WO1994011353A1

WO1994011353A1 - Process for the preparation of (3r)- and (3s)-piperazic acid derivatives

Info

Publication number: WO1994011353A1
Application number: PCT/GB1993/002327
Authority: WO
Inventors: Karl Joseph Hale
Original assignee: University College London
Priority date: 1992-11-12
Filing date: 1993-11-12
Publication date: 1994-05-26
Also published as: GB9223739D0

Abstract

A process of preparing a piperazic acid derivative of formula (1) wherein R represents an amino, hydroxyl or thiol group or an organic group as defined below and each of A and B represents a hydrogen atom or a non-interfering substituent, A and B being separate or joined directly together, so that together with the nitrogen atoms shown they form a fused ring group, in the form of a free base or an acid addition salt, the said process comprising: (a) reacting a valeric acid derivative of formula (3) wherein R represents an amino, hydroxyl or thiol group protected to prevent self-cyclisation of the valeric acid derivative into a lactam, lactone or thiolactone respectively, or an organic group which is not cleavable from the rest of the molecule in this reaction step and L represents a leaving group which is displaceable in the cyclisation step defined below, with a strong base under enolisation conditions to produce an enolate; (b) hydrazinating the enolate with a diazo compound of formula (5) wherein A and B are as defined above; (c) cyclising the product of the hydrazination; (d) optionally cleaving the R group from the cyclised product; and (e) optionally replacing the A and B substituents by hydrogen atoms, said steps (d) and (e) being carried out in either order or simultaneously.

Description

PROCESS FOR THE PREPARATION OF (3R)- AND (3S)-PIPERAZIC ACID DERIVATIVES

1. Field of the invention

This invention relates to the preparation of 3R and 3S-piperazic acid derivatives of formula (1):

whi ch can be sub-divided into formul ae for the 3R- and 3S- i somers :

Isomer (1S)

wherein 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.

R₁, R₂ and R₃ 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. a hydrogen atom, an aliphatic group of between 1 and 12 carbon atoms, an ali cyclic or heterocyclic group, an aromatic or ataliphatic group or a group which comprises moieties of more than one of the above-mentioned groups. X is O, S or Se. The chiral auxiliary can be enantiomeric with any of the structural formulae shown.

In formulae (1R) and (1S) groups 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.

2. Uses of 3R and 3S-Piperazic Acid Derivatives

Compounds of formula (1) wherein the groups R, A, and B are hydrogen atoms are commonly known as (3R)- and (3S)-Piperazic acids (hereinafter "3R-Pip" and "3S-Pip") respectively. These enantiomers are present in a derivatized state in a number of naturally occurring, and synthetic, drug molecules that possess significant biological activity. Examples of some pharmacologically active natural products that contain 3R-Pip and 3S-Pip as structural components are the Monamycins¹, Azinothricin², A83586C³, Citropeptin⁴, Variapeptin⁵, L-156,602⁶, and L-156,373⁷.

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-14950²; A83586C³, Citropeptin⁴, and Variapeptin⁵, are antibiotic substances related to Azinothricin that possess good anti tumour properties. L-156,602 is a competitive C5a antagonist⁶, 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 balance⁷. 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. 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

(Cilazapril) of formula (A):

(* = S configuration at asymmetric C-atom)

It 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):

(* = S configuration at asymmetric C-atom)

which is required in Cilazapril, the invention includes a direct enantioselective synthesis thereof. 3S-Pip and 3R-Pip have also been found to be potent GABA (γ-aminobutryric acid) uptake inhibitors and are useful for the treatment of audiogenic seizures¹⁰.

3. Description of the Prior Art

The currently available route for preparing optically active compounds of formula (1) consists of a multistep cycloaddition sequence to provide (3RS)-N¹-benzyloxycarbonylpiperazic acid¹¹. Specifically, this racemic material is synthesised by Diels-Alder condensation of phthalazinedione with penta-2,4-dienoic acid, hydrolysis of the phthalyl group and selective N¹-protection with benzyloxycarbonyl chloride and aqueous sodium hydroxide¹¹. Racemic (3RS) N¹-benzyloxycarbonylpiperazic acid is then resolved with (+)- and (-)-ephedrines¹², 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)-N¹-benzyloxycarbonyl- piperazic acid has since been reported by Adams et al¹³.

4. Summary of the invention

We have now invented an improved synthetic route for obtaining compounds of formula (1). This new route can deliver compounds of formula (1) with enantiomeric excesses greater than 96%. An enantiomeric excess (ee) is herein defined as the percentage of one enantiomer in the product, i.e. a totally stereospecific synthesis would yield the desired isomer at 100% ee. Alternatively, by choosing a different starting material, it can provide mixtures of enantiomers. The new process of this invention is defined by Claim 1 and illustrated by Scheme 1:

Scheme 1

(* = optical isomer generated at the asymmetric carbon atom) when R is a chiral auxiliary group). 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. Preferably 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 N¹-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. 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. Admittedly, piperazic acid is produced only when deprotection leads to R= -OH, but it will be appreciated that the other piperazic acid derivatives are useful as convertible into piperazic acid or directly into ACE inhibitors by simple reactions known per se. When 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:

(1) The use of a chiral auxiliary to generate the 3R- or 3S- asymmetric centre in 3R- and 3S-Pip derivatives by an asymmetric alkylation reaction. The synthesis provides either enantiomeric series of 3R- and 3S-Pip derivatives in ee's greater than 96 , depending on the choice of chiral auxiliary.

(2) Alternatively, by dispensing with the chiral auxiliary and using a simple R substituent, the synthesis can be used to make a racemic product.

(3) 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.

(4) The ease of displacement of the valeryl leaving group by the N¹-aza anion that is generated after the addition of the azo compound to the enolate.

(5) The fact that E₂ elimination of the leaving group in the valeryl chain does not occur at the low temperatures used for generating the enolate with a sterically hindered strong base.

(6) The chiral auxiliary can be recovered and recycled, making this an attractive industrial process.

5. Description of the preferred embodiments

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. Thus, it could be alkoxy, thioalkoxy or disubstituted amino, or any other group simply convertible into a hydroxy group, but which will survive the conditions used in the enolisation stage. In the disubstituted amino group 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. To ensure that cyclisation proceeds, 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.

The processes of this invention are further illustrated by a synthesis of (3R)-Pip (1) (where R=OH and A - B = H-atom), shown in Scheme 2, quo vide. The chiral auxiliary chosen for this synthesis was (4R)-(phenylmethyl)-2-oxazolidinone (6). The preparation of (6) and its enantiomer have already been described in the literature; alternatively, this material can be purchased from Aldrich Chemical Company, Gillingham, UK. Any of the other chiral auxiliary groups of formulae (2a) to (2v) and their enantiomers could be used instead. As explained above, R₁, R₂ and R₃ in these formulae can be any to provide the necessary steric effects and hence a chiral system. They may be e.g. hydrogen, alkyl, aralkyl, cycloalkyl, cycloalkylalkyl etc., usually of 1 to 12 C-atoms, substituted or unsubstituted. R₁ and R₂ could together form a cyclic group. Preferred alkyl groups are methyl and ethyl and preferred aralkyl groups benzyl and 2-phenylethyl.

The first step in the sequence was to attach a bromovaleryl group to the nitrogen atoms of (6) to provide (4R)-3-(5-bromo- valeryl)-4-phenylmethyl)-2-oxazolidinone (3), where R = auxiliary (2a) from Table 1 with R ₁ = H, R₂ = PhCH₂ and X = O and where L is bromo. 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. - 100°C to, -30°C, but especially -80°C to -70°C, and an appropriately functional ised valeric acid derivative, 5-bromovaleryl chloride, over 15 min. (Scheme 2). After warming the reactants to room temperature, conventional extractive workup furnished an oily residue which crystallises from ether-light petroleum after storage at 0°C.

