WO2006134482A1 - Procédé pour la fabrication d’atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires - Google Patents

Procédé pour la fabrication d’atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires Download PDF

Info

Publication number
WO2006134482A1
WO2006134482A1 PCT/IB2006/001613 IB2006001613W WO2006134482A1 WO 2006134482 A1 WO2006134482 A1 WO 2006134482A1 IB 2006001613 W IB2006001613 W IB 2006001613W WO 2006134482 A1 WO2006134482 A1 WO 2006134482A1
Authority
WO
WIPO (PCT)
Prior art keywords
seq
dera
amino acid
acid sequence
aldolase
Prior art date
Application number
PCT/IB2006/001613
Other languages
English (en)
Other versions
WO2006134482A8 (fr
Inventor
Shanghui Hu
Junhua Tao
Zhiyi Xie
Original Assignee
Pfizer 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.)
Filing date
Publication date
Application filed by Pfizer Inc. filed Critical Pfizer Inc.
Priority to EP06765533A priority Critical patent/EP1893767A1/fr
Priority to CA002612293A priority patent/CA2612293A1/fr
Publication of WO2006134482A1 publication Critical patent/WO2006134482A1/fr
Publication of WO2006134482A8 publication Critical patent/WO2006134482A8/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom

Definitions

  • High levels of blood cholesterol and blood lipids are conditions involved in the onset of atherosclerosis.
  • the conversion of HMG-CoA to mevalonate is an early and rate-limiting step in the cholesterol biosynthetic pathway. This step is catalyzed by the enzyme HMG-CoA reductase.
  • HMG-CoA reductase It is known that inhibitors of HMG-CoA reductase are effective in lowering the blood plasma level of low density lipoprotein cholesterol (LDL-C), in man. (cf. M.S. Brown and J.L. Goldstein, New England Journal of Medicine, 305, No. 9, 515-517 (1981)). It has been established that lowering LDL-C levels affords protection from coronary heart disease ⁇ cf . Journal of the American Medical Association, 251 , No. 3, 351-374 (1984)).
  • LDL-C low density lipoprotein cholesterol
  • statins interfere with and/or inhibit HMG-CoA reductase from catalyzing the conversion of HMG-CoA to mevalonate.
  • statins are collectively potent lipid lowering agents.
  • statins are the drugs of first choice for management of many lipid disorders.
  • One representative statin is atorvastatin.
  • Other representative statins include lovastatin, pravastatin, simvastatin and rosuvastatin.
  • Atorvastatin and pharmaceutically acceptable salts thereof are selective, competitive inhibitors of HMG-CoA reductase.
  • Atorvastatin calcium is currently sold as Lipitor ® having the chemical name [R-(R * , R * )]-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5-(1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1 H-pyrrole-1-heptanoic acid calcium salt (2:1) trihydrate and the formula
  • atorvastatin calcium is a potent lipid-lowering compound and is thus useful as a hypolipidemic and/or hypocholesterolemic agent. Atorvastatin calcium is also useful in the treatment of osteoporosis, benign prostatic hyperplasia (BPH) and Alzheimer's disease.
  • DERA deoxyribose aldolase
  • the present invention is directed to a an efficient and cost-effective synthetic route for producing atorvastatin, pharmaceutically acceptable salts thereof (e.g. atorvastatin calcium) and intermediates thereof.
  • the present invention provides a process comprising the step of reacting an aldehyde with an aminoaldehyde substrate, a N-protected aminoaldehyde substrate or a pyrrole aldehyde substrate under aldolase-catalyzed aldol condensation conditions to form the corresponding lactol.
  • the present invention also provides a process for producing atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:
  • the present invention also provides a process for producing atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of:
  • the present invention also provides a process for producing atorvastatin or a pharmaceutically acceptable salt thereof comprising the steps of: (a) reacting an aldehyde with an aminoaldehyde substrate, a N-protected aminoaldehyde substrate or a pyrrole aldehyde substrate under aldolase-catalyzed aldol condensation conditions to form the corresponding lactol;
  • Novel intermediates useful in the preparation of atorvastatin or a pharmaceutically acceptable salt thereof are also provided.
  • aldolase-catalyzed aldol condensation conditions refers to any aldol condensation conditions known in the art that can be catalyzed by an aldolase, as described herein.
  • condition sufficient to produce atorvastatin or a pharmaceutically . acceptable salt thereof refers to those means described in the art, including those means described herein.
  • a pharmaceutically acceptable salt refers to the relatively non-toxic salts of atorvastatin which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use. These salts can be prepared by any means known in the art.
  • a pharmaceutically acceptable salt of atorvastatin examples include, but are not limited to, all atorvastatin salts known in the art including, but not limited to, atorvastatin calcium and atorvastatin sodium.
  • a pharmaceutically acceptable salt of atorvastatin is atorvastatin calcium.
  • the aldehyde for use in the present invention may be any aldehyde that will undergo an aldol condensation with a substrate, as described herein, in the presence of an aldolase, as described herein.
  • An example of suitable aldehyde is, but is not limited to, acetaldehyde.
  • a substrate for use in the present invention may be any aminoaldehyde or N-protected aminoaldehyde. Such an aminoaldehyde or N-protected aminoaldehyde will react with an aldehyde under aldolase-catalyzed aldol condensation conditions, each as described herein.
  • a substrate for use in the invention is of the general formula (I): -A-
  • R' is hydrogen
  • R" is hydrogen or a N-protecting group; or R' and R" taken together with nitrogen to which they are attached form a cyclic moiety.
  • Suitable N-protecting groups for the aminoaldehyde include, but are not limited to, benzyloxycarbonyl (CBz), butoxycarbonyl (Boc), 9- fluorenylmethoxycarbonyl (Fmoc), benzyl, and dibenzyl.
  • Suitable aminoaldehyde substrate include, but are not limited to:
  • the aminoaldehyde substrate is N-CBz-3- aminopropionaldehyde or N-Fmoc-3-aminopropionaldehyde. In one embodiment of the invention, the aminoaldehyde substrate is 3-amino-propionaldehyde. In one embodiment of the invention, the aminoaldehyde substrate is amino-acetaidehyde. In one embodiment of the invention, the aminoaldehyde substrate is N-CBz-3-aminopropionaldehyde (commercially available from Aldrich). In one embodiment of the invention, the aminoaldehyde substrate is N- acetyl-3-aminopropionaldehyde. In one embodiment of the invention, the aminoaldehyde substrate is N-Fmoc-3-aminopropionaldehyde.
  • N-Fmoc-aminoaldehydes were obtained via standard Dess-Martin oxidation of the corresponding N-Fmoc aminoalcohol.
  • N-acetyl-3-aminopropionaldehyde was obtained from 3-amino-1-propanol by a two step procedure: N-acetylation of the 3-amino-1-propanol by methyl actetate followed by Dess- Martin oxidation to give the desired product with the correct ESI-MS [M+H] + 116.25 and [M+Na] + 138.20.
  • a substrate for use in the present invention may be a pyrrole aldehyde.
  • the pyrrole aldehyde has the following structure:
  • the pyrrole aldehyde was prepared from diketone 9 by a two-step procedure: Paal-Knorr reaction with 3-amino-1-propanol followed by Dess-Martin oxidation to give the desired product with correct ESI-MS [M+H] + 455.4 and [M+Na] + 477.3.
  • an aldolase for use in the present invention may be any compound that has aldolase activity towards an aminoaldehyde substrate, N-protected aminoaldehyde substrate, or pyrrole aldehyde substrate, each as described herein.
  • the aldolase is a 2-deoxyribose-5-phosphate aldolase (DERA).
  • DERA • aldolase examples include, but are not limited to:
  • DERA 03 E. CoIi
  • DERA 04 Wood A. Greenberg, et al., PNAS, (2004), Vol. 101 ,, No. 16, pp. 5788-
  • DERA 08 GenBank Accession NP_465519 or a modified version thereof
  • DERA 11 (GenBank Accession NP_439273); DERA 12 (GenBank Accession NP_229359); or
  • the aldolase is an aldolase having an amino acid sequence identity of at least about 20% thereof; preferably, at least 70% thereof, to a DERA aldolase described herein.
  • the DERA aldolase is DERA 04 or DERA 06.
  • the DERA aldolase is DERA 06.
