[go: up one dir, main page]

WO1994011353A1 - PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES - Google Patents

PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES Download PDF

Info

Publication number
WO1994011353A1
WO1994011353A1 PCT/GB1993/002327 GB9302327W WO9411353A1 WO 1994011353 A1 WO1994011353 A1 WO 1994011353A1 GB 9302327 W GB9302327 W GB 9302327W WO 9411353 A1 WO9411353 A1 WO 9411353A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
process according
cyclisation
acid derivative
Prior art date
Application number
PCT/GB1993/002327
Other languages
English (en)
Inventor
Karl Joseph Hale
Original Assignee
University College London
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 University College London filed Critical University College London
Publication of WO1994011353A1 publication Critical patent/WO1994011353A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members

Definitions

  • This invention relates to the preparation of 3R and 3S-piperazic acid derivatives of formula (1):
  • R represents any group which is not cleavable from the remainder of the molecule by strong base during the preparative reaction, before cyclisation has taken place, and is especially an amino or hydroxyl group, or a chiral auxiliary group, for example a group of any of formulae (2a) to (2v) in Table 1 that is linked via the heteroatom thereof shown.
  • R 1 , R 2 and R 3 in any of these chiral auxiliaries can be any substituent (having due regard to commonsense considerations, such as preserving the stability of the chiral auxiliary group and avoiding groups so enormously bulky as to impede completely the reactions described hereinafter) e.g.
  • X is O, S or Se.
  • the chiral auxiliary can be enantiomeric with any of the structural formulae shown.
  • a and B represent hydrogen or a non-interfering substituent, especially a nitrogen atom - protecting group.
  • a and B can be separate or joined together to form a cyclic group.
  • the monamycins are a family of cyclodepsipeptide antibiotics produced by Streptomyces iamaicensis, 1
  • Azinothricin is a potent antibiotic substance obtained form the culture filtrate of Streptomyces sp. X-14950 2 ; A83586C 3 , Citropeptin 4 , and Variapeptin 5 , are antibiotic substances related to Azinothricin that possess good anti tumour properties.
  • L-156,602 is a competitive C5a antagonist 6 , used for the treatment of allergic and inflammatory diseases such as asthma and rheumatoid arthritis.
  • L-156,373 is a cyclic peptide obtained from the actinomycete Streptomyces siIvensis and is a potent oxytocin/- arginine vasopressin antagonist; it is useful for preventing pre-term labour, and disturbances in water balance 7 .
  • L-156,602 is synthesised via a piperazic acid intermediate and the other compounds mentioned will doubtless also require piperazic acid in their synthesis.
  • 3R-Pip and 3S-Pip are components of a number of synthetic drug molecules that are potent inhibitors of angiotensin converting enzyme (ACE) 8,9 . ACE inhibitors are valuable for the treatment of hypertension and congestive heart failure in man.
  • ACE angiotensin converting enzyme
  • Bicyclic piperazic acids are a particularly important class of ACE inhibitor.
  • One commercially available ACE inhibitor is the bicyclic (3S) - piperazic acid derivative, (lS,9S-9-[(1S-(ethoxycarbonyl)-3-phenylpropylamino]octahydro-10- oxo-6H-pyridazo[1,2-a][1,2]diazepine-1-carboxylic acid
  • 3S-Pip contains a modified 3S-Pip unit and 3S-Pip is a key intermediate for its preparation 8,9 since the present invention can be carried out on the diazacyclic compound 2,3-diaza-6S-C(1S-ethoxycarbonyl-3-phenyl)propylamino]cyclohept- anone of formula (B):
  • the invention includes a direct enantioselective synthesis thereof.
  • 3S-Pip and 3R-Pip have also been found to be potent GABA ( ⁇ -aminobutryric acid) uptake inhibitors and are useful for the treatment of audiogenic seizures 10 .
  • the currently available route for preparing optically active compounds of formula (1) consists of a multistep cycloaddition sequence to provide (3RS)-N 1 -benzyloxycarbonylpiperazic acid 11 .
  • this racemic material is synthesised by Diels-Alder condensation of phthalazinedione with penta-2,4-dienoic acid, hydrolysis of the phthalyl group and selective N 1 -protection with benzyloxycarbonyl chloride and aqueous sodium hydroxide 11 .
  • Racemic (3RS) N 1 -benzyloxycarbonylpiperazic acid is then resolved with (+)- and (-)-ephedrines 12 , to give 3R-Pip and 3S-Pip respectively, after deprotection of the benzyloxyurethane groups with hydrogen bromide in acetic acid.
  • An improved variant of the cycloaddition sequence for preparing (3RS)-N 1 -benzyloxycarbonyl- piperazic acid has since been reported by Adams et al 13 .
  • the process comprises the "alkylation" of valeryl enolates of formula (4) with diazo compounds of formula (5).
  • the valeryl enolates of formula (4) are obtained from compounds of formula (3) by the action of a strong base.
  • R in formulae (3) and (4) is a chiral auxiliary group effective (through its spatial occupation) to cause the "alkylation" (hydrazi nation) to proceed stereoselectively and thereby produce a compound of formula (1) in which one enantiomer is present in excess over the other.
  • Substituents A and B in diazo compounds of formula (5) can be hydrogen, or virtually any which do not interfere with the hydrazination reaction. They may be, in particular, conventional nitrogen atom - protecting groups. These enolates undergo intermolecular nucleophilic addition to compounds of formula (5) to generate N 1 -aza anions which intramolecularly displace a suitable leaving substituent L, preferably an alkyl or aryl sulphonate ester or a chloro, bromo, or iodo substituent. After displacement, cyclic hydrazo derivatives of structure (1) are obtained.
  • chiral auxiliary group R Subsequent removal of the chiral auxiliary group R with any appropriate reagent, usually a base, an acid, a thionucleophile, an amine or a hydroxylamine derivative, or through metal-ion catalysed hydrolysis depending on the nature of R group, affords derivatives of structure (1) where R can be OH, or SH, or NRxRy or N-OR, wherein Rx and Ry represent hydrogen, alkyl of 1-6 carbon atoms, hydroxyalkyl, or aralkyl such as benzyl or 2-phenylethyl.
  • the A or B substituents are nitrogen atom-protecting groups, the appropriate N-deprotection method will afford the free hydrazi no group.
  • the absolute configuration of the products at each stage of the processes is determined by the identity of the chiral auxiliary group R that is employed. The order of executing these last two steps may be reversed. What is novel and inventive herein comprises any one or more of the following aspects:
  • the chiral valeryl enolate containing a leaving group at C-5 of the valeryl chain can be generated without undergoing intramolecular carbocyclisation, and this enolate will preferentially undergo intermolecular addition to substituted azo derivatives followed by intramolecular nucleophilic displacement of the leaving group to give 3R and 3S-Pip derivatives, depending on the choice of chiral auxiliary.
  • the R group in compound (3) can be any which survives trs action of the strong base without being cleaved from the remainder of the molecule.
  • the strong base used to convert compound (3) to its enolate (4) can be any known for such a purpose, preferably a non-nucleophilic,
  • sterically-hindered base having a lithium, sodium, potassium or magnesium counter-cation.
  • Lithium diisopropyl amide and lithium tetramethyl piperidide are preferred examples.
  • R is preferably a chiral auxiliary group effective to produce an excess of the (3S)-enantiomer in the final product, since this enantioner Is required for the synthesis of "Cilazapril". It is also preferred that it be cleavable from the rest of the molecule, after cyclisation, under basic or acidic conditions. However, if stereoselectivity is not required, R could be a hydroxy, thiol, or amino group protected to prevent self-cyclisation of the valeric acid derivative.
  • the substituents can be the same or different and are preferably alkyl or hydroxyalkyl of 1 to 6 carbon atoms or aralkyl such as benzyl or 2-phenylethyl.
  • the hydrazination step is preferably carried out at a temperature within the range -100°C to 0°C, and, where possible, directly on the reaction mixture produced by the enolisation. It is possible, at least in some embodiments, to isolate an uncyclised hydrazino intermediate. Indeed, this is very desirable when using the titanium chloride/tertiary amine enolisation procedure, referred to below.
  • the temperature is preferably allowed to rise, e.g. to 30°C and most preferably 15 to 30°C (room temperature).
  • the cyclisation which is a nucleophilic displacement reaction, is greatly helped by use of a dipolar aprotic solvent: this is believed to solvate the counter-cation of the strong base and thereby facilitate the cyclisation.
  • alkyl groups may be e.g. hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl etc., usually of 1 to 12 C-atoms, substituted or unsubstituted.
  • R 1 and R 2 could together form a cyclic group.
  • Preferred alkyl groups are methyl and ethyl and preferred aralkyl groups benzyl and 2-phenylethyl.
  • This can be accomplished by deprotonating (4R)-phenylmethyl)-2-oxazolidinone (6) with a strong base, for example n-butyl lithium or lithium diisopropyl amide at low temperature, e.g.
  • the A and B groups are preferably the same, to avoid formation of a mixture of different products (although such a mixture is tolerable if treated appropriately to produce the same piperazic acid derivative).
  • Each of A and B can be hydrogen or any non-interfering substituent such as an aliphatic, especially alkyl groups, 1 - 12 carbon atoms, aromatic, especially phenyl, araliphatic, especially benzyl or 2-phenylethyl, cycloaliphatic, heteroaliphatic, especially alkoxycarbonyl or aralkoxycarbonyl etc.
  • a and B are conventional N-atom protecting groups and/or electron- withdrawing substituents, especially t-butoxycarbonyl ("Boc"), benzyloxycarbonyl, trichloroethoxycarbonyl, trimethylsilylethoxy- carbonyl, or fluorenyloxycarbonyl, for ease of removal.
  • a and B can together form a ring, which could be e.g. 5, 6 or 7 - membered and substituted or unsubstituted.
  • a and B have up to 12 C-atoms when separate substi tuents or when joi ned together.
  • Microanalytical data further corroborated the identity of the product as (4R)-3-(5-bromovaleryl)-4-(phenylmethyl)-2-oxazolidinone, indicating an empirical formula of C 15 H 18 NO 3 Br.
  • DBAD di-tert-butylazo- dicarboxylate
  • An alternative Evans' procedure uses titanium tetrachloride followed by addition of diisopropylethyl amine, at 0°C to -10°C, generating a titanium enolate.
  • the titanium enolate is reacted with di-tert-butylazodicarboxylate pre-cooled to only -10°C to 0°C.
  • the hydrazinated bromide intermediate is isolated and reacted with sodium hydride in an anhydrous solvent at room temperature or below, e.g. 0 to 30°C.
  • the second step of this process is to remove the chiral auxiliary from the hydrazo product.
  • the oxazolidinone was detached by dissolving the starting material in THF and treating this solution with a suspension of lithium hydroxide in H 2 O at -5°C for 15 h.
  • Methyl (3S)-N 1 -(2,4-dinitro- phenyl) hexahydropyridazine-3-carboxylate has also been synthesised by an identical route starting from (4S)-(phenyl- methyl)-2-oxazolidinone.
  • the ee of methyl (3S)-N 1 -(2,4-dinitro- phenyl)hexahydropyridazine-3-carboxylate was determined to be greater than 96% by chiral HPLC analysis.
  • Methyl (3S)-N 1 -(2,4- dinitrophenyl)piperazate had a retention time of 18 min. and the (3R) 27 mins. on the above analytical column when 75:25 hexane/isopropanol was employed as the eluant.
  • Example 1 step (d) was repeated on the 3S-N,N'-bis- (t-butoxycarbonyl)hexahydropyridazine-3-carboxylie-acid (8.57 g), on 10 x larger scale.
  • the analytically purified sample of the title compound had [ ⁇ ] D +18.7° ( c 0.48, MeOH); 400 MHz 1 H NMR (D 2 O): ⁇ 3.87 (m, 1H),3.30 (m, 1H), 3.19 (m, 1H) 2.17 (m.1H), 1.90 (m, 3H); FAB Mass Spectrum: (M+1) 131; Anal. Calcd for C 7 H 11 F 3 N 2 O 4: C, 34.43: H, 4,54; N, 11.48. Found: C, 34.51; H, 4.55; N, 11.49.
  • This example illustrates an alternative procedure to replace step (b) of Example 1 or 2.
  • the procedure is described for the S isomer, but could be applied to the R isomer.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un procédé de préparation des dérivés de l'acide pipérazique de la formule (1). Dans cette formule, R représente un groupe amino, hydroxyle ou thiol, ou un groupe organique comme défini ci-dessous et chacun d'entre A et B représente un atome d'hydrogène ou un substituant qui n'interfère pas, A et B sont séparés ou réunis ensemble directement en formant avec les atomes d'azote un cycle appartenant à un système de cycles condensés. Ces dérivés sont obtenus sous la forme de base libre ou d'un sel d'addition avec un acide. Le procédé en question consiste: (a) à faire réagir un dérivé de l'acide valérique de la formule (3) (dans laquelle R représente un groupe amino, hydroxyle ou thiol, protégés pour empêcher la cyclisation interne de l'acide valérique respectivement en lactame, lactone ou thiolactone ou encore un acide organique que l'on ne peut pas détacher du reste de la molécule dans cette étape de réaction et L représente un groupe partant qui est éliminé dans l'étape de cyclisation définie ci-dessus), avec une forte base dans des conditions d'énolisation pour produire un énolate; (b) à former un dérivé hydrazinique de l'énolate par réaction avec un composé diazo de la formule (5) dans laquelle A et B sont tels que définis ci-dessus; c) à effectuer une cyclisation du produit de l'hydrazination de l'étape précédente; d) éventuellement, à effectuer un clivage du groupe R du produit cyclisé; et e) éventuellement à remplacer les substituants A et B par des atomes d'hydrogène, les étapes (d) et (e) étant effectuées dans n'importe quel ordre ou simultanément.
PCT/GB1993/002327 1992-11-12 1993-11-12 PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES WO1994011353A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9223739.5 1992-11-12
GB929223739A GB9223739D0 (en) 1992-11-12 1992-11-12 Process for the preparation of (3r) and (3s) piperazic acid derivatives

Publications (1)

Publication Number Publication Date
WO1994011353A1 true WO1994011353A1 (fr) 1994-05-26

Family

ID=10724977

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB1993/002327 WO1994011353A1 (fr) 1992-11-12 1993-11-12 PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES

Country Status (2)

Country Link
GB (1) GB9223739D0 (fr)
WO (1) WO1994011353A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010979A1 (fr) * 1998-08-19 2000-03-02 Vertex Pharmaceuticals Incorporated Procede de preparation de l'acide piperazique; et sa transformation en un noyau bicyclique contenant des liaisons n,n acyle, utiles pour la fabrication d'inhibiteurs de la caspase
WO2001056997A1 (fr) * 2000-02-04 2001-08-09 Lonza Ag Procede de preparation de derives d'acide piperazique de ce dernier
US6559304B1 (en) 1998-08-19 2003-05-06 Vertex Pharmaceuticals Incorporated Method for synthesizing caspase inhibitors
US6703500B2 (en) 1998-08-19 2004-03-09 Vertex Pharmaceuticals, Incorporated Method of preparing bicyclic intermediates from piperazic acid or an ester thereof useful in the manufacture of caspase inhibitors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0042100A1 (fr) * 1980-06-13 1981-12-23 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de la pyrazolopyridazine, intermédiaires et leur procédés de préparation, et médicaments les contenant

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0042100A1 (fr) * 1980-06-13 1981-12-23 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés de la pyrazolopyridazine, intermédiaires et leur procédés de préparation, et médicaments les contenant

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMISTRY LETTERS no. 11, 27 August 1991, pages 1953 - 1956 NAKAMURA 'Useful synthesis os (3s)-2,3,4,, 5-Tetrahydropyridazine-3-carboxylic Acid and its Dehydrotetrapeptide Derivatives' Schemes 1 and 2 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000010979A1 (fr) * 1998-08-19 2000-03-02 Vertex Pharmaceuticals Incorporated Procede de preparation de l'acide piperazique; et sa transformation en un noyau bicyclique contenant des liaisons n,n acyle, utiles pour la fabrication d'inhibiteurs de la caspase
US6177565B1 (en) 1998-08-19 2001-01-23 Vertex Pharmaceuticals Inc. Process for synthesizing piperazic acid
US6559304B1 (en) 1998-08-19 2003-05-06 Vertex Pharmaceuticals Incorporated Method for synthesizing caspase inhibitors
US6703500B2 (en) 1998-08-19 2004-03-09 Vertex Pharmaceuticals, Incorporated Method of preparing bicyclic intermediates from piperazic acid or an ester thereof useful in the manufacture of caspase inhibitors
WO2001056997A1 (fr) * 2000-02-04 2001-08-09 Lonza Ag Procede de preparation de derives d'acide piperazique de ce dernier

Also Published As

Publication number Publication date
GB9223739D0 (en) 1992-12-23

Similar Documents

Publication Publication Date Title
TWI413638B (zh) 新穎方法
US4349480A (en) Process for preparing 1-(3-bromo-2-alkylpropanoyl-L-proline derivatives
JP2010525007A (ja) Ｈｃｖプロテアーゼ阻害剤中間体の製造方法
HK1007140A1 (en) Process and intermediates for beta-lactam antibiotics
RU2730006C1 (ru) Способ получения 5r-[(бензилокси)амино]пиперидин-2s-карбоновой кислоты или её производного
KR950013767B1 (ko) 키랄성 아제티디논 화합물 및 이의 제조방법
WO2022232948A1 (fr) Procédés de préparation des énantiomères de la 3,4-méthylènedioxyméthamphétamine (mdma) et de la n-méthyl-1,3-benzodioxolylbutanamine (mbdb)
FR2945533A1 (fr) Derives de cyclopenta°c!pyrrolyl-alkylcarbamates d'heterocycles a 5 chainons, leur preparation et leur application en therapeutique
WO1994011353A1 (fr) PROCEDE DE PREPARATION DES DERIVES DES ACIDES (3R)- et (3S)-PIPERAZIQUES
JPS6335571A (ja) 抗生物質の中間体
US3887606A (en) Process for the preparation of DL-phenylglycine esters
US5618949A (en) Process for synthesis of chiral cis- and trans-3-amino-4-substituted pyrrolidine compounds
US6951946B2 (en) Large scale synthesis of 1,2,4- and 1,3,4-oxadiazole carboxylates
EP2473492B1 (fr) Procédé de préparation de (1s,4r)-2-oxa-3-azabicyclo[2.2.1]hept-5-enes
WO2019062027A1 (fr) Procédé de préparation écologique d'un ester d'acide l-pyroglutamique n-substitué
US4652665A (en) α-Chlorinated carbonates
EP0670305B1 (fr) Procede de production d'un derive de 3-amino-2-hydroxy-1-propanol
US7064199B2 (en) Process for the manufacture of 3-amino-pyrrolidine derivatives
US4014915A (en) Oxime carbonates
EP0536512B1 (fr) Procédé et intermédiaire pour la préparation de 6-fluoro benzisothiazoles
KR102152445B1 (ko) 의약품 합성용 중간체 화합물의 제조 방법
EP1109782A1 (fr) Procede de production d'acides azetidine-2-carboxyliques n-proteges
WO2009037229A1 (fr) Procédé de fabrication d'intermédiaires de monobactam ponté
US5952506A (en) Process for the synthesis of 4- 6- (hexylcarbamoyloxy) hexylcarbamoyloxy!-piperidine-1-carboxylic acid 4-phenoxyphenyl ester
Akasaka et al. Synthesis of a new dual metalloprotease inhibitor. II. Stereoselective synthesis of peptidomimetic [5.7]-bicyclic compounds

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase