WO2011141805A2 - Procédé de production amélioré de lamivudine - Google Patents

Procédé de production amélioré de lamivudine Download PDF

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Publication number
WO2011141805A2
WO2011141805A2 PCT/IB2011/001013 IB2011001013W WO2011141805A2 WO 2011141805 A2 WO2011141805 A2 WO 2011141805A2 IB 2011001013 W IB2011001013 W IB 2011001013W WO 2011141805 A2 WO2011141805 A2 WO 2011141805A2
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WO
WIPO (PCT)
Prior art keywords
oxathiolane
isopropyl
methyl
carboxylic acid
cis
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PCT/IB2011/001013
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English (en)
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WO2011141805A3 (fr
Inventor
Bhairab Nath Roy
Girij Pal Singh
Dhananjai Shrivastava
Harishchandra Sambhaji Jadhav
Umesh Parashram Aher
Sharad Chandrabhan Deokar
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Lupin Limited
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Publication of WO2011141805A2 publication Critical patent/WO2011141805A2/fr
Publication of WO2011141805A3 publication Critical patent/WO2011141805A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an improved process for the Manufacture of Lamivudine. Background of the invention
  • Lamivudine (I) (CAS No. 134678-1 . 7-4) is chemically known as (-)-[2R,5S]-4-amino-l - (hydroxymethyl)-l ,3-oxathiolan-5-yl]-2(lH)-pyrimidin-2-one.
  • Lamivudine is a reverse transcriptase inhibitor used alone or in combination with other classes of Anti-HIV drugs in the treatment of HIV infection. It is available commercially as a pharmaceutical composition under the brand name EPIVIR ® , marketed by Glaxo SmithKline, and is covered under US 5,047,407.
  • This molecule has two stereo-centres, thus giving rise to four stereoisomers: ( ⁇ )-Cis Lamivudine and ( ⁇ )-Trans Lamivudine.
  • the pharmaceutically active isomer however is the (-)-Cis isomer which has the absolute configuration [2R,5S] as show in Formula (I).
  • US 5,248,776 describes an asymmetric process for the synthesis of enantiomerically pure ⁇ - L-(-)-l,3-oxathiolone-nucleosides starting from optically pure 1 ,6-thioanhydro-L-gulose, which in turn can be easily prepared from L-Gulose.
  • the condensation of the 1,3-oxathiolane derivative with the heterocyclic base is carried out in the presence of a Lewis acid, most preferably SnCl 4: to give the [2R,5R] and [2R,5S] diastereomers that are then separated chromatographically.
  • Dissolving compound C in a mixture of 3:7 ethyl acetate-hexane separates the cis isomer.
  • the product containing predominantly the cis-2R,5S isomer and some trans-2R,5R compound is reduced with NaBH 4 and subjected to column chromatography (30% MeOH- EtOAc) to yield the below compound.
  • the glycosylation is carried out in the presence of TiCl 3 (OiPr) which is stereoselective and the cis-2R,5S-isomer is obtained in excess over the trans-2S,5S-isomer. These diastereomers are then separated by fractional crystallization.
  • US 6,600,044 relates a method for converting the undesired trans-l,3-oxathiolane nucleoside to the desired cis isomer by a method of anomerization or transglycosylation and the separation of the hydroxy-protected form of cis-, trans-(-)-nucleosides by fractional crystallization of their hydrochloride, hydrobromide, methanesulfonate salts.
  • these cis-trans isomers already bear the [R] configuration at C2 and only differ in their configuration at C5; i.e. the isomers are [2R,5Rj and [2R,5S].
