DK173115B1 - Fremgangsmåde til fremstilling af tetrahydropyran-2-on-forbindelser ved lactonisering af mevinsyreforbindelser - Google Patents

Fremgangsmåde til fremstilling af tetrahydropyran-2-on-forbindelser ved lactonisering af mevinsyreforbindelser Download PDF

Info

Publication number: DK173115B1
Authority: DK; Denmark
Prior art keywords: acid; process according; water; lactonization; lactone
Prior art date: 1988-07-19

Application number

DK198903541A

Other languages

Danish (da)

English (en)

Other versions

DK354189A (da

DK354189D0 (da

Inventor

Laszlo R Treiber

Original Assignee

Merck & Co Inc

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1988-07-19

Filing date

1989-07-18

Publication date

2000-01-31

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22827965&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=DK173115(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

1989-07-18 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

1989-07-18 Publication of DK354189D0 publication Critical patent/DK354189D0/da

1990-01-22 Publication of DK354189A publication Critical patent/DK354189A/da

2000-01-31 Application granted granted Critical

2000-01-31 Publication of DK173115B1 publication Critical patent/DK173115B1/da

Links

238000000034 method Methods 0.000 title claims abstract description 38
150000001875 compounds Chemical class 0.000 title claims description 12
238000002360 preparation method Methods 0.000 title claims description 5
OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical class O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 title claims description 4
238000007273 lactonization reaction Methods 0.000 title abstract description 17
239000002253 acid Substances 0.000 title description 15
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
150000002596 lactones Chemical class 0.000 claims description 25
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 20
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 16
239000003054 catalyst Substances 0.000 claims description 14
239000000203 mixture Substances 0.000 claims description 14
239000003960 organic solvent Substances 0.000 claims description 13
230000002378 acidificating effect Effects 0.000 claims description 11
229940098779 methanesulfonic acid Drugs 0.000 claims description 10
-1 tetrahydropyran-2-one compound Chemical class 0.000 claims description 9
150000001768 cations Chemical class 0.000 claims description 7
229910052751 metal Inorganic materials 0.000 claims description 5
239000002184 metal Substances 0.000 claims description 5
239000011541 reaction mixture Substances 0.000 claims description 5
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 4
125000000217 alkyl group Chemical group 0.000 claims description 4
229910052739 hydrogen Inorganic materials 0.000 claims description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
239000012298 atmosphere Substances 0.000 claims description 2
235000019253 formic acid Nutrition 0.000 claims description 2
230000001376 precipitating effect Effects 0.000 claims 1
229940121710 HMGCoA reductase inhibitor Drugs 0.000 abstract description 2
239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract description 2
BOZILQFLQYBIIY-INTXDZFKSA-N mevinic acid Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)CCC=C21 BOZILQFLQYBIIY-INTXDZFKSA-N 0.000 abstract description 2
229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 abstract description 2
239000000047 product Substances 0.000 description 15
239000000539 dimer Substances 0.000 description 8
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 7
239000012535 impurity Substances 0.000 description 7
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
230000015572 biosynthetic process Effects 0.000 description 6
238000006243 chemical reaction Methods 0.000 description 6
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
150000001261 hydroxy acids Chemical class 0.000 description 5
150000003839 salts Chemical class 0.000 description 5
239000002904 solvent Substances 0.000 description 5
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical class [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 4
239000000758 substrate Substances 0.000 description 4
FHSAZOGISLHXPK-SCSAIBSYSA-N (3r)-3-hydroxyoxan-2-one Chemical compound O[C@@H]1CCCOC1=O FHSAZOGISLHXPK-SCSAIBSYSA-N 0.000 description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
229910052782 aluminium Inorganic materials 0.000 description 3
239000006227 byproduct Substances 0.000 description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
229910052757 nitrogen Inorganic materials 0.000 description 3
239000012429 reaction media Substances 0.000 description 3
125000000008 (C1-C10) alkyl group Chemical group 0.000 description 2
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
239000004255 Butylated hydroxyanisole Substances 0.000 description 2
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
229910052783 alkali metal Inorganic materials 0.000 description 2
150000001340 alkali metals Chemical class 0.000 description 2
229910052784 alkaline earth metal Inorganic materials 0.000 description 2
150000001342 alkaline earth metals Chemical class 0.000 description 2
XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
229910021529 ammonia Inorganic materials 0.000 description 2
239000000908 ammonium hydroxide Substances 0.000 description 2
150000003863 ammonium salts Chemical group 0.000 description 2
