WO2004113314A1 - Nouveaux esters de boronate - Google Patents
Nouveaux esters de boronate Download PDFInfo
- Publication number
- WO2004113314A1 WO2004113314A1 PCT/IN2004/000175 IN2004000175W WO2004113314A1 WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1 IN 2004000175 W IN2004000175 W IN 2004000175W WO 2004113314 A1 WO2004113314 A1 WO 2004113314A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- aryl
- alkyl
- carbons
- Prior art date
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- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical class OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 19
- 125000003118 aryl group Chemical group 0.000 claims abstract description 19
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 15
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- FJLGEFLZQAZZCD-MCBHFWOFSA-N (3R,5S)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-MCBHFWOFSA-N 0.000 claims abstract description 5
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims abstract description 5
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960005370 atorvastatin Drugs 0.000 claims abstract description 5
- 229960005110 cerivastatin Drugs 0.000 claims abstract description 5
- SEERZIQQUAZTOL-ANMDKAQQSA-N cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims abstract description 5
- 229960003765 fluvastatin Drugs 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 5
- 229960002797 pitavastatin Drugs 0.000 claims abstract description 5
- VGYFMXBACGZSIL-MCBHFWOFSA-N pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims abstract description 5
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 5
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 5
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 14
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical class CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 abstract description 5
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 abstract description 3
- 239000002532 enzyme inhibitor Substances 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- 239000000047 product Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012267 brine Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 3,4-dihydroxybutyric acid Chemical compound OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- PSCXFXNEYIHJST-QPJJXVBHSA-N (e)-4-phenylbut-3-enoic acid Chemical compound OC(=O)C\C=C\C1=CC=CC=C1 PSCXFXNEYIHJST-QPJJXVBHSA-N 0.000 description 1
- WHBMMWSBFZVSSR-UHFFFAOYSA-N 3-hydroxybutyric acid Chemical class CC(O)CC(O)=O WHBMMWSBFZVSSR-UHFFFAOYSA-N 0.000 description 1
- ANTBRXMMNBUYMS-UHFFFAOYSA-N 5-hydroxy-3-oxopentanoic acid Chemical class OCCC(=O)CC(O)=O ANTBRXMMNBUYMS-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 0 CB(*C(CC(C)CO*)CC(O*)=O)N=C Chemical compound CB(*C(CC(C)CO*)CC(O*)=O)N=C 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GYHQXJTYSBEDPP-UHFFFAOYSA-N [1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane;ruthenium Chemical compound [Ru].C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 GYHQXJTYSBEDPP-UHFFFAOYSA-N 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- 150000004648 butanoic acid derivatives Chemical class 0.000 description 1
- 125000000837 carbohydrate group Chemical group 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- KCKWOJWPEXHLOQ-UHFFFAOYSA-N methyl 3,4-dihydroxybutanoate Chemical compound COC(=O)CC(O)CO KCKWOJWPEXHLOQ-UHFFFAOYSA-N 0.000 description 1
- NQIXPBJBTPYBQH-UHFFFAOYSA-N methyl 3-hydroxy-4-trityloxybutanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(=O)OC)C1=CC=CC=C1 NQIXPBJBTPYBQH-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 238000005949 ozonolysis reaction Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010963 scalable process Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- GAJZMSCUUOBKDJ-UHFFFAOYSA-N tert-butyl 5-hydroxy-3-oxo-6-trityloxyhexanoate Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(O)CC(=O)CC(=O)OC(C)(C)C)C1=CC=CC=C1 GAJZMSCUUOBKDJ-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical class [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- PSCXFXNEYIHJST-UHFFFAOYSA-N trans-styrilacetic acid Natural products OC(=O)CC=CC1=CC=CC=C1 PSCXFXNEYIHJST-UHFFFAOYSA-N 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila and more particularly to compounds of formula II which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin. BACKGROUND OF THE INVENTION
- Ri and R 2 are independently chosen alkyl of one to three carbons and R 3 is alkyl of from 1 to 8 carbon atoms, alternatively compounds of formula la,
- ⁇ and R 2 are independently chosen from alkyl of one to three carbons, phenyl or Ri and R 2 taken together as - (CH2)n- wherein n is 4 or 5 and R 3 is alkyl of from 1 to 8 carbon atoms and also compounds of Formula lb
- R x and R 2 are alkyl of from 1-5 carbons and R 3 is as defined above is a valuable structural element for synthesizing compounds, which are known as ant hypercholesterolemic agents having an inhibitory effect on HMG-CoA reductase.
- EP 0 319 847 describes a process for the preparation of compounds of formula 1 starting from L-Malic acid. This process, however, suffers from the fact that the process is not industrially scalable and also possesses purification problems due to the non- crystalline nature of the intermediates.
- US 5,998,633 describes a process for the preparation of protected esters of 3,4-dihydroxy butyric acid from a carbohydrate moiety which is transformed into the desired 3,4-dihydroxy butanoic acid derivatives in about 4 steps.
- the 3,4-dihydroxy butanoic acid derivative is then functionalized into compounds of formula I involving a multiple number of steps.
- Ar ' unsubstituted or substituted aryl or heteroaryl
- R 3 alkyl from 1 to 8 carbons, aryl or aralkyl
- the present invention also provides for a process for the manufacture of compounds of formula II
- Ar unsubstituted or substituted aryl or heteroaryl
- R 3 alkyl from 1 to 8 carbons, aryl or aralkyl which comprises of:
- the compound of formula II is oxidized to a compound of formula VIII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl and Ar is unsubstituted or substituted aryl or heteroaryl using pyridinium chloro chromate or DMSO/oxalyl chloride.
- Formula IX The compound of formula IX is further converted to a compound of formula VII, where R 3 is alkyl from 1 to 8 carbons, aryl or aralkyl, Ar is unsubstituted or substituted aryl or heteroaryl.
- Compound of formula II serves as a good intermediate for the synthesis of important substrates, which are useful in the synthesis of statins.
- Compound of formula II can be converted into a facile leaving group by treating with tosyl chloride, methane sulfonyl chloride and the resulting intermediate can be displaced with cyanide to give compounds of formula VII.
- Compound of formula II can be converted to formula IX by reacting with aqueous HBr solution or by reaction with triphenyl phosphine and CBr 4 which is then converted to compound of formula VII.
- Compound of formula II can be oxidized using standard procedures to give a compound of formula VIII.
- the present invention relates to optically active dihydroxy hexanoate derivatives of formula Ila which are useful intermediates for the synthesis of HMG-CoA enzyme inhibitors like atorvastatin, cerivastatin, rosuvastatin, pitavastatin, fluvastatin.
- Example 4 Synthesis of tert-Butyl 6-triphenylmethyIoxy- 3,5-phenylboranatohexanoate (Formula VI)
- the crude product from example-3 was dissolved in 100ml of toluene and 5.6g of phenyl boronic acid was added. Water was removed by azeotropic distillation over a period of 3h.
- the reaction mixture was cooled to RT and toluene was removed under reduced pressure. 30ml of methanol was added and the precipitated solid was filtered to give lOg of the title product.
- Example 5 Synthesis of tert-butyl 6-hydroxy-3,5- (phenylboranato)hexanoate (Formula II)
- Rl and R2 are alkyl 1 to 3 carbons
- R3 is alkyl from 1 to 8 carbons
- Rl and R2 are alkyl from 1 to 5 carbons
- R 3 is alkyl from 1 to 8 carbons
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN508MA2003 | 2003-06-23 | ||
IN508/MAS/2003 | 2003-06-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004113314A1 true WO2004113314A1 (fr) | 2004-12-29 |
Family
ID=33524014
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IN2004/000175 WO2004113314A1 (fr) | 2003-06-23 | 2004-06-18 | Nouveaux esters de boronate |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2004113314A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7416865B2 (en) | 2000-05-09 | 2008-08-26 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7442811B2 (en) | 2002-06-17 | 2008-10-28 | Astrazeneca Uk Limited | Process for the preparation of dioxane acetic acid esters |
KR100933172B1 (ko) | 2007-11-30 | 2009-12-21 | 씨제이제일제당 (주) | 아토르바스타틴 칼슘염의 개선된 제조방법 |
US7642363B2 (en) | 2000-07-19 | 2010-01-05 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives |
US7718812B2 (en) | 2001-12-27 | 2010-05-18 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates |
US7879585B2 (en) | 2006-10-02 | 2011-02-01 | Codexis, Inc. | Ketoreductase enzymes and uses thereof |
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US7416865B2 (en) | 2000-05-09 | 2008-08-26 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7732171B2 (en) | 2000-05-09 | 2010-06-08 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7888083B2 (en) | 2000-05-09 | 2011-02-15 | Astrazeneca Uk Limited | Process for the preparation of dihydroxy esters and derivatives thereof |
US7642363B2 (en) | 2000-07-19 | 2010-01-05 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-YL) acetic acid derivatives |
US7989643B2 (en) | 2000-07-19 | 2011-08-02 | Astrazeneca Uk Ltd. | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivatives |
US7718812B2 (en) | 2001-12-27 | 2010-05-18 | Astrazeneca Uk Limited | Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl) acetic acid derivates |
US7442811B2 (en) | 2002-06-17 | 2008-10-28 | Astrazeneca Uk Limited | Process for the preparation of dioxane acetic acid esters |
US7879585B2 (en) | 2006-10-02 | 2011-02-01 | Codexis, Inc. | Ketoreductase enzymes and uses thereof |
US8273547B2 (en) | 2006-10-02 | 2012-09-25 | Codexis, Inc. | Engineered ketoreductases and methods for producing stereoisomerically pure statins |
US8617864B2 (en) | 2006-10-02 | 2013-12-31 | Codexis, Inc. | Polynucleotides encoding ketoreductases for producing stereoisomerically pure statins and synthetic intermediates therefor |
KR100933172B1 (ko) | 2007-11-30 | 2009-12-21 | 씨제이제일제당 (주) | 아토르바스타틴 칼슘염의 개선된 제조방법 |
JP2015513556A (ja) * | 2012-05-17 | 2015-05-14 | 株式会社エフエヌジーリサーチFng Research Co., Ltd. | 新規なスタチン中間体、並びにこれを用いたピタバスタチン、ロスバスタチン、セリバスタチン及びフルバスタチンの製造方法 |
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