  • diastereomeric separation directly yields the desired [2R, 5S] enantiomer of Lamivudine.
  • 'R' is an acyl group and 'Rl ' represents the purine or pyrimidine base.
  • 'R' may be alkyl carboxylic, substituted alkyl carboxylic and preferably an acyl group that is significantly electron- withdrawing, eg. a-haloesters.
  • this patent also refers to the use of the enzyme cytidine- deoxycytidine deaminase, which is enantiomer-specific, to catalyze the deamination of the cytosine moiety and thereby converting it to uridine.
  • the enantiomer that remains unreacted is still basic and can be extracted by using an acidic solution.
  • WO 2006/096954 describes the separation of protected or unprotected enantiomers of the cis nucleosides of below formula by using a chiral acid to form diastereomeric salts that are isolated by filtration.
  • Some of the acids used are R-(-)-Camphorsulfonic acid, L-(-)-Tartaric acid, L-(-)-Malic acid, et cetera.
  • these CIS-nucleosides are [2R.4R] and [2S,4S] as the heterocyclic base is attached at the 4 position of the oxathiolane ring and the overall stereo-structure of the molecule changes from that of the 2,5-substituted oxathiolane ring.
  • CN 1223262 (Deng et al) teaches the resolution of a certain class of compounds called Prazoles by using chiral host compounds such as dinaphthalenephenols (BINOL), diphenanthrenols or tartaric acid derivatives.
  • BINOL dinaphthalenephenols
  • the method consists of the formation of a 1 : 1 complex between the chiral host (BINOL) and one of the enantiomers, the guest molecule. The other enantiomer remains in solution.
  • (S)-Omeprazole which is pharmaceutically active as a highly potent inhibitor of gastric acid secretion, has been isolated from its racemic mixture in this manner by using S-BINOL.
  • BINOL is a versatile chiral ligand that has found its uses in various reactions involving asymmetric synthesis (Noyori, R. Asymmetric Catalysis in Organic Synthesis) and optical resolution (Cram, D. J. et al J. Org. Chem. 1977, 42, 4173-4184). Some of these reactions include BINOL-mediated oxidation and reduction reactions, C-C bond formation reactions such as Aldol reaction, Michael addition, Mannich reaction et cetera (Brunei Chem, Rev. 2005 105, 857-897) and kinetic resolution, resolution by inclusion complexation et cetera.
  • BINOL or 1,1 '-bi-2-Naphthol, being an atropoisomer possesses the property of chiral recognition towards appropriate compounds.
  • One of the uses of BINOL in resolution that is known in literature is in Host-Guest complexation.
  • 1,1-binaphthyl derivatives have been successfully incorporated into optically active crown ethers for the enantioselective complexation of amino acid esters and chiral primary ammonium ions (Cram, D. J. Acc. Chem. Res. 1978, 11, 8-14).
  • the chiral 'host' is thus able to discriminate between enantiomeric compounds by the formation of hydrogen bonds between the ether oxygen and the enantiomers.
  • the complex formed with one of the isomers, the 'guest' will be less stable on steric grounds and this forms the basis for its separation.
  • one object of the present invention is to provide a process for the synthesis of Lamivudine which is cost effective, uses less hazardous and easily available reagents, yet achieves good yields with superior quality of product without resorting to column chromatography.
  • a further object of the present invention is to provide an improved process for the synthesis of Lamivudine, by separating the mixture of diastereomers: Cis-[2R,5S], [2S,5R] from Trans-[2R,5R], [2S,5S] and then resolving the Cis isomers using BINOL to obtain (-)- [2R,5S]-Cis-Lamivudine with at least 99% ee.