In the diazo compound (5), 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. Most preferably 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. Further, as mentioned above, A and B can together form a ring, which could be e.g. 5, 6 or 7 - membered and substituted or unsubstituted. Preferably A and B have up to 12 C-atoms when separate substi tuents or when joi ned together.

Scheme 2

(1 R;R=OH,A=B= -C(O)OBu-t)

(1 R;R=OH,A=B=H,CF₃CO₂H salt)

The structure of the product (4R)-3-(5-bromovaleryl)-4-(phenyl- methyl)-2-oxazolidinone (3), where R = chiral auxiliary (2a) from Table 1 with R₁ = H, R_2-= PhCH₂ and X = O and L = Br, was readily ascertained from its ¹³C NMR spectrum: resonances at δ 172.5 and 153.3 ppm were highly characteristic of carbonyl groups in this type of structure¹⁴. In addition, the IR spectrum contained two intense carbonyl absorptions at 1786 and 1698 cm^-1 and the mass spectrum displayed a molecular ion peak at m/e 340. Microanalytical data further corroborated the identity of the product as (4R)-3-(5-bromovaleryl)-4-(phenylmethyl)-2-oxazolidinone, indicating an empirical formula of C₁₅H₁₈NO₃Br. Enolisation of (4R)-3-(5-bromovaleryl)-4-(phenylmethyl)-2- oxazolidinone (3), where R = chiral auxiliary (2a) from Table 1 with R₁ = H, R₂ = PhCH₂ and X = 0, can be accomplished using the Evans procedure ^14,15, wherein a precooled solution of (3) was added to lithium diisopropylamide at -100°C to -30°C, especially at about -78°C, to produce an enolate intermediate. A precooled solution of di-tert-butylazo- dicarboxylate (hereinafter "DBAD") can then be added to the enolate intermediate (4), where R = chiral auxiliary (2a) from Table 1 with R₁ = H, R₂ = PhCH₂ and X = O and where L = Br, in one portion, and the mixture maintained at the low temperature indicated above, for a further 30 min.

Cyclisation to (1), where R = chiral auxiliary (2a) from Table 1 with R₁ = H, R₂ = PhCH₂ and X = O, and A = B = -C(O)OBu-tert), occurs most readily when a dipolar aprotic solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) or hexamethyl phosphoric triamide (HMPA) is introduced to the reaction mixture from the Evans' procedure. The reactants are then allowed to warm to room temperature, e.g. 15 to 30°C. The reaction mixture is worked up, e.g. by addition of excess 1.25 M KH₂PO₄ buffer and ether extraction. This gives a crude syrup that can be purified by flash chromatography to remove DBAD by-products. Thus, (4R)-3-(3R-N,N'-bis-(t-butoxycarbonyl) hexahydropyridazine-3-carboxy)-4-(phenylmethyl)-2-oxazolidinone (1), where R = auxiliary (2a) from Table 1 with R₁ = H, R₂ = PhCH₂ and X = O, and A = B = -C(O)OBu-t, was obtained pure in 55-63% yield.

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.

It is not necessary rigorously to purify the resultant cyclised product by chromatography. The crude product can be used for the next step and purification carried out at this stage by recrystallisation, a feature which makes the process of this invention particularly attractive for use on an industrial scale. (It should be noted that a small amount of hydrolysis (1-4%) of the chiral auxiliary occurs during the 1.25 M KH₂PO₄ quench; it is not reduced significantly by quenching with glacial acetic acid or with 10% aq. HCl). (3R)-N,N'-bis-(t-butoxy- carbonyl)hexahydropyridazine-3-carboxylic acid can be recovered in pure condition by acidification of the NaHCO₃ washings with 10% aq. HCl), and extraction with ethyl acetate.

The second step of this process is to remove the chiral auxiliary from the hydrazo product. In the case of (4R)-3- (3R-N,N'-bis(t-butoxycarbonyl)-hexahydropyridazine-3-carboxy)-4- (phenylmethyl)-2-oxazolidinone, (1), where R = chiral auxiliary (2a) with R₁ = H, R₂ = PhCH₂ and X = O, and A = B = -C(O)OBu-t, the oxazolidinone was detached by dissolving the starting material in THF and treating this solution with a suspension of lithium hydroxide in H₂O at -5°C for 15 h. This delivered (3R)-N,N'-bis-(t-butoxycarbonyl)-hexahydropyridazine-3-carboxylic acid (1), where R = OH, and A = B = C(O)OBu-t, as an amorphous solid (m.p. 115-118°C) in 89% yield. In this system, the nitrogen protecting groups (tert-butoxycarbonyls) were readily detached from the hydrazi no nitrogen atoms in 94% yield by the standard literature method, which involved treatment with anhydrous trifluoroacetic acid in dichloromethane. This provided (3R)-piperazic acid trifluoroacetic acid salt which was selectively converted to its N¹-2,4-dinitrophenyl derivative (m.p. 150.5-151.5°C, [α]_D+341°(c 1 MeOH), Lit.¹² [α]_D+324.6 (c l MeOH) by treatment with excess 1-fluoro-2,4-dinitrobenzene (18.7 eq.) and sodium bicarbonate (11.1 eq.) in ethanol (ca. 0.1 M). Methylation of the product acid with excess ethereal diazomethane gave methyl (3R)-N¹-(2,4-dinitrophenyl) hexahydro- pyridazine-3-carboxylate as a yellow crystalline solid, the enantiomeric purity of which was judged to be at least 96% by HPLC comparison with methyl (3RS)-N'-(2,4-dinitrophenyl)- piperazate on a "CHIRALCEL" (Registered Trade Mark) high- performance analytical column. Methyl (3S)-N¹-(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)-N¹-(2,4-dinitro- phenyl)hexahydropyridazine-3-carboxylate was determined to be greater than 96% by chiral HPLC analysis. Methyl (3S)-N¹-(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.

The following Examples illustrate the invention. "Ether" is diethyl ether.

EXAMPLE 1

(a) Preparation of (4R)-3-(5-bromovaleryl)-4-(phenylmethyl)-2- oxazolidinone [(3); R=(2a; R₁-H, R₂=PhCH₂ and X=O), L=Br]

------------------------------------------------------------------------------------------------

To a stirred solution of (4R)-(phenylmethyl)-2-oxazolidinone (6) (5.6g, 0.0316 moles) in dry tetrahydrofuran (50 ml) under nitrogen at -78°C was added 1.6 M n-BuLi in hexanes (19.8 ml, 0.0316 moles) dropwise over 5 minutes. After the addition was complete the reactants were stirred at -78°C for 15 minutes, 5-Bromovaleryl chloride (4.7 ml, 0.0348 moles) was then added dropwise over 3 min., and when the addition was complete, the reactants were maintained at -78°C for 15 min. The cooling bath was then removed and the reaction mixture allowed to warm to room temperature, and then stirred for a further 30 min. at room temperature. The reaction mixture was quenched with excess saturated aqueous ammonium chloride solution at room temperature and extracted three times with dichloromethane (3 x 100 ml). The organic layer was washed with water (200 ml), dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The syrupy residue crystallised from cold hexanes when left overnight, in the refrigerator (yield 9.78 g, 91%). An analytically pure sample of the title compound can be obtained by recrystallisation from hexane/ether; m.p. 66-67°C; [α]_D -83° (c 1, MeOH); 100 MHz ¹³C NMR (CDCI₃): 172.5, 153.3, 135.1, 129.3, 128.9, 127.3, 66.2, 55.0, 37.8, 34.5, 33.1, 31.9, 22.7; Anal. Calcd for C₁₅H₁₈NO₃Br: C, 52.95; H, 5.33; N, 4.12; Br, 23.49. Found: C, 52.79; H, 5.43; N, 4.02; Br, 23.39

