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WO2012146085A1 - Intermédiaire utilisable en vue de la synthèse de médicaments de type prostaglandine et procédé de préparation de celui-ci - Google Patents

Intermédiaire utilisable en vue de la synthèse de médicaments de type prostaglandine et procédé de préparation de celui-ci Download PDF

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Publication number
WO2012146085A1
WO2012146085A1 PCT/CN2012/071839 CN2012071839W WO2012146085A1 WO 2012146085 A1 WO2012146085 A1 WO 2012146085A1 CN 2012071839 W CN2012071839 W CN 2012071839W WO 2012146085 A1 WO2012146085 A1 WO 2012146085A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
hydrogen
hydroxy protecting
formula
protecting group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CN2012/071839
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English (en)
Chinese (zh)
Inventor
张富尧
江宏
金青青
孙飘扬
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Unitris Biopharma Co Ltd
Original Assignee
Unitris Biopharma Co Ltd
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 Unitris Biopharma Co Ltd filed Critical Unitris Biopharma Co Ltd
Publication of WO2012146085A1 publication Critical patent/WO2012146085A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being unsaturated and containing rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0041—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention relates to an intermediate for the synthesis of prostaglandins and a process for the preparation thereof. Background technique
  • Prostaglandins are a class of fatty acid derivatives having 20 carbon atoms. Prostaglandins regulate a variety of physiological effects in the body at hormone levels, and regulate blood pressure, smooth muscle contraction, gastric juice secretion, and platelet aggregation. Among them, prostaglandin F-type derivatives are clinically used to treat open-angle glaucoma and ocular hypertension to reduce intraocular hypertension in patients.
  • Prostaglandins are trace components widely found in human and animal tissues. They are extremely low in content, and the prostaglandin F-type derivatives have excellent therapeutic effects on glaucoma and intraocular hypertension. Natural prostaglandins cannot be satisfied. Clinical medication needs. To this end, scientists have been working on the full synthesis of prostaglandin derivatives, and so far have achieved fruitful results.
  • the present invention relates to an intermediate for the synthesis of prostaglandins and a process for the preparation thereof.
  • the intermediate Through the intermediate, the synthesis step of the prostaglandins can be shortened, thereby improving the synthesis efficiency of prostaglandins such as bemelaline, travoprost, and latanoprost.
  • RR 2 and R 3 are each independently hydrogen or a hydroxy protecting group, preferably, RR 2 and R 3 are each independently selected from hydrogen, THP, -C (0) R 6 , or -SiR 7 R 8 R 9, wherein R 6, R 7, R 8 and R 9 are each independently a straight-chain or branched d- 10 alkyl, C 3 - 8 cyclic alkyl, or.
  • a substituted or unsubstituted aryl group; R 4 and R 5 are each independently hydrogen, amino, methoxy, C.
  • R 4 and R 5 are independently selected from hydrogen, methyl, ethyl, propyl, butyl, phenyl, amine or methoxy; or R 4 , R 5 together with the nitrogen atom form a 5-8 membered heterocyclic ring, preferably a five-membered ring and a six-membered ring, more preferably a five-membered ring.
  • R 4 and R 5 cannot be an amino group or a methoxy group at the same time.
  • R 1 is THP; R 2 is THP; R 3 is TIPS; R 4 is ethyl; R 5 is hydrogen; or, R 1 is THP; R 2 is THP; R 3 is TIPS; R is hydrogen; and R 5 is ethyl.
  • the object of the present invention is to provide a preparation method
  • X in the formula III is a halogen
  • X may be selected from Cl, Br or I, preferably Br
  • Ar is C 6 - i.
  • the non-substituted or substituted aryl group is preferably a phenyl group.
  • the intermediate la is prepared as described in Formula I by hydroxy protection, or hydroxy deprotection, or a hydroxy protecting group, as needed.
  • R 1 and R 2 are a hydroxy protecting group and are -8 fluorenyl, wherein the method comprises the steps of:
  • the intermediate VIII is deprotected to give beimiprost.
  • the hydroxy protecting group of the present invention is a suitable group for hydroxy protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th . Ed. TW Greene & P. GM. Wuts) Hydroxy protecting group.
  • the hydroxy protecting group may be a (d- 8 alkyl or aryl) 3 silane group, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyl Phenylsilyl or the like; may be d- 8 alkyl or substituted alkyl, for example: methyl, tert-butyl, allyl, benzyl, methoxymethyl, ethoxyethyl, 2-tetrahydro Pyridyl (THP) or the like; may be (d- 8 alkyl or aryl) acyl group, for example: formyl group, acetyl group, benzoyl group, etc.; may be (d- 6 alkyl or C 6 - 1() Aryl)sulfonyl; may also be ( -6 alkoxy or aryloxy)carbonyl.
  • the substituted aryl group according to the invention means that the aromatic ring is substituted by one or more residues, for example selected from the group consisting of: halogen, hydroxy, cyano, nitro, amine, trifluoromethyl, d- 8 alkyl , - 8 alkoxy, C 2 - 8 alkanoyl group, C 6 - i. Aryl, allyl and the like.
  • residues for example selected from the group consisting of: halogen, hydroxy, cyano, nitro, amine, trifluoromethyl, d- 8 alkyl , - 8 alkoxy, C 2 - 8 alkanoyl group, C 6 - i. Aryl, allyl and the like.
  • step 1 :
  • Triethylamine (2.5 mL) was added to a solution of Compound IV (1.0 g, purchased from Shanghai Julong Pharmaceutical Research and Development Co., Ltd.) in dichloromethane (50 mL) under a nitrogen atmosphere.
  • the reaction system was cooled to -78 ° C, and a solution of triisopropylsilyl trifluoromethanesulfonate (2.9 g) in dichloromethane (10 mL) was added. After two hours, the cold bath was removed and the reaction system was stirred at 20 ° C for 30 minutes. The reaction system was concentrated under reduced pressure, and the residue was purified by column chromatography to afford compound Vaa.
  • Wig ⁇ : ⁇ carried by: by m- ⁇ ⁇ mm ⁇ m. ⁇ 3 ⁇ 4 ⁇ m ⁇ mm
  • a compound Iap was synthesized in a similar manner to the synthesis of compound Iaa.
  • step 1 :
  • the 2849 process was prepared) and a mixture of lithium chloride (200 mg) in acetonitrile (10 mL) was cooled to -15 °C. Diisopropylethylamine (0.3 mL) was added to the reaction system, and the mixture was stirred at -15 ° C for 30 minutes. The compound obtained in step 1 A solution of Via in acetonitrile (3 mL) was added to the reaction system. The reaction system was stirred at -15 ° C for 30 minutes and then gradually returned to room temperature and stirred overnight. Diethyl ether (50 mL) was added to the mixture. The residue was purified by column chromatography to give Compound VIIa.
  • the compound Villa obtained in the step 3 was dissolved in methanol (5 mL), and p-toluenesulfonic acid monohydrate (500 mg) was added. The system was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography to afford bimatoprost.

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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

La présente invention concerne un intermédiaire (de formule développée I) utilisable en vue de la synthèse de médicaments de type prostaglandine et un procédé de préparation de celui-ci. Ledit intermédiaire est utilisé en vue de la synthèse de médicaments de type prostaglandine, tels que le bimatoprost, le travoprost, le latanoprost, etc. L'intermédiaire est préparé par une réaction de Wittig conduisant à l'obtention d'un hémiacétal, cela étant suivi d'une dérivatisation de ce dernier.
PCT/CN2012/071839 2011-04-29 2012-03-02 Intermédiaire utilisable en vue de la synthèse de médicaments de type prostaglandine et procédé de préparation de celui-ci Ceased WO2012146085A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110113844.3A CN102757459B (zh) 2011-04-29 2011-04-29 用于合成前列腺素类药物的中间体及其制备方法
CN201110113844.3 2011-04-29

Publications (1)

Publication Number Publication Date
WO2012146085A1 true WO2012146085A1 (fr) 2012-11-01

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Country Status (3)

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CN (1) CN102757459B (fr)
TW (1) TWI532711B (fr)
WO (1) WO2012146085A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020034181A1 (fr) * 2018-08-17 2020-02-20 中国农业大学 Composé de sel de triphényl-phosphonium quaternaire, son procédé de préparation et son application
US11332433B2 (en) * 2020-07-24 2022-05-17 Chirogate International Inc. Process for the preparation of latanoprostene bunod and intermediate thereof and compositions comprising the same
CN116332992B (zh) * 2023-03-29 2024-10-01 厦门大学 季磷盐酰肼类寡糖质谱衍生化试剂的合成及应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3954741A (en) * 1972-06-07 1976-05-04 Pfizer Inc. N-substituted prostaglandin carboxamides
US6248783B1 (en) * 2000-09-20 2001-06-19 Allergan Sales, Inc. Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents
WO2010097672A1 (fr) * 2009-02-27 2010-09-02 Sifavitor S.R.L. Procédé pour la préparation de dérivés de prostaglandine
WO2010109476A2 (fr) * 2009-01-19 2010-09-30 Matrix Laboratories Ltd Procédé amélioré de préparation de prostaglandines et de leurs analogues

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000511530A (ja) * 1996-05-28 2000-09-05 アラーガン・セイルズ・インコーポレイテッド 高眼圧処置用の医薬としてのシクロペンタン（エン）酸，２―アルケニル誘導体
CN1639117A (zh) * 2002-03-01 2005-07-13 阿勒根公司 前列腺酰胺的制备

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3954741A (en) * 1972-06-07 1976-05-04 Pfizer Inc. N-substituted prostaglandin carboxamides
US6248783B1 (en) * 2000-09-20 2001-06-19 Allergan Sales, Inc. Cyclopentane 1-hydroxy alkyl or alkenyl-2-one or 2-hydroxy derivatives as therapeutic agents
WO2010109476A2 (fr) * 2009-01-19 2010-09-30 Matrix Laboratories Ltd Procédé amélioré de préparation de prostaglandines et de leurs analogues
WO2010097672A1 (fr) * 2009-02-27 2010-09-02 Sifavitor S.R.L. Procédé pour la préparation de dérivés de prostaglandine

Also Published As

Publication number Publication date
TW201309636A (zh) 2013-03-01
CN102757459A (zh) 2012-10-31
TWI532711B (zh) 2016-05-11
CN102757459B (zh) 2016-01-27

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