WO2001087816A1 - Procede et intermediaires pour preparer du latanoprost - Google Patents

Procede et intermediaires pour preparer du latanoprost Download PDF

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Publication number
WO2001087816A1
WO2001087816A1 PCT/US2001/011758 US0111758W WO0187816A1 WO 2001087816 A1 WO2001087816 A1 WO 2001087816A1 US 0111758 W US0111758 W US 0111758W WO 0187816 A1 WO0187816 A1 WO 0187816A1
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Prior art keywords
process according
compound
phenyl
reaction mixture
mixture
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PCT/US2001/011758
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English (en)
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Kevin E. Henegar
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Pharmacia & Upjohn Company
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Priority to AU2001261019A priority Critical patent/AU2001261019A1/en
Publication of WO2001087816A1 publication Critical patent/WO2001087816A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/48—Unsaturated compounds containing hydroxy or O-metal groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings

Definitions

  • the present invention is a process, including intermediates, to produce latanoprost, a pharmaceutical agent useful in treating ophthalmic conditions.
  • R 3 is -H and R 4 is -0-CH 3 and (3) R 3 and R 4 are taken together to form a five mem ⁇ r ring attached to the 3- and 4- positions of the phenyl ring where the second ring from the R 3 - position to the R - position is -CH-CH-O- and where is a single or double bond and pharmaceutically acceptable salts thereof.
  • R 3 , R 4 and are as defined above and where X ⁇ ⁇ is phenyl or phenyl substituted with one thru three -C 4 alkyl, one thru three C 1 -C 4 alkoxy, one phenyl, one thru three -F, -CI, -Br and -I and compound (XNIJJ)
  • Xn is defined above which comprises:
  • step (2) (2) contacting the reaction mixture of step (1) with a boron complexing agent.
  • Latanoprost (XVI) is known, see US Patent 5,422,368, Example 2.
  • the process of the present invention is set fort in CHARTs A and B and in
  • the enone (LU), as well as the other compounds of the invention, has three possibilities for the substitution on the phenyl ring of the bottom side chain. These are where R 3 and R 4 are: ( 1 ) R 3 is -H and R 4 is -H which gives phenyl,
  • R 3 is -H and R is -O-CH 3 which give 4-methoxyphenyl and
  • R 3 and R are taken together to form a five member ring attached to the 3- and 4- positions of the phenyl ring where the second ring from the R 3 - position to the R 4 - position is -CH-CH-0-; where is a single or double bond and where Xn is phenyl or phenyl substituted with one thru three C ⁇ -C 4 alkyl, one thru three C ⁇ -C alkoxy, one phenyl, one thru three -F, -CI and -Br. It is preferred that R 3 and P ⁇ are both -H. It is preferred that X u is phenyl.
  • enone (in) must be protected at the C-l 1 position as is known to those skilled in the art. It is preferred that for the protecting group -CO-X] i , Xn is phenyl or phenyl substituted with one thru threeC ⁇ -C 4 alkyl, one thru three -C 4 alkoxy, one phenyl, one thru three -F, -CI and -Br.
  • Xn is phenyl or phenyl substituted with one thru threeC ⁇ -C 4 alkyl, one thru three -C 4 alkoxy, one phenyl, one thru three -F, -CI and -Br.