(b) Preparation of (4R)-3-(3R-N,N'-bis-(t-butoxycarbonyl) hexahydro-pyridazine-3-carboxy)-4-(phenylmethyl)-2-oxazolidinone [(1R;R=(2a; R₁=H,R₂=-CH₂Ph and X=O), A=B=-C(O)OBu-t]

To a stirred solution of diisopropylamine (2.36 ml, 0.0169 moles) in dry tetrahydrofuran (19.8 ml) under nitrogen at -78°C was added 2.5 M n-butyl lithium in hexanes (6.81 ml, 0.0169 moles) dropwise over 4 min. The mixture was stirred at this temperature for 35 min, whereupon a precooled (-78°C) solution of the (4R)-3-(5-bromovaleryl)-4-(phenylmethyl)-2-oxazolidinone (5.49 g, 0.0161 moles) in tetrahydrofuran (19.8 ml) was added in one portion via cannula. Stirring was continued at -78°C for 40 min., whereupon a precooled (-78°C) solution of di-tert-butylazodicarboxylate (4.45 g, 0.0193 moles) in dry dichloromethane (29.1 ml) was added in one portion via cannula. When the addition was complete, the reactants were stirred at -78°C for 30 min.; 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (dried over activated 4 Angstrom molecular sieves) (50 ml) was then added dropwise over 40 min. By the end of the addition the reaction mixture had frozen. The cooling bath was removed, the reaction mixture was warmed to room temperature, and stirring was continued at this temperature for 18 min. The reaction mixture was worked up by addition of ether and rapidly adjusted to pH 7 with 1.25 M potassium hydrogen phosphate buffer. The aqueous fraction was extracted with ether (5 x 150 ml), the ether layer washed with saturated sodium bicarbonate (3 x 150 ml), then with water and dried (MgSO₄). The solvent was removed in vacuo to give a yellow oily residue that was purified by flash chromatography, eluting with 3:2 ether/hexanes; the cyclised title compound was obtained as an oil (yield: 4.96 g, 63%); [α]_D -34° (c. 1, MeOH); 400 MHz ¹H NMR (CDCI₃): 6 7.34-7.15 (m, 5H), 6.01 (br s) and 5.74 (br d, 1H combined), 4.62 (br s, 1H), 4.19-3.86 (br m, 4H), 3.34 (br m, 1H), 3.1-2.54 (br m, 2H), 2.10-1.6 (br m, 3H), 1.45 (s) and 1.42 (s, 18H combined); El (electron impact) mass spectrum M+ 489; Anal. Calcd for C₂₅H₃₅N₃O₇: C, 61-33: H, 7.21; N, 8.58. Found: C, 61.17; H, 7.36; N, 8.31.

(c) Preparation of 3R-N,N'-bis-(t-butoxycarbonyl)hexahydro- pyridazine-3-carboxylic acid [(1R): R=OH, A=B=-C(O)O-Bu-t].

To a stirred solution of (4R)-3-(3R-N,N'-bis-(t-butoxy- carbonyl)hexahydropyridazine-3-carboxy)-4-phenylmethyl)-2- oxazolidinone (2.0g, 0.0041 moles) in tetrahydrofuran (16.1 ml) at 5°C was added a chilled (-5°C) suspension of lithium hydroxide monohydrate (0.39 g) in water (8 ml). The reactants were vigorously stirred at between -5 and 0°C for 1 h. 40 min. The mixture was then extracted with, dichloromethane (3 x 30 ml), and the organic layer washed with water and dried (MgSO₄). After removal of the solvent in vacuo, the (4R)-(phenyl- methyl)-2-oxazolidinone was recovered. Both the aqueous layers were combined, acidified to pH 2 with 1M NaHSO₄ solution, and extracted with ethyl acetate (3 x 50 ml). The organic extract was then dried (MgSO₄), and concentrated in vacuo, to give pure (3R-N,N'-bis-(t-butoxycarbonyl)-hexahydropyridazine-3-carboxylic acid as white crystals (yield: 1.2 g, 89%); m.p. 115-118°C; IR (KBr): 3209, 2986, 1738, 1705, 1667, 1456, 1431, 1394, 1371, 1163, 1136, 1090, 880, 753, 738 cm.^-1. Anal. Calcd. for C₁₅H₂₆N₂O₆: C, 54.53; H, 7.93; N, 8.48. Found: C, 54.36; H, 7.85; N, 8.37.

(d) Preparation of 3R-piperazic acid

[(1R): R=OH. A=B=H], trifluoroacetic acid salt

To a stirred solution of (3R-N,N'-bis-(t-butoxycarbonyl) hexahydropyridazine-3-carboxylie-acid) (0.85 g, 0.00257 mol) in dry dichloromethane (8.5 ml) under nitrogen at room temperature was added trifluoroacetic acid (8.5 ml) in one portion. The mixture was stirred for 1 h, 35 min, and the trifluoroacetic acid and dichloromethane removed in vacuo. A white solid was obtained (yield: 0.7422 g, 94%). An analytical sample of the title compound was obtained by recrystallisation of the crude residue from ethyl acetate and ethanol; [α]_D -12.0° (c 1, MeOH); m.p. 147-149°C; 400 MHz ¹H NMR (D₂O): δ 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 C₇H₁₁F₃N₂O₄: C, 34.43: H, 4,54; N, 11.48. Found: C, 34.64; H, 4.48; N, 11.38.

EXAMPLE 2

(a) Preparation of (4S)-3-(5-bromovaleryl)-4-(phenylmethyl)-2- oxazolidinone [(3); R=4S enantiomer of 2a; R₂=H, R₂=-CH₂Ph and X=O, L=Br]

---------------------------------------------------------------------------------------------------- To a stirred solution of (4S)-(phenylmethyl)-2-oxazolidinone (15.Og, 0.085 moles) in dry tetrahydrofuran (150 ml) under nitrogen at -78°C was added 2.5 M n-BuLi in hexanes (37.6 ml, 0.094 moles) dropwise over 7 .minutes. After the addition was complete the reactants were stirred at -78°C for 58 minutes, 5-Bromovaleryl chloride (12.6 ml, 0.094 moles) was then added dropwise over 20 min., and when the addition was complete, the reactants were maintained at -78°C for 10 min. The cooling bath was then removed and the reaction mixture allowed to warm to room temperature, and then stirred for a further 2h. 40 min. at room temperature. The reaction mixture was quenched with excess saturated aqueous ammonium chloride solution at room temperature and extracted three times with dichloromethane (3 x 300 ml). The organic layer was washed with saturated sodium chloride solution (500 ml), dried over anhydrous magnesium sulphate, filtered, and concentrated in vacuo. The syrupy residue crystallised from cold hexanes when left for 3 days in the refrigerator. The product was filtered off and recrystallised from hexane/ether to give pure title compound (yield 24.17g, 84%);m.p. 66-67°C; [α]_D +88° (c 1, MeOH); 100 MHz ¹³C NMR (CDCI₃): 172.5, 153.3, 135.1, 129.3, 128.9, 127.3, 66.2, 55.0, 37.8, 34.5, 33.1, 31.9, 22.7; Anal. Calcd for C₁₅H₁₈NO₃Br: C, 52.95; H, 5.33; N, 4.12; Br, 23.49. Found: C, 52.78; H, 5.16; N, 3.95; Br, 23.27. (b) Preparation of (4S)-3-(3S-N.N'-bis-(t-butoxycarbonyl)hexahydro -pyridazine-3-carboxy)-4-(phenylmethyl)-2-oxazolidinone [1S;

R=4S-enantiomer of 2a; R₁=H, R₂=-CH₂Ph and X=O), A=B= =C(O)OBu-t] To a stirred solution of diisopropylamine (8.69 ml, 0.062 moles) in dry tetrahydrofuran (100 ml) under nitrogen at -50 to -55°C was added 2.5 M n-butyl l i thi um i n hexanes (24.8 ml , 0.062 mol es) dropwise over 5 min. The mixture was stirred at this temperature for 45 min, and then cooled to -78°C. A precooled (-78°C) solution of the (4S)-3-(5-bromovaleryl)-4-(phenylmethyl)- 2-oxazolidinone (20.0 g, 0.059 moles) in tetrahydrofuran (100 ml) was added in one portion via cannula. Stirring was continued at -78°C for 40 min., whereupon a precooled (-78°C) solution of di-tert-butylazodicarboxylate (16.28 g, 0.0703 moles) in dry dichloromethane (150 ml) was added dropwise over 10 min via cannula. Proceeding as in Example 1, step (b), using 150 ml. of DMPU, the cyclised title compound was obtained as an oil (yield: 17.86g, 62%); 400 MHz ¹H NMR (CDCI₃): δ 7.34-7.15 (m, 5H), 6.01 (br s) and 5.74 (br d, 1H combined), 4.62 (br s, 1H), 4.19-3.86 (br m, 4H), 3.34 (br m, 1H), 3.1-2.54 (br m, 2H), 2.10-1.6 (br m, 3H), 1.45 (s) and 1.42 (s, 18H combined); El mass spectrum M+ 489.

(c) Preparation of 3S-N,N'-bis-(t-butoxycarbonyl)hexahydro- pyridazine-3-carboxyl i c acid [(IS): R=OH, A=B=-CO(O)O-Bu-t]

To a stirred solution of (4S)-3-(3S-N,N'-bis-(t-butoxy- carbonyl)hexahydropyridazine-3-carboxy)-4-phenylmethyl)-2- oxazolidinone (15.18g, 0.031 moles) in tetrahydrofuran (122.3 ml) at -5°C was added a chilled (-0°C) suspension of lithium hydroxide monohydrate (2.95 g) in water (61 ml). The reactants were stirred vigorously at between -5 and 0°C for 1 h. 45 min. The mixture was then worked up as in Example 1, step (c), to give pure the compound as an amphorous solid (yield: 8.57 g, 84%); m.p. 114-117°C; IR (KBr): 3209, 2986, 1738, 1705, 1667, 1456, 1431, 1394, 1371, 1163, 1136, 1090, 880, 753, 738 cm^-1. Anal. Calcd. for C₁₅H₂₆N₂O₆: C, 54.53; H, 7.93; N, 8.48. Found: C, 54.50; H, 8.07; N, 8.37. (d) Preparation of 3S-piperazic acid [1S); R=OH, A=B=H] trifluoroacetic acid salt

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 [α]_D +18.7° ( c 0.48, MeOH); 400 MHz ¹ H NMR (D₂O): δ 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 C₇H₁₁F₃N₂O_4: C, 34.43: H, 4,54; N, 11.48. Found: C, 34.51; H, 4.55; N, 11.49.

EXAMPLE 3

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.

To a stirred solution of (4S)-3-(5-bromovaleryl)-4-(phenyl- methyl)-2-oxazolidinone (3.5 g, 0.0103 moles) in dry CH₂Cl₂ (19.8 ml) under nitrogen at between 0 and -5°C was added titanium tetrachloride (1.0 M solution in CH₂Cl₂ 11.4 ml, 0.0114 moles) in one portion. The mixture was stirred at this temperature for 15 min, whereupon diisopropylethylamine (2.0 ml, 0.0114 moles) was added in one portion. Stirring was continued at between 0°C and -5°C for 1 hr 10 min, whereupon a precooled (-5°C) solution of di-tert-butylazodicarboxylate (2.85 g, 0.0124 moles) in dry dichloromethane (21.0 ml) was added in one portion via cannula. When the addi tion was complete the reactants were stirred at -5°C for 1.5 h, and then at 25°C for 13 h. The reaction mixture was worked up by addition to diethyl ether and 1.25 M potassium hydrogen phosphate buffer. The aqueous fraction was extracted with ether (5 x 150 ml), the ether layer washed with saturated sodium bicarbonate (3 x 150 ml), then with water, dried (MgSO₄). The solvent was removed in vacuo to give a yellow oily residue that was purified by flash chromatography, eluting with 5:1 hexanes/EtOAc. The pure hydrazi de was obtained as an oil that was used directly for the next step (Yield: 2.81 g, 48%).

To the hydrazide (0.53 g, 0.93 mmol) was added 60% sodium hydride dispersion in mineral oil (39 mg, 98.2 mmol). Dry dimethylformamide (5.0 ml) was then added and the mixture stirred under a nitrogen atmosphere at 25°C for 50 min. The reaction mixture was then diluted with Et₂O (50 ml), and then carefully poured into 10% aqueous HCl (30 ml). The organic layer was separated, and the aqueous phase extracted with Et₂O (3 x 60 ml). The combined Et₂O layers were dried over MgSO₄, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (3:2 Et₂O/Hexanes) to give 0.27 g (60%) of pure (4S)-3-(3S-N,N'-bis-(t-butoxycarbonyl)hexahydropyridazine- 3-carboxy)-4-phenylmethyl)-2-oxazolidinone as a foam. Its spectral properties were identical with those reported in Example 2.

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Claims

1. A process of preparing a piperazic acid derivative of formula

wherein R represents an amino, hydroxyl or thiol group or an organic group as defined below and each of A and B represents a hydrogen atom or a non-interfering substituent, A and B being separate or joined directly together, so that together with the nitrogen atoms shown they form a fused ring group, in the form of a free base or an acid addition' salt, the said process comprising:

(a) reacting a valeric acid derivative of formula

wherein R represents an amino, hydroxyl or thiol group protected to prevent self-cyclisation of the valeric acid derivative into a lactam, lactone or thiolactone respectively, or an organic group which is not cleavable from the rest of the molecule in this reaction step and L represents a leaving group which is displaceable in the cyclisation step defined below, with a strong base under enolisation conditions to produce an enolate;

(b) hydrazinating the enolate with a diazo compound of formula

(5)

wherein A and B are as defined above; (c) cyclising the product of the hydrazi nation;

(d) optionally cleaving the R group from the cyclised product; and

(e) optionally replacing the A and B substituents by hydrogen atoms, said steps (d) and (e) being carried out in either order or simultaneously.

2. A process according to Claim 1 wherein R represents a chiral auxiliary group effective to cause the hydrazination to proceed stereoselectively and thereby produce a compound of formula (1) in which one enantiomer is present in excess over the other.

3. A process according to Claim 2, wherein the chiral auxiliary group is effective to produce an excess of the (3S)-enantiomer.

4. A process according to Claim 2 or 3, wherein the chiral auxiliary group is cleavable from the cyclised molecule.

5. A process according to Claim 1, 2, 3 or 4 wherein A and B are joined together to form the cyclic group which is required for one-step synthesis of the Cilazapril molecule, whereby the diazo compound of formula (5) is 2,3-diaza-6S-[(1S-ethoxycarbonyl-3- phenyl)propylaminolcycloheptanone.

6. A process according to Claim 1, 2, 3, 4 or 5, wherein A and B are each electron-withdrawing organic groups.

7. A process according to Claim 1, 2, 3, 4, 5 or 6, wherein the cyclisation is carried out at a temperature of 0 to 30°C and in an aprotic dipolar solvent.

8. A process according to Claim 1 for preparing (3S)-piperazic acid, wherein:

- R represents a 2-oxo-(4S)-phenylmethyloxazolidin-3-yl group;- L represents a bromine atom;

- step (a) is carried out at a temperature of from -100°C to

60°C;

- A and B represent electron-withdrawing organic groups;

- the hydrazi nation is carried out at a temperature of 0°C or below;

- the cyclisation is carried out at a temperature of from 15 to

30°C; and

- the R group is cleaved with a base and the electron-withdrawing groups converted to hydrogen atoms.