  • a mixture of dipotassium hydrogen phosphate, water, ethanol and 5-(4-Amino-2-oxo-2H- pyrimidin-l-yl)-[l,3]oxathiolane-2-carboxylic acid (lR,2S,5R)-2-isopropyl-5-methyl- cyclohexyl ester was prepared at 25 to 30°C and cooled the reaction mass to 10 to 15°C to which was added a solution of sodium borohydride (prepared by dissolving sodium borohydride in aqueous sodium hydroxide solution) at 10 to 15°C slowly. The reaction mass was maintained for 4 to 5 hours at 10 to 15°C or till completion of reaction, which was monitored by TLC.
  • the layers were separated and the pH of the organic layer was adjusted to 4 to 4.5 using cone, hydrochloric acid. Then the pH was adjusted to 6.8 to 7.2 using 2M sodium hydroxide solution. The reaction mixture was then stirred for 10 to 15 minutes at 25 to 30°C. Further, the reaction mass was concentrated under vacuum. Water and charcoal was then added to the residue and the mixture was subjected to heating to 70 to 75 °C and maintained for 30 to 60 minutes. The reaction mass was then cooled to 30 to 35°C and the charcoal was filtered out using celite cake. The clear filtrate was then concentrated under vacuum at 40 to 45°C.
  • the aspect of the present invention is to improve the yield of cis ( ⁇ )-Lamivudine by utilizing the chemistry provided below:
  • Another aspect of the present invention provides a method for the separation of (-)-[2R,5S]- Cis-Lamivudine from its (+)-enantiomer using optically pure (S)-2,2'-dihydroxy-l,l '- binaphthyl [(S)-BINOI .J.
  • the process is operationally simple and comprises the following steps:
  • Example 2 Preparation of racemic 5-(4-Amino-2-oxo-2H-pyrimidin-l-yl)-[l ,3]oxathiolane- 2-carboxylic acid (lR,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester. Charged dichloromethane (500 ml) in 1.0 lit 4-neck RBF and 5-Hydroxy [1,3] oxathiolane-2- carboxylic acid 2S-isopropyl-5R-methyl-lR-cyclohexyl ester (125 gm) followed by DMF (6.4 gm).
  • reaction mixture upto 5-10°C and thionyl chloride (61.2 gm) was added by dropping funnel. Stirred the mass for 30 min and raise the temp upto 25-30°C. Monitor the progress of reaction by TLC. After consumption of starting materials distill out solvent atmospherically. To remove the traces of thionyl apply vacuum. Charged fresh DCM (125 ml) into concentrated residue. In another 2.0 lit round bottom flask charged cytosine (48.22 gm), HMDS (54.12 gm) and TMSCl (22.76 gm) and heated reaction mass upto 110-120°C, till clear solution appears.
  • Example 4 Preparation of (-)-l-(2R-Cis)-4-amino-l- [(2-hydroxymethyl)-l ,3-oxathiolan-5- yl]-2(lH)-pyrimidin-2-one- (5)-Binol Co-Crystal.
  • Example 5 Preparation of 4-amino-l- [(2R, 5S)-2-(hydroxymethyl)-l ,3-oxathiolan-5-yl]- 1 ,2-dihydropyrimidin-2-one; (Lamivudine).
  • Example 6 Preparation of 4-amino-l- [(2R, 5S)-2-(hydroxymethyl)-l ,3-oxathiolan-5-yl]- 1 ,2-dihydropyrimidin-2-one; (Lamivudine).
  • S BINOL Cocrystal (20g) in ethyl acetate (100ml) and D.M. water (100ml) at RT.
  • Cone. Hydrochloric acid (4 to 5 ml) was added to the mixture gradually and stirred (pH of the mixture was between about 3 to 4) for an hour and allowed the layers to settle, separated the layers.
  • Aqueous layer was washed with fresh ethyl acetate to remove S(-) BINOL completely. pH of the solution was adjusted to about 7 using 10% sodium hydroxide solution. The solution was then passed though activated resin 225-H column. The column was then washed with purified water, thereafter with 15% aqueous ammonia solution.
  • Cis (-) 99.94 %
  • Cis (-) 99.95%