  • DERA 03, DERA 04, DERA 06, DERA 08, DERA 11 , DERA 12, and DERA 15 are identified by their nucleotide sequences and amino acid sequences set forth in Examples 10-23. More specifically, DERA 03 is an aldolase having a nucleotide sequence of SEQ ID NO: 10
  • DERA 04 is an aldolase having a nucleotide sequence of SEQ ID NO: 2 and an amino acid sequence of SEQ ID NO: 9.
  • DERA 06 is an aldolase having a nucleotide sequence of SEQ ID NO: 3 and an amino acid sequence of " SEQ ID NO: 10.
  • OERA 08 is an aldolase having a nucleotide sequence of SEQ ID NO: 4 and an amino acid sequence of SEQ ID NO: 11.
  • DERA 11 is an aldolase having a nucleotide sequence of SEQ ID NO: 5 and an amino acid sequence of SEQ ID NO: 12.
  • DERA 12 is an aldolase having a nucleotide sequence of SEQ ID NO: 6 and an amino acid sequence of SEQ ID NO: 13.
  • DERA 15 is an aldolase having a nucleotide sequence of SEQ ID NO: 7 and an amino acid sequence of SEQ ID NO: 14.
  • DERA aldolases described herein can be prepared by any means known in the art, including but not limited to standard protocols for protein expression in recombinant E. coli (Sambrook and Russell, Molecular Cloning: A Laboratory Manual, 3 rd Ed., Cold Spring Harbor, NY 2001). As would be understood by one of skill in the art, modified versions of known DERA aldolases may be necessary or may result depending on cloning conditions and are encompassed by the present invention.
  • R H, CBz, Boc, Fmoc, benzyl, or dibenzyl
  • Atorvastatin Calcium Scheme 1 describes in general a process encompassed by the present invention.
  • a DERA aldolase catalyzes an aldol condensation reaction between an aminoaldehyde or a N-protected aminoaldehyde and 2 mol of acetaldehyde to give the desired amino-lactol (A).
  • Amino-lactol (A) can then be selectively oxidized to the corresponding lactone (B).
  • the resulting lactone (B) can then be converted into atorvastatin lactone via deprotection followed by Parl-Knorr condensation with diketone (9): diketone 9 to give the corresponding atorvastatin lactone.
  • the opening of the atorvastatin lactone with Ca(OH) 2 will give atorvastatin calcium.
  • amino-lactol (A) can undergo catalytic (e.g. Pt/C, Pd/C) dehydrogenation to form carboxylic acid (C), which can then undergo lactonization to form (B) which in turn can then be converted into atorvastatin calcium as described above.
  • catalytic e.g. Pt/C, Pd/C
  • carboxylic acid (C) is condensed with diketone (9) to give atorvastatin calcium.
  • the stereoselectivity of the enzymatic step can be confirmed via chemical preparation of racemic standards and the development of the related chiral chromatographic methods.
  • Oxidation of the lactol (A) to lactone (B) or carboxylic acid (C) can be performed by use of any oxidation means known in the art that will achieve the desired transformation. In one embodiment of the invention, selective oxidation can be achieved according to the methods described in Examples 2 and 3.
  • any catalytic dehydrogenation means known in the art to convert (A) to (C) are encompassed by the present invention.
  • suitable catalysts include, but are not limited to, Pt/C, Pd/C, Pt/Bi/C, Pd/Bi/C and any other dehydrogenation catalysts.
  • the catalytic dehydrogenation is performed at about pH 7 to about pH 10 using air or oxygen as terminant oxidant.
  • lactonization means known in the art to convert carboxylic acid (C) to lactone (B) are encompassed by the present invention including, but not limited to, the use of acid catalysts such as, but not limited to, HCI, H 2 SO 4 , Methanesulfonic acid (MSA), p-Toluenesulfonic acid (TSA) and any other lactonization acids known in the art.
  • acid catalysts such as, but not limited to, HCI, H 2 SO 4 , Methanesulfonic acid (MSA), p-Toluenesulfonic acid (TSA) and any other lactonization acids known in the art.
  • Scheme 2 illustrates three possible routes for the preparation of atorvastatin calcium from lactol (1).
  • Lactol (1) can be prepared by a chemoeznymatic process described herein.
  • Route 1 Amino-lactone (2) can be prepared by acid-catalyzed lactonization of (3), followed by deprotection of benzyloxycarbonyl (CBz) of (2) by Pd/C catalyzed hydrogenation.
