 7. This can be accomplished by adding an acid directly to the reaction mixture after reduction of compound 5 has run to completion.
- the conjugate acid of compound 6 can be isolated as the aldehyde, hydrate, or cyclic hemi-acetal, and mixtures thereof illustrated in Scheme 2. These isolated compounds or mixtures thereof can then be subjected to the acid catalyzed cyclization conditions.
- Scheme 2 Two
- Suitable acids for the cyclization reaction include Br ⁇ nsted and Lewis acids.
- Br ⁇ nsted acids useful in the cyclization reaction include, but are not limited to inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, metal hydrogen sulfate, sulfurous acid, metal hydrogensulfite, phosphoric acid, metal dihydrogen phosphate, metal hydrogen phosphate, phosphonic acid, metal hydrogen phosphate, pyrophosphoric acid, metal trihydrogen pyrophosphate, metal dihydrogen pyrophosphate, and metal hydrogen pyrophosphate, and organic acids, such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, trifluoroacetic acid, trichloracetic acid, methanesulfonic, trifluormethanesulfonic acid, ethanesulfonic, benzenesulfonic,/>to
- Lewis acids can also be employed in the acid catalyzed cyclization reaction.
- Such Lewis acids include, but are not limited to TMSOTf, AlCl 3 , A1(OR 4 ) 3 , BF ⁇ , BCl 3 , SbF 5 , SnCl 4 , TiCl 4 , Ti(OR 4 ) 4 , where R 4 independently for each occurrence is as defined above.
- the acid catalyzed cyclizition reaction can be conducted in any solvent, including but not limited to diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran 1 ,4- dioxane, tert-butyl methyl ether, dichloromethane, dichloroethane, chloroform, carbontetrachloride, acetonitrile, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, ethylacetate, hexamethylphosphoramide, water and mixtures thereof.
- solvent including but not limited to diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran 1 ,4- dioxane, tert-butyl methyl ether, dichloromethane, dichloroethane, chloroform, carbontetrachloride
- NaHSO 4 is used as the acid for the cyclization reaction in a mixture of water and tetrahydrofuran.
- Enantiomerically and/or diastereomerically enriched hexahydro-furo[2,3-b]furan- 3-ol can be prepared using optically active starting materials. Chirality present in the starting material can be preserved through the synthetic process. For example,
- Optically enriched hexahydro-furo[2,3-b]furan-3-ol can also be prepared from racemic starting material and separating optical isomers at any step in the synthesis using any method known to those of ordinary skill in the art, e.g., separating optical isomers using chiral chromatography (e.g., HPLC or SFC using columns with chiral stationary phase) or by forming diasteromers with an optically enriched compound, e.g., optically active amines can be used to make diasteromeric salts (e.g., with compound 3), diasteremeric amides (e.g., of compound 5) and separated using traditional purification techniques, or by enzymatic resolution of a racemic mixture (e.g. compound 7 or its esters) using the appropriate esterase enzyme.
- chiral chromatography e.g., HPLC or SFC using columns with chiral stationary phase
- diasteromers with an optically enriched compound e.g.,
- Some or all of the steps described herein can be conducted in the same reaction vessel, e.g., as a "one pot method" or in different reaction vessels. Reactions conducted in the same reaction vessel can be run in the same or different solvents. Solvent transfers can be used when changing solvents between synthetic steps, e.g., at the end of a particular reaction the solvent is removed (e.g, by distillation), and another solvent can be added.
- the anhydride ring opening reaction can be conducted in methanol, after the reaction is complete, the methanol can be removed, reagents and solvents for the acylation step (i.e., the reaction of compound 3 with nucleophile 4 to give compound 5) can be added to the reaction vessel, and the acylation reaction can be carried our in the same vessel.
- an acid can be added directly to the reduction reaction mixture in the same reaction vessel to perform the acid catalyzed cyclization.
- hexahydro-furo[2,3-b]furan-3-ol can be prepared efficiently and in high yield from readily available isocitric acid lactone anhydride 1.
- the synthetic routes described herein can provide the final product in at least 40%, at least, 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% overall yield from isocitric acid lactone anhydride 1.
- Certain compounds are useful synthetic intermediates in the processes described herein. These compounds include compounds of Formula 3, 5, and 6.
- compounds of Formula 3 are useful in the acylation reaction with nucleophile 4.
- Compounds of Formula 3 can be represented by:
- R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 )2] m -R n ;
- R 10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
- R 11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR 12 , -N(R 12 )COR 13 , - N(R 12 )C(
- R can be alkyl, cycloalkyl, haloalkyl, aryl, or aralkyl; and X can be O or S; or R can be alkyl and X can be O.
- the compound of Formula 3 can be:
- the compound of Formula 3 is prepared according to a method as described herein.
- Compounds of Formula 5 are useful in the methods as described herein.
- Compounds of Formula 5 can be represented by:
- X is S or O; Y is O, -N(R 3 )-, or a bond; R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n ; each of R 1 , R 2 , and R 3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ⁇ ] 1n -R 11 ⁇ or R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R 3 taken together with
- R is alkyl
- Y is a bond
- R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring.
- the compound of Formula 5 can be:
- the compound of Formula 5 is prepared according to a method as described herein.
- Compounds of Formula 6 are useful in the methods as described herein.
- Compounds of Formula 6 can be represented by:
- Y is O, -N(R )-, or a bond
- R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or - [C(R 10 ) 2 ] m -R n
- each of R 1 , R 2 , and R 3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R 10 ) 2 ] m -R n
- R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring; or R 1 and R taken together with the nitrogen to which they are bonded represent a 3-10
- the compound of Formula 6 can have a syn relationship (e.g., 2S, 3R and 2R, 3 S as labelled above) between groups attached at carbons labelled 2 and 3 above.
- the compound of Formula 6 can have the absolute stereochemistry depicted below:
- Y is a bond and R 1 and R 2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring, e.g., pyrrolidine, piperidine, and morpholine.
- the compound of Formula 6 can be:
- the compound of Formula 6 is prepared according to a method as described herein.
- a number of HIV protease inhibitors contain the hexahydro-furo[2,3-b]furan-3-ol (Compound 7) moiety.
- Examples of such protease inhibitors include darunavir, brecanevir, UIC-94003, and GS-9005 (shown below), which incorporate (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol.
- HIV protease inhibitors incorporate hexahydro-furo[2,3-b]furan-3-ol, such as the compounds described in published Japanese patent application number JP20050478474, published PCT application WO2008112289 (herein incorporated by reference). These compounds include those represented by structures 18a and 19a illustrated below.
- Compounds represented by structure 18a include compounds where Ar is an aryl group; A is CH 2 , S, or O, and R ⁇ independently for each occurrence is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.
- Compounds of structure 19a include compounds where R ⁇ ⁇ is an alkyl or a water soluble oligomer, e.g., a polyalkylene oxide, a polyolefinic alcohol, a polyhydroxyalkyl methacrylamide a polymethacrylate, and a poly-N-acryloylmorpholine; and Ar' independently for each occurrence is aryl optionally substituted with a water soluble oligomer; provided that at least one of Ar' or R" comprises a water soluble oligomer.
- the hexahydro-furo[2,3-b]furan-3-ol moiety is also incorporated in certain HCV protease inhibitors.
- R ⁇ ⁇ ⁇ independently for each occurrence is hydrogen, alkyl, heteroaryl, aralkyl, or heterocycloalkyl; and Ar is an aryl group.
- the hexahydro-furo[2,3-b]furan-3-ol moiety is attached via a carbamate linker to an amine.
- Any method known to one of ordinary skill in the art can be employed for coupling hexahydro-furo[2,3-b]furan-3-ol using a carbamate linker.
- Such methods include the steps of reacting hexahydro-furo[2,3- b]furan-3-ol or a salt thereof with a carbamate coupling agent to give an activated hexahydro-furo[2,3-b]furan-3-yl carbonate; and combining the activated carbonate with an amine containing protease inhibitor precursor.
- the protease inhibitor is prepare by first reacting an amine containing protease inhibitor precursor with a carbamate coupling agent to give an activated protease inhibitor precursor carbonate,
- the carbamate coupling reaction can be the final step in the synthesis of the protease inhibitor, in which case the product of the reaction is the desired protease inhibitor, or can be done at an earlier step in the synthetic sequence.
- Coupling agents useful in the coupling reaction include, but are not limited to phosgene, trichloromethyl chloroformate, bis(trichloromethyl) carbonate, bis(4- nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, 7V,7V-disuccinimidyl carbonate, 4-nitrophenyl chloroformate, 2,2'-dipyridyl carbonate, and iV,iV'-carbonyldiimidazole (CDI).
- a base is added to the coupling reaction.
- bases include organic and inorganic bases including, but not limited to tertiary amines, such as triethylamine, diisopropylethylamine, and TV-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, and pyridine; and inorganic bases, including NaH, alkali and alkali earth carbonates, bicarbonates, and hydroxides.
- tertiary amines such as triethylamine, diisopropylethylamine, and TV-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, and pyridine
- the coupling reaction can be performed in any solvent, including, but not limited to acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, methylacetate, ethylacetate, «-propyl acetate, isopropyl acetate, «-butyl acetate, isobutyl acetate, hexamethylphosphoramide, and mixtures thereof.
- solvent including, but not limited to acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, methylacetate, eth
- the carbamate coupling reaction can be conducted at temperatures ranging from about -40 0 C to about 100 0 C (e.g., about -40 0 C to about -0 0 C, about 0 0 C to about 30 0 C, about 30 0 C to about 60 0 C, or about 60 0 C to about 100 0 C). In certain instances the coupling reaction is conducted at about 0 0 C or about room temperature.
- Protease inhibitors can be prepared by reacting an activated hexahydro-furo[2,3- b]furan-3-yl carbonate with the following amine containing protease inhibitor precursors:
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Abstract
Provided herein are compounds and methods useful for preparing hexahydrofuro[2,3-b]furan-3-ol. Hexahydrofuro[2,3-b]furan-3-ol can be efficiently synthesized in four steps from readily available starting materials.
Description
METHODS AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF HEXAHYDROFURO[2,3-B]FURAN-3-OL
TECHNICAL FIELD The present disclosure relates to methods for the synthesis of hexahydro-furo[2,3- b]furan-3-ol compounds and novel synthetic intermediates useful therein. Optically enriched hexahydro-furo[2,3-b]furan-3-ol, e.g., the 3R, 3aS, 6aR isomer, can be prepared using the methods described herein.
BACKGROUND The compound (3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol is a pharmacological moiety present in various protease inhibitors that have proven useful in the treatment of human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Examples of such inhibitors include HIV protease inhibitors, darunavir, brecanavir, UIC- 94003, and GS-9005. Inhibition of the protease enzymes has proven to be an effective treatment against AIDS, and can be used in combination with reverse transcriptase inhibitors. In view of the importance of the above protease inhibitors and the consequent need to manufacture these compounds there exists a need to develop cost effective and efficient methods of preparing hexahydro-furo[2,3-b]furan-3-ol compounds.
SUMMARY Described herein are novel methods for preparing hexahydro-furo[2,3-b]furan-3- ol and novel intermediates useful in the synthesis of the same. The synthetic routes employed herein can be used to prepare diastereomerically and/or enantiomerically enriched hexahydro-furo[2,3-b]furan-3-ol from inexpensive and readily available starting materials.
Certain embodiments relate to a process for preparing a compound of Formula 7:
7 comprising (a) combining a reducing agent and a compound of Formula 5:
5 or a salt thereof, where X can be S or O; Y can be O, -N(R3)-, or a bond; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, - N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, - CO2R12, -OC(O)R12, -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and
R13 taken together form can represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8; to give a compound of Formula 6:
6 or a salt thereof, where each of Y, R1 and R2 is as defined above; and combining the compound of Formula 6 with an acid to give the compound of Formula 7.
Certain embodiments relate to the aforementioned process, where the reducing agent can be MBH4, MHB(R3)3, MH2B(R4)2, MH3BR4, MHB(OR4)3, MH2B(OR4)2, MH3BOR4, MAlH4, MHA1(OR4)3, MH2A1(OR4)2, MH3Al(OR4), HB(R4)2, H2BR4, BH3 , H2A1(R4)2, H2AlR4, or H3Al;
M is Li, Na, K, R3 4N, 1/2Zn or 1/2Ca; and R4 can be alkyl or aralkyl.
Certain embodiments relate to any one of the aforementioned processes, where the acid can be hydrochloric acid, hydrobromic acid sulfuric acid, phosphoric acid, nitric acid, metal hydrogen sulfate, metal dihydrogen phosphorate, trifluoroacetic acid, trichloroacetic acid, citric acid, oxalic acid, tartaric acid, oxalic acid, formic, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- toluenesulfonic acid, 10-camphorsulfonic acid, 1,5-napthalene disulfonic acid, or 1,2-ethane disulfonic acid.
Certain embodiments relate to any one of the aforementioned processes where, the compound of Formula 7 can be
Certain embodiments relate to any one of the aforementioned processes, where R can be alkyl.
Certain embodiments relate to any one of the aforementioned processes, where Y can be a bond; and each of R1 and R2 independently for each occurrence can be alkyl, cycloalkyl, aryl, or
wherein independently for each occurrence R10 can
be hydrogen or alkyl, R11 is alkoxy; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 5-8 membered optionally substituted heterocyclic ring.
Certain embodiments relate to any one of the aforementioned processes, where Y is a bond; R is alkyl; and each of R1 and R2 independently for each occurrence is alkyl, cycloalkyl, aryl, or -[C(R10)2]m-RU, wherein independently for each occurrence R10 is hydrogen or alkyl, R11 is alkoxy; or R1 and R2 taken together with the nitrogen to which they are bonded represent a 5-8 membered optionally substituted heterocyclic ring.
Certain embodiments relate to any one of the aforementioned processes, where Y can be a bond; R can be methyl, ethyl, «-propyl, or /-propyl; X is O; and R1 and R2 taken together with the nitrogen to which they are bonded can form a heterocyclic ring selected from piperidine, pyrrolidine, or morpholine.
Certain embodiments relate to any one of the aforementioned processes, further comprising combining a compound of Formula 3:
3 or a salt thereof, where X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl; or R and R1 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8; a coupling agent; and a compound of Formula 4:
R1-Y
NH
R^
or a salt thereof, where Y can be O, -N(R3)-, or a bond; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rπ; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give the compound of Formula 5.
Certain embodiments relate to the aforementioned process, where the coupling agent is dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N,N'- carbonyldiimidazole (CDI), 3~(diεthoxyphosphorylcxy)~ 1 ,2,3~benzohiazin~4GH)~cne
(DEPBT), l -ethy]-3-(3-diϊiiεthy[lattπnopropyl)carbodiimide hydrochloride (EDCL), 2-iJ- aza- 1 Ii-benzolriazole-1-y I)-IJ ,3,3-tetramethylαronmm hexafluorophosphatε UiATU), 2- (1 Ii-benzotriazole-1 -yl)-l ,1,3,3-tetramεthyhi.romum hexalluorophosphate (HBTIJ ϊ, 2-(6- chloro-l H-benzotriazole-l -yl)-l ,1,3,3-tetrarnεthylaminiuJit hexafluorophosphate (HCTIJ), benzotriazoie-l -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (FyBOF), bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP), O-{7- azabenzolriazole-l-y])-N,N,N\lNl'-tetramεthyiuromuni tεtrafluoroborate (TATU), 2-iJ H- benzotriazole-i -yl)-l
tetramεthy]-O-(3,4-dihydro-4-oxo-l ,2,3-benzoiriazin-3-_vI)uronium tetrafiiioroboratc(TBTU), O-(N-succinimidyl )» 1 , 1 ,3,3-tetramethylurorimra tctrafluoroboratc (TSlIJ ), 4»(4,6-dimethoxy4.3,54riazin»2-y1 }-4-niethy1rnorpholiniurn chloride (DMTMM), 2-chloro-4,6-dimetlioxy- 1 ,3,5-triazinε/N-methylmoφholine (CDMTz1NMM), oxalyl chloride, SOCb, SOCl >, FOCI,, PCl3, FC!,, FBr,, PBr,, FOBr5, pivaloyl chloride, or pivaloyi anhydride.
Certain embodiments relate to any one of the aforementioned processes, where the coupling agent can be CDL DMTMM, or EDCL. and the compound of Formula 4 can he rnorphoime.
Certain embodiments relate to any one of the aforementioned processes, where R can he methyl, ethyl, /∑-propyl, or 2 -propyl. X can be (J; and the compound of Formula 4 can be morpholine.
Certain embodiments relate to any one of the aforementioned processes, further comprising combining a compound of Formula 1:
RXH
2 or a salt thereof, where X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give the compound of Formula 3.
Certain embodiments relate to any one of the aforementioned processes, where the compound of Formula 1 can be
Certain embodiments relate to a process for preparing a compound of Formula 7a:
HO H
H 7a comprising (a) combining methanol, ethanol, «-propanol, or z-propanol, and a compound of Formula Ia:
Ia to give a compound of Formula 3a:
5a
(c) combining the compound of Formula 5a with LiAlH4 to give a compound of Formula 6a:
OH
,OH
6a or a salt thereof; and (d) combining the compound of Formula 6a or a conjugate acid thereof, andNaHSO4 to give the compound of Formula 7a.
Certain embodiments relate to a compound of Formula 5:
or a salt thereof, where X can be S or O; Y can be O, -N(R3)-, or a bond;
R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl; or R and R1 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8.
Certain embodiments relate to the compound of Formula 5, where Y can be a bond; R can be alkyl; and R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3- 10 membered optionally substituted heterocyclic ring.
Certain embodiments relate to the compound of Formula 5, where the compound can have the absolute stereochemistry shown below:
Certain embodiments relate to the compound of Formula 5, where the compound of Formula 5 can be prepared by a process comprising: (a) combining a compound of Formula Ia:
Ia and a compound of Formula 2: RXH
2 or a salt thereof, where X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl; or R and R1 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give a compound of Formula 3a:
3a or a salt thereof, where R is as defined above; (b) combining the compound of Formula 3a with a coupling agent; and a compound of Formula 4:
R1-Yχ
NH R2
4 or a salt thereof, where Y can be O, -N(R3)-, or a bond; each of R1, R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give the compound of Formula 5.
Certain embodiments relate to a compound of Formula 3:
3 or a salt thereof, where X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -
OC(O)N(R12XR13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or - SO2N(R12XR13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; provided that when R is t-buty\, then X is not O; further provided that when R is menthyl, then X is not O; further provided that when R is benzyl, then X is not O.
Certain embodiments relate to the compound of Formula 3 where R can be alkyl and X can be O.
Certain embodiments relate to the compound of Formula 3 where the compound can have the absolute stereochemistry shown below:
O
RχΛry°
Certain embodiments relate to the compound of Formula 3 prepared by a process comprising (a) combining a compound of Formula Ia:
Ia and a compound of Formula 2:
RXH 2 or a salt thereof, wherein:
X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10^]nI-R1 x; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -N(R12)C(O)OR13, - N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, - OC(O)R12, -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give the compound of Formula 3.
Certain embodiments relate to a compound of Formula 6:
N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8.
Certain embodiments relate to a compound of Formula 6, where the compound can have the absolute stereochemistry shown below:
HOΛN'R2
Certain embodiments relate to any of the aforementioned compounds of Formula 6, where Y can be a bond and R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring.
Certain embodiments relate to any one of the aforementioned compounds of Formula 6, where the compound of Formula 6 is prepared by a process comprising: (a) combining a compound of Formula Ia:
Ia and a compound of Formula 2:
RXH 2 or a salt thereof, where X can be S or O; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -
N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
heteroaralkyl; or R and R1 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give a compound of Formula 3a:
3a or a salt thereof, where R is as defined above; (b) combining the compound of Formula 3a with a coupling agent; and a compound of Formula 4:
R1-Yχ
NH R2
4 or a salt thereof, where Y can be O, -N(R3)-, or a bond; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; to give a compound of Formula 5a:
5a or a salt thereof, where each of R, R1, and R2, are as defined above; and (c) combining the compound of Formula 5a with a reducing agent to give the compound of Formula 6.
Certain embodiments relate a compound selected from the group consisting of:
Certain embodiments relate to a process for preparing a compound of Formula 7:
6 or a salt thereof, where Y can be O, -N(R3)-, or a bond; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or
R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), - N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give the compound of Formula 7. Certain embodiments relate to a process for preparing a protease inhibitor comprising (a) combining a reducing agent and a compound of Formula 5:
5 or a salt thereof, where X can be S or O; Y can be O, -N(R3)-, or a bond; R can be alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; each of R1 R2, and R3 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded can represent a 3-10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together can represent a 5-8 membered optionally substituted heterocyclic ring; and m can be 0-8; to give a compound of Formula 6:
6 or a salt thereof, where each of Y, R1 and R2 is as defined above; (b) combining the compound of Formula 6 with an acid to give a compound of Formula 7:
(c) combining the compound of Formula 7 with a carbamate coupling agent to give an activated carbonate; and (d) combining the activated carbonate with an amine containing protease inhibitor precursor.
Certain embodiments relate to the aforementioned process where the amine containing protease inhibitor precursor can be: (i) a compound of Formula 13:
13a or a salt thereof;
(ii) a compound of Formula 14:
14 or a salt thereof; and the protease inhibitor can be a compound of Formula 14a:
14a or a salt thereof;
(iii) a compound of Formula 15:
15
or a salt thereof; and the protease inhibitor can be a compound of Formula 15a:
15a or a salt thereof;
(iv) a compound of Formula 16:
16 or a salt thereof; and the protease inhibitor can be a compound of Formula 16a:
16a or a salt thereof;
(v) a compound of Formula 17:
17
or a salt thereof; where Ar independently for each occurrence can be aryl; and the protease inhibitor can be a compound of Formula 17a:
17a or a salt thereof; where Ar independently for each occurrence is as defined above; (vi) a compound of Formula 18:
18a or a salt thereof; where each of Ar, A, and RΛ are defined as above; (vii) a compound of Formula 19:
19a or a salt thereof; where each of Ar' and RΛ Λ are as defined above; or
(viii) a compound of Formula 20:
20 or a salt thereof, where Ar can be aryl; each of RΛ Λ' independently for each occurrence can be hydrogen, alkyl, heteroaryl, aralkyl, or heterocycloalkyl; and the protease inhibitor can be a compound of Formula 20a:
20a or a salt thereof; where each of Ar and RΛ Λ Λ are as defined above. Certain embodiments relate to the aforementioned process, where the carbamate coupling agent can be selected from the group consisting of phosgene, trichloromethyl chloroformate, bis(trichloromethyl) carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, N,N'-disuccinimidyl carbonate, 4-nitrophenyl chloroformate, 2,2'-dipyridyl carbonate, and N,N'-carbonyldiimidazole (CDI). Certain embodiments relate to any one of the aforementioned processes where R can be alkyl; X can be O; and each of R1 and R2 independently for each occurrence can be alkyl, cycloalkyl, aryl, or -[C(R10)2]m-Rn, wherein independently for each occurrence
R10 can be hydrogen or alkyl, R11 is alkoxy; or R1 and R2 taken together with the nitrogen to which they are bonded can represent a 5-8 membered optionally substituted heterocyclic ring.
Certain embodiments relate to a protease inhibitor prepared by any of the aforementioned processes.
Other features, objects, and advantages of the compounds and methods described herein will be apparent from the description and drawings, and from the claims.
DETAILED DESCRIPTION
Definitions The term "heteroatom" refers to an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium.
The term "alkyl" includes saturated aliphatic groups, including straight- chain alkyl groups and branched-chain alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C1-C30 for branched chain), and alternatively, about 20 or fewer. In certain instances, alkyl groups can be optionally substituted.
The term "cycloalkyl" include saturated, cycloalkyl groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. Cycloalkyls include monocyclic and polycylic rings. Cycloalkyls can have from about 3 to about 15 carbon atoms in their ring structure, and alternatively about 5, 6, 7, or 10 carbons in the ring structure. In certain instances, cycloalkyl groups can be optionally substituted.
The term "aryl" includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, naphthalene, anthracene, pyrene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as "aryl heterocycles" or
"heteroaromatics." The aromatic ring may be substituted at one or more ring positions with such substituents as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido,
phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF3, -CN, or the like. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.
The terms "heterocyclyl", "heteroaryl", or "heterocyclic group" include 3- to about 10-membered ring structures, alternatively 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be poly cycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described herein, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, or the like.
The term "optionally substituted" refers to any chemical group, such as alkyl, cycloalkyl aryl, and the like, wherein one or more hydrogens may be replaced with a a substituent as described herein, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, - CF3, -CN, or the like; or has the formula -[(CR5oR5i)n]Rs2, wherein each of R50 and R51 independently for each occurrence is hydrogen, alkyl, aralkyl, cycloalkyl, or aryl; R52 is hydrogen, amino, acylamino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate,
carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester; and n is an integer selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
The term "salt" includes any ionic form of a compound and one or more counter- ionic species (cations and/or anions). Salts also include zwitterionic compounds (i.e., a molecule containing one more cationic and anionic species, e.g., zwitterionic amino acids). Counter ions present in a salt can include any cationic, anionic, or zwitterionic species. Exemplary ions include, but are not limited to chloride, bromide, iodide, nitrate, sulfate, bisulfate, sulfite, phosphate, acid phosphate, chlorate, perchorate, hypochlorite, iodate, periodate, hypoiodite, carbonate, bicarbonate, isonicotinate, acetate, trichloroacetate, trifluroacetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, trifluormethansulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate, p-trifluormethylbenzenesulfonate, hydroxide, earth metals, such as aluminium (e.g., aluminates) and boron (e.g., borates and tetraborates), alkali metals, such as lithium, sodium, potassium, and cesium, alkaline earth metals, such as beryllium, magnesium, calcium, strontium, and barium, silver, zinc, ammounium salts.
The definition of each expression, e.g., alkyl, m, n, and the like, when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure.
As used herein, chemical structures which contain one or more stereocenters depicted with wedged shaped bonds, i.e., f ' are meant to indicate absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, chemical structures which contain one or more stereocenters depicted with non-wedge shaped bonds, i.e., > * I or - M ', are meant to indicate relative stereochemistry of the stereocenter(s) present in the chemical structure. Unless otherwise indicated to the contrary, chemical structures, which include one or more stereocenters, illustrated herein without indicating absolute or relative stereochemistry encompass all possible steroisomeric forms of the compound (e.g., diastereomers, enantiomers, cis/trans isomers, etc) and mixtures thereof.
Provided herein are efficient methods for the preparation of hexahydro-furo[2,3- b]furan-3-ol 7. The methods employed can be modified to access different stereoisomers, enantiomers, and diastereomers of hexahydro-furo[2,3-b]furan-3-ol from readily available precursors. Compound 7 can be prepared in 4 steps from isocitric acid lactone anhydride 1 (Scheme 1). Scheme 1.
* or a salt thereof
Compound 1 can be prepared according to the procedure described in DE226473, from isocitric acid (e.g., (2R,3S), (2S, 3R), racemic isocitric acid), which is readily produced on large scale by fermentation (DE2065207, JP35014494, JP50155683). The anhydride lactone 1 can be reacted with a nucleophile, e.g., an alcohol, to yield carboxylic acid 3. Carboxylic acid 3 can be coupled with, e.g., an amine to yield compound 5, which can then be reacted with a reducing agent, such as LiAlH4, and subjected to acid catalyzed cyclization to yield the desired compound 7. Optically enriched hexahydro-furo[2,3-b]furan-3-ol is readily available by starting from optically enriched lactone anhydride 1, or by separating the desired enantiomer at any step in the synthesis starting from racemic compound 1.
Anhydride 1 when reacted with nucleophile 2, such as an alcohol or thiol, under suitable conditions, undergoes anhydride ring opening in a regioselective fashion to afford compound 3. In certain instances, the nucleophile is an alcohol, thiol, or salts thereof. Examples of nucleophiles useful for reaction with the anhydride include, but are not limited to methanol, ethanol, «-propanol, sec-propanol, «-butanol, seobutanol, tert-
butanol, benzyl alcohol, methylthiol, «-propanthiol, seopropanthiol, «-butanthiol, sec- butanthiol, tert-butanthiol, and benzylthiol.
In certain instances, the nucleophile 2 is a compound of formula RXH, where X is S or O; R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn, where R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; and R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -N(R12)C(O)OR13, - N(R12)SO2(R13), -CON(R12XR13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -
OC(O)R12, -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12) S(O)2OR13; each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8. In the examples provided below, RXH is methanol.
In certain instances, a salt of nucleophile 2 can be used for the anhydride ring opening. Such salts include alkali metal, alkaline earth metal, and ammonium salts of the nucleophile. The anhydride ring opening can be accomplished using a number of well known procedures. For example, an alcohol or thiol can be reacted with compound 1 to afford compound 3. In certain instances, the alcohol or thiol can serve as the solvent for the reaction. Other solvents may be used in this reaction, such as tetrahydrofuran, tetrahydropyran, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, 1,2-dimethoxyethane, ethylacetate, acetonitrile, dichloromethane, chloroform, carbon tetrachloride, 1,2- dichloroethane, acetone, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, alcohols, water, and mixtures thereof.
The reaction can be run at a temperature from about -10 0C to about 120 0C, from about -10 0C to about 100 0C, from about -100C to about 80 0C, from about -10 0C to about 60 0C, form about -10 0C to about 40 0C, from about 0 0C to about 40 0C, or from about 20 0C to about 30 0C. In certain instances, the reaction can be run from about -30 0C to about 0 0C,. from about -10 0C to about 30 0C, from about 30 0C to about 70 0C, from about 70 0C to about 120 0C. In certain instances, more reactive nucleophiles, such
salts of alcohols and tniols, can be run at lower temperatures. In the examples below, methanol is used as the nucleophile and the reaction is run at room temperature. An organic or inorganic base can optionally be used in the reaction of the nucleophile 2 (e.g., alcohol or thiol) with compound 1. Inorganic bases, such as alkali and alkali earth, oxides, hydroxides, carbonates, bicarbonates, and hydrides; and ammonium hydroxide can be used in the anhydride ring opening. Organic bases useful in the anhydride ring opening include but are not limited to tertiary amines, such as triethylamine N, N-diisopropylethyl amine (Hύnig's base), N-methyl morpholine, and 1,4- diazabicyclo[2.2.2]octane (DABCO), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine, imidazole, and alkali and alkaline earth metal alkoxides, such as sodium tert-butoxide.
Lewis acids can also be utilized to catalyze the addition of the nuecleophile 2 to the anhydride. Lewis acids useful in the reaction include, but are not limited to rare earth salts, such as scandium, ytterbium, and lanthanum, magnesium, zinc salts, manganese, cobalt, copper, and silver salts.
The crude carboxylic acid 3 can either be used directly in the next reaction, without purification, or purified prior to the acylation reaction. The crude lactone can be purified by any number of techniques, including Ii quid- Ii quid extraction, solid- Ii quid extraction, chromatography, distillation and crystallization. The carboxylic acid 3 can be reacted directly or indirectly with nucleophile 4 under conditions suitable to form compound 5. Indirect methods for forming compound 5 include first preparing an activated carboxyl intermediate, which is then reacted with nucleophile 4. Examples of reagents useful for preparing activated carboxyl intermediates include, halogenating agents, such as SOCl2, SO2Cl2, PCI3, PBr3, POCI3, POBr3, oxalyl chloride, dichlorotriphenylphosphorane, and N,N- dimethylchloromethylenammonium chloride, 1,1-carbonyldiimidazole (CDI), and reagents which generate mixed anhydrides, such as pivaloyl chloride and isobutyl chloroformate (IBCF). The resulting activated carboxyl containing compound can then be reacted with an amine as described herein. A base can optionally be used in the acylation reaction. In certain instances, the amine to be coupled acts as the base.
In certain instances, the carboxylic acid 3 is activated in situ and the resulting activated carboxyl containing compound is reacted with the nucleophile 4 to afford compound 5. In situ generation of the activated carboxyl compounds can provide synthetic efficiencies and lower material costs. Reagents useful for generating the activated carboxyl include, but are not limited to carboiimides, such as \-tert-hvXy\-1- ethylcarbodiimide, N,7V-di-fert-butylcarbodiimide, 7V,7V-dicyclohexylcarbodiimide, N,N- diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide, 1 -[3- (dimethylamino)propyl]-3-ethylcarbodiimide methiodide, and l,3-di-/>tolylcarbodiimide, phosphonium reagents, such as (7-azabenzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate, (benzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate, (benzotriazol- 1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, bromotris(dimethylamino)phosphonium hexafluorophosphate, and chlorotripyrrolidinophosphonium hexafluorophosphate, uronium reagents such as o-(7- azabenzotriazol- 1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, o- benzotriazol-l-yl-N,7V,N',N'-bis(pentamethylene)uronium hexafluorophosphate, and o- (benzotriazol- 1 -yl)-N,N,N',iV-bis(tetramethylene)uronium hexafluorophosphate, formamidinium such as chloro-N,N,N',N'-bis(tetramethylene)formamidinium tetrafluoroborate and chloro-N,Λ/,N',N'-tetramethylformamidinium hexafluorophosphate, imidazolidinium reagents such as 2-chloro-l,3-dimethylimidazolidinium chloride and 2- fluoro-l,3-dimethylimidazolidinium hexafluorophosphate, 4-{4,6-dinιethoxy-l,3,5~ tτiazin-2-y])-4-inei]u'lτnoφholiniuin chloride (DMTMM), and 2~eh]oro-4,6~dimetboxy~ I,3,54ria2ine/N~mεthyimorphoiine (CDMT/NMM). Methods employing in situ formation of the activated carboxyl containing compound can further include an organic or inorganic base and additional coupling agents, such as N-hydroxybenzotriazole.
Suitable organic bases include tertiary amines, such as Hunig's base, triethylamine, TV- methyl morpholine, piperidine and pyridine. Inorganic bases, including alkali and alkali earth carbonates, bicarbonates, hydroxide, and alkoxides can be used in the coupling reaction. Various nucleophiles can be used in the acylation reaction. The nucleophile 4 can be a primary or secondary amine, a hydrazine, or alkoxyamine. Examples of suitable
amines include, but are not limited to pyrrolidine, piperidine, and morpholine, or can be represented by the formula R1YNR2, where Y can be a bond (i.e., a single bond) between N and R1 or oxygen; each of R1 and R2 independently for each occurrence can be C1-C8- alkyl, C5-C8-cycloalkyl, optionally substituted phenyl or benzyl; or R1 is a Cl-C8-alkyl, C5-C8-cycloalkyl, optionally substituted phenyl or benzyl, and R2 is a Cl-C8-alkyloxy, C5-C8-cycloalkyloxy; or R1 and R2 together with the N atom form a five- to eight- membered optionally substituted ring. In certain instances, R1 and R2 are identical radicals, e.g., each Cl-C4-alkyl, such as methyl, ethyl, n- or /-propyl or n-, i- or ^-butyl; or R1 is a Cl-C4-alkyl, such as methyl, ethyl, «-propyl, /-propyl or n- or /-butyl, and R2 is a Cl-C4-alkyloxy, such as methoxy, ethoxy, n- or /-propyloxy, n- or i- or t-butyloxy; or Y is oxygen, R1 is methyl and R2 is methoxy.
In certain instances, the nucleophile 4 used in the acylation reaction is represented by R1YNR2, where Y is a bond (i.e., a single bond between R1 and N) between N and R1, oxygen, or -N(R3)-; each of R1, R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl (i.e., alkyl radicals having one or more halogens), or -[C(R10)2]m- R11; or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3- 10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, - N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), -
N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together form a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8. In the examples below, EDCI and HOBT are used to couple morpholine to carboxylic acid 3 in acetonitrile. Other solvents useful in the reaction include, but are not
limited to propionitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1 ,2-dimethoxy ethane, dimethylformamide, dimethylsulfoxide, methylacetate, ethylacetate, «-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, and hexamethylphosphoramide. The acylation reaction can be run at any temperature from about -40 to about 100 0C {e.g., about -400C to about 00C, about -200C to about 200C, about 200C to about 600C, or about 600C to about 100 0C). In certain instances the acylation reaction is run at about room temperature or about 0 0C.
Crude compound 5 can be purified prior to reduction or can be reduced without purification. Any number of methods can be used to purify compound 5, including liquid-liquid extraction, solid-liquid extraction, chromatography, and crystallization.
Compound 5 can then be reacted with a reducing agent. In certain instances, the reducing agent is any reagent capable of reducing the lactone and ester or thioester functional groups to primary alcohols and the amide to an N, O- aminal or aldehyde. Reducing agents useful for reducing compound 5 include but are not limited to zinc, N(R4K alkali (e.g., Li, Na, and K), and alkali earth salts (e.g., Ca)of ©BH4, ©HBR4 3, ©H2BR4 2, S H3BR4, Θ HB(OR4)3, ©H2B(OR4)2, and © H3BOR4, boranes, such as HBR42, H2BR4, and BH3, including borane amine complexes, and aluminum reducing agents, such as ©A1H4, ©HA1R4 3, ΘH2A1R4 2, ©H3A1R4, ©HA1(OR4)3, ©H2A1(OR4)2, and © H3AlOR4, and organo-aluminum reagents such as HA1R4 2, H2AlR4, and AlH3, including aluminum amine complexes, where R4 independently for each occurrence is alkyl or aralkyl. In reaction sequences illustrating the reduction step, i.e., the transformation of compound 5 into compound 6, (i.e., Scheme 1) "M" can be a cation, e.g., zinc(I), ©N(R4)4, alkali(I) (e.g., Li, Na, and K), and alkali earth(II) salts (e.g., Ca and Mg) ,where R4 is as defined above.
Suitable solvents for the reduction include diethyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, or alcohols, such as methanol, ethanol, n-propanol, ώo-propanol, «-butanol, s-butanol, tert-butanol, and mixtures thereof. The reduction can be run at temperatures of from about -100 0C to about 80 0C (e.g., about -100 0C to about -40 0C, about -40 0C to about 20 0C, about 20 0C to about
40 0C, about 40 0C to about 100 0C, or about -80 0C to about 0 0C). Protic solvents, such
as water and alcohols, can be used to increase the reactivity of the reducing agent employed.
In certain instances, reaction of a reducing agent with compound 5 yields a salt of compound 6. Salts of compound 6 include alkali, alkali earth, boron (e.g., borate ester, boronic ester, borinic ester), aluminum (e.g., aluminates, aluminum alkoxides, and organo-aluminum alkoxides), and ammonium salts, mixtures thereof, and/or polymeric complexes thereof. When the phrase "salts thereof is used in connection with compounds of Formula 6 it is meant to include the crude product(s) of the reduction reaction of compounds of Formula 5 with a reducing agent, e.g., boron and aluminum reducing agents described herein.
Compound 6 and salts thereof can be subjected directly to acid catalyzed cyclization to afford the desired product 7. This can be accomplished by adding an acid directly to the reaction mixture after reduction of compound 5 has run to completion. In certain instances, the conjugate acid of compound 6 can be isolated as the aldehyde, hydrate, or cyclic hemi-acetal, and mixtures thereof illustrated in Scheme 2. These isolated compounds or mixtures thereof can then be subjected to the acid catalyzed cyclization conditions. Scheme 2.
Suitable acids for the cyclization reaction include Brønsted and Lewis acids. Brønsted acids useful in the cyclization reaction include, but are not limited to inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, metal hydrogen sulfate, sulfurous acid, metal hydrogensulfite, phosphoric acid, metal dihydrogen phosphate, metal hydrogen phosphate, phosphonic acid, metal hydrogen phosphate, pyrophosphoric acid, metal trihydrogen pyrophosphate, metal
dihydrogen pyrophosphate, and metal hydrogen pyrophosphate, and organic acids, such as citric, fumaric, maleic, malic, ascorbic, succinic, tartaric, benzoic, acetic, trifluoroacetic acid, trichloracetic acid, methanesulfonic, trifluormethanesulfonic acid, ethanesulfonic, benzenesulfonic,/>toluenesulfbnic acid,/> trifluoromethylbenzenesulfonic acid, camphorsulfonic acid, naphthalene- 1,5-disulfonic acid, ethan-l,2-disulfonic acid, cyclamic acid, thiocyanic acid, naphthalene-2-sulfonic acid, and oxalic acid.
Lewis acids can also be employed in the acid catalyzed cyclization reaction. Such Lewis acids include, but are not limited to TMSOTf, AlCl3, A1(OR4)3, BF^, BCl3, SbF5, SnCl4, TiCl4, Ti(OR4)4, where R4 independently for each occurrence is as defined above.
The acid catalyzed cyclizition reaction can be conducted in any solvent, including but not limited to diethyl ether, diisopropyl ether, tetrahydrofuran, tetrahydropyran 1 ,4- dioxane, tert-butyl methyl ether, dichloromethane, dichloroethane, chloroform, carbontetrachloride, acetonitrile, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, ethylacetate, hexamethylphosphoramide, water and mixtures thereof.
In the examples below, NaHSO4 is used as the acid for the cyclization reaction in a mixture of water and tetrahydrofuran.
Enantiomerically and/or diastereomerically enriched hexahydro-furo[2,3-b]furan- 3-ol can be prepared using optically active starting materials. Chirality present in the starting material can be preserved through the synthetic process. For example,
(3R,3aS,6aR)-hexahydro-furo[2,3-b]furan-3-ol can be prepared from (2R,3S) isocitric acid as illustrated in Scheme 3. Scheme 3.
OH HO H acid cyclization CL)
HO-^N'R2
Y>
R1
* or a salt thereof
Optically enriched hexahydro-furo[2,3-b]furan-3-ol can also be prepared from racemic starting material and separating optical isomers at any step in the synthesis using any method known to those of ordinary skill in the art, e.g., separating optical isomers using chiral chromatography (e.g., HPLC or SFC using columns with chiral stationary phase) or by forming diasteromers with an optically enriched compound, e.g., optically active amines can be used to make diasteromeric salts (e.g., with compound 3), diasteremeric amides (e.g., of compound 5) and separated using traditional purification techniques, or by enzymatic resolution of a racemic mixture (e.g. compound 7 or its esters) using the appropriate esterase enzyme.
Some or all of the steps described herein can be conducted in the same reaction vessel, e.g., as a "one pot method" or in different reaction vessels. Reactions conducted in the same reaction vessel can be run in the same or different solvents. Solvent transfers can be used when changing solvents between synthetic steps, e.g., at the end of a particular reaction the solvent is removed (e.g, by distillation), and another solvent can be added. For example, the anhydride ring opening reaction can be conducted in methanol, after the reaction is complete, the methanol can be removed, reagents and solvents for the acylation step (i.e., the reaction of compound 3 with nucleophile 4 to give compound 5) can be added to the reaction vessel, and the acylation reaction can be carried our in the same vessel. In another example, after compound 3 is subjected to the reduction reaction, an acid can be added directly to the reduction reaction mixture in the same reaction vessel to perform the acid catalyzed cyclization.
Using the methods described herein hexahydro-furo[2,3-b]furan-3-ol can be prepared efficiently and in high yield from readily available isocitric acid lactone anhydride 1. The synthetic routes described herein can provide the final product in at least 40%, at least, 50%, at least 60%, at least 70%, at least 80%, at least 90% or at least 95% overall yield from isocitric acid lactone anhydride 1.
Certain compounds are useful synthetic intermediates in the processes described herein. These compounds include compounds of Formula 3, 5, and 6. For example, compounds of Formula 3 are useful in the acylation reaction with nucleophile 4. Compounds of Formula 3 can be represented by:
3 or a salt thereof, where X can be S or O; R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, - N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, - CO2R12, -OC(O)R12, -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8; provided that when R is ^-butyl, then X is not O; further provided that when R is menthyl, then X is not O; further provided that when R is benzyl, X is not O. In certain
instances, the compound of Formula 3 can have a cis relationship between groups attached at carbons labelled 4 and 5 above. In certain instances, the compound of Formula 3 can have the absolute stereochemistry depicted below:
In certain instances, the compound of Formula 3 can be:
Compounds of Formula 5 are useful in the methods as described herein. Compounds of Formula 5 can be represented by:
In certain instances, R is alkyl, Y is a bond, and R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring.
In certain instances, the compound of Formula 5 can be:
In certain instances, the compound of Formula 5 is prepared according to a method as described herein.
Compounds of Formula 6 are useful in the methods as described herein. Compounds of Formula 6 can be represented by:
OH
HO"^N'R2
In certain instances, Y is a bond and R1 and R2 taken together with the nitrogen to which they are bonded represent a 3-10 membered optionally substituted heterocyclic ring, e.g., pyrrolidine, piperidine, and morpholine.
In certain instances, the compound of Formula 6 can be:
A number of HIV protease inhibitors contain the hexahydro-furo[2,3-b]furan-3-ol (Compound 7) moiety. Examples of such protease inhibitors include darunavir, brecanevir, UIC-94003, and GS-9005 (shown below), which incorporate (3R,3aS,6aR) hexahydro-furo[2,3-b]furan-3-ol.
Darunavir
GS-9005
Other HIV protease inhibitors incorporate hexahydro-furo[2,3-b]furan-3-ol, such as the compounds described in published Japanese patent application number JP20050478474, published PCT application WO2008112289 (herein incorporated by reference). These compounds include those represented by structures 18a and 19a illustrated below.
Compounds represented by structure 18a include compounds where Ar is an aryl group; A is CH2, S, or O, and RΛ independently for each occurrence is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl. Compounds of structure 19a include compounds where R Λ Λ is an alkyl or a water soluble oligomer, e.g., a polyalkylene oxide, a polyolefinic alcohol, a polyhydroxyalkyl methacrylamide a polymethacrylate, and a poly-N-acryloylmorpholine; and Ar' independently for each occurrence is aryl optionally substituted with a water soluble oligomer; provided that at least one of Ar' or R" comprises a water soluble oligomer.
The hexahydro-furo[2,3-b]furan-3-ol moiety is also incorporated in certain HCV protease inhibitors. Published PCT applications WO2007025307 and WO2008106139 (herein incorporated by reference) describe the use of HCV protease inhibitors that incorporate the hexahydro-furo[2,3-b]furan-3-ol moiety. These compounds included those represented by structure 20a illustrated below.
The methods and intermediates described herein can be used to prepare the protease inhibitors described above and other protease inhibitors that contain the hexahydro-furo[2,3-b]furan-3-ol moiety.
In the compounds shown above, the hexahydro-furo[2,3-b]furan-3-ol moiety is attached via a carbamate linker to an amine. Any method known to one of ordinary skill in the art can be employed for coupling hexahydro-furo[2,3-b]furan-3-ol using a carbamate linker. Such methods include the steps of reacting hexahydro-furo[2,3- b]furan-3-ol or a salt thereof with a carbamate coupling agent to give an activated hexahydro-furo[2,3-b]furan-3-yl carbonate; and combining the activated carbonate with an amine containing protease inhibitor precursor. In other instances, the protease inhibitor is prepare by first reacting an amine containing protease inhibitor precursor with a carbamate coupling agent to give an activated protease inhibitor precursor carbonate,
and combining hexahydro-furo[2,3-b]furan-3-ol or a salt thereof, to give a coupled carbonate (as illustrated below). Route A
H
The carbamate coupling reaction can be the final step in the synthesis of the protease inhibitor, in which case the product of the reaction is the desired protease inhibitor, or can be done at an earlier step in the synthetic sequence.
Any method known for coupling an amine to an alcohol via a carbamate linker can be employed at the carbamate coupling step in the preparation of the protease inhibitor. Coupling agents useful in the coupling reaction include, but are not limited to phosgene, trichloromethyl chloroformate, bis(trichloromethyl) carbonate, bis(4- nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, 7V,7V-disuccinimidyl carbonate, 4-nitrophenyl chloroformate, 2,2'-dipyridyl carbonate, and iV,iV'-carbonyldiimidazole (CDI).
In certain instances, a base is added to the coupling reaction. Such bases include organic and inorganic bases including, but not limited to tertiary amines, such as triethylamine, diisopropylethylamine, and TV-methyl morpholine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), imidazole, and pyridine; and inorganic bases, including NaH, alkali and alkali earth carbonates, bicarbonates, and hydroxides. The coupling reaction can be performed in any solvent, including, but not limited to acetonitrile, propionitrile, dichloromethane, dichloroethane, chloroform, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, 1,2-dimethoxyethane, dimethylformamide, dimethylsulfoxide, methylacetate, ethylacetate, «-propyl acetate, isopropyl acetate, «-butyl acetate, isobutyl acetate, hexamethylphosphoramide, and
mixtures thereof. The carbamate coupling reaction can be conducted at temperatures ranging from about -400C to about 100 0C (e.g., about -400C to about -00C, about 00C to about 300C, about 300C to about 600C, or about 600C to about 100 0C). In certain instances the coupling reaction is conducted at about 0 0C or about room temperature.
Protease inhibitors can be prepared by reacting an activated hexahydro-furo[2,3- b]furan-3-yl carbonate with the following amine containing protease inhibitor precursors:
19 20 or a salt thereof and/or a suitably protected derivative thereof, where Ar, Ar', R\ R \ and RΛΛΛ are as defined above.
EXAMPLES
The following examples serve to illustrate the process of the present invention without limiting the scope thereof. Example 1. Synthesis of Hexahydrofuror2,3-b1furan-3-ol Step A.
A suspension of racemic cis-isocitric acid lactone anhydride (2.30 g, 14.8 mmol) in methanol (15 mL) was stirred for 20 h at room temperature. The solvent was removed under reduced pressure to give the product (2.78 g, 100%) as an oil. 1H NMR (CDCU, 300 MHz): δ 2.79 (dd, IH, J = 9.2 and 17.7 Hz), 3.09 (dd, IH, J = 9.5 and 17.7 Hz), 3.77 (dd, IH, J = 9.2 and 17.5 Hz), 3.80 (s, 3H), 5.13 (d, IH, J = 8.5 Hz). 13C NMR (CDCl3, 75 MHz): δ 30.16, 43.28, 53.16, 76.14, 168.15, 173.05, 173.49.
Step B.
To a stirring solution of compound 8 (2.63 g, 14 mmol) in acetonitrile (20 mL) was added HOBT (2.45 g, 16 mmol) and EDCI (2.88 g, 15 mmol). After the mixture was stirred at room temperature for 20 min, morpholine (1.30 mL, 15 mmol) and Et3N (2.10 mL, 15 mmol) were added. The mixture was stirred overnight at room temperature. After removal of acetonitrile under reduced pressure, the residue was partitioned between 4 M HCl (10 mL) and CH2Cl2 (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2x15 ml). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, EtOAc-hexane: 1:1) to give the product 9 (3.31 g, 92%) as white
crystals. 1H NMR (CDCl3, 300 MHz): δ 2.61 (dd, IH, J = 9.7 and 17.5 Hz), 3.28 (dd, IH, J = 10.2 and 17.7 Hz), 3.57 (m, 4H), 3.70 (m, 4H), 3.78 (s, 3H), 3.95 (dd, IH, J = 8.8 and 17.5 Hz), 5.03 (d, IH, J= 8.6 Hz). 13C NMR (CDCl3, 75 MHz): δ 30.48, 41.45, 42.79, 46.11, 52.96, 66.30, 66.54, 76.00, 166.05, 168.00, 174.32.
Step C.
To a solution of compound 9 (515 mg, 2 mmol) in THF (10 mL) was added dropwise 1 M LiAlH4 solution in THF at -78 0C. After stirring for 1 h at -78 0C, the o cooling bath was removed, and the mixture was stirred for another 1 h. The mixture was cooled to -10 0C and 50% NaHSO4 aqueous solution was added dropwise. The mixture was stirred overnight at room temperature and dried (MgSO4). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, EtOAc-hexane: 4: 1) to give product 7a (198 mg, 76%) as pale yellow oil. 1H5 NMR (CDCl3, 300 MHz): δ 1.89(m, IH), 2.05 (m, IH), 2.32 (m, IH), 2.87 (m, IH),
3.64(dd, IH, J =7.1 and 8.6 Hz), 3.92 (m, IH), 3.99 (m, 2H), 4.46 (m, IH), 5.70 (d, IH, J = 5.0 Hz). 13C NMR (CDCl3, 75 MHz): δ 24.93, 46.54, 69.92, 70.63, 73.02, 109.53.
A number of embodiments of a method for preparing hexahydrofuro[2,3-b]furan- 3-ol and intermediates useful therein have been described. Nevertheless, it will be0 understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other embodiments are within the scope of the following claims.
Claims
1. A process for preparing a compound of Formula 7:
7 comprising:
(a) combining a reducing agent and a compound of Formula 5:
5 or a salt thereof, wherein:
X is S or O;
Y is O, -N(R3)-, or a bond; R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-R11 ; each of R1 R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl, or 
or R1 and R2 taken together with the nitrogen to which they are bonded represent a 3- 10 membered optionally substituted heterocyclic ring; or R1 and R3 taken together with the nitrogen to which they are bonded represent a 3- 10 membered optionally substituted heterocyclic ring; R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl; or R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, - N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or - SO2N(R12)(R13), -N(R12)S(O)2OR13; each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and m is 0-8; to give a compound of Formula 6:
2. The process of claim 1, wherein said reducing agent is MBH4, MHB(R3)3, MH2B(R4)2, MH3BR4, MHB(OR4)3, MH2B(OR4)2, MH3BOR4, MAlH4, MHA1(OR4)3, MH2A1(OR4)2, MH3Al(OR4), HB(R4)2, H2BR4, BH3 , H2A1(R4)2, H2AlR4, or H3Al; M is Li, Na, K, R3 4N, 1/2Zn or 1/2Ca; and R4 is alkyl or aralkyl.
3. The process of claim 1, wherein said acid is hydrochloric acid, hydrobromic acid sulfuric acid, phosphoric acid, nitric acid, metal hydrogen sulfate, metal dihydrogen phosphorate, trifluoroacetic acid, trichloroacetic acid, citric acid, oxalic acid, tartaric acid, oxalic acid, formic, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, 1,5-napthalene disulfonic acid, or 1,2-ethane disulfonic acid.
4. The process of claim 1, wherein said compound of Formula 7 is
H 
5. The process of claim 1, wherein R is alkyl. 6. The process of claim 1, wherein Y is a bond; and each of R1 and R2 independently for each occurrence is alkyl, cycloalkyl, aryl, or -[C(R10)2]m-Rn, wherein independently for each occurrence R10 is hydrogen or alkyl, R11 is alkoxy; or R1 and R2 taken together with the nitrogen to which they are bonded represent a 5-8 membered optionally substituted heterocyclic ring. 7. The process of claim 1, wherein Y is a bond; R is alkyl; and each of R1 and R2 independently for each occurrence is alkyl, cycloalkyl, aryl, or -[C(R10)2]m-Rn, wherein independently for each occurrence R10 is hydrogen or alkyl, R11 is alkoxy; or R1 and R2 taken together with the nitrogen to which they are bonded represent a 5-8 membered optionally substituted heterocyclic ring. 8. The process of claim 1 , wherein Y is a bond; R is methyl, ethyl, « -propyl, or i- propyl; X is O; and R1 and R2 taken together with the nitrogen to which they are bonded form a heterocyclic ring selected from piperidine, pyrrolidine, or morpholine. 9. The process of claim 1, further comprising: combining a compound of Formula 3 :
79 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
80 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
81 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
82 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
83 SO2N(R12XR13), -N(R12)S(O)2OR13;
84 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
85 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
86 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
87 optionally substituted heterocyclic ring; and
88 m is 0-8;
89 a coupling agent; and
90 a compound of Formula 4:
R1-Yχ NH
91 R2
92 4
93 or a salt thereof, wherein
94 Y is O, -N(R3)-, or a bond;
95 each of R1 R2, and R3 independently for each occurrence is hydrogen,
96 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
97 heteroaryl, heteroaralkyl, haloalkyl, or 
or R1 and R2 taken
98 together with the nitrogen to which they are bonded represent a 3- 10
99 membered optionally substituted heterocyclic ring; or R1 and R3 taken
100 together with the nitrogen to which they are bonded represent a 3- 10
101 membered optionally substituted heterocyclic ring;
102 to give said compound of Formula 5.
103 10. The process of claim 9, wherein said coupling agent is dicyclohexylcarbodiimide
104 (DCC), diisopropylcarbodiimide (DIC), N,N'-carbonyldiimidazole (CDI), 3-
105 (diethoxyphosphoryloxy)-l,2,3-benzotπazm-4(3H)-one (DtPBf), 1 -cthy!-3-{3-
106 Jimethyllammopropy Dcarbodimiidc hydrochloride (EDt1L). 2-(7-aza- 1 H-benzotπazole-
107 1 -y 1 )- 1 , 1 ,3.3-tctramethy luromum hcxafluorophosphatc (HΛ f U ), 2-( 1 H-bcnzotriazolo 1 - 108 yl)- 1 , 1 ,3,3-tctramcthyluronium hexafluorophosphatc (HBTl1)- 2-(ό-ch3oro- 1 H-
109 benzotriazolc- 1 -y3 )- 1, 1 ,3,3-tctramethylammium hexafluorophosphatc { HCTU),
I 1 o bcnzotriazolc- 3 -yl-oxy-tris-pyrrolidino-phosphoniuni hexafluorophosphatc (FyBOF ),
I 11 bromo-tris-pyrro3idino-phosphonium hexafluorophosphate (PyBrOP), O-(7-
112 azabcnzotriazo3c-l-yl)-N,N,N*,N"4etramethyliironium tetrafluoroboratc (TATO ), 2-(1 H-
113 benzotriazolc- 1 -y3 )- 1 , 3 ,3 ,3-tctramethyiuromum tetrafluoroboratc ( 'TBTlJ), TN JM ,M ' ,M ' -
114 tctramethyi-O-(3,4-dihydro-4-oxo-l,2,3-bcnzotriazin-3-yl)uronium
115 tetrafluoroboratc^ TBTU), O-fiNl-succimniidyl)-Ll ,3,3-tctramcthyluronium
116 tetrafluoroborate (TSTU), il-M ,6-dimcthoxy-l,3.5-triazin-2-yD-'-t-methylmoφholinium
117 chloride (DMTMM), 2-chloiO-456-dinicthoxy- 1 ,3,5'triazine/N-nicthyliiiorplioline
118 (CDMT/NMMV oxalyl chloride, SOCl2, SO2Cl2, POCl-,, PCh, PCU, PBr3, PBr,, POBr.,
119 pivaloyl chloride, or pivaloyl anhydride.
120 11. The process of claim 9, wherein said coupling agent is CDl. DMT1MM, or EDCL
121 and said compound of Formula 4 is morplioline.
122 12. The process of claim 10, wherein R is methyl, ethyl, ?? -propyl, or /-propyl; X is O;
123 and said compound of Formula 4 is moipholine.
124 13. The process of claim 9, further comprising:
125 combining a compound of Formula 1 :
127 1
128 and a compound of Formula 2 :
129 RXH
130 2
131 or a salt thereof, wherein:
132 X is S or O;
133 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
134 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10^]1n-R11 ; 135 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
136 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
137 heteroaralkyl;
138 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
139 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
140 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
141 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
142 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
143 SO2N(R12XR13), -N(R12)S(O)2OR13;
144 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
145 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
146 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
147 optionally substituted heterocyclic ring; and
148 m is 0-8;
149 to give said compound of Formula 4.
150 14. The process of claim 13, wherein said compound of Formula 1 is
152 and said compound of Formula 2 is methanol, ethanol, /j-propanol, or /-propanol.
153 15. A process for preparing a compound of Formula 7a:
155 7a 156 comprising:
157 (a) combining methanol, ethanol, «-propanol, or z-propanol, and a compound of Formula
158 Ia:
160 Ia
161 to give a compound of Formula 3a:
163 3a
164 (b) combining said compound of Formula 3a, morpholine, and EDCL to give a
165 compound of Formula 5a:
167 5a
168 (c) combining said compound of Formula 5a with LiAlH4 to give a compound of
169 Formula 6a:
OH
171 6a
172 or a salt thereof; and
173 (d) combining said compound of Formula 6a or a conjugate acid thereof, and NaHSθ4 to
174 give said compound of Formula 7a.
175 16. A compound of Formula 5:
178 or a salt thereof, wherein: 179 X is S or O; 180 Y is O, -N(R3)-, or a bond; 181 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, 182 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10^]1n-R1 h, 183 each of R1 R2, and R3 independently for each occurrence is hydrogen, 184 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, 185 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rπ; or R1 and R2 taken 186 together with the nitrogen to which they are bonded represent a 3-10 187 membered optionally substituted heterocyclic ring; or R1 and R3 taken 188 together with the nitrogen to which they are bonded represent a 3-10 189 membered optionally substituted heterocyclic ring; 190 R10 independently for each occurrence is hydrogen, alkyl, alkenyl, 191 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or 192 heteroaralkyl; 193 R11 independently for each occurrence is hydrogen, alkyl, alkenyl, 194 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, 195 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, - 196 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13), 197 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or - 198 SO2N(R12XR13), -N(R12)S(O)2OR13; 199 each of R12 and R13 independently for each occurrence is hydrogen, alkyl, 200 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, 201 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
202 optionally substituted heterocyclic ring; and
203 m is 0-8.
204 17. The compound of claim 16, wherein Y is a bond; R is alkyl; and R1 and R2 taken
205 together with the nitrogen to which they are bonded represent a 3-10 membered
206 optionally substituted heterocyclic ring.
207 18. The compound of claim 16, wherein said compound has the absolute
208 stereochemistry shown below:
210 19. The compound of claim 16, wherein said compound of Formula 5 is prepared by a
211 process comprising:
212 (a) combining a compound of Formula Ia:
214 Ia
215 and a compound of Formula 2 :
216 RXH
217 2
218 or a salt thereof, wherein:
219 X is S or O;
220 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
221 heteroaryl, heteroaralkyl, haloalkyl, or 
222 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
223 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
224 heteroaralkyl;
225 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
226 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, 227 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
228 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
229 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
230 SO2N(R12)(R13), -N(R12)S(O)2OR13;
231 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
232 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
233 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
234 optionally substituted heterocyclic ring; and
235 m is 0-8;
236 to give a compound of Formula 3a:
238 3a
239 or a salt thereof, wherein: R is as defined above;
240 (b) combining said compound of Formula 3a with a coupling agent; and
241 a compound of Formula 4:
R1-Yv NH
242 R2
243 4
244 or a salt thereof, wherein
245 Y is O, -N(R3)-, or a bond;
246 each of R1, R2, and R3 independently for each occurrence is hydrogen,
247 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
248 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R^)2]H1-R1 ! ; or R1 and R2 taken
249 together with the nitrogen to which they are bonded represent a 3- 10
250 membered optionally substituted heterocyclic ring; or R1 and R3 taken
251 together with the nitrogen to which they are bonded represent a 3- 10
252 membered optionally substituted heterocyclic ring;
253 to give said compound of Formula 5.
254 20. A compound of Formula 3a:
256 3a
257 or a salt thereof, wherein:
258 X is S or O;
259 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
260 heteroaryl, heteroaralkyl, haloalkyl, or 
261 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
262 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
263 heteroaralkyl;
264 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
265 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
266 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
267 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
268 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
269 SO2N(R12XR13), -N(R12)S(O)2OR13;
270 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
271 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
272 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
273 optionally substituted heterocyclic ring; and
274 m is 0-8;
275 provided that when R is t-butyl, then X is not O ;
276 further provided that when R is menthyl, then X is not O
277 further provided that when R is benzyl, then X is not O.
278 21. The compound of claim 20, wherein R is alkyl and X is O.
279 22. The compound of claim 20, wherein said compound has the absolute
280 stereochemistry shown below:
282 23. The compound of claim 20, wherein said compound of Formula 3a is prepared by
283 a process comprising:
284 (a) combining a compound of Formula Ia:
286 Ia
287 and a compound of Formula 2 :
288 RXH
289 2
290 or a salt thereof, wherein:
291 X is S or O;
292 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
293 heteroaryl, heteroaralkyl, haloalkyl, or 
294 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
295 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
296 heteroaralkyl;
297 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
298 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
299 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
300 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
301 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
302 SO2N(R12XR13), -N(R12)S(O)2OR13;
303 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
304 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, 305 heteroaralkyl; or R12 and R taken together represent a 5-8 membered
306 optionally substituted heterocyclic ring; and
307 m is 0-8;
308 to give said compound of Formula 3a.
309 24. A compound of Formula 6a:
311 6a
312 or a salt thereof, wherein:
313 Y is O, -N(R3)-, or a bond;
314 each of R1, R2, and R3 independently for each occurrence is hydrogen, alkyl, alkenyl,
315 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, haloalkyl,
316 or -[C(R10)2]m-Rn; or R1 and R2 taken together with the nitrogen to which they are
317 bonded represent a 3-10 membered optionally substituted heterocyclic ring; or R1 and R3
318 taken together with the nitrogen to which they are bonded represent a 3 - 10 membered
319 optionally substituted heterocyclic ring;
320 R10 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
321 heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;
322 R11 independently for each occurrence is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,
323 heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halide, nitrile, nitro, -OR12, -
324 N(R12)COR13, -N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
325 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -SO2N(R12)(R13), -
326 N(R12)S(O)2OR13;
327 each of R12 and R13 independently for each occurrence is hydrogen, alkyl, alkenyl,
328 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl; or R12 and
329 R13 taken together represent a 5-8 membered optionally substituted heterocyclic ring; and
330 m is 0-8.
331 25. The compound of claim 24, wherein said compound has the absolute
332 stereochemistry shown below:
OH
HO^N'R2
333 K
334 26. The compound of claim 24, wherein Y is a bond and R1 and R2 taken together
335 with the nitrogen to which they are bonded represent a 3-10 membered optionally
336 substituted heterocyclic ring.
337 27. The compound of claim 24, wherein said compound of Formula 6a is prepared by
338 a process comprising:
339 (a) combining a compound of Formula Ia:
341 Ia
342 and a compound of Formula 2:
343 RXH
344 2
345 or a salt thereof, wherein:
346 X is S or O;
347 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
348 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-R1 ' ;
349 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
350 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
351 heteroaralkyl;
352 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
353 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
354 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
355 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
356 -OC(O)OR12, -CO2R12, -OC(O)R12, 357 -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13;
358 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
359 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
360 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
361 optionally substituted heterocyclic ring; and
362 m is 0-8;
363 to give a compound of Formula 3a:
365 3a
366 or a salt thereof, wherein: R is as defined above;
367 (b) combining said compound of Formula 3a with a coupling agent; and
368 a compound of Formula 4:
R1-YN NH
369 R2
370 4
371 or a salt thereof, wherein
372 Y is O, -N(R3)-, or a bond;
373 each of R1 R2, and R3 independently for each occurrence is hydrogen,
374 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
375 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-Rn; or R1 and R2 taken
376 together with the nitrogen to which they are bonded represent a 3- 10
377 membered optionally substituted heterocyclic ring; or R1 and R3 taken
378 together with the nitrogen to which they are bonded represent a 3- 10
379 membered optionally substituted heterocyclic ring;
380 to give a compound of Formula 5a:
O κχΛrv° 382 5a
383 or a salt thereof, wherein each of R, R1, and R2, are as defined above; and
384 (c) combining said compound of Formula 5a with a reducing agent to give said
385 compound of Formula 6a.
386 28. A compound selected from the group consisting of:
391 29. A process for preparing a compound of Formula 7:
392 
393 7 394 comprising:
395 (a) combining an acid and a compound of Formula 3:
396 
397 6
398 or a salt thereof, wherein:
399 Y is O, -N(R3)-, or a bond;
400 each of R1 R2, and R3 independently for each occurrence is hydrogen,
401 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
402 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R^)2Jm-R1 !; or R1 and R2 taken
403 together with the nitrogen to which they are bonded represent a 3- 10
404 membered optionally substituted heterocyclic ring; or R1 and R3 taken
405 together with the nitrogen to which they are bonded represent a 3- 10
406 membered optionally substituted heterocyclic ring;
407 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
408 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
409 heteroaralkyl;
410 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
411 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
412 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
413 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
414 -OC(O)OR12, -CO2R12, -OC(O)R12, -C(O)N(OR12)(R13), or -
415 SO2N(R12XR13), -N(R12)S(O)2OR13;
416 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
417 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
418 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
419 optionally substituted heterocyclic ring; and
420 m is 0-8; to give said compound of Formula 7.
421 30. A process for preparing a protease inhibitor comprising:
422 (a) combining a reducing agent and a compound of Formula 5a:
424 5a
425 or a salt thereof, wherein:
426 X is S or O;
427 Y is O, -N(R3)-, or a bond;
428 R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
429 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10^]1n-R11 ;
430 each of R1 R2, and R3 independently for each occurrence is hydrogen,
431 alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl,
432 heteroaryl, heteroaralkyl, haloalkyl, or -[C(R10)2]m-R1 ! ; or R1 and R2 taken
433 together with the nitrogen to which they are bonded represent a 3- 10
434 membered optionally substituted heterocyclic ring; or R1 and R3 taken
435 together with the nitrogen to which they are bonded represent a 3- 10
436 membered optionally substituted heterocyclic ring;
437 R10 independently for each occurrence is hydrogen, alkyl, alkenyl,
438 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or
439 heteroaralkyl;
440 R11 independently for each occurrence is hydrogen, alkyl, alkenyl,
441 alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl,
442 heteroaralkyl, halide, nitrile, nitro, -OR12, -N(R12)COR13, -
443 N(R12)C(O)OR13, -N(R12)SO2(R13), -CON(R12)(R13), -OC(O)N(R12)(R13),
444 -OC(O)OR12, -CO2R12, -OC(O)R12,
445 -C(O)N(OR12XR13), or -SO2N(R12)(R13), -N(R12)S(O)2OR13;
446 each of R12 and R13 independently for each occurrence is hydrogen, alkyl,
447 alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, 448 heteroaralkyl; or R12 and R13 taken together represent a 5-8 membered
449 optionally substituted heterocyclic ring; and
450 m is 0-8;
451 to give a compound of Formula 6a:
453 6a
454 or a salt thereof, wherein: each of Y, R1 and R2 is as defined above;
455 (b) combining said compound of Formula 6a with an acid to give a compound of
456 Formula 7a:
458 7a
459 (c) combining said compound of Formula 7a with a carbamate coupling agent to give an
460 activated carbonate; and
461 (d) combining said activated carbonate with an amine containing protease inhibitor
462 precursor.
463 31. The process of claim 30, wherein said amine containing protease inhibitor
464 precursor is:
465 (i) a compound of Formula 13:
471 or a salt thereof; 472 (ii) a compound of Formula 14:
475 or a salt thereof; and said protease inhibitor is a compound of Formula 14a:
497 inhibitor is a compound of Formula 17a:
509 or a salt thereof; wherein each of Ar, A, and RΛ are defined as above; 510 (vii) a compound of Formula 19:
516 protease inhibitor is a compound of Formula 19a:
518 19a
519 or a salt thereof; wherein each of Ar' and R Λ Λ are as defined above; or
520 (viii) a compound of Formula 20:
522 20
523 or a salt thereof, wherein Ar is aryl; each of RΛ Λ Λ independently for each occurrence is
524 hydrogen, alkyl, heteroaryl, aralkyl, or heterocycloalkyl; and said protease inhibitor is a
525 compound of Formula 20a:
527 20a
528 or a salt thereof; wherein each of Ar and RΛ Λ Λ are as defined above.
529 32. The process of claim 30, wherein said carbamate coupling agent is selected from
530 the group consisting of phosgene, trichloromethyl chloroformate, bis(trichloromethyl)
531 carbonate, bis(4-nitrophenyl) carbonate, bis(pentafluorophenyl) carbonate, N,N'-
532 disuccinimidyl carbonate, 4-nitrophenyl chloroformate, 2,2'-dipyridyl carbonate, and
533 N,N'-carbonyldiimidazole (CDI).
534 33. The process of claim 30, wherein R is alkyl; X is O; and each of R1 and R2
535 independently for each occurrence is alkyl, cycloalkyl, aryl, or -[C(R10)2]m-Rn, wherein
536 independently for each occurrence R10 is hydrogen or alkyl, R11 is alkoxy; or R1 and R2 537 taken together with the nitrogen to which they are bonded represent a 5-8 membered
538 optionally substituted heterocyclic ring.
539 34. A protease inhibitor prepared by the process of claim 30.
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| PCT/EP2008/068354 WO2010075887A1 (en) | 2008-12-30 | 2008-12-30 | Methods and intermediates useful in the synthesis of hexahydrofuro[2,3-b]furan-3-ol |
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| PCT/EP2008/068354 WO2010075887A1 (en) | 2008-12-30 | 2008-12-30 | Methods and intermediates useful in the synthesis of hexahydrofuro[2,3-b]furan-3-ol |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2019196263A1 (en) * | 2018-04-12 | 2019-10-17 | 江苏瑞科医药科技有限公司 | Method for preparing hexahydrofuro-furanol derivative, intermediate thereof and preparation method therefor |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5643958A (en) * | 1994-08-11 | 1997-07-01 | Banyu Pharmaceutical Co., Ltd. | Substituted amide derivatives |
| US6083985A (en) * | 1995-08-09 | 2000-07-04 | Banyu Pharmaceutical Co., Ltd. | Medicinal composition |
| WO2004002975A1 (en) * | 2002-06-27 | 2004-01-08 | Smithkline Beecham Corporation | PREPARATION OF STEREOISOMERS OF (3ALPHA, 3ALPHA/BETA, 6ALPHA/BETA) HEXAHYDROFURO[2,3-b]FURAN-3-OL |
| WO2008055970A2 (en) * | 2006-11-09 | 2008-05-15 | Tibotec Pharmaceuticals Ltd. | Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol |
-
2008
- 2008-12-30 WO PCT/EP2008/068354 patent/WO2010075887A1/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5643958A (en) * | 1994-08-11 | 1997-07-01 | Banyu Pharmaceutical Co., Ltd. | Substituted amide derivatives |
| US6083985A (en) * | 1995-08-09 | 2000-07-04 | Banyu Pharmaceutical Co., Ltd. | Medicinal composition |
| WO2004002975A1 (en) * | 2002-06-27 | 2004-01-08 | Smithkline Beecham Corporation | PREPARATION OF STEREOISOMERS OF (3ALPHA, 3ALPHA/BETA, 6ALPHA/BETA) HEXAHYDROFURO[2,3-b]FURAN-3-OL |
| WO2008055970A2 (en) * | 2006-11-09 | 2008-05-15 | Tibotec Pharmaceuticals Ltd. | Methods for the preparation of hexahydrofuro[2,3-b]furan-3-ol |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019196263A1 (en) * | 2018-04-12 | 2019-10-17 | 江苏瑞科医药科技有限公司 | Method for preparing hexahydrofuro-furanol derivative, intermediate thereof and preparation method therefor |
| CN110372641A (en) * | 2018-04-12 | 2019-10-25 | 江苏瑞科医药科技有限公司 | The preparation method of hexahydro furyl and furans 01 derivatives, wherein mesosome and preparation method thereof |
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