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production amélioré de lamivudine. Cette invention se rapporte à un procédé pour préparer une (-)-[2R, 5S]-4-amino-1-[2- (hydroxyméthyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidin-2-one sensiblement pure d'un point de vue énantiomérique, qui présente la formule (I), à partir de glyoxylate de L-menthyle. L'invention concerne en outre un procédé pour préparer une (+)-1- (2R/S-Cis)-4-amino-1-[(2-hydroxyméthyl)-1,3-oxathiolan-5-y1]-2(1H)-pyrimidin-2-one de formule (XII), à partir de glyoxylate de L-menthyle.
PCT/IB2011/001013 2010-05-14 2011-05-12 Procédé de production amélioré de lamivudine WO2011141805A2 (fr)

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IN535KO2010 2010-05-14
IN535/KOL/2010 2010-05-14

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WO2011141805A2 true WO2011141805A2 (fr) 2011-11-17
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116199679A (zh) * 2022-12-23 2023-06-02 吉斯凯(苏州)制药有限公司 一种拉米夫定的工业化制备方法

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US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5248776A (en) 1990-12-05 1993-09-28 University Of Georgia Research Foundation, Inc. Process for enantiomerically pure β-L-1,3-oxathiolane nucleosides
US5728575A (en) 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US5756706A (en) 1991-05-21 1998-05-26 Biochem Pharma Inc. Processes for the diastereoselective synthesis of nucleoside analogues
CN1223262A (zh) 1998-12-28 1999-07-21 中国科学院成都有机化学研究所 光学纯的苯并咪唑类抗消化性溃疡药物的包结拆分制备法
US6175008B1 (en) 1988-04-11 2001-01-16 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US6600044B2 (en) 2001-06-18 2003-07-29 Brantford Chemicals Inc. Process for recovery of the desired cis-1,3-oxathiolane nucleosides from their undesired trans-isomers
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
US6939965B2 (en) 1998-08-12 2005-09-06 Gilead Sciences, Inc. Process of manufacture of 1,3-oxathiolane nucleosides using titanium trichloride mono-isopropoxide
WO2006096954A1 (fr) 2005-03-14 2006-09-21 Shire Biochem Inc. Procedes de preparation du cis-2-hydroxymethyl-4-(cytosin-1’-yl)-1,3-oxathiolane optiquement actif ou de sels de celui-ci acceptables sur le plan pharmaceutique
WO2008053496A2 (fr) 2006-10-30 2008-05-08 Lupin Limited Procédé amélioré de fabrication de lamivudine

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US6175008B1 (en) 1988-04-11 2001-01-16 Biochem Pharma Inc. Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
US5047407A (en) 1989-02-08 1991-09-10 Iaf Biochem International, Inc. 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties
US5204466A (en) 1990-02-01 1993-04-20 Emory University Method and compositions for the synthesis of bch-189 and related compounds
US5728575A (en) 1990-02-01 1998-03-17 Emory University Method of resolution of 1,3-oxathiolane nucleoside enantiomers
US6703396B1 (en) 1990-02-01 2004-03-09 Emory University Method of resolution and antiviral activity of 1,3-oxathiolane nuclesoside enantiomers
US5248776A (en) 1990-12-05 1993-09-28 University Of Georgia Research Foundation, Inc. Process for enantiomerically pure β-L-1,3-oxathiolane nucleosides
US5756706A (en) 1991-05-21 1998-05-26 Biochem Pharma Inc. Processes for the diastereoselective synthesis of nucleoside analogues
US6939965B2 (en) 1998-08-12 2005-09-06 Gilead Sciences, Inc. Process of manufacture of 1,3-oxathiolane nucleosides using titanium trichloride mono-isopropoxide
CN1223262A (zh) 1998-12-28 1999-07-21 中国科学院成都有机化学研究所 光学纯的苯并咪唑类抗消化性溃疡药物的包结拆分制备法
US6600044B2 (en) 2001-06-18 2003-07-29 Brantford Chemicals Inc. Process for recovery of the desired cis-1,3-oxathiolane nucleosides from their undesired trans-isomers
WO2006096954A1 (fr) 2005-03-14 2006-09-21 Shire Biochem Inc. Procedes de preparation du cis-2-hydroxymethyl-4-(cytosin-1’-yl)-1,3-oxathiolane optiquement actif ou de sels de celui-ci acceptables sur le plan pharmaceutique
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BRUNEL, CHEM. REV., vol. 105, 2005, pages 857 - 897
CRAM, D. J. ET AL., J. ORG. CHEM., vol. 42, 1977, pages 4173 - 4184
CRAM, D. J., ACC. CHEM. RES., vol. 11, 1978, pages 8 - 14
GOODYEAR ET AL.: "Practical enantioselective synthesis of lamivudine (3TC™) via a dyanamic kinetic resolution", TETRAHEDRON LETTER, vol. 46, 2005, pages 8535 - 8538

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116199679A (zh) * 2022-12-23 2023-06-02 吉斯凯(苏州)制药有限公司 一种拉米夫定的工业化制备方法

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