IE49836B1 - 2-piperazinone-6-carboxylates - Google Patents

Description

This invention relates to novel compounds which are derivatives of 2-piperazinone-6-carboxylate. The novel compounds are of utility as intermediates in the preparation of the pharmaceutically active enkephalin derivatives dis5 closed and claimed in Patent Specification No. 41834-.

The novel compounds of this invention have the formula H wherein R is hydrogen, C^_4 alkyl or benzyl; Z is hydrogen or n-alkyl; Y is hydrogen or a blocking group; and either Rc is hydrogen, halogen or benzyloxy and Rfl is hydrogen or Rc and R^ are each benzyloxy.

Preferred compounds of the invention include those wherein R is alkyl or benzyl and Y is hydrogen; R is alkyl or benzyl and Y is a blocking group; or R is hydrogen and Y is a blocking group. Z is preferably hydrogen, Rc is preferably benzyloxy.

Suitable blocking groups, and their chemistry, are described in the above-identified Patent Specification.

A process for the preparation of compounds of the invention will now be described. A phenylalanine derivative of formula X wherein R* is Cj_4 alkyl or benzyl, and Rc, R^ and z are as defined above, is reacted with an excess, for example 1¾ to 3 equivalents, of fornalin at a temperature of from -20 to 25°C, preferably about 0°C, in the presence of a suitable organic solvent, e.g. ethyl acetate, toluene or methylene chloride, for from 1 to 8 hours, preferably 2 hours, to yield a trimeric product, a 1,3,5-triazinetriacetate of formula XI wherein R', Rc, R^, and Z are as defined above.

This product is isolated by standard methods, for example by extraction into an organic solvent and evaporat ion of the solvent.

Phenylalanine derivatives of Formula X are well known compounds, which are commercially available or may be prepared by well known methods, for example by the genera 1.procedure disclosed in Belgian patent 868,881. Preferably the L-enantiomer of the phenylalanine derivative is used in the preparation of the compounds of this invention.

The 1,3,5-triazinetriacetic acid derivative of Formula XI is cleaved by treatment with a Lewis acid and the resulting methyleneimine is subjected to a 2 + 2 cycloaddition reaction with an excess of an aminoacetyl reagent in the presence of a strong tertiary amine base, such as triethylamine of diazabicyclononane. The reaction is carried out under an inert atmosphere, for example under dry argon, for from 1 to 24 hours, preferably 2 to 3 hours, at a temperature of from -25°C to -5°C in the presence of an anhydrous halogenated solvent, for example methylene 20 chloride or chloroform. The Lewis acid is preferably boron trifluoride etherate, but may also be, for example tin (IV) chloride, titanium (IV) chloride, aluminum chloride or other Lewis acids, and is employed in the molar ratio of 3 equivalents of Lewis acid per equivalent of 1,3,5-tri25 azinetriacetate trimer.

Suitable aminoacetyl reagents include phthalimidoacetyl halides, mixed anhydrides of tertiary butoxycarbonyl aminoacetic acid, and azidoacetyl halides. The preferred aminoacetyl reagent is phthalimidoacetyl chloride. In the ° preferred cycloaddition method, a solution of 1-1/2 to 2 equivalents of phthalimidoacetyl chloride in dry methylene chloride is added dropwise to a stirred mixture of the trimer with 3 equivalents of BFs‘Et20 in dry methylene chloride under argon and, following this addition, a similar excess of triethylamine, which has been dried by storage over potassium hydroxide, is added dropwise, maintaining the temperature at -25°C tc -5°C, and the reaction allowed to continue for 2 to 3 hours at -20°C tc -5°C. The reaction is quenched and the resulting mixture of diastereomeric N-substituted g-lactams isolated by conventional methods, for example by extraction or chromatography, and the residue of the aminoacetyl cycloaddition reagent is cleaved or modified by an appropriate method to yield a 3-amino-B-lactam of general Formula XII wherein R', R , R, and Z are as defined above, c a Appropriate methods for removal of the residue of the phthaloyl and t-butoxycarbonyl groups and reduction of the azido group are well known. For example, the azido group may be reduced to yield a β-lactam of general Formula XII by catalytic hydrogenation in the presence of a platinum catalyst. When Rc ie benzyloxy, such hydrogenation may also serve to debenzylate the phenolic residue, necessitating the additional step of reprotecting the hydroxy substituent. When a t-butoxycarbonylaminoacetic acid mixed anhydride is employed as the cyclization reagent, the t-boc moiety may be removed by any of the known method e.g by treatment with trifluoroacetic acid at 0 to 25°C, or by treatment with gaseous HCl in methanol or ether for 10 to 30 minutes. The phthaloyl moiety is cleaved by reaction of the phthaimido lactam with one equivalent of 3-(dimethylamino) propylamine or, preferably, hydrazine, in the presence of a suitable solvent, such as a primary alcohol of the formula R'OH, wherein R' has the meaning defined above, at a temperature of from 0°C to the boiling temperature of the solvent, preferably at about room temperature, or about 25°C, for from 4 to 48 hours, preferably about 24 hours.

