EP0876381A1 - Ifosfamide, analogues de ladite substance et leur preparation - Google Patents

Ifosfamide, analogues de ladite substance et leur preparation

Info

Publication number
EP0876381A1
EP0876381A1 EP96942509A EP96942509A EP0876381A1 EP 0876381 A1 EP0876381 A1 EP 0876381A1 EP 96942509 A EP96942509 A EP 96942509A EP 96942509 A EP96942509 A EP 96942509A EP 0876381 A1 EP0876381 A1 EP 0876381A1
Authority
EP
European Patent Office
Prior art keywords
compound
reaction
optically
compound according
formula
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.)
Pending
Application number
EP96942509A
Other languages
German (de)
English (en)
Inventor
Joseph John Chiroscience Limited BRENNAN
William Paul Armstrong
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.)
Darwin Discovery Ltd
Original Assignee
Darwin Discovery 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
Priority claimed from GBGB9525891.9A external-priority patent/GB9525891D0/en
Priority claimed from GBGB9602519.2A external-priority patent/GB9602519D0/en
Application filed by Darwin Discovery Ltd filed Critical Darwin Discovery Ltd
Publication of EP0876381A1 publication Critical patent/EP0876381A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/06—Phosphorus compounds without P—C bonds
    • C07F9/062—Organo-phosphoranes without P-C bonds
    • C07F9/065—Phosphoranes containing the structure P=N-
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
    • C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
    • C07F9/65842—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring
    • C07F9/65846—Cyclic amide derivatives of acids of phosphorus, in which one nitrogen atom belongs to the ring the phosphorus atom being part of a six-membered ring which may be condensed with another ring system

Definitions

  • This invention relates to processes for the preparation of ifosfamide and analogues thereof, and to the purified compounds themselves.
  • R ⁇ R 2 and R 3 are chloroalkyl groups, are potent anti-cancer drugs.
  • WO-A-9600075 and WO-A-9600076 disclose additional therapeutic benefit by the use of non-racemic ifosfamide.
  • WO-A-9624600 discloses a synthesis utilising borane generated in situ, sodium borohydride and cone, sulphuric acid.
  • the diborane process is reportedly low-yielding and inconsistent. From a process scale-up perspective, it is uneconomical.
  • Panckiewicz et al, JACS (1979) 101 :7712 disclose a synthesis of optically- enriched ifosfamide and similar agents. This process has the problem that the chiral auxiliary, used in a stoichiometric amount, is necessarily destroyed in the process. This is undesirable, from a cost perspective. Summary of the Invention
  • This impurity can be removed, but 2-3 crystallisations are required to give ifosfamide in greater than 99.9% purity.
  • the level of dechloro impurity is a consequence of the length of exposure of the phosphoramidate and/or the product to sodium borohydride.
  • ifosfamide and its analogues can be prepared in a form containing less than 0.5 % , preferably less than 0.2% , and most preferably less than 0.1 % , by weight of the dechloro impurity.
  • pregeneration of borane using sodium borohydride and an acidic reagent, prior to contact with the substrate, is a more efficient system for the conversion of compounds of formula I, wherein R' is COCH 2 Cl, and also of compounds where R 2 is COCH 2 Cl.
  • the acidic reagent may either be a Lewis acid (e.g. BFj.OEt;) or a Bronsted acid (e.g. CF 3 COOH or H 2 SO 4 ).
  • a second process aspect of the present invention is based on the discovery that novel trichloroimino-phosporanes, derived from chiral amines, undergo cyclisation reactions with 3-amino-l -propanol and N-alkylated derivatives thereof, with useful levels of diastereoselectivity. T e resultant products can then be converted to, say, optically-enriched ifosfamide, with recovery of the chiral amine.
  • the system In the first novel process, the system generates borane in ethereal solvent at temperatures less than 10°C. This reducing system is then preferably used by being syphoned into an ethereal solution of the phosphoramidate amide to be reduced.
  • This simple procedure involving a new mode of addition, represents significant advantages over the prior art because the dechloro impurity is reduced sufficiendy that multiple crystallisations are not required.
  • novel optically-enriched trihaloiminophosphoranes used in the second process of the invention may be prepared by the Kirsanov reaction; see, for example, Kirsanov, Zh. Obshch. Khi . (1952) 22:269, and Johnston, in Ylides and Imines of Phosphorus, Ch. 13, pub. Wiley, New York (1993).
  • Kirsanov reaction see, for example, Kirsanov, Zh. Obshch. Khi . (1952) 22:269, and Johnston, in Ylides and Imines of Phosphorus, Ch. 13, pub. Wiley, New York (1993).
  • R*-NH 2 is a chiral amine (e.g. 1-phenethylamine) or a chiral sulphonamide (e.g.
  • 10-camphorsulphon- amide gives optically-enriched trichloroiminophosphoranes.
  • These compounds can be considered as chiral phosphorus oxychloride equivalents, and are useful intermediates for the preparation of the cytotoxic oxazaphosphorinanes such as ifosfamide and cyclophosphamide.
  • reaction of the trichloroimino-phosphorane 1 with N-(2- chloroethyl)-3-amino-l -propanol gives the key intermediate 2 for the synthesis of ifosfamide.
  • reaction of 1 with 3-amino-l -propanol gives the key intermediate in the synthesis of cyclophosphamide.
  • Such conversions are synthetically useful since cyclisation products such as 2 are formed with appreciable levels of diastereoselectivity.
  • Subsequent reaction of intermediate 2 with 2- chloroethylamine, followed by hydrolysis of the auxiliary gives optically-enriched ifosfamide.
  • any suitable base may be readily chosen by one of ordinary skill in the art.
  • Examples are trialkylamines, N,N-disubstituted anilines and heterocyclic compounds which are basic, for example pyridine or imidazole.
  • any suitable solvent may be chosen by one of ordinary skill in the art. Examples are alkanes, aromatic hydrocarbons (e.g. toluene, xylene, etc), chlorinated solvents (such as dichloromethan), ethers and esters.
  • Example 1 illustrates the invention.
  • Example 3 (5)-( ⁇ -Methylbenzyl)iminotrichlorophosphorane
  • Example 5 3-Benzyl-2-[N-(15 -10-camphorsulfonylimino]-2-chlorotetrahydro-2H- 1,3,2-oxazophosphorinane (R p S p -diastereomeric mixture)
  • a mechanically-stirred solution of the product of Example 4 (10.0 g, 27.2 mmol) in dry toluene (150 ml) at -I0°C, under nitrogen, was added a mixture of ⁇ - benzyl-3-aminopropanol (4.5 g, 27.2 mmol) and triethylamine over 30 min.
  • the reaction mixture was stirred vigorously and allowed to warm to room temperature over 4 h.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)

Abstract

Composé de formule (I) dans laquelle R1 et R2 sont chacun (CH¿2?)mX, R?3¿ est H, chaque X est Cl ou Br et m est 2 ou 3, en combinaison avec moins de 0,5 % en poids du composé correspondant dans lequel R1 est (CH¿2?)mH. Ces composés peuvent être préparés par (i) réaction d'un acide de Bronsted ou d'un acide de Lewis avec NaBH4 dans un solvant organique et (ii) par ajout de la solution qui en résulte à une solution d'un composé correspondant, R?1 ou R2¿ étant l'un CO(CH¿2?)nX et l'autre CO(CH2)nX ou (CH2)mX, n étant égal à m-1. Lesdits composés peuvent également être préparés, sous une forme optiquement enrichie, à partir d'un trihalo-iminophosphorane optiquement enrichi de formule R*N = Phal3, dans laquelle NR* est une fraction chirale pouvant être dérivée d'une amine chirale ou d'un sulphonamide chiral de formule R*NH2, qui peut constituer un cycle avec HO(CH2)3NHR.
EP96942509A 1995-12-19 1996-12-19 Ifosfamide, analogues de ladite substance et leur preparation Pending EP0876381A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
GBGB9525891.9A GB9525891D0 (en) 1995-12-19 1995-12-19 Therapeutic agents and their preparation
GB9525891 1995-12-19
GB9602519 1996-02-08
GBGB9602519.2A GB9602519D0 (en) 1996-02-08 1996-02-08 Cyclisation
PCT/GB1996/003157 WO1997022614A1 (fr) 1995-12-19 1996-12-19 Ifosfamide, analogues de ladite substance et leur preparation

Publications (1)

Publication Number Publication Date
EP0876381A1 true EP0876381A1 (fr) 1998-11-11

Family

ID=26308323

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96942509A Pending EP0876381A1 (fr) 1995-12-19 1996-12-19 Ifosfamide, analogues de ladite substance et leur preparation

Country Status (3)

Country Link
EP (1) EP0876381A1 (fr)
AU (1) AU1164597A (fr)
WO (1) WO1997022614A1 (fr)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7205404B1 (en) 1999-03-05 2007-04-17 Metabasis Therapeutics, Inc. Phosphorus-containing prodrugs
MXPA01008937A (es) * 1999-03-05 2004-04-05 Metabasis Therapeutics Inc Nuevos profarmacos que contienen fosforo.
JP2017512183A (ja) 2014-02-13 2017-05-18 リガンド・ファーマシューティカルズ・インコーポレイテッド プロドラッグ化合物およびそれらの使用
JP2017520545A (ja) 2014-07-02 2017-07-27 リガンド・ファーマシューティカルズ・インコーポレイテッド プロドラッグ化合物およびそれらの使用
CA2997762A1 (fr) 2015-09-10 2017-03-16 Becton, Dickinson And Company Analogues de cyclophosphamides destines a etre utilises en tant qu'immunogenes et conjugues de dosage pour un dosage immunologique de cyclophosphamide et d'ifosfamide
CA3075773A1 (fr) 2017-09-21 2019-03-28 Becton, Dickinson And Company Kit de collecte de contaminants dangereux et analyse rapide
EP3737676B1 (fr) 2018-01-09 2024-03-06 Ligand Pharmaceuticals, Inc. Composés acétal et leurs utilisations thérapeutiques
AU2020215639A1 (en) 2019-01-28 2021-08-05 Becton, Dickinson And Company Hazardous contaminant collection device with integrated swab and test device
CN114965770B (zh) * 2022-05-24 2023-03-28 江苏海洋大学 一种异环磷酰胺原料药中起始物料、杂质d、杂质f的检测方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PL100390B1 (pl) * 1975-10-06 1978-09-30 Sposob wytwarzania 2-tlenku-2-/bis/2-chloroetylo/-amino/-1-/okso-3-aza-2-fosfacykloheksanu/cyklofosfamidu/o czynnosci optycznej
PL150330B1 (en) * 1987-06-13 1990-05-31 Method of obtaining derivatives of 1,3,2-oxazaphosphorinate
GB9412618D0 (en) * 1994-06-23 1994-08-10 Chiroscience Ltd Cytotoxic agent and its use
GB9412689D0 (en) * 1994-06-23 1994-08-10 Chiroscience Ltd Cytotoxic agent and its use
DE4425070A1 (de) * 1994-07-15 1996-01-18 Degussa Verfahren zur Herstellung optisch aktiver l-substituierter 2-(Aminomethyl)pyrrolidine
GB9502637D0 (en) * 1995-02-08 1995-03-29 Chiroscience Ltd Reduction

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9722614A1 *

Also Published As

Publication number Publication date
AU1164597A (en) 1997-07-14
WO1997022614A1 (fr) 1997-06-26

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