EP1115696A1 - Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine - Google Patents

Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine

Info

Publication number
EP1115696A1
EP1115696A1 EP99947408A EP99947408A EP1115696A1 EP 1115696 A1 EP1115696 A1 EP 1115696A1 EP 99947408 A EP99947408 A EP 99947408A EP 99947408 A EP99947408 A EP 99947408A EP 1115696 A1 EP1115696 A1 EP 1115696A1
Authority
EP
European Patent Office
Prior art keywords
difluoromethyl
ornithine
toluoyl
tartaric acid
water
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.)
Withdrawn
Application number
EP99947408A
Other languages
German (de)
English (en)
Inventor
Thomas Meul
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.)
Lonza AG
Original Assignee
Lonza AG
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 Lonza AG filed Critical Lonza AG
Priority to EP99947408A priority Critical patent/EP1115696A1/fr
Publication of EP1115696A1 publication Critical patent/EP1115696A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine

Definitions

  • the present invention relates to a process for the resolution of racemates of ( ⁇ ) - ⁇ - (difluoromethyl) ornithine of the formula
  • racemate H which must first be prepared from the racemic DL- ⁇ - (difluoromethyl) ornithine monohydrochloride monohydrate via formation of the methyl ester and cyclization with alcoholate.
  • the racemate resolution of the piperidone is described with classic racemate resolution agents such as, for example, with (+) - camphor-10-sulfonic acid or with (+) - or (-) - binaphthylphosphoric acid.
  • the object of the invention was to develop a simpler and improved yield and optical purity access to the desired isomer.
  • the invention therefore relates, according to claim 1, to diastereomeric salts of (+) - or (-) - ⁇ - (difluoromethyl) ornithine of the formula
  • Another object of the invention is the method according to claim 4. Therein, the resolution of ( ⁇ ) - ⁇ - (difluoromethyl) ornithine is carried out with (-) - O, O'-di-p-toluoyl-L-tartaric acid.
  • Suitable water miscible polar organic solvents are e.g. lower aliphatic alcohols, such as methanol or ethanol or acetonitrile.
  • the preferred water-miscible polar organic solvent is acetonitrile.
  • the components are expediently brought together in solution by heating.
  • the desired diastereomer of (-) - ⁇ - (difluoromethyl) ornithine generally crystallizes out with (-) - O, O'-Di-p-toluoyl-L-tartaric acid, while the diastereomer of (+) - ⁇ - (Difluoromethyl) ornithine with (-) - O, O'-Di-p-toluoyl-L-tartaric acid remains in solution.
  • the water / water-miscible polar organic solvent mixture is selected so that the desired diastereomer of (-) - ⁇ - (difluoromethyl) ornithine with (-) - O, O'-Di-p-toluoyl-L-tartaric acid Cooling of the solution crystallized easily and quantitatively.
  • the (-) - ⁇ - (difluoromethyl) ornithine monohydrochloride monohydrate can be obtained in high yield and high optical purity by extraction with a suitable solvent.
  • the (-) - O, O'-di-p-toluoyl-L-tartaric acid can also be recovered from this extraction.
  • the diastereomer of (+) - ⁇ - (difluoromethyl) ornithine with (-) - di-O, O'-p-toluoyl-L-tartaric acid, which is usually in the solution, can also be analogous, for example after evaporation of the solution, by acidification with a mineral acid as (+) - ⁇ - (difluoromethyl) ornithine monohydrochloride monohydrate are released, which can then be obtained by extraction.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

De la (+/-)-α-(difluorométhyl)ornithine est clivée en ses isomères à l'aide d'acide (-)-O,O'-di-p-toluoyl-L-tartrique. Le monohydrate de monohydrochlorure de (+/-)-α-(difluorométhyl)ornithine et en particulier le (-)-isomère sont des inhibiteurs de l'ornithinedécarboxylase et possèdent ainsi de nombreuses actions pharmacologiques.
EP99947408A 1998-09-23 1999-09-22 Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine Withdrawn EP1115696A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP99947408A EP1115696A1 (fr) 1998-09-23 1999-09-22 Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP98117982 1998-09-23
EP98117982 1998-09-23
PCT/EP1999/007060 WO2000017153A1 (fr) 1998-09-23 1999-09-22 PROCEDE DE PREPARATION DE MONOHYDRATE DE MONOHYDROCHLORURE DE (-)-α-(DIFLUOROMETHYL)ORNITHINE
EP99947408A EP1115696A1 (fr) 1998-09-23 1999-09-22 Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine

Publications (1)

Publication Number Publication Date
EP1115696A1 true EP1115696A1 (fr) 2001-07-18

Family

ID=8232678

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99947408A Withdrawn EP1115696A1 (fr) 1998-09-23 1999-09-22 Procede de preparation de monohydrate de monohydrochlorure de (-)-alpha-(difluoromethyl)ornithine

Country Status (16)

Country Link
US (1) US6462229B1 (fr)
EP (1) EP1115696A1 (fr)
JP (1) JP2002526468A (fr)
KR (1) KR20010079913A (fr)
CN (1) CN1319085A (fr)
AU (1) AU764154B2 (fr)
BR (1) BR9914034A (fr)
CA (1) CA2345112A1 (fr)
CZ (1) CZ20011043A3 (fr)
HU (1) HUP0103658A3 (fr)
IL (1) IL142218A0 (fr)
MX (1) MXPA01003032A (fr)
NO (1) NO20011480L (fr)
PL (1) PL195164B1 (fr)
SK (1) SK4092001A3 (fr)
WO (1) WO2000017153A1 (fr)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063141A1 (fr) * 2003-01-16 2004-07-29 Toray Fine Chemicals Co,. Ltd. Procede de recuperation d'acides diacyltartarique optiquement actifs
WO2005021502A1 (fr) * 2003-08-29 2005-03-10 Takeda Pharmaceutical Company Limited Procede de production d'un derive de threo-$g(b)-alkyltryptophane actif optiquement et de son intermediaire
TW201617326A (zh) * 2014-03-06 2016-05-16 Ａｌｐｈｏｒａ研發股份有限公司 （ｓ）－１－（（２ｒ，３ｒ，４ｓ，５ｓ）－５－烯丙－３－甲氧－４－（對甲苯磺醯甲基）四氫呋喃－２－基）－３－氨基丙－２－醇之結晶衍生物
JP2018507910A (ja) * 2015-02-12 2018-03-22 ジ・アリゾナ・ボード・オブ・リージェンツ・オン・ビハーフ・オブ・ジ・ユニバーシティ・オブ・アリゾナ 神経芽細胞腫を治療する方法
CN105660637B (zh) * 2016-01-07 2018-04-24 南京中医药大学 防治当归早薹的药物及其应用

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4309442A (en) * 1977-07-11 1982-01-05 Merrell Toraude Et Compagnie Method for controlling fertility in mammals
US4414141A (en) 1980-11-21 1983-11-08 The Lummus Company Hydrotreating catalyst
US4931557A (en) 1988-10-17 1990-06-05 Eli Lilly And Company Method of resolving cis 3-amino-4-(2-furyl)vinyl)-1-methoxycarbonylmethyl-azetidin-2-one and di-p-toluoyl-tartaric acid salts thereof
EP0871441B1 (fr) * 1996-10-04 2003-08-13 Ilex Oncology, Inc. Dfmo et taxol pour le traitement ou la prevention du cancer du sein
AU5526898A (en) 1996-12-13 1998-07-03 Ilex Oncology, Inc. Isomeric pharmaceutical formulation containing dfmo for the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0017153A1 *

Also Published As

Publication number Publication date
US6462229B1 (en) 2002-10-08
NO20011480L (no) 2001-03-23
PL346900A1 (en) 2002-03-11
HUP0103658A3 (en) 2003-03-28
CZ20011043A3 (cs) 2001-09-12
CN1319085A (zh) 2001-10-24
MXPA01003032A (es) 2002-07-02
BR9914034A (pt) 2001-08-14
SK4092001A3 (en) 2002-06-04
AU6086599A (en) 2000-04-10
WO2000017153A1 (fr) 2000-03-30
HU0103658D0 (en) 2002-02-28
JP2002526468A (ja) 2002-08-20
IL142218A0 (en) 2002-03-10
NO20011480D0 (no) 2001-03-22
CA2345112A1 (fr) 2000-03-30
KR20010079913A (ko) 2001-08-22
PL195164B1 (pl) 2007-08-31
AU764154B2 (en) 2003-08-14
HUP0103658A2 (hu) 2002-12-28

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