The e-lactam of Formula XII is isolated, according to standard methods, for example by solution in an organic solvent, filtration and evaporation of the solvent, and dissolved in an alcohol solvent of formula R'OH. The solution is saturated with a strong acid, for example dry HCl, and the solution is either allowed to stand at room temperature for from 8 hours to 4 days or is refluxed at the boiling temperature of the solvent for 1 to 4 hours, until the cleavage of the fi-lactam is complete, yielding the diastereomers of the diester of the Fonnula XIII wherein R', Rc, Rj and Z are as defined above. The diester of formula XIII may be isolated, for example, by neutralization with an inorganic base, such as NaHCOg and extraction with an appropriate organic solvent, for example methylene chloride.

The diester of Formula XIII is cyclized by incubation in a protic solvent at pH 8.5-12, for from 8 hours ' to 3 days, preferably about 1 day, at room temperature to yield a ccnpound of the invention in which Y is hydrogen and R is alkyl or benzyl. The solution may be made basic with a suitable base, elg. an alkali metal bicarbonate or carbonate, a tertiary amine, such as triethylamine, or an anionic exchange resin. Suitable solvents are protic solvents, such as alcohols of formula ROH* The preferred base for cyclization of the diester of Formula XIII is an anion exchange resin adjusted, for example with sodium hydroxide, to pH 8.5-9. Suitable anion exchange resins are well known in the art and examples include AG2-X8, a crosslinked polystyrene resin produced by Bio-Rad Laboratories Inc., and Dowex 2-X8, a similar resin produced by the Dow Chemical Co. (1310-Rad and Dowex Cyclization prooedes spontaneously in the absence of added base in polar protic t solvents, such as methanol, in about 3 days.

Following cyclization, the product is isolated by standard procedures, the 4-position of the piperazine ring protected with a blocking reagent by standard methods, as described above, and the ester hydrolyzed, to yield a compound of the invention. The procedure described above yields a mixture of diastereomeric 6-oxo-2-piperazinecarboxylic acid derivatives. When optically active forms of the phenylalanine derivative of Formula X are employed, crystallization or chromatography effects resolution of the two isomers generated by introduction of an additional asymmetric carbon atom. The individual diastereomers may be separated by standard methods at any convenient point in the synthetic process after the cycloaddition step. Preferably, the diastereomers of the protected precursor of the β-lactam of Formula XII are separated, using conventional methods, by fractional crystallization, column chromatography, or thin layer chromatography with a suitable solvent system. Alternatively, a ccnpound of the invention may similarly be separated - 49836 into individual diastereomers by fractional crystallization or chromatography.

The following Examples illustrate how the compounds of the invention may be prepared. The Preparations illustrate the synthesis of starting materials. o (Celite is a Trade Mark). 48836 Preparation 1 Trimethy1 α,α1 ,g-TrIbenzy1-1,5,5(28,4H,6H)-tri azine1,3,5-triacetate .0 g (46.4 mmole) of L-phenylalanine methyl ester hydrochloride are dissolved in 60 ml HjO and cooled to 0’C. 1.90 g (47.5 mmole) of NaOH pellets are added with vigorous stirring. After solution is complete, ml of ethyl acetate are added, followed by dropwise addition of 7.6 ml (100 mmole) of 37 S formalin solution. The mixture is stirred at 0eC for 2 hours, then poured into dilute aqueous NaCl and extracted twice with ethyl acetate. The extract are washed with brine, dried over NaeSO*, and concentrated in vacuo to give 8.3 g of semi-crystal 1ine material. Recrystallization from cyclohexane/EtOAc gives 7.95 9 (89.7%) of white needles 14a: M.p. 134-137-5'C; [a]25*-101.1 (C=4.37, EtOAc).