  • (+)- chlorodiisopinocampheylborane reduction of the , ⁇ -unsaturated enone (ILT) the reduction can be performed in any chemically inert solvent that adequately dissolves the enone (DT). Suitable solvents include THF, methylene chloride and DME and mixtures thereof.
  • MTBE and toluene alone are not operable.
  • a cosolvent such as hexane, heptane, isooctane or similar hydrocarbons is not necessary but is preferred. This is important since (+)-chlorodiisopinocampheylborane is available commercially as a solution in these solvents.
  • MTBE and toluene can be used as the cosolvent.
  • the nature of the solvent has virtually no effect with regard to the 15(S)/15(R) ratio in the product.
  • (+)-chlorodiisopinocampheylborane it is more preferred that at least 3.5 equivalents of (+)-chlorodiisopinocampheylborane be used. With fewer equivalents the reaction is incomplete; there is no improvement in rate or selectivity with more equivalents.
  • the (+)-chlorodiisopinocampheylborane is contacted with the ⁇ , ⁇ -unsaturated enone (HI)
  • the temperature should be maintained less than 0°. It is preferred that the temperature be maintained at less than -20°; it is more preferred that the temperature be maintained in the range of from about -35 to about - 45°. Above
  • a boron complexing agent which is selected from the group consisting of water, -C ⁇ alcohols and diols, ethanolamine, diethanolamine, triethanolamine and mixtures thereof. It is preferred that the boron complexing agent be group be water and diethanolamine; it is more preferred that the complexing agent be water.
  • step (2) the reaction mixture of step (1) is contacted with a readily reducable aldehyde or ketone.
  • the readily reducable aldehyde or ketone is selected from the group consisting of -C ⁇ aldehydes and ketones and benzaldehyde; it is more preferred that the readily reducable aldehyde or ketone is acetone or methylethylketone.
  • a base When adding the boron complexing agent it is preferred that a base also be added.
  • the base is selected from the group consisting of carbonate, bicarbonate, mono- di- and tri- Ci-C ⁇ alkylamines, pyridine and pyridine substituted with C ⁇ -C 4 alkyl; it is more preferred that the base be bicarbonate or carbonate. It is even more preferred that the base be bicarbonate. Either prior to, or after, step (2), it is preferred to warm the reaction mixture to about 15 to about 25°. It is preferred that the reaction mixture is warmed from about 1 to about 3 hr.
  • Latanoprost (XVI) is known to be useful as an ophthalmic pharmaceutical agent, see US Patents 5,296,504 and 5,422,368.
  • International Publication WO98/30900 discloses that latanoprost (XVI) is useful in treating another ophthalmic condition, myopia.
  • R 3 is -H and R 4 is -0-CH 3 and where R 3 and R are taken together to form a five member ring attached to the 3- and 4- positions of the phenyl ring where the second ring from the R 3 - position to the R*- position is -CH-CH-O- are also known to be useful pharmaceutical agents. Those two agents can also be prepared by the process of the present invention.
  • Latanoprost (XVI) refers to (5Z)-(9CI)-7-[(lR,2R,3R,5S)-3,5-dihydroxy-2- [(3R)-3-hydroxy-5- ⁇ henylpentyl]cyclopentyl]-5-heptenoic acid 1-methylethyl ester. It is also known as 17-phenyl-18,19,20-trinor-PF 2 ⁇ isopropyl ester.
  • MTBE refers to methyl t-butyl ether.
  • TLC refers to thin-layer chromatography.
  • THF refers to tetrahydrofuran.
  • THP refers to tetrahydropyranyl.
  • Saline refers to an aqueous saturated sodium chloride solution. Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
  • CMR C-13 magnetic resonance spectroscopy
  • chemical shifts are reported in ppm ( ⁇ ) downfield from TMS.
  • NMR nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from tetramethylsilane.
  • TMS refers to trimethylsilyl
  • - ⁇ refers to phenyl (C 6 H 5 ).
  • MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit.
  • [M + H] + refers to the positive ion of a parent plus a hydrogen atom.
  • El refers to electron impact.
  • CI refers to chemical ionization.
  • FAB refers to fast atom bombardment.
  • HRMS refers to high resolution mass spectrometry.
  • Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability. psi refers to pounds per square inch.
  • the ratios of solvents used are volume/volume (v/v).
  • the ratio of the solid to the solvent is weight/volume (wt/v).
  • DEB AL refers to diisobutyl aluminum hydride.
  • THAM refers to tris(hydroxymethyl)aminomethane.
  • Potassium t-butoxide (20% w/v, 7.6 mL) solution in THF is cooled to 0°.
  • the butoxide solution is added to the slurry dropwis ' e maintaining the temperature at 0 to 5° and then stirring for 1 hour.
  • the resulting ylide solution is then cooled to -10°.
  • the organic phase is separated and concentrated under reduced pressure to a volume of ⁇ 100 mL.
  • Ethyl acetate 200 mL is added and the mixture is concentrated to a volume of 50 mL.
  • MTBE 100 mL is added and the mixture is allowed to cool to 20- 25deg for 1 hour. The mixture is then cooled to -20° for 2 hours.
  • (+)- chlorodiisopinocampheylborane (2M in hexane; 43 mL) is added to the enone (HI) mixture maintaining the internal temperature at less than -35°.
  • the mixtue is stirred at -38 to -42° for 18 hours.
  • acetone (12.7 mL) is added and the mixture is allowed to warm to 20-25° and stirred for two hours.
  • MTBE 100 mL
  • a solution of sodium bicarbonate (10 g) in water (150 mL) is added.
  • the two phase mixture is stirred for 15 min.
  • the phases are separated and the organic phase is washed with water (100 mL).
  • the organic phase is concentrated under reduced pressure.
  • the mixture is stirred and heated in an 80° oil bath for about 2 hours. When the reaction is complete, the mixture is concentrated under reduced pressure. Water (100 mL) and MTBE (100 mL) are added and the mixture stirred at 20-25° for 15 min. The phases are allowed to separate. The product is in the aqueous phase and the organic phase is removed and discarded. The pH of the aqueous phase is adjusted to 1 to 1.5 by the addition of hydrochloric acid (3 N, about 60 mL are required). The solution is stirred at 20-25°. After 30 min, MTBE (100 mL) is added and the mixture stirred at 20-25° for about 12 hours. The phases are separated and the aqueous phase extracted once with MTBE (50 mL).
  • the MTBE phases are combined and washed with sodium carbonate (1 N, 50 mL).
  • the MTBE mixture is stirred with a solution of potassium hydroxide (2.8 g, 42.5 rnmole) in water (100 mL) for 30 min.
  • the phases are separated and the aqueous phase is added to a slurry of citric acid monohydrate (8.90 g) and ethyl acetate (100 mL) at 20-25deg.
  • the mixture is stirred for 15 min and the phases are separated.
  • the aqueous phase is extracted with ethyl acetate (5 x 50 mL).
  • the combined organic phases are dried over anhydrous sodium sulfate (8.90 g) for 15 min.
  • the ethyl acetate extract is concentrated under reduced pressure to a volume of 100 mL maintaining the internal temperature less than 30°.
  • Ethyl acetate (200 mL) is added and the mixture is again concentrated to a volume of 100 mL.
  • the resulting slurry is stirred at 0-5° for 30 min.
  • the solids are filtered and washed with heptane/ethyl acetate (1/1, 35 mL), then dried on a nitrogen press to give the title compound.
  • DIBAL 1.0 M, 3.78 mL in toluene
  • DIBAL 1.0 M, 3.78 mL in toluene
  • the rnixtue is stirred for 15 minutes after the completion of the addition, then ethyl acetate (0.38 mL) is added.
  • the mixture is poured into a solution of potassium sodium tartarate (lOg in 30 mL of water) and warmed to 20-25°.
  • the two phase mixture is heated to 45° for 1 hr and then cooled.
  • the phases are separated and the organic phase is concentrated.
  • EXAMPLE 8 7-[(lR,2R,3R,5S)-3-(l-Ethoxyethoxy)-5-hydroxy-2-[(3R)-3-(l- ethoxyethoxy)-5-phenyl ⁇ entyl]cyclopentyl-5-heptenoic acid (XH) (3aR,4R,5R,6aS)-5-(l-Ethoxyethoxy)-4-[(3R)-3-(l-ethoxyethoxy)-5- phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol (XI, EXAMPLE 7) is dissolved in dry THF (10 mL) and added to a mixture containing potassium 5- (triphenylphos ⁇ horanylidene)pentaonate (PREPARATION 1) solution at -10° to -5°.
  • PREPARATION 1 potassium 5- (triphenylphos ⁇ horanylidene)pent
  • the resulting mixture is stirred for about 3 hours at less than -5°.
  • Water (30 mL; 0°) is added over 10 minutes, then ethyl acetate (20 mL) and aqueous THAM solution (10 mL) is added .
  • the phases are separated and the organic phase is washed with aqueous THAM solution (15%, 2 x 15 mL).
  • the aqueous phases are combined and washed once with ethyl acetate (15 mL).
  • MTBE 50 mL
  • the organic phase is separated and concentrated under reduced pressure to 20 mL.
  • Acetone (12.3 mL) is added and the solution stirred at 20-25° for 2 hours.
  • MTBE (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) are added and the two-phase mixture is stirred for 5 min.
  • the organic phase is separated and washed once with water (50 mL), then concentrated under reduced pressure.
  • the mixture is stirred at reflux with methanol (75 mL), water ( 7.5 mL) and potassium hydroxide (4.76 g) for 2 hours.
  • the mixture is concentrated under reduced pressure.
  • the concentrate is partitioned between water (75 mL) and MTBE (75 mL).
  • the aqueous phase is separated and extracted with MTBE (2 x 50 mL).
  • the pH of the aqueous phase is adjusted to about 1.2 with hydrochloric acid (3 M) and stirred for 2.5 hours.
  • the mixture is saturated with sodium chloride and then extracted with MTBE (4 x 75 mL).
  • the MTBE mixtures are combined and washed with sodium carbonate solution (1 M, 2 x 50 mL).
  • the sodium carbonate solutions are back extracted with MTBE (2 x 50 mL).
  • the combined MTBE extracts are concentrated to a volume of about 100 mL, then stirred for one hour with a solution of potassium hydroxide (3.29 g) in water (30 mL).
  • the aqueous phase is separated and added to a slurry of anhydrous citric acid (9.68 g) in ethyl acetate (100 mL).
  • the phases are separated and the aqueous phase is extracted with ethyl acetate (4 x 50 mL).
  • the combined ethyl acetate extracts are filtered through anhydrous sodium sulfate (about lOg).
  • the filtrate is concentrated under reduced pressure (30° maximum temperature) to a volume of about 100 mL.
  • Ethyl acetate (100 mL) is added and the mixture is concentrated under reduced pressure (30° maximum temperature) to a volume of about 80 mL.