235000019282 butylated hydroxyanisole Nutrition 0.000 description 2
CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
229940043253 butylated hydroxyanisole Drugs 0.000 description 2
229910052791 calcium Inorganic materials 0.000 description 2
239000011575 calcium Substances 0.000 description 2
239000003795 chemical substances by application Substances 0.000 description 2
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
230000000694 effects Effects 0.000 description 2
239000012065 filter cake Substances 0.000 description 2
239000001257 hydrogen Substances 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
229960004844 lovastatin Drugs 0.000 description 2
QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 2
229940099246 mevacor Drugs 0.000 description 2
230000007935 neutral effect Effects 0.000 description 2
239000012299 nitrogen atmosphere Substances 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
239000000523 sample Substances 0.000 description 2
229910052708 sodium Inorganic materials 0.000 description 2
239000011734 sodium Substances 0.000 description 2
239000007858 starting material Substances 0.000 description 2
238000005406 washing Methods 0.000 description 2
HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 1
JTGHBEFBQXGABE-UHFFFAOYSA-N 2,2-dihydroxyheptanoic acid Chemical compound CCCCCC(O)(O)C(O)=O JTGHBEFBQXGABE-UHFFFAOYSA-N 0.000 description 1
206010003210 Arteriosclerosis Diseases 0.000 description 1
208000024172 Cardiovascular disease Diseases 0.000 description 1
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
208000035150 Hypercholesterolemia Diseases 0.000 description 1
FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
239000003377 acid catalyst Substances 0.000 description 1
150000007513 acids Chemical class 0.000 description 1
230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
208000011775 arteriosclerosis disease Diseases 0.000 description 1
238000010533 azeotropic distillation Methods 0.000 description 1
239000003613 bile acid Substances 0.000 description 1
238000007664 blowing Methods 0.000 description 1
235000012000 cholesterol Nutrition 0.000 description 1
229910017052 cobalt Inorganic materials 0.000 description 1
239000010941 cobalt Substances 0.000 description 1
GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
238000001816 cooling Methods 0.000 description 1
229910052802 copper Inorganic materials 0.000 description 1
239000010949 copper Substances 0.000 description 1
230000007812 deficiency Effects 0.000 description 1
230000018044 dehydration Effects 0.000 description 1
238000006297 dehydration reaction Methods 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
238000000855 fermentation Methods 0.000 description 1
230000004151 fermentation Effects 0.000 description 1
238000010438 heat treatment Methods 0.000 description 1
230000002401 inhibitory effect Effects 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
230000000302 ischemic effect Effects 0.000 description 1
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
229940011051 isopropyl acetate Drugs 0.000 description 1
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
150000002739 metals Chemical class 0.000 description 1
AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
229950009116 mevastatin Drugs 0.000 description 1
BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
229910052759 nickel Inorganic materials 0.000 description 1
229910000069 nitrogen hydride Inorganic materials 0.000 description 1
150000007524 organic acids Chemical class 0.000 description 1
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000011591 potassium Substances 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000035484 reaction time Effects 0.000 description 1
238000010992 reflux Methods 0.000 description 1
230000003248 secreting effect Effects 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
239000000126 substance Substances 0.000 description 1
239000000725 suspension Substances 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-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
- C07D309/28—Heterocyclic compounds containing six-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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Public Health (AREA)
Obesity (AREA)
Diabetes (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Bioinformatics & Cheminformatics (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Hematology (AREA)
Veterinary Medicine (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Steroid Compounds (AREA)
Pyrane Compounds (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Saccharide Compounds (AREA)
Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Polysaccharides And Polysaccharide Derivatives (AREA)

DK198903541A 1988-07-19 1989-07-18 Fremgangsmåde til fremstilling af tetrahydropyran-2-on-forbindelser ved lactonisering af mevinsyreforbindelser DK173115B1 (da)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US07/221,475 US4916239A (en)	1988-07-19	1988-07-19	Process for the lactonization of mevinic acids and analogs thereof
US22147588		1988-07-19

Publications (3)

Publication Number	Publication Date
DK354189D0 DK354189D0 (da)	1989-07-18
DK354189A DK354189A (da)	1990-01-22
DK173115B1 true DK173115B1 (da)	2000-01-31

Family

ID=22827965

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
DK198903541A DK173115B1 (da)	1988-07-19	1989-07-18	Fremgangsmåde til fremstilling af tetrahydropyran-2-on-forbindelser ved lactonisering af mevinsyreforbindelser

Country Status (26)