Substituting DL-phenyialanine methyl ester HCI for L-phenylalanine methyl ester HCI, one obtains the DL product which is recrystallized from cyclohexane to give white crystals: M.p. 106-108.2°C.

Preparation 2 Trimethyl α,α1.g'^Tris (4-benzy1oxybenzyl)-l,3,5(2H,4B,6h)tri azine-1,3,5-triacetate Substituting O-benzyi-L-tyrosine methyl ester hydrochloride for L-phenylalanine methyl ester hydrochloride in Preparation 1, the title conpound is obtained in 96% yield as a yellow oil which partially crystallizes on standing.

NMR (CDCla) 5 7.4-6.6 (m, 9H), 4.87 (s, 2H), 3.8-3-3 (m, 6H, -OCHs at 3.53), 2.78 (d, J =7Hz, 2H).

Preparation 3 Methyl 3~Phthalimido-2-oxo-c-benzyl-l-azetidineacetete To a stirred solution of 21.4 g (37.3 mmole) of the product of Preparation 1 in 750 ml dry CHjClj (freshly distilled fran PgOg) under Ar is added 13.8 ml (112 itmole) of BFyCEtg distilled fran CaHg. The solution is stirred 20 minutes at 25°C, before being cooled to -25°C to -20°C. A solution of 30,1 g (135 mmole) of phthalimidoacetyl chloride in 70 ml dry CH2CI2 is added dropwise over 20 minutes. Thirty-five (35) minutes after the completion of the addition of acid chloride, 34.3 ml (247 mmole) of EtaN, dried by storing over KOH pellets, is added dropwise over 10 minutes while keeping the solution at -25°C to -20°C. A bright orange color appears but rapidly dissipates upon addition of each drop of EtaN in the early stages of the addition; the orange color persists near the end of the addition. The reaction mixture is maintained at -25°C to -5°C for 2-1/2 hours, then poured into ice water and extracted twice with CH2Cl2/Et0Ac/' 15 ether. The extracts are washed twice with cold 5% HCI, once with H20, twice with aqueous NaHCOa, and with brine and dried over Na2S04. Concentration in vacuo gives a semi-crystalline orange oil which is suspended in ethyl acetate and filtered. The filtrate is concentrated and recrystallized frcm 175 mi of CHsOH/EtOA to give 12.8 g (30.3%) of pure 15a (syn) as white needles. A second recrystallization gives analytically pure 15a (syn); m.p. 153155.5°C; [cjg5 = -135.7 (C = 2.4958, EtOAc).

The mother liquid is chromatographed on 650 c of silica gel eluting with 1.68¾ CHSOH/CH2C12, to give 18.9 g of a mixture of (syn) and (anti) product, which was predominately (anti), as a yellow oil, and an unidentified third product; the product (syn and anti) constitutes about 2/3 of the mixture.

The purified mixture of °- lactams (syn and anti) prepared from DL-phenylalanine methyl ester exhibited the following spectral characteristics: IR (neat) 1765, 1740, 1720 cm1; NMR (CDCls) 6 7-90-7-58 (m, 4H). 7-24 and 7.22 (2s, 5H), 5.40 (dd, J = 4, 5 Hz) 5-22 (dd, J =3-5, 6 Hz) 4.93-4.10 (m, 2H total for all signals 6 5.4-4.10), 3.953.53 (rn, IH), 3.79 and 3.67 (2s, 3H), 3-55-3.05 (m, 2H). 4983 6 Preparation 4 Methyl ?-Phtha1imido-2-oxo-g-(4-benzyloxybenzyl)-l-azetidineacetate Substituting the product of Preparation 2 for that of Preparation 1 in Preparation 3, and after chromatography of the crude reaction mixture, in the title conpound is obtained 34-43% yield as offwhite sani-crystalline material, which is recrystallized from CH^OH/EtOAc to yield white crystalline 15b (syn): m.p. 147-148.5°C, /ά/25 = -105.3 (c = 2.039, EtOAc). The mother liquid is concentrated to give a yellow oil which is a mixture of (syn) and (anti), predominately (anti), product.

The purified mixture of g-lactams (syn and anti) exhibits the following spectral characteristics: IR (neat) 1770, 1745, 1720cm'1; NMR (COCI3) 6 7-68 (bs, 4h), 7-33 (s, 5H) 7.08-6.80 (m, 4h), 5.38-5.13 (m, IH), 5.00 (s, 2H), 4.9-4.61 (m, IH), 3.96-3.38 (m, 4H, -OCH3 at 3.78 and 3.68), 3.33-2.95 (m, 2H).

Preparation 5 Methyl 3-Amino-2-oxo-a-benzyl-l-azetidineacetate (syn) To a stirred suspension of 6.42 g (17.0 nmole) of the product of Preparation 3 (syn) in 75 ml of dry methanol under argon is added dropwise via syringe θ.6θθ ml (18.3 mmole) of 97^ anhydrous hydrazine. The solution is stirred at 25°C for 21 hours and then concentrated in vacuo. CH2Cls is added, and the mixture filtered through celite to remove phthalhydrazide.

The filtrate is concentrated to give 4.7 g of 16a as a clear colorless oil. NMR (CDCI3) 6 7-20 (s, 5H), 4.63 (dd, J = 6, 9 Hz, IH), 3.90 (dd, J = 2.5, 5-5 Hz, IH), 3-70 (s, 3H), 3.55-3.3 (m,~2H), 3-2-2.8 (m,/-/2H), 2.5-1.8 (bs, 2H).

Preparation 6 N-ί 2-Amino-2(rnethoxvcarbony1 ethyl) 1-L-phenylalanine methyl ester di hydrochloride (syn)) The product of Preparation 5 is dissolved in 150 ml of dry methanol, the solution saturated with HCl gas, becoming very hot during saturation, and the solution allowed to stand at room temperature for 1 day. The solution is concentrated _in vacuo, 200 ml of water is added and the mixture filtered and washed with ethyl acetate. The filtrate is made basic with NaHCOs and extracted twice with CH2ClE.

The combined extracts are dried (Na?SO^) and concentrated in vacuo to give 4.5 g of 17a (syn) as a colorless oil. NMR (CDCl?) δ 7.20 (s, 5H), 3.73-3.3 (m, 8H, -OCHg at 3.65 and 3.62), 3.03-2.66 (m, 4H), 1.73 (bs, 3H).

EXAMPLE 1 trans-Methyl 6-oxo-5-benzyl-2-piperazinecarboxylate The oil produced in Preparation 6 is dissolved in 200 ml of methanol and 4.5 g of AG2-X8 anion exchange resin, made basic by washing with 2N NaOH, with water until the filtrate was neutral, and finally with methanol, added and the mixture is stirred at room temperature for 10 minutes, then filtered, washing the resin with 2x25 ml of methanol. The filtrate is allowed to stand at room temperature for 18 hours, then concentrated in vacuo to give 3.97 g (94% over15 all from Preparation 3) of the title compound as colorless crystals. Recrystallization from cyclohexane/EtOAc gives white crystals. M.p. 101.5-103.5°C. NMR (CDClg) δ 7.21 (s, 5H) 6.26 (bs, IH), 4.09 (dd, j = 4.5, 10 Hz, IH), 3.72 (s, 3H), 3.66-3.26 (m, 3H), 3.00-2.69 (m, 2H), 1.64 (s, IH).

EXAMPLE 2 cis-Methyl 6-oxo-5-benzyl-2-piperazinecarboxylate (cis) When the anti product of Preparation 2 is substituted for the syn starting material in the procedure of Preparation 5 and the product reacted according to the procedures of Preparation 6 and in the manner described above, the cis title compound is obtained as a pale yellow viscous oil.

EXAMPLE 3 trang-Methyl 6-oxo-5-(4-benzyloxybenzyl)-2-piperazinecarboxylate When the syn product of Preparation 4 Is substituted 5 for the syn product of Preparation 3 in the procedure of Preparation 5 and the product reacted according to the procedures of Preparation 6 and Example 1, the title compound is obtained as white crystals. M.P. 126-128°C.

EXAMPLE 4 10 cls-Methyl 6-oxo-5-(4-benzyloxybenzyl)-2-piperazinecarboxylate hydrochloride When the anti product of Preparation 4 is substituted for the syn product of Preparation 3 in the procedure of Preparation 5 and the product reacted according to the procedures of Preparation 6 and Example 1, and the product (an oil) is stirred in ethanolic HCl, the title compound is reerystallized from butanone/methanol.

M.p. 207-209°C (dec.).

EXAMPLE 5 trans-5-0xo-6-benzy1-1,3-piperazinedicarboxylic acid 1-t5 butyl ester A mixture of 7.40 g (29.8 ironole) of the crude cis and trans products of Exanples 1 and 2 and 7.6 ml (33 imole) of di-tert-butyl dicartonate in 75 ml of tetrahydrofuran is heated at 5O-55°C for 2 hours. The solution is concentrated in vacuo and chroma10 tographed on J00 g of silica gel with 2.8)? CH3OH./CH2C 12 to obtain 3.2 g of t-Boc-substituted cis and 1.6 g of the corresponding trans starting materials. Recrystallization of each from CHjClj/cyclohexane gives the cis compound, m.p. 152-155.5°C, and the trans compound, M.p. 174-176°C, each as fine white crystals.

A solution of 1.15 g (3.30 imole) of the trans intermadiate and 1-32 g (9-90 mmole) of Lil in 10 ml of pyridine is heated at reflux under argon for 3 hours. The solution is cooled and concentrated in vacuo. The oil is dissolved in water and washed twice with ether. The aqueous layer is then acidified with cold dilute aqueous HCl and extracted with EtOAc/CH2Cl2. The extract is washed with H20 and brine and dried (Na2SO4). Concentration in vacuo gives 0.77 g (70&) of off-white solid. Recrystallization from EtOAc/ CHgOH gives pure title compound. M.p. 193-194°C (dec).

EXAMPLE 6 Cis 5 -oxo-6-benzyl-l,3-piperazinedicarboxylic acid l-t-butyl ester To a solution of 0.25 g (0.72 mmole) of the cis intermediate of Exanple 5 in 10 ml of methanol is added 1.2 ml of 1.0M LiCH and the resulting solution is allowed to stir at 25 C for 18 hours. The solution is concentrated in vacuo and the residue partitioned between water and ether. The aqueous layer is acidified with cold dilute aqueous HCl and extracted with ether. The extract is dried (MgSO4) and concentrated _i_n vacuo to give 0.16 g (67%) of the title cenpound as white crystals. Recrystallization fran EtOAc/CHgOH gives pure title carpound.

NMR (CDCI3) 6 7-73 (bs, IH), 7.5 (bs, IH), 7.22 (s, 5H), 4.63-3-93 (m, 3H), 3.27-2.5 (m, 3H), 1.25 (s, 9H).

EXAMPLE 7 Cis 5-Oxo-6-(4-benzyloxybenzyl)-1,3-piperazinedicarboxylic acid, 1-t-butyl ester When in the procedure of Example 5, the cis product of Example 4 is substituted for the trans product of Example 1, the crude t-Boc derivative of the Example 4 compound is obtained. NMR (CDClj) δ 7.3 (s), 7.15-6.73 (m), 4.96 (s), 4.8-3.9 (m), 3.71 (s), 3.2-2.65 (m), 1.25 (s). Subsequent hydrolysis gives the title compound.

EXAMPLE 8 trans 5-Oxo-6-(4-benzyloxybenzyl)-1,3-piperazinedicarboxylic acid, 1-t-butyl ester When in the procedure of Example 7, the product of Example 7 is substituted for that of Example 1, the t-Boc derivative of the Exanple 3 product is obtained. NMR (CDClj) δ 7.55 (m, IH), 7.33 (s, 5H), 7.13-6.75 (m, 4H), 5.00 1.28 (s, 9H). Subsequent hydrolysis gives the title compound.

Claims (4)

1. CLAIMS:1. A compound of the formula R c H wherein R is hydrogen, C^_ 4 alkyl or benzyl; 5 Z is hydrogen or C 1-4 n-alkyl; Y is hydrogen or a blocking group; and either R c is hydrogen, halogen or benzyloxy and R^ is hydrogen or R c and R^ are each benzyloxy.

2. A compound as claimed in Claim 1, wherein Z is 10 hydrogen.

3. A compound as claimed in Claim 1 or Claim 2, wherein R c is benzyloxy.

4. A compound as ciaimed in Claim 1, which is named herein.