WO2013143481A1 - Procédé de synthèse et de préparation du laropiprant et de ses analogues - Google Patents

Procédé de synthèse et de préparation du laropiprant et de ses analogues Download PDF

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Publication number
WO2013143481A1
WO2013143481A1 PCT/CN2013/073363 CN2013073363W WO2013143481A1 WO 2013143481 A1 WO2013143481 A1 WO 2013143481A1 CN 2013073363 W CN2013073363 W CN 2013073363W WO 2013143481 A1 WO2013143481 A1 WO 2013143481A1
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WIPO (PCT)
Prior art keywords
formula
compound
group
alkyl
catalytic hydrogenation
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Application number
PCT/CN2013/073363
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English (en)
Chinese (zh)
Inventor
周益峰
任峰波
李佶
杨·P·彼得
Original Assignee
杨·P·彼得
中国计量学院
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Application filed by 杨·P·彼得, 中国计量学院 filed Critical 杨·P·彼得
Publication of WO2013143481A1 publication Critical patent/WO2013143481A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to the synthesis of active pharmaceutical ingredients of lipid-lowering drugs in the field of medicinal chemistry. Background technique
  • Tredaptive Naacin / Lalo Piran
  • This medicine is used to treat hyperlipidemia, especially mixed hyperlipidemia.
  • Niacin is a lipid regulator and loroxilan is a potent, selective prostaglandin DPI receptor antagonist. Niacin reduces very low density lipoprotein in plasma
  • VLDL low-density lipoprotein
  • LDL low-density lipoprotein
  • apoB apolipoprotein B
  • Lp(a) triglyceride
  • HDL high-density lipoprotein
  • apoA-I The level of apolipoprotein AI
  • Lalopiram inhibits PGD2-mediated facial flushing, a common side effect of taking niacin.
  • Lalopiram has no effect on lipid levels and does not affect the action of niacin on lipids.
  • Lalo Piran its structural formula (Formula X//, chemical name:
  • the method of US2005222428 comprises (E)-2-(4-(4-chlorobenzyl)-7-fluoro-5-(indolyl)-1,2-dihydrocyclopenta[b]indole -3(4H)-Pyridyl)acetic acid provides optically pure lopoliram by asymmetric catalysis.
  • the catalysts used are chiral phosphorus ligands and metal ruthenium compounds. Although the preparation method has good atomic economy for producing no disintegrated waste, the reaction needs to be carried out under strict anhydrous anaerobic and high pressure, and the chiral ligand and the metal ruthenium compound used are relatively expensive, so Not practical. Summary of the invention
  • the inventors have surprisingly discovered that the monolithic catalyst, Raney Ni, is hydrogenated, and by resolution, the recrystallization of the cartridge can be carried out to optically pure rallopram.
  • the invention therefore proposes an improved process for the preparation of rallopram comprising hydrogenation of a compound of formula X Preparation of a compound of formula XI
  • One embodiment of the invention is the preferred catalysis using Raney nickel as the catalytic hydrogenation step Further, another embodiment of the invention is the use of an optically active reagent to efficiently isolate the highly optically active R-enantiomer.
  • this invention provides a) a catalytic hydrogenation of a compound of formula I
  • X is halogen
  • R1 is C1 to C4 alkyl, halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -
  • R 2 H, CI to C4 alkyl, unsubstituted benzyl , or substituted benzyl (substituted
  • the group may be an alkyl group of CI to C4, OH, OR 4 , (R 4 may be an alkyl group of CI to C4), halogen, 4- ⁇ 0 2 , 4-amino group, or 4-trifluorodecyl group; 3 may be hydrogen or a C1 to C4 alkyl group.
  • the preferred catalyst is Raney nickel or Pd/C. From the viewpoint of reaction rate and product purity, Raney nickel is more preferable.
  • the preferred ratio of catalyst to starting material is between 5% and 40%, more preferably between 10% and 20%.
  • the hydrogenation step is preferably carried out in a solvent, and optional solvents include tetrahydrofuran, 2-mercaptotetrahydrofuran, decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, butyl Ketone, pentanone, 1,4-dioxane, water, dinonyl amide, and dimethyl sulfoxide.
  • solvents include tetrahydrofuran, 2-mercaptotetrahydrofuran, decyl alcohol, ethanol, propanol, isopropanol, n-butanol, isobutanol, tert-butanol, acetone, butyl Ketone, pentanone, 1,4-dioxane, water, dinonyl amide, and dimethyl sulfoxide.
  • Y may be any of the following: tetradecyl hydrazine (TMG), 1,8-diazabicyclo [5.4.0] undecane-7-ene (DBU), 1,4-diaza a ring [2.2.2] octane (DABCO), potassium t-butoxide (t-BuOK), sodium t-butoxide (t-BuONa), potassium hydroxide, sodium hydroxide, etc., preferably tetradecyl hydrazine or 1, A salt of 8-diazabicyclo[5.4.0]undec-7-ene and formula I.
  • TMG tetradecyl hydrazine
  • DBU 1,8-diazabicyclo [5.4.0] undecane-7-ene
  • DBU 1,4-diaza a ring [2.2.2] octane
  • t-BuOK potassium t-butoxide
  • t-BuONa sodium t-butoxide
  • the temperature of the hydrogenation reaction is 5 to 189 ° C, preferably 40 to 55 ° C; the pressure is 0.1 Mpa to 10 Mpa, preferably 1.8 to 2.5 Mpa.
  • X is a halogen
  • R1 is a C1 to C4 alkyl group, a halogen, CH 3 S0 2 - or CH 3 CH 2 S0 2 -
  • R 2 H, a CI to C4 alkyl group, an unsubstituted benzyl group, Or a substituted benzyl group (the substituent may be a C1 to C4 alkyl group, OH, OR 4 (R 4 may be a C1 to C4 alkyl group), Halogen, 4-N0 2 , 4-amino group, or 4-trifluorodecyl);
  • R 3 may be hydrogen or a C1 to C4 alkyl group.
  • This process is a compound of formula II
  • the optical resolving agent is particularly preferably S- ⁇ -phenethylamine from the viewpoints of resolution and cost.
  • the molar ratio of a suitable resolving agent to the compound of formula II is between 0.3 and 3.0, preferably between 0.5 and 1.5.
  • the solvent used in the resolution of the compound of formula II is one of the following: decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, Dichlorodecane, ethyl acetate, acetone, 1,4-dioxane, nonyl tert-butyl ether, DMF, DMSO, water or any mixed solvent between these solvents.
  • the temperature at the time of splitting is 0 to 189 ° C, preferably 15 to 78 ° C.
  • the time is from 30 minutes to 12 hours, preferably from 1 to 4 hours.
  • the compound obtained according to the procedure of the invention has an optical purity of not less than 75%.
  • the optically active separation may also include a recrystallization step of the compound of Formula III.
  • the solvent used in the recrystallization is decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, isobutanol, tetrahydrofuran, 2-mercaptotetrahydrofuran, toluene, dichlorodecane, acetic acid Ester, acetone, 1,4-dioxane, nonyl tert-butyl ether, n-hexane, n-heptane, cyclohexane, petroleum ether or a mixed solvent of these solvents.
  • optically pure lorololine can be obtained without using an expensive metal ruthenium and a chiral catalyst ligand, without forming a chiral complex to complete asymmetric hydrogenation, and without harsh reaction conditions.
  • EtOAc EtOAc
  • EtOAc EtOAc
  • the organic phase is dried and dried to give an off-white solid (2-(4-(4-chlorobenzyl)-7-fluoro-1,2,3,4-tetrahydro-5-(sulfonyl)cyclopentadiene And [b] ⁇ -3-yl) acetic acid, 2-(4-(4-chlorobenzyl)-7-f uoro-l,2,3,4-tetrahydro-5-(methylsulfonyl)cyclopen ta[b]indol -3-yl)acetic acid ) (9.3g, 92.5%).
  • both Raney nickel and Pd/C can be used for catalytic hydrogenation. Since Raney nickel does not remove chlorine from the substrate during catalytic hydrogenation, the purity of the product is higher than Pd/C. In addition, Raney nickel has a faster reaction rate than Pd/C, so that Raney nickel is more preferable in practical use.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de synthèse et de préparation, ledit procédé comprenant : a) l'hydrogénation catalytique d'un composé de formule I ou d'un sel pharmaceutiquement acceptable de celui-ci pour synthétiser un composé de formule II ; b) effectuer une résolution optique du composé de formule II pour obtenir un composé de formule III. La présente invention a aussi trait à un procédé de préparation d'un composé optiquement pur de formule III.
PCT/CN2013/073363 2012-03-28 2013-03-28 Procédé de synthèse et de préparation du laropiprant et de ses analogues WO2013143481A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201210085602.2A CN102659664B (zh) 2012-03-28 2012-03-28 合成分离拉洛皮兰及其类似物的方法
CN201210085602.2 2012-03-28

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WO2013143481A1 true WO2013143481A1 (fr) 2013-10-03

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CN (1) CN102659664B (fr)
WO (1) WO2013143481A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011094008A1 (fr) * 2010-01-27 2011-08-04 Arena Pharmaceuticals, Inc. Procédés de préparation d'acide (r)-2-(7-(4-cyclopentyl-3-(trifluorométhyl)benzyloxy)-1,2,3,4-tétrahydrocyclopenta]indol-3-yl) acétique et de ses sels

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR038136A1 (es) * 2002-01-24 2004-12-29 Merck Frosst Canada Inc Cicloalcanindoles con sustitucion con fluor composiciones que contienen estos compuestos y metodos de tratamiento
AU2005230897B2 (en) * 2004-04-02 2011-03-03 Merck Sharp & Dohme Corp. Asymmetric hydrogenation process useful for the preparation of cycloalkanoindole derivatives
CA2598273A1 (fr) * 2005-02-17 2006-08-24 Merck & Co., Inc. Methode de traitement de l'atherosclerose, de dyslipidemies et de troubles lies

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011094008A1 (fr) * 2010-01-27 2011-08-04 Arena Pharmaceuticals, Inc. Procédés de préparation d'acide (r)-2-(7-(4-cyclopentyl-3-(trifluorométhyl)benzyloxy)-1,2,3,4-tétrahydrocyclopenta]indol-3-yl) acétique et de ses sels

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAVID, M.T. ET AL.: "On the Mechanism of an Asymmetric a, beta-Unsaturated Carboxylic Acid Hydrogenation: Application to the Synthesis of a PGD2 Receptor Antagonist", JOURNAL OF AMERICAN CHEMICAL SOCIETY, vol. 128, no. 51, 6 December 2006 (2006-12-06), pages 17063 - 17073 *
LIU, WENTAO ET AL.: "Improvement on Synthesis Process of Mitiglinide Calcium", FOOD AND DRUG, vol. 11, no. 11, 10 November 2009 (2009-11-10), pages 21 - 23 *

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CN102659664B (zh) 2015-01-21
CN102659664A (zh) 2012-09-12

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