Country	Link
US (1)	US4916239A (cs)
EP (1)	EP0351918B1 (cs)
JP (3)	JPH0273078A (cs)
KR (1)	KR970011286B1 (cs)
CN (1)	CN1022831C (cs)
AT (1)	ATE111459T1 (cs)
AU (1)	AU609319B2 (cs)
CA (1)	CA1287639C (cs)
CS (1)	CS274640B2 (cs)
CY (1)	CY1813A (cs)
DE (1)	DE68918191C5 (cs)
DK (1)	DK173115B1 (cs)
ES (1)	ES2058475T3 (cs)
FI (1)	FI92695C (cs)
HK (1)	HK136894A (cs)
HR (1)	HRP930685B2 (cs)
HU (2)	HU202511B (cs)
IE (1)	IE64304B1 (cs)
IL (1)	IL90925A (cs)
LV (1)	LV11033B (cs)
NO (1)	NO172800C (cs)
NZ (1)	NZ229879A (cs)
PT (1)	PT91191B (cs)
SI (1)	SI8911362A (cs)
YU (1)	YU47492B (cs)
ZA (1)	ZA895458B (cs)

Families Citing this family (98)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4916239A (en) *	1988-07-19	1990-04-10	Merck & Co., Inc.	Process for the lactonization of mevinic acids and analogs thereof
GB9007738D0 (en) *	1990-04-05	1990-06-06	British Bio Technology	Compounds
US5223415A (en) *	1990-10-15	1993-06-29	Merck & Co., Inc.	Biosynthetic production of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid)
US5250435A (en) *	1991-06-04	1993-10-05	Merck & Co., Inc.	Mutant strains of Aspergillus terreus for producing 7-[1,2,6,7,8,8a(R)-hexa-hydro-2(S),6(R)-dimethyl-8(S)-hydroxy-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid),I)
AU660132B2 (en) *	1992-12-21	1995-06-08	Bayer Aktiengesellschaft	Substituted 4-phenyl-pyridones and 4-phenyl-2-alkoxypyridine
JP3254219B2 (ja) *	1993-01-19	2002-02-04	ワーナー−ランバート・コンパニー	安定な経口用のｃｉ−９８１製剤およびその製法
IN186879B (cs) *	1997-10-28	2001-12-01	Ranbaxy Lab Ltd
IN186880B (cs) *	1997-10-28	2001-12-01	Ranbaxy Lab Ltd
ZA9810764B (en) *	1998-04-22	1999-08-13	Ranbaxy Lab Ltd	An improved process of lactonization in the preparation of statins.
CA2240983A1 (en)	1998-06-18	1999-12-18	Yong Tao	Process to manufacture simvastatin and intermediates
KR100672269B1 (ko) *	1998-12-10	2007-01-23	카네카 코포레이션	심바스타틴의 제조 방법
SK282679B6 (sk) *	1999-04-16	2002-11-06	Biotika, A. S.	Spôsob izolácie lovastatínu z vyfermentovanej pôdy
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1988
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1989
- 1989-07-10 YU YU136289A patent/YU47492B/sh unknown
- 1989-07-10 SI SI8911362A patent/SI8911362A/sl not_active IP Right Cessation
- 1989-07-10 NZ NZ229879A patent/NZ229879A/en unknown
- 1989-07-11 IL IL90925A patent/IL90925A/xx not_active IP Right Cessation
- 1989-07-11 FI FI893363A patent/FI92695C/fi not_active IP Right Cessation
- 1989-07-17 CN CN89104960A patent/CN1022831C/zh not_active Expired - Fee Related
- 1989-07-17 DE DE68918191T patent/DE68918191C5/de not_active Expired - Fee Related
- 1989-07-17 EP EP89201879A patent/EP0351918B1/en not_active Expired - Lifetime
- 1989-07-17 AT AT89201879T patent/ATE111459T1/de not_active IP Right Cessation
- 1989-07-17 CS CS435489A patent/CS274640B2/cs not_active IP Right Cessation
- 1989-07-17 PT PT91191A patent/PT91191B/pt not_active IP Right Cessation
- 1989-07-17 NO NO892938A patent/NO172800C/no not_active IP Right Cessation
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- 1989-07-18 AU AU38240/89A patent/AU609319B2/en not_active Ceased
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- 1989-07-18 ZA ZA895458A patent/ZA895458B/xx unknown
- 1989-07-18 KR KR1019890010127A patent/KR970011286B1/ko not_active Expired - Fee Related
1993
- 1993-04-02 HR HRP930685AA patent/HRP930685B2/hr active IP Right Review Request
1994
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1995
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KR970011286B1 (ko)	1997-07-09
JP2718422B2 (ja)	1998-02-25
JPH07196642A (ja)	1995-08-01
EP0351918B1 (en)	1994-09-14
CS435489A2 (en)	1990-12-13
ZA895458B (en)	1990-03-28
CY1813A (en)	1995-10-20
DE68918191D1 (de)	1994-10-20
HK136894A (en)	1994-12-09
SI8911362A (en)	1997-02-28
IL90925A (en)	1993-04-04
LV11033B (en)	1996-06-20
FI92695B (fi)	1994-09-15
YU136289A (en)	1991-02-28
IL90925A0 (en)	1990-02-09
HRP930685A2 (en)	1998-06-30
ATE111459T1 (de)	1994-09-15
IE892324L (en)	1990-01-19
AU3824089A (en)	1990-01-25
LV11033A (lv)	1996-02-20
PT91191B (pt)	1995-03-01
HU202511B (en)	1991-03-28
JPH09188672A (ja)	1997-07-22
NO892938D0 (no)	1989-07-17
JPH0273078A (ja)	1990-03-13
US4916239A (en)	1990-04-10
DE68918191C5 (de)	2005-06-09
CA1287639C (en)	1991-08-13
NZ229879A (en)	1991-12-23
FI92695C (fi)	1994-12-27
CN1022831C (zh)	1993-11-24
CS274640B2 (en)	1991-09-15
NO892938L (no)	1990-01-22
HRP930685B1 (en)	1999-06-30
IE892324A1 (en)	1991-06-19
DK354189A (da)	1990-01-22
KR910002828A (ko)	1991-02-26
PT91191A (pt)	1990-02-08
HRP930685B2 (hr)	2006-11-30
DE68918191T2 (de)	1995-03-02
NO172800B (no)	1993-06-01
FI893363A7 (fi)	1990-01-20
EP0351918A1 (en)	1990-01-24
AU609319B2 (en)	1991-04-26
HUT50804A (en)	1990-03-28
IE64304B1 (en)	1995-07-26
DK354189D0 (da)	1989-07-18
HU210533A9 (en)	1995-04-28
FI893363A0 (fi)	1989-07-11
YU47492B (sh)	1995-10-03
ES2058475T3 (es)	1994-11-01
NO172800C (no)	1993-09-08
CN1039420A (zh)	1990-02-07
JPH0575752B2 (cs)	1993-10-21