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

Abstract

L'invention concerne un composé intermédiaire de formule (VI) et ses sels. L'invention concerne en outre un procédé pour préparer des composés intermédiaires de prostaglandine, comprenant (1) la mise en contact d'énones avec (+)-chlorodiisopinocampheylborane en maintenant la température du mélange réactionnel dans une fourchette allant d'environ -50° à environ 0°, et (2) la mise en contact du mélange réactionnel de l'opération (1) avec un agent complexant du bore.
PCT/US2001/011758 2000-05-15 2001-05-09 Procede et intermediaires pour preparer du latanoprost WO2001087816A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001261019A AU2001261019A1 (en) 2000-05-15 2001-05-09 Process and intermediates to prepare latanoprost

Applications Claiming Priority (2)

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US20424200P 2000-05-15 2000-05-15
US60/204,242 2000-05-15

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003008368A1 (fr) * 2001-07-17 2003-01-30 Pharmacia & Upjohn Company Procede et produits intermediaires utilises pour produire du latanoprost
WO2002096898A3 (fr) * 2001-05-24 2003-03-20 Resolution Chemicals Ltd Procede de preparation de prostaglandines et d'analogues de ces dernieres
WO2003037857A2 (fr) * 2001-10-31 2003-05-08 Johnson Matthey Public Limited Company Ameliorations apportees a des prostaglandines et leurs analogues
US6927300B2 (en) 2000-01-27 2005-08-09 Finetech Laboratories Ltd Process for the preparation of Latanoprost
US7157590B2 (en) 2001-05-31 2007-01-02 Finetech Laboratories Ltd. Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives
WO2013026149A1 (fr) * 2011-08-24 2013-02-28 Apotex Pharmachem Inc. Phosphonate de diméthyl-(3,3-difluoro-2,2-dihydroxyheptyle) et ses procédés de préparation
CN105998030A (zh) * 2016-05-17 2016-10-12 温州医科大学 一种前列腺素F2α受体激动剂在制备抑制近视药物上的应用及其使用方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1433971A (en) * 1973-06-28 1976-04-28 Upjohn Co Prostaglandin intermediates
US4346228A (en) * 1975-04-18 1982-08-24 Schering Aktiengesellschaft Novel 11-oxoprostaglandin derivatives
US5422368A (en) * 1988-09-06 1995-06-06 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
WO1997022602A2 (fr) * 1995-12-20 1997-06-26 CHINOIN, Gyógyszer és Vegyészeti PROCEDE POUR LA REDUCTION STEREOSELECTIVE DE CETONES α,β-INSATUREES

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1433971A (en) * 1973-06-28 1976-04-28 Upjohn Co Prostaglandin intermediates
US4346228A (en) * 1975-04-18 1982-08-24 Schering Aktiengesellschaft Novel 11-oxoprostaglandin derivatives
US5422368A (en) * 1988-09-06 1995-06-06 Kabi Pharmacia Ab Prostaglandin derivatives for the treatment of glaucoma or ocular hypertension
WO1997022602A2 (fr) * 1995-12-20 1997-06-26 CHINOIN, Gyógyszer és Vegyészeti PROCEDE POUR LA REDUCTION STEREOSELECTIVE DE CETONES α,β-INSATUREES

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
E.J. COREY ET AL, J. AM. CHEM. SOC., vol. 109, no. 25, 1987, pages 7925 - 7926, XP002177843 *
H.C. BROWN ET AL, J. AM CHEM. SOC., vol. 110, no. 5, 1988, pages 1539 - 1546, XP001024128 *
J. SOON CHA ET AL, BULL. KOREAN CHEM. SOC., vol. 15, no. 12, 1994, pages 1033 - 1034, XP000926360 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6927300B2 (en) 2000-01-27 2005-08-09 Finetech Laboratories Ltd Process for the preparation of Latanoprost
WO2002096898A3 (fr) * 2001-05-24 2003-03-20 Resolution Chemicals Ltd Procede de preparation de prostaglandines et d'analogues de ces dernieres
US7268239B2 (en) 2001-05-24 2007-09-11 Resolution Chemicals Limited Process for the preparation of prostaglandins and analogues thereof
US7157590B2 (en) 2001-05-31 2007-01-02 Finetech Laboratories Ltd. Process for the preparation of 17-phenyl-18,19,20-thinor-pgf 2a and its derivatives
WO2003008368A1 (fr) * 2001-07-17 2003-01-30 Pharmacia & Upjohn Company Procede et produits intermediaires utilises pour produire du latanoprost
US6689901B2 (en) * 2001-07-17 2004-02-10 Pharmacia & Upjohn Company Process and intermediates to prepare latanoprost
WO2003037857A2 (fr) * 2001-10-31 2003-05-08 Johnson Matthey Public Limited Company Ameliorations apportees a des prostaglandines et leurs analogues
WO2003037857A3 (fr) * 2001-10-31 2003-09-12 Johnson Matthey Plc Ameliorations apportees a des prostaglandines et leurs analogues
WO2013026149A1 (fr) * 2011-08-24 2013-02-28 Apotex Pharmachem Inc. Phosphonate de diméthyl-(3,3-difluoro-2,2-dihydroxyheptyle) et ses procédés de préparation
CN105998030A (zh) * 2016-05-17 2016-10-12 温州医科大学 一种前列腺素F2α受体激动剂在制备抑制近视药物上的应用及其使用方法

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