WO2001055097A1 - Preparation of nitrogen mustard derivatives - Google Patents
Preparation of nitrogen mustard derivatives Download PDFInfo
- Publication number
- WO2001055097A1 WO2001055097A1 PCT/GB2001/000218 GB0100218W WO0155097A1 WO 2001055097 A1 WO2001055097 A1 WO 2001055097A1 GB 0100218 W GB0100218 W GB 0100218W WO 0155097 A1 WO0155097 A1 WO 0155097A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- compound
- acid
- chloro
- reaction
- Prior art date
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
- C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/54—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to an improved synthesis of 5-(N-[(S)-N- ⁇ N,N-bis(2- chloroethyl)amino ⁇ phenoxycarbonyl)- ⁇ -glutamyl]amino)isophthalic acid (also named ZD9063P herein), a prodrug used in Antibody Directed Enzyme Prodrug Therapy (ADEPT), a targeted cytotoxic cancer therapy.
- ADEPT Antibody Directed Enzyme Prodrug Therapy
- cytotoxic drugs are limited by their general toxicity and a highly desirable aim is the targeted delivery of the active cytotoxic agent.
- a novel approach under development is the dosing of the patient with an antibody / enzyme complex which binds specifically at the site of the tumour.
- Subsequent treatment with a synthetic compound, the Prodrug which bears a masked cytotoxic entity and has been specifically designed to be cleaved by the enzyme, delivers the cytotoxic agent, the Drug, at the site of the tumour.
- ZD9063P The known synthesis of ZD9063P involved a using a nitrogen mustard, N,N-bis(2- chloroethyl)aminophenol, and being the actual cytotoxic agent and would pose very significant containment problems if used on a manufacturing scale (see US 5,405,990; Example 46). Therefore there was a need for an improved synthetic route, particularly a route more suited to large scale manufacture.
- the present invention is based on the discovery of a new, efficient and convergent route to ZD9063P and structurally related prodrugs by converting a readily available starting material to a key intermediate suitable for both chemical and enantiomeric purification.
- the success of the synthetic approach arose from the use of a catalyst to obtain regiospecific opening of an anhydride ring, incorporation of a reaction at an elevated pressure to avoid a solvent exchange and the development of an improved practical procedure for the deprotection of t-butyl esters.
- R 1 and R 2 independently represent chloro, bromo, iodo or OSO 2 Me;
- R 3 represents COOH or a salt of carboxylic acid ;
- n is 1,2, 3 or 4;
- R 4 represents a protected form of COOH, tetrazol-5-yl or SO 3 H; and in which the method comprises reacting a compound of Formula II
- R 1 and R 2 are preferably chloro.
- R 3 is preferably an alphamethylbenzylamine salt of carboxylic acid.
- R 4 is preferably a protected form of COOH, especially COOBn.
- n is 2 and especially a 3,5 dicarboxylic acid in protected form is preferred.
- the asterisked chiral carbon in Formula I has S configuration. 15
- the reaction is performed in the presence of a highly nucleophilic but weakly basic amine.
- the amine is DMAP (4-dimethylaminopyridine) or 4- pyrrolidinopyridine, especially DMAP. This has the advantage of regioselective opening of the cyclic anhydride ring.
- the reaction is performed at a temperature of -50° to 30°, more preferably - 20 40 to 0°, more preferably -40 to -10° and especially at about -35 to -25°.
- Preferred temperature ranges have the advantage of giving improved yield of desired reaction products.
- R 1 and R 2 are chloro
- R 3 is an alphamethylbenzylamine salt of carboxylic acid
- (R 4 ) n represents a benzyl protected 3,5-dicarboxylic acid.
- the compound is in crystalline form.
- Another aspect of the invention comprises a compound of Formula I
- R 1 and R 2 are chloro
- R 3 is an alphamethylbenzylamine salt of carboxylic acid
- (R 4 ) n represents a benzyl protected 3,5-dicarboxylic acid and the asterisked chiral carbon in
- Formula I has S configuration.
- the compound is in crystalline form wherein said alphamethylbenzylamine is in enantiomerically pure (R)- or (S)- configuration.
- the crystalline form of this compound gives the advantage of ease of handling during manufacture, particularly at large scale.
- Scheme 2 shows options for key transformations in which the bold arrows show the route developed with key intermediates and the dotted arrows show alternative route options with possible intermediates
- NMR spectra were run at 270 MHz (proton) and at 67.7 MHz (carbon) in d 6 -DMSO or d 6 -DMSO/TFA solution and are reported in parts per million down field from internal TMS.
- HPLC analyses were conducted using a HiChromeTM RPB column, solvent system acetonitrile/water/TFA 640/360/1 (v/v/v), flow rate 1 or 2 mL/min and detection at 254 ⁇
- DCC DCC
- DCCI dicyclohexylcarbodiimide
- j_j-toluenesulphonate salt of the dibenzylester of 5-aminoisophthalic acid in the presence of an excess of a tertiary amine.
- Two products were seen in the reactions involving triethylamine and 4-methylmorpholine whereas, completely unexpectedly, a single product resulted when DMAP was used as the base.
- the compounds were isolated and shown to be 11 and 12, the regioisomers from the opening of the anhydride ring system. v " (Scheme 3)
- the single compound formed in the DMAP catalysed reaction corresponded to the more polar regioisomer 12 which possesses the ZD9063P substitution pattern.
- This key observation means that the basic carbon skeleton of ZD9063P can be assembled without the need for an expensive, differentially protected, glutamic acid derivative.
- the solvent used must be compatible with the strongly acidic reaction conditions required for removal of the t-butyl groups as the isolation of 10 as a crystalline solid is not easy and it is more convenient to proceed directly with the deprotection stage.
- both 10 and 14 contain the nitrogen mustard system, albeit in a less activated form, and handling of such intermediates would cause concern on a production scale.
- the problem of the slow rate of the displacement reaction at reflux in methylene chloride solution (40°C) was overcome, without introducing a change to a higher boiling solvent, by operating the reaction under pressure. Complete exchange occurs after 18 hours at 75°C and the pressure generated in the system, about 2 BarG, is entirely consistent with operation in a standard production plant.
- the de-esterification of 10 could be readily achieved by the extended reaction of trifluoroacetic acid but a significant practical problem encountered was the complete removal of the excess trifluoroacetic acid prior to the activation step.
- a large excess of trifluoroacetic acid is required to displace the equilibrium set up between its t-butyl ester and the corresponding t-butyl ester of the substrate.
- Complete reaction is normally only achieved by multiple treatments removing volatile substances by distillation, a time-consuming procedure for large scale operation.
- the t-butyl ester of methanesulphonic acid is unstable and so the corresponding equilibrium can be displaced by the formation of isobutylene which escapes from the system.
- the solution was 5 cooled to -50°C and a solution of DMAP (48.8 g, 0.40 mol) in methylene chloride 200 mL) followed by a solution of the dibenzylester of 5-aminoisophthalic acid (144 g, 0.40 mol) in methylene chloride(800 mL), the temperature being maintained throughout at -50°C. Periodic analysis of the reaction mixture showed it to be essentially complete after 3h and it was allowed to reach ambient temperature over night. Water (2.5 L) was added, the mixture
- the salt 16 (20. Og, 22.9 mmol) was dissolved in acetonitrile (700 mL) at reflux and cooled to 20°C. The crystalline product was filtered, washed with acetonitrile (100 mL) and
- the above salt 16 (5.0g, 5.74 mmol) was partitioned between ethyl acetate (150 mL) and an aqueous solution of citric acid (100 mL of 20% w/v ). The resulting organic phase was re- washed with an aqueous solution of citric acid (50 mL of 20% w/v ) followed by water (3 x 50 mL). The organic phase was filtered through Whatman IPSTM filter paper and the solvent removed under reduced pressure to give the desired product 9 as an amorphous foam. Yield 4.0g, 5.34 mmol (93% yield)
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US10/169,344 US6737541B2 (en) | 2000-01-26 | 2001-01-13 | Preparation of nitrogen mustard derivatives |
EP01901285A EP1255729A1 (en) | 2000-01-26 | 2001-01-23 | Preparation of nitrogen mustard derivatives |
JP2001555039A JP2003520845A (en) | 2000-01-26 | 2001-01-23 | Preparation of nitrogen mustard derivatives |
AU2001226944A AU2001226944A1 (en) | 2000-01-26 | 2001-01-23 | Preparation of nitrogen mustard derivatives |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0001653.5A GB0001653D0 (en) | 2000-01-26 | 2000-01-26 | Chemical compound |
GB0001653.5 | 2000-01-26 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2001055097A1 true WO2001055097A1 (en) | 2001-08-02 |
Family
ID=9884279
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB2001/000218 WO2001055097A1 (en) | 2000-01-26 | 2001-01-23 | Preparation of nitrogen mustard derivatives |
Country Status (6)
Country | Link |
---|---|
US (1) | US6737541B2 (en) |
EP (1) | EP1255729A1 (en) |
JP (1) | JP2003520845A (en) |
AU (1) | AU2001226944A1 (en) |
GB (1) | GB0001653D0 (en) |
WO (1) | WO2001055097A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0102239D0 (en) * | 2001-01-29 | 2001-03-14 | Cancer Res Ventures Ltd | Methods of chemical synthisis |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5405990A (en) * | 1992-07-23 | 1995-04-11 | Zeneca Limited | Chemical compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9709421D0 (en) * | 1997-05-10 | 1997-07-02 | Zeneca Ltd | Chemical compounds |
GB9910077D0 (en) * | 1999-05-01 | 1999-06-30 | Univ Manchester | Chemical compounds |
-
2000
- 2000-01-26 GB GBGB0001653.5A patent/GB0001653D0/en not_active Ceased
-
2001
- 2001-01-13 US US10/169,344 patent/US6737541B2/en not_active Expired - Fee Related
- 2001-01-23 JP JP2001555039A patent/JP2003520845A/en active Pending
- 2001-01-23 AU AU2001226944A patent/AU2001226944A1/en not_active Abandoned
- 2001-01-23 WO PCT/GB2001/000218 patent/WO2001055097A1/en not_active Application Discontinuation
- 2001-01-23 EP EP01901285A patent/EP1255729A1/en not_active Withdrawn
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5405990A (en) * | 1992-07-23 | 1995-04-11 | Zeneca Limited | Chemical compounds |
Non-Patent Citations (1)
Title |
---|
MARTIN: "Preparation of the key intermediate in a novel synthesis of ZD9063P", ORGANIC PROCESS RESEARCH & DEVELOPPMENT, vol. 4, - 2000, pages 259 - 263, XP000985382 * |
Also Published As
Publication number | Publication date |
---|---|
US6737541B2 (en) | 2004-05-18 |
US20030162990A1 (en) | 2003-08-28 |
AU2001226944A1 (en) | 2001-08-07 |
EP1255729A1 (en) | 2002-11-13 |
JP2003520845A (en) | 2003-07-08 |
GB0001653D0 (en) | 2000-03-15 |
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