Legal Events

Date	Code	Title	Description
2000-01-31	B1	Patent granted (law 1993)
2009-03-02	PBP	Patent lapsed	Country of ref document: DK

Publication	Publication Date	Title
EP0351918B1 (en)	1994-09-14	Process for the lactonization of mevinic acids and analogs thereof
DK157292B (da)	1989-12-04	Fremgangsmaade til fremstilling af 6(r)-(2-(8'-acyloxy-2'-methyl-6'-methyl-(eller hydrogen)-polyhydronaphthyl-1')-ethyl)-4-hydroxy-3,4,5,6-tetrahydro-2h-pyran-2-oner eller tilsvarende hydroxysyrer eller farmaceutisk acceptable salte af hydroxysyrerne eller c1-4alkylestere deraf eller phenyl-, dimethylamino- eller acetylaminosubstituerede alkylestere deraf
US5917058A (en)	1999-06-29	Process of lactonization in the preparation of statins
KR20030018202A (ko)	2003-03-06	스타틴의 제조에 있어서 락톤화 방법
SI20527A (sl)	2001-10-31	Postopek za selektivno laktonizacijo
US5939564A (en)	1999-08-17	Process of lactonization in the preparation of statins
CZ20023201A3 (cs)	2003-09-17	Způsob čištění lovastatinu a simvastatinu na produkt se sníženou hladinou dimerních nečistot
EP0296810A1 (en)	1988-12-28	Novel intermediates and processes for preparing HMG-COA reductase inhibitors
RU2214407C2 (ru)	2003-10-20	Усовершенствованный способ лактонизации при получении статинов
AU2005326565B2 (en)	2011-09-15	Process for manufacture of simvastatin
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JP2004520444A5 (cs)	2005-02-17
EA007012B1 (ru)	2006-06-30	Способ получения 4-окситетрагидропиран-2-онов
HK1023572B (en)	2005-02-25	An improved process of lactonization in the preparation of statins
AU2001241833A2 (en)	2003-03-20	A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities