Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
  • C07D473/32—Nitrogen atom
  • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
  • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
  • B01J31/0234—Nitrogen-, phosphorus-, arsenic- or antimony-containing compounds
  • B01J31/0235—Nitrogen containing compounds
  • B01J31/0245—Nitrogen containing compounds being derivatives of carboxylic or carbonic acids
  • B01J31/0247—Imides, amides or imidates (R-C=NR(OR))
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B53/00—Asymmetric syntheses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
  • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/07—Optical isomers

Definitions

• the present invention relates to methods and intermediates for the synthesis of haloaldehydes.
• Nucleosides play key roles in diverse cellular processes ranging from cell signalling to metabolism (1).
• Nucleosides are composed of a nucleobase - canonically composed of adenine, guanine, cytosine, thymine and uracil, and a sugar moiety, typically ribose of 2’- deoxyribose.
• Nucleosides can be further modified with a 5’-phosphate or phosphate-like group, and RNA oligomers include nucleotides linked via phosphate or phosphate-like linkages from 5’ to 3’.
• Nucleosides can be modified in several ways, including modifications to the ribose moiety, modifications to the base moiety or modifications to the phosphate moiety, leading to compounds referred to as “nucleoside analogues” (NAs).
• NAs nucleoside analogues
• NAs have a long and rich history in the field of medicinal chemistry and as tool compounds in chemical biology.
• the naturally occurring nucleosides are a unique and valuable starting point for drug design due to their involvement in numerous biological processes.
• Synthetic NAs have been designed to mimic their natural counterparts (2-18).
• Single NAs have been primarily used as treatments for parasitic, bacterial and fungal infections as well as potent and effective anticancer drugs.
• NAs can be incorporated into oligomeric structures that can modulate gene expression, thus bypassing the complexities associated with protein inhibition.
• Such oligomeric structures can include short interfering RNA (siRNA), microRNA (miRNA), inhibitory antisense oligonucleotides (ASOs), small activating RNA (saRNA) and messenger RNA (mRNA).
• NAs have been used in the treatment of cancer (2, 6) and represent the largest class of small molecule antivirals (3, 4). Mechanistically, NAs can operate as toxic antimetabolites that interfere with nucleic acid synthesis (4). Alternatively, following in vivo phosphorylation, the resulting nucleotide analogues can inhibit enzymes involved in cancer cell growth or viral replication (e.g., DNA/RNA polymerases, ribonucleotide reductases or nucleoside phosphorylases) (2, 4). NAs have also demonstrated promise as epigenetic modulators, and both decitabine and azacitidine inhibit DNA methyltransferase and have been approved for cancer therapy (4).
• enzymes involved in cancer cell growth or viral replication e.g., DNA/RNA polymerases, ribonucleotide reductases or nucleoside phosphorylases
• nucleoside analogues are often synthesized from naturally occurring carbohydrate, which limits patterns of substitution and furanose stereochemistry (e.g., 19- 29).
• the addition of nucleobases to activated ribose derivatives often fails or proceeds with poor diastereoselectivity with C2’ or C4’ modified nucleosides and efficient strategies for producing C4’ modified nucleosides, including thionucleosides are limited. Synthesis of nucleosides and nucleoside analogues have been described in Meanwell et a/., (30) and WO 2021/191830.
• the present invention relates to methods and intermediates for the synthesis of haloaldehydes.
• the present invention provides a method of synthesizing a haloaldehyde compound by reacting a halogen or halogen-containing compound with an aryl- or heteroaryl-substituted compound in the presence of a catalyst compound according to Formula (I):
• Ri, R2, R3, and R4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion, to yield the haloaldehyde compound.
• the present invention provides a method of preparing an intermediate in the synthesis of a nucleoside or analogue thereof by reacting a halogen or halogen-containing compound with an aryl- or heteroaryl-substituted compound in the presence of a catalyst compound according to Formula (I):
• Ri, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion; and performing an enantioselective aldol reaction by proline catalysis to yield a halohydrin compound that is an intermediate in the synthesis of a nucleoside or analogue thereof.
• the method may further include reducing the halohydrin compound to obtain a halohydrin diol compound.
• the present invention provides a method of synthesizing a nucleoside or analogue thereof by reacting a halogen or halogen-containing compound with an aryl- or heteroaryl-substituted compound in the presence of a catalyst compound according to Formula (I):
• R1, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion; performing an enantioselective aldol reaction by proline catalysis to yield a halohydrin compound; reducing the halohydrin compound to yield a halohydrin diol compound; and contacting the halohydrin diol compound with a Lewis acid or a base in an annulative halide displacement (AHD) reaction, to yield a nucleoside or analogue thereof.
• AHD annulative halide displacement
• the halogenation may be enantioselective.
• the proline may be L-proline or D-proline. In some embodiments, the proline may be a halophilic Lewis acid.
• the Lewis acid may be lnCI 3 or Sc(OTf) 3 .
• the Lewis acid-promoted AHD may yield a C2',C3'-protected nucleoside or analogue thereof, a nucleoside or analogue thereof with a migrated acetonide protecting group, or results in deprotection.
• the halohydrin diol compound may be separated prior to treatment with the base.
• the base may be NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , KOH, LiOH, Li 2 CO 3 , LiHCO 3 , Cs 2 CO 3 , CsHCO 3 , or CsOH.
• the base-promoted AHD may yield a C3’,C5’-protected nucleoside or analogue thereof.
• the halohydrin compound may be: where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.
• the halohydrin compound may be:
• the halohydrin diol compound may be: where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and X may be a halogen.
• the halogen may be fluorine, bromine, chlorine, or iodine.
• the halogen-containing compound may be an electrophilic halogenating agent, such as N-Fluorobenzenesulfonimide (NFSI), SelectfluorTM, XtalfluorTM, N-halosuccinimide, N-chlorinated hydantoin, Palau’chlorTM, or N-fluoropyridinium.
• NFSI N-Fluorobenzenesulfonimide
• SelectfluorTM SelectfluorTM
• XtalfluorTM XtalfluorTM
• N-halosuccinimide N-chlorinated hydantoin
• Palau’chlorTM or N-fluoropyridinium
• the salt counterion may be HCI, TFA, HBr, or MsOH.
• the catalyst compound may be:
• the aryl- or heteroaryl- substituted compound may include the following chemical structure: or where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
• the haloaldehyde compound may include the following chemical structure:
• NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl
• X may be a halogen
• * refers to enantioenrichment
• the haloaldehyde compound is may be:
• the nucleoside or analogue thereof may be:
• NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl and each R may be independently -OH, -OC(CH3)2O-, -(CH2)3-, - CH2SCH2-, or -CH 2 OCH 2 -.
• the nucleoside or analogue thereof may be a C3VC5' protected NA, a C4' modified NA, a C2' modified NA, a C-linked NA, a L-configured NA, a D- nucleoside or analogue thereof, a L-nucleoside or analogue thereof, a locked nucleic acid, an iminonucleoside, or a thionucleoside.
• the present invention provides a halohydrin compound that is:
• the present disclosure provides, in part, methods for the synthesis of a haloaldehyde compound and uses thereof.
• the method for the synthesis of a haloaldehyde compound includes reacting a halogenating agent (a halogen or halogen-containing compound) with an aryl- or heteroaryl-substituted compound in the presence of a catalyst compound according to Formula (I):
• Ri, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion.
• aryl- or heteroaryl- substituted compound is meant a compound having a structure as follows: or where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl.
• a catalyst compound as used herein, is a compound according to Formula (I):
• R1, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion.
• a catalyst compound in accordance with the present disclosure may be “enantiopure” or “enantioenriched.”
• a catalyst compound in accordance with the present disclosure may include, without limitation, the following compounds:
• haloaldehyde compound or “haloaldehyde,” as used herein, is meant a compound containing a functional group in which a halogen and an aldehyde, e.g, an acetaldehyde, are bonded to adjacent groups.
• a haloaldehyde can have the following the general structure: or
• NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and X may be a halogen.
• haloaldehyde compounds may include, without limitation, the following compounds:
• alkyl refers to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including, for example, from one to ten carbon atoms, or any value in between, such as 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, and which is attached to the rest of the molecule by a single bond.
• alkyl may refer to a straight or branched hydrocarbon chain group consisting solely of carbon and hydrogen atoms, containing no unsaturation and including from one to six carbon atoms, or any value in between, such as 1 , 2, 3, 4, 5, or 6 carbon atoms, and which is attached to the rest of the molecule by a single bond.
• the alkyl group may be optionally substituted by one or more substituents as described herein. Unless stated otherwise specifically herein, it is understood that the substitution can occur on any carbon of the alkyl group.
• Acyl refers to a group of the formula -C(O)R a , where R a is a C1-10 alkyl or a Ci- 6 alkyl group as described herein.
• the alkyl group may be optionally substituted as described herein.
• aryl is meant a monocyclic or bicyclic aromatic ring containing only carbon atoms, including for example, 5-14 members, such as 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, or 14 members.
• aryl groups include without limitation phenyl, biphenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1 ,4- benzodioxanyl, and the like.
• the term “aryl” is meant to include aryl groups optionally substituted by one or more substituents as described herein.
• Heteroaryl refers to a single or fused aromatic ring group containing one or more heteroatoms in the ring, for example N, O, S, including for example, 5-14 members, such as 5, 6, 7, 8, 9, 10, 11 , 12, 13, or 14 members.
• heteroaryl groups include without limitation furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, 1 ,2,3-oxadiazole, triazole (e.g., 1 ,2,3-triazole or 1 ,2,4-triazole), 1 ,3,4-thiadiazole, tetrazole, pyrazole, pyridine, pyridazine, pyrimidine, 2,6-dichloropyrimidine pyrazine, 1 ,3,5- triazine, imidazole, benzimidazole, benzoxazole, benzothiazole, indolizine, indole, isoindole, benzofuran, benzothiophene, 1 H-indazole, purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline, phthala
• arylalkyl is meant a group of the formula -R a R b where R a is a C1-10 alkyl group as described herein and R b is one or more aryl moieties as described herein.
• the arylalkyl group(s) may be optionally substituted as described herein.
• Examples of arylalkyl groups include without limitation benzyl, phenethyl, phenylpropyl, (4-methylphenyl)methyl, (4- methylphenyl)ethyl, (2-methylphenyl)methyl, (2,4,6-trimethylphenyl), etc.
• Heteroarylalkyl refers to a group of the formula -R a R c where R a is a C1-10 alkyl group as described herein and R c is one or more heteroaryl moieties as described herein.
• the heteroarylalkyl group(s) may be optionally substituted as described herein. Examples of heteroarylalkyl groups include without limitation, furanylmethyl, thiphenylmethyl, pyridylmethyl, imidazolylmethyl, uridinylmethyl, etc.
• Cx refers to a salt counterion.
• Cx may be without limitation hydrochloric acid (HCI), trifluoroacetic acid (TFA), hydrobromic acid (HBr), methanesulfonic acid (MsOH), etc.
• X refers to a halogen, such as bromine, chlorine, fluorine, iodine, etc.
• a halogen may include chlorine or fluorine.
• halo refers to bromo, chloro, fluoro, iodo, etc.
• a halide is a halogen atom bearing a negative charge. By “halogenating” is meant introducing a halogen atom into a compound or molecule.
• a halogen may be in a “halogen-containing compound”, for example, N- Fluorobenzenesulfonimide (NFSI), SelectfluorTM, XtalfluorTM, N-halosuccinimide (e.g., N- chlorosuccinimide (NCS)), N-chlorinated hydantoins, Palau’chlorTM, N-fluoropyridinium salts, etc.
• a halogen-containing compound may be an electrophilic halogenating agent. Accordingly, a halogen, as used herein, includes a halogen-containing compound or “halogenating agent.”
• “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs one or more times and instances in which it does not.
• “optionally substituted alkyl” means that the alkyl group may or may not be substituted and that the description includes both substituted alkyl groups and alkyl groups having no substitution, and that the alkyl groups may be substituted one or more times.
• optionally substituted alkyl groups include, without limitation, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, etc.
• Suitable optional substituents include, without limitation, H, F, Cl, CH3, OH, OCH3, CF3, CHF2, CH2F, CN, halo, and C1-10 alkoxy.
• optionally substituted aryl- or heteroaryl- means aryl- or heteroaryl- groups that may or may not be substituted and that the description includes both substituted aryl- or heteroaryl- groups and aryl- or heteroaryl- groups having no substitution, and that the aryl- or heteroaryl- groups may be substituted one or more times.
• suitable optional substituents include, without limitation, H, F, Cl, CH 3 , OH, OCH3, CF 3 , CHF 2 , CH 2 F, CN, halo, and C1-10 alkoxy.
• the present disclosure includes a method for the synthesis of a haloaldehyde compound for example in accordance with Scheme 1 :
• R1, R2, R3, and R4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion, of the catalyst compound according to Formula (I); NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl; X may be halogen and X+ may be an electrophilic halogenating agent (for example, NFSI, NCS, etc).
• the haloaldehyde compound may be used to prepare a halohydrin compound, for example in accordance with Scheme 2:
• NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
• X may be halogen;
• Y may be CH 2 , O, S, NR’, where R’ may be alkyl or aryl, and
• Z may be a protecting group for an alcohol, including without limitation, acetonide, silyl protecting group, alkyl protecting group or aryl protecting group (including cyclic or acyclic).
• halohydrin is meant a compound containing a functional group in which a halogen and a hydroxyl are bonded to adjacent groups.
• a halohydrin can have the following the general structure, where R may be any suitable group, and X may be halogen:
• the halohydrin compound may have the following general structure, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl and X may be halogen:
• the halohydrin compound may be:
• the halohydrin diol compound may have the following general structure, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl and X may be halogen:
• the halohydrin compound may be used in the synthesis of a nucleoside or analogue thereof, for example, in accordance with Scheme 3:
• NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
• X may be halogen;
• Y may be CH 2 , O, S, NR’, where R’ may be alkyl or aryl, and
• Z may be a protecting group for an alcohol, including without limitation, acetonide, silyl protecting group, alkyl protecting group or aryl protecting group (including cyclic or acyclic).
• the compounds disclosed herein such as catalyst compounds, haloaldehydes, halohydrins, etc. may be enantiopure or enantioenriched, i.e, available predominantly in a single, specific enantiomeric form or “enantioenrichment.”
• enantiomeric purity or enrichment will depend on the stereochemistry of the catalyst compound. It is to be understood that, while full enantiomeric purity or enrichment is not required, an enantiopure or enantioenriched compound in accordance with the present disclosure may be at least 95% enantioenriched.
• the enantiopure or enantioenriched compound in accordance with the present disclosure is fully i.e., 100% enriched. Accordingly, methods of obtaining enantiopure or enantioenriched compounds are referred to herein as “enantioselective” or “enantioselection” reactions.
• the present disclosure provides a method of preparing an intermediate in the synthesis of a nucleoside or analogue thereof, the method comprising: reacting a halogen or halogen-containing compound with an aryl- or heteroarylsubstituted compound in the presence of a catalyst compound according to Formula (I): Cx
• Ri, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion; performing an enantioselective aldol reaction by proline catalysis to yield a halohydrin compound; and reducing the halohydrin compound to obtain a halohydrin diol compound, to yield an intermediate in the synthesis of a nucleoside or analogue thereof.
• the present disclosure provides a method of synthesizing a nucleoside or analogue thereof, the method comprising: reacting a halogen or halogen-containing compound with an aryl- or heteroarylsubstituted compound in the presence of a catalyst compound according to Formula (I):
• R1, R 2 , R3, and R 4 may each independently be H, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, or acyl; and Cx may be a salt counterion; performing an enantioselective aldol reaction by proline catalysis to yield a halohydrin compound; reducing the halohydrin compound to yield a halohydrin diol compound; and contacting the halohydrin diol compound with a Lewis acid or a base in an annulative halide displacement (AHD) reaction, to yield a nucleoside or analogue thereof.
• AHD annulative halide displacement
• the proline may be L-proline or D-proline.
• the Lewis acid may be, without limitation, a halophilic Lewis acid.
• the Lewis acid may be, without limitation, lnCI 3 or Sc(OTf) 3 .
• Lewis acid-promoted AHD may yield a C2',C3'-protected nucleoside or NA.
• Lewis acid-promoted AHD may result in protecting group migration, i.e., may yield a NA with a migrated acetonide protecting group.
• Lewis acid-promoted AHD may result in deprotection.
• the base may be, without limitation, NaOH, K 2 CO 3 , KHCO 3 , Na 2 CO 3 , NaHCO 3 , KOH, LiOH, Li 2 CO 3 , LiHCO 3 , Cs 2 CO 3 , CsHCO 3 , or CsOH.
• the base-promoted AHD may yield a C3’,C5’-protected NA.
• the aHAR reaction products may be reduced and separated prior to treatment with a Lewis base.
• the present disclosure provides the following nucleosides or analogues thereof, including without limitation diastereomers thereof, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl and each R may independently be -OH, -OC(CH 3 ) 2 O-, -(CH 2 ) 3 -, -CH 2 SCH 2 -, or -CH 2 OCH 2 -:
• the present disclosure provides the following compounds, or enantiomers thereof, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl; X may be halogen and each R may independently be -OH, -OC(CH 3 ) 2 O-, - (CH 2 ) 3 -, -CH 2 SCH 2 -, or -CH 2 OCH 2 -, for use as an intermediate in the synthesis of a nucleoside or analogue thereof:
• the present disclosure provides the following compounds, or enantiomers thereof, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl; X may be halogen; Y may be CH 2 , O, S, NR’, where R’ may be alkyl or aryl, and Z may be a protecting group for an alcohol, including without limitation, acetonide, silyl protecting group, alkyl protecting group or aryl protecting group (including cyclic or acyclic), for use as an intermediate in the synthesis of a nucleoside or analogue thereof:
• the present disclosure provides the following compounds, or enantiomers thereof, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl and X may be halogen, for use as an intermediate in the synthesis of a nucleoside or analogue thereof:
• the present disclosure provides the following compounds, or enantiomers thereof, where NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl; X may be halogen; and Y may be CH 2 , O, S, NR’, where R’ may be alkyl or aryl, for use as an intermediate in the synthesis of a nucleoside or analogue thereof:
• the methods disclosed herein provide rapid access to intermediates in the synthesis of nucleosides or analogues thereof in good enantioselectivity and/or yield, for example, greater than about 10g to about 400g, or any value in between, for example 10g, 15g, 20g, 25g, 50g, 75g, 100g, 125g, 150g, 200g, 250g, 300g, 350g, or 400g. Accordingly, the methods disclosed herein may be used in the process scale production of nucleosides and/or NAs.
• the methods disclosed herein enable direct access to C3VC5' protected NAs, where R may be alkyl, alkynyl or aryl and NB may be optionally substituted aryl, arylalkyl, heteroaryl, or heteroarylalkyl (and hence C2' modified NAs), provide flexibility in nucleobase substitution, and/or offer a direct route to C4' modified NAs:
• R alkyl, alkynyl, aryl
• the methods disclosed herein enable direct incorporation of a wide range of nucleobases and the selective functionalization of the C2' position of the furanose core of natural nucleosides and NAs including, without limitation, C-linked or L- configured NAs.
• replacement of the reductant with an organomagnesium reagent provides direct access to an array of C4'-modified NAs including, without limitation, locked nucleic acids (LNAs).
• LNAs locked nucleic acids
• the synthesis methods disclosed herein may be useful, without limitation, in the production of D- and L-nucleosides and nucleoside analogues, locked nucleic acids, iminonucleosides, thionucleosides, C4'-modified nucleosides and/or C2'-modified nucleosides.
• the methods disclosed herein may be useful as a tool for drug design.
• nucleoside analogues disclosed herein may be used as small molecule therapeutics or as monomers in oligonucleotide therapeutics.
• the methods disclosed herein may be useful in the preparation of diversity libraries.
• larger collections of C4'-modified NAs e.g., focused screening libraries
• nucleoside is meant a glycosylamine having a nitrogenous base or “nucleobase” or “NB,” and a sugar ring (e.g., ribose or deoxyribose), in which the anomeric carbon is linked through a glycosidic bond to the N9 of a purine (e.g., adenine or guanine) or the N1 of a pyrimidine (e.g., cytosine, thymine, or uracil).
• Nucleosides include both L- and D- nucleoside isomers. Examples of nucleosides include cytidine, uridine, adenosine, guanosine, thymidine and inosine.
• NAs Nucleoside analogues
• NAs are compounds that are structurally similar to naturally occurring nucleosides.
• NAs may include, without limitation, compounds with modifications at positions C1’, C2’, C3’, C4’ and/or C5’ of the sugar ring.
• NAs may exist as a free triol or may be phosphorylated at C3’ and/or C5’.
• NAs may include, without limitation, compounds with a saturated or unsaturated carbocyclic ring.
• NAs may include nitrogen or sulfur in the sugar ring, for example as a replacement for the naturally occurring oxygen, and/or may include N-R groups, where R may be without limitation alkyl, allyl, alkynyl or benzyl.
• the nucleoside analogues disclosed herein may be modified to function as a phosphoramidate or phosphonamidate compound, e.g., a “ProTide,” which includes a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which can be enzymatically metabolized to deliver free 5'- monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue, once delivered to a cell.
• the “NB” or nucleobase of an NA may be any aryl or heteroaryl attached from the C1 position to a carbon or nitrogen atom.
• NBs may also be modified, for example, may be 5,6- dihydrouracil, 5-methylcytosine, 5-hydroxymethylcytosine, 5,5,5-trifluoromethylthymine, 5- fluorouracil, 2-thiouracil, 4-methylbenzimidazole, hypoxanthine, 7-deazaguanine, 7- deazaadenine, indole, imidazole, triazole, pyrrole, pyrazole, etc.
• Enantiomers of aldol products can be produced using proline (e.g., L-proline or D-proline) catalysis.
• L-proline or D-proline will depend on the stereochemistry of the catalyst compound such that the proline will be appropriately paired with the catalyst compound.
• the stereochemistry of the resulting NA will be configured naturally while, when D-catalyst 1 is appropriately paired with D-proline, the stereochemistry of the resulting NA will be the enantiomer of the naturally- configured NA. If, however, D-catalyst 1 is paired with L-proline, the stereochemistry of the resulting NA can be unpredictable and therefore unknown.
• Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent; chromatography, using, for example a chiral HPLC column; or derivatizing the racemic mixture with a resolving reagent to generate diastereomers, separating the diastereomers via chromatography, and removing the resolving agent to generate the original compound in enantiomerically enriched form. These procedures can be repeated, if desired, to increase the enantiomeric purity of a compound.
• the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless otherwise specified, it is intended that the compounds include the cis, trans, Z- and E- configurations. Likewise, all tautomeric forms are also intended to be included.
• the starting materials can be obtained from commercial sources, prepared from commercially available organic compounds, and/or prepared using known synthetic methods.
• Signal positions (6) are given in parts per million from tetramethylsilane (6 0) and were measured relative to the signal of the solvent ( 1 H NMR: CDCI 3 : 6 7.26; CD 3 OD: 6 3.31 ; (CD 3 ) 2 CO: 6 2.05; CD 3 CN: 6 1.96; DMSO-C/ 6 : 6 2.50; 13 C NMR: CDCI 3 : 6 77.16; CD 3 OD: 6 49.00; (CD 3 ) 2 CO: 6 29.84; CD 3 CN: 6 1.32; DMSO-cfe: 39.5).
• Coupling constants J values are given in Hertz (Hz) and are reported to the nearest 0.1 Hz.
• 1 H NMR spectral data are tabulated in the order: multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; sept, septet; m, multiplet; br broad), coupling constants, number of protons.
• NMR spectra were recorded on a Bruker Avance 600 equipped with a QNP or TCI cryoprobe (600 MHz), Bruker 400 (400 MHz) or Bruker 500 (500 MHz). Diastereomeric ratios (dr) are based on analysis of crude 1 H NMR. Assignments of 1 H are based on analysis of 1 H- 1 H-COSY and nOe spectra. Assignments of 13 C are based on analysis of HSQC spectra.
• reaction mixture was warmed to RT, and 400 mL DCM was added, followed by L-proline (6.86 g, 59.6 mmol) and 2,2-dimethyl-1 ,3-dioxan-5-one (14 mL, 119.8 mmol). The resulting reaction mixture was stirred at RT overnight.
• the product was collected ( ⁇ 18 g) and crystallized from 50 mL 10% iPrOH in toluene.
• the crystals were filtered and washed with ice-cold toluene to yield 8.3 g crystals. These crystallize with % an equivalent of toluene. This can be removed by dissolving the crystals in hot CH 3 CN, then reconcentrating.
• N-(6-oxo-9-(2-oxoethyl)-6,9-dihydro-1 H-purin-2-yl)isobutyramide hydrochloride protected guanidine aldehyde hydrochloride (91 .2 mg, 0.304 mmol), (R)-5-benzyl-2,2,3- trimethylimidazolidin-4-one-HCI (15.5 mg, 0.0608 mmol) and NFSI (144.5 mg, 0.456 mmol) were slurried in dimethylformamide (1 .22 mL).
• 2,6-lutidine (106 mL, 0.913 mmol) was added and the reaction mixture was stirred at 3 °C overnight (3 °C). After 18 hours, 2,2-dimethyl- 1 ,3-dioxan-5-one (72 mL, 0.609 mmol) was added, followed by L-proline (70.1 mg, 0.609 mmol) and acetonitrile (4.88 mL), and the reaction mixture was stirred overnight at room temperature. After 23 hours, acetonitrile was removed via rotary evaporation. Water was added, and the solution was extracted with 3 x EtOAc. The combined organic layers were washed with 2 x satd. NaCI.
• N-(9-(2-oxoethyl)-9H-purin-6-yl)benzamide (protected adenine aldehyde) (1.01 g, 3.59 mmol), (R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one-HCI (91 1 mg, 3.59 mmol) and selectfluor (1 .40 g, 3.95 mmol) was placed in a round bottom flask. Acetonitrile (10 mL) was added, followed by lutidine (831 uL, 7.18 mmol). The reaction mixture was then stirred overnight at 3 °C.
• Example 8 [00120] Weigh out 2-(1 H-pyrazol-1 -yl)ethane-1 ,1-diol (103 mg, 0.80 mmol, 1.0 eq), (R)-5-benzyl-2,2,3-trimethylimidazolidin-4-one-HCI (51 mg, 0.20 mmol, 0.25 eq), and sodium bicarbonate (135 uL,1 .60 mmol, 2.0 eq) in a flame-dried round bottom flask. Slurry in 2.7 mL of dry MeCN. Cool the reaction mix to 3°C while stirring. Add NFSI (256 mg, 0.80 mmol, 1 .0 eq) into the stirring reaction mix. Stir at 3°C for 24h.
• 2-(1 H-pyrazol-1 -yl)ethane-1 ,1-diol 103 mg, 0.80 mmol, 1.0 eq

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Materials Engineering (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=92903486

Family Applications (1)

Country Status (3)

Family Cites Families (2)

• 2024
  • 2024-03-28 EP EP24778431.7A patent/EP4688781A1/de active Pending
  • 2024-03-28 WO PCT/IB2024/053061 patent/WO2024201390A1/en not_active Ceased
  • 2024-03-28 CN CN202480030887.0A patent/CN121057734A/zh active Pending

Also Published As

Similar Documents

Legal Events