  • CBz benzyloxycarbonyl
  • ⁇ -Aminoacid-diol (5) can be prepared via CBz deprotection of (3) by Pd/C catalyzed hydrogenation. Subsequent condensation of (5) with di-ketone (9):
  • Compound (8) (TBIA) can be prepared through acid-catalyzed diol protection of (3) to form (6); t-BuOH coupling of (6) to form (7); and CBz deprotection of (7) by Pd/C catalyzed hydrogenation to form (8).
  • Compound (8) can then be taken on to form atorvastatin calcium by condensation with diketone (9), deprotection, lactonization and lactone ring opening by Ca(OH) 2 .
  • carboxylic acid (3) can be converted to tert-butyl-isopropylidine amine (8), followed by condensation with diketone (9), deprotection, lactonization and the opening of lactone to give atorvastatin calcium.
  • Scheme 3 describes another route for the formation of atorvastatin calcium from lactol (1) prepared by the process described herein.
  • Protected amino-lactol (12) is prepared by conversion of lactol (1) to ethyl-protected lactol (11); followed by CBz deprotection of (11) via Pd/C catalyzed hydrogenation. Subsequent condensation of (12) with diketone (9) gives ⁇ 13) which is then deprotected to give (14) which, in turn, is then oxidized to give atorvastatin lactone (10) which is then converted to atorvastatin calcium.
  • atorvastatin calcium is prepared starting with diketone 9.
  • Diketone 9 can be prepared according to procedures known in the art including, for example, Baumann, Kelvin L., Tetrahedron Letters (1992), 33(17), 2283-4.
  • Diketone 9 is treated with pivalic acid to form the corresponding pyrrole alcohol which is then oxidized under Dess-Martin conditions to form the corresponding pyrrole aldehyde.
  • the pyrrole aldehyde then undergoes an aldolase-catalyzed aldol condensation to form the corresponding pyrrole lactol.
  • the resulting pyrrole lactol can then be converted to the pyrrole lactone by standard oxidation.
  • the pyrrole lactone can then be converted to atorvastatin calcium by means known in the art.
  • DERA 04 deoxyribose aldolase, 42,000 units, 14.0 mL
  • phosphate buffer 60 mL, pH 7.3, 0.05 M
  • HPLC high performance liquid chromatography
  • Lactone 2 (100 mg, 0.341 mmol; prepared according to Example 4) in THF (2 mL) was hydrogenated with Pd/C (5%, 100 mg, Aldrich) at 23 0 C for 1 h. After filtration of the catalyst, the free aminoethyl-lactone 4 was produced, which was directly used for the subsequent Paal- Knorr condensation (see Example 8).
  • LC-ESIMS m/z [M+THF] + 232.3.
  • Example 10 SEQ ID NO: 1 - Nucleotide sequence of DERA03 atgactgatctgaaagcaagcagcctgcactgaaattgatggacctgaccaccaccctgaatgacgacaccgacgagaaa gtgatcgccctgtcatcaggccaaaactccggtcggcaataccgccgctatctgtatctatctatcctcgctttatcccgattgctcgcaaaa ctctgaaagagcagggcaccccggaaatccgtatcgctacggtaaccaacttcccacacggtaacgacgacatcgacategcgct ggcagaaacccgtgcggcaatcgctacggtgctgatgaagttgtgtgtgtgtgtgtg
  • Example 15 SEQ ID NO: 6 - Nucleotide Sequence of DERA12 atgatagagtacaggattgaggaggcagtagcgaagtacagagagttctacgaattcaagcccgtcagagaaagcgcaggtattg aagatgtgaaagtgctatagagcacacgaatctgaaaccgtttgccacaccagacgatataaaaaaactctgtcttgaagcaagg gaaaatcgtttccatggagtctgtgtgtgtgtgtgaatccgtgttatgtgtgaaactggctcgtgtgaagaactcgaaggaaccgatgtgaaagtcgtcac cgtgtgaagaactcgaaggaaccgatgtgaaagtcg
  • SEQ ID NO: 8 Amino Acid Sequence of DERA03 mtdlkasslralklmdlttlndddtdekvialchqaktpvgntaaiciyprfipiarktlkeqgtpeiriatvtnfphgnddidialaetraaiay gadevdwfpyralmagneqvgfdlvkackeacaaanvllkviietgelkdealirkaseisikagadfiktstgkvavnatpesarim mevirdmgvektvgfkpaggvrtaedaqkylaiadelfgadwadarhyrfgassllasllkalghgdgksassy Example 18
  • SEQ ID NO: 14 Amino acid sequence of DERA15 mpsardilqqgldrlgspedlasridstllsprateedvrnivreasdygfrcavltpvytvkisglaeklgvklcsvigfplgqaplevklve aqtvleagateldvvphlslgpeavyrevsgivklaksygavvkvileaplwddktlslivdssrragadivktstgvytkggdpvtvfrla slakplgmgvkasggirsgidavlavgagadiigtssavkvlesfkslv .
  • AII publications including but not limited to, issued patents, patent applications, and journal articles, cited in this application are each herein incorporated by reference in their entirety.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • General Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biotechnology (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

La présente invention décrit un nouveau procédé de fabrication de l’atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires en utilisant une aldolase. Des composés ainsi préparés sont utiles comme inhibiteurs de l’HMG-CoA réductase et peuvent ainsi être utilisés comme agents hypolipémiant et hypocholestérolémique.
PCT/IB2006/001613 2005-06-16 2006-06-06 Procédé pour la fabrication d’atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires WO2006134482A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP06765533A EP1893767A1 (fr) 2005-06-16 2006-06-06 Procédé pour la fabrication d atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires
CA002612293A CA2612293A1 (fr) 2005-06-16 2006-06-06 Procede pour la fabrication d'atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermediaires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US69106505P 2005-06-16 2005-06-16
US60/691,065 2005-06-16

Publications (2)

Publication Number Publication Date
WO2006134482A1 true WO2006134482A1 (fr) 2006-12-21
WO2006134482A8 WO2006134482A8 (fr) 2008-03-06

Family

ID=36928182

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2006/001613 WO2006134482A1 (fr) 2005-06-16 2006-06-06 Procédé pour la fabrication d’atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires

Country Status (6)

Country Link
EP (1) EP1893767A1 (fr)
JP (1) JP2006345863A (fr)
AR (1) AR055975A1 (fr)
CA (1) CA2612293A1 (fr)
TW (1) TW200724688A (fr)
WO (1) WO2006134482A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2017267A1 (fr) * 2007-07-16 2009-01-21 LEK Pharmaceuticals D.D. Synthèse de statine
WO2009019561A3 (fr) * 2007-08-03 2009-05-14 Pfizer Prod Inc Procédé de préparation de composés chiraux
US8183397B2 (en) 2007-04-03 2012-05-22 Lek Pharmaceuticals D.D. Synthesis of statins
EP2465936A1 (fr) 2010-12-20 2012-06-20 LEK Pharmaceuticals d.d. Synthèse enzymatique de statines et intermédiaires associés
WO2012095244A2 (fr) 2010-12-20 2012-07-19 Lek Pharmaceuticals D.D. Synthèse enzymatique d'un principe actif pharmaceutique et de ses intermédiaires
US8404870B2 (en) 2008-01-23 2013-03-26 Lek Pharmaceuticals D.D. ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl carboxylate and process for the production thereof
CN103060396A (zh) * 2011-10-21 2013-04-24 武汉启瑞药业有限公司 一种生产高手性纯度的阿托伐他汀钙的新方法
WO2013068917A1 (fr) * 2011-11-07 2013-05-16 Dr. Reddy's Laboratories Limited Procédés de production d'un intermédiaire de statine lactone par oxydation enzymatique
CN103384659A (zh) * 2011-02-21 2013-11-06 公益财团法人微生物化学研究会 硫代酰胺化合物、生产硫代酰胺化合物的方法、生产 [(4r,6r)-6-氨乙基-1,3-二噁烷-4-基]乙酸酯衍生物的方法和生产阿托伐他汀的方法
CN105272954A (zh) * 2014-06-27 2016-01-27 南京博优康远生物医药科技有限公司 一种6-取代甲基-4-羟基四氢吡喃-2-酮及其衍生物的制备方法
US11060079B2 (en) 2016-06-30 2021-07-13 Ardra Inc. Methods and microorganisms for producing flavors and fragrance chemicals

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004027075A2 (fr) * 2002-09-20 2004-04-01 Diversa Corporation Procedes chimioenzymatiques de synthese de statines et d'intermediaires de statine

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004027075A2 (fr) * 2002-09-20 2004-04-01 Diversa Corporation Procedes chimioenzymatiques de synthese de statines et d'intermediaires de statine

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
ESPELT LAIA ET AL: "Aldol additions of dihydroxyacetone phosphate to N-Cbz-amino aldehydes catalyzed by L-fuculose-1-phosphate aldolase in emulsion systems: inversion of stereoselectivity as a function of the acceptor aldehyde.", CHEMISTRY (WEINHEIM AN DER BERGSTRASSE, GERMANY) 18 FEB 2005, vol. 11, no. 5, 18 February 2005 (2005-02-18), pages 1392 - 1401, XP002397813, ISSN: 0947-6539 *
HUNG R R ET AL: "ALPHA-AMINO ALDEHYDE EQUIVALENTS AS SUBSTRATES FOR RABBIT MUSCLE ALDOLASE: SYNTHESIS OF 1,4-DIDEOXY-D-ARABINITOL AND 2(R),5(R)-BIS(HYDROXYMETHYL)-3(R),4(R)-DIHYDROXYPYRROLIDINE", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY. EASTON, US, vol. 56, no. 12, 1991, pages 3849 - 3855, XP001120216, ISSN: 0022-3263 *
LIU J ET AL: "Sequential aldol condensation catalyzed by DERA mutant Ser238Asp and a formal total synthesis of atorvastatin", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 45, no. 11, 8 March 2004 (2004-03-08), pages 2439 - 2441, XP004491468, ISSN: 0040-4039 *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8471045B2 (en) 2007-04-03 2013-06-25 Lek Pharmaceuticals D.D. Synthesis of statins
US8183397B2 (en) 2007-04-03 2012-05-22 Lek Pharmaceuticals D.D. Synthesis of statins
EP2017267A1 (fr) * 2007-07-16 2009-01-21 LEK Pharmaceuticals D.D. Synthèse de statine
WO2009019561A3 (fr) * 2007-08-03 2009-05-14 Pfizer Prod Inc Procédé de préparation de composés chiraux
US20110118476A1 (en) * 2007-08-03 2011-05-19 Pfizer Inc. Process for Preparing Chiral Compounds
US9079877B2 (en) 2007-08-03 2015-07-14 Pfizer Inc. Process for preparing chiral compounds
EP2532660A1 (fr) * 2007-08-03 2012-12-12 Pfizer Products Inc. Procédé de préparation de composés chiraux
US8642783B2 (en) * 2007-08-03 2014-02-04 Pfizer Inc. Process for preparing chiral compounds
US8404870B2 (en) 2008-01-23 2013-03-26 Lek Pharmaceuticals D.D. ((2S,4R)-4,6-dihydroxytetrahydro-2H-pyran-2-yl)methyl carboxylate and process for the production thereof
EP2465936A1 (fr) 2010-12-20 2012-06-20 LEK Pharmaceuticals d.d. Synthèse enzymatique de statines et intermédiaires associés
WO2012095244A2 (fr) 2010-12-20 2012-07-19 Lek Pharmaceuticals D.D. Synthèse enzymatique d'un principe actif pharmaceutique et de ses intermédiaires
CN103384659A (zh) * 2011-02-21 2013-11-06 公益财团法人微生物化学研究会 硫代酰胺化合物、生产硫代酰胺化合物的方法、生产 [(4r,6r)-6-氨乙基-1,3-二噁烷-4-基]乙酸酯衍生物的方法和生产阿托伐他汀的方法
CN103384659B (zh) * 2011-02-21 2015-11-25 公益财团法人微生物化学研究会 硫代酰胺化合物及生产该化合物、[(4r,6r)-6-氨乙基-1,3-二噁烷-4-基]乙酸酯衍生物和阿托伐他汀的方法
CN103060396A (zh) * 2011-10-21 2013-04-24 武汉启瑞药业有限公司 一种生产高手性纯度的阿托伐他汀钙的新方法
CN103060396B (zh) * 2011-10-21 2017-09-12 武汉启瑞药业有限公司 一种生产高手性纯度的阿托伐他汀钙的新方法
WO2013068917A1 (fr) * 2011-11-07 2013-05-16 Dr. Reddy's Laboratories Limited Procédés de production d'un intermédiaire de statine lactone par oxydation enzymatique
CN105272954A (zh) * 2014-06-27 2016-01-27 南京博优康远生物医药科技有限公司 一种6-取代甲基-4-羟基四氢吡喃-2-酮及其衍生物的制备方法
CN105272954B (zh) * 2014-06-27 2017-10-13 上海弈柯莱生物医药科技有限公司 一种6‑取代甲基‑4‑羟基四氢吡喃‑2‑酮及其衍生物的制备方法
US11060079B2 (en) 2016-06-30 2021-07-13 Ardra Inc. Methods and microorganisms for producing flavors and fragrance chemicals

Also Published As

Publication number Publication date
TW200724688A (en) 2007-07-01
WO2006134482A8 (fr) 2008-03-06
CA2612293A1 (fr) 2006-12-21
AR055975A1 (es) 2007-09-12
EP1893767A1 (fr) 2008-03-05
JP2006345863A (ja) 2006-12-28

Similar Documents

Publication Publication Date Title
EP1893767A1 (fr) Procédé pour la fabrication d atorvastatine, de ses sels pharmaceutiquement acceptables et de ses intermédiaires
EP0915866B1 (fr) Procede ameliore de synthese d'esters proteges de l'acide (s)-3,4-dihydroxybutyrique
JP5788457B2 (ja) キラル化合物の調製方法
EP0680963B1 (fr) (Hydroxyphénylamino)carbonyl-pyrroles
JP4234429B2 (ja) 水酸化カルシウムによる〔Ｒ（Ｒ＊，Ｒ＊）〕−２−（４−フルオロフェニル）−β，δ−ジヒドロキシ−５−（１−メチルエチル）−３−フェニル−４−〔（フェニルアミノ）カルボニル〕−１Ｈ−ピロール−１−ヘプタン酸エステルの加水分解
CA2713009C (fr) Carboxylate de ((2s,4r)-4,6-dihydroxytetrahydro-2h-pyran-2-yl)methyle et son procede de fabrication
RU2335500C2 (ru) Способ получения производных мевалоновой кислоты, ингибирующих гмг-соа редуктазу
US6521762B2 (en) Process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities
WO2008075165A1 (fr) Nouveau procédé pour la synthèse de l'acide [r-(r*, r*)]-2-(4-fluorophényl)-bêta, delta-dihydroxy-5-(1-méthyléthyl)-3-phényl-4-[(phénylamino)carbonyl]-1h-pyrrole-1-heptanoïque ou d'un sel pharmaceutiquement acceptable de celui-ci
US6825362B2 (en) Process for lactonization to produce highly pure simvastatin
JPH06279280A (ja) エステル化合物
정경수 Stereoselective synthesis of L-threo-β-hydroxy aspartate
AU2001241833A2 (en) A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities
GB2340489A (en) 5-(2-Halo-1-hydroxyethyl)-1,3-benzodioxoles and their preparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2006765533

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2612293

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

WWW Wipo information: withdrawn in national office

Country of ref document: DE

WWP Wipo information: published in national office

Ref document number: 2006765533

Country of ref document: EP