FI62833C - SOM MELLAN PROCEDURES WITH FRAMSTATION OF ANTIBACTERIA WITH PENICILLIN AND OXYCALOSPORINDERIVAT ANVAENDBARA 2,3-DIOXOPIPERAZINDERIVAT OCH FOERFARANDE FOER FRAMSTAELLNING AV DEM - Google Patents

Description

μ 'advertisement publication ^ 9 83 3

JgSg lBJ OV UTLAGGNINGSSKRIFT OZöOJ

C Patent oyInnotly 3 0 03 1923 ^ (51) Kannua} C 07 D 241/08 FINLAND — FINLAND (il) f — Mtämm —Htm * n6Mnt 7Ö0330 (22) HakambpUvft - Amekf »l« t | «4af 01.02.78 ( Fl) (23) AlkupUvt — GlMgtocstfag 07.05-75 (41) Interpreters julklMfcjl - Bltvfc ottundlg 01.02.78

Pttanttl · and raklrtarharamtu * HmMk + mm * moonlight date. - 30.11.82 Pätene · odt rafiatarrtyralMn 'AmMu uttagd och «UkrtftM puMiemd ¢ 32) (33) (31) ^« tty oeuotkout — Boc * rtl prtorttot 09-05-7 ^ 13.05.7 ^, 31.05.7 ^, 13 .O8.7J +, 26.09.7 ^, 13.12.7 ^, 27.03.75 Japan-Japan (JP) 50663/71 *, 5225UM, 60787M, 91996/7 ^, 10995 ^ / 7 ^) li + 21 + 99 / 74, 37207/75 (71) Toyama Chemical Co., Ltd., 1-18 Kayabacho Nihonbashi, Chuo-ku, Tokyo,

Jap ani-Japan (JP) (72) Isamu Saikava, Toyama-shi, Shuntaro Takano, Toyama-shi,

Chosaku Yoshida, Takaoka-shi, Okuta Takashima, Toyama-shi,

Kaishu Momonoi, Shinminato-shi, Seietsu Kuroda, Toyama-shi,

Miwako Komatsu, Toyama-ken, Takashi Yasuda, Toyama-ken,

Yutaka Kodama, Toyama-shi, Japan-Japan (JP) (7 * 0 Oy Kolster Ab (5 * 0 2,3-Dioxopiperazine derivatives used as intermediates in the preparation of antibacterial penicillin and cephalosporin derivatives and method for their preparation - Som mellanprodukter vid fram-ställning av antibakteriella The present invention relates to novel 2β-dioxopiperazines and to a process for their preparation, and to a process for the preparation of these 2β-dioxopiperazines, and to a process for their preparation,

The compounds of the invention are novel and can be represented generally by formula (I): O O

6

A- N N - B

^ 2 XR

wherein R2 is a hydrogen atom or a methyl group; A is a C 1-12 alkyl group which may be substituted by chlorine or acetoxy, or an allyl, C 1 -C 6 cycloalkyl, phenyl or benzyl group; and B is a reactive derivative of a carboxyl group 62 8 3 3

The novel capped compounds of formula I of the invention are useful intermediates in the preparation of penicillins and cephalosporins having broad and effective antibacterial activity against gram-positive and gram-negative bacteria, in particular microorganisms Pseudomonas aeruginosa, Klebsiella pneumoniae against species which are of great clinical importance for micro-organisms, These penicillins and cephalosporins have good resistance to the β-lactamase produced by bacteria,

The compounds of the formula I according to the invention are not previously known. The new compounds of the formula IV and their non-toxic salts disclosed in a previous patent application of the same applicant (Finnish patent application No. 751 340) were found to have the above-mentioned properties and very valuable therapeutic effects:

C0NH1-S \ IV

^ 2 ° R5 oJ— ^ \ CH I z 4 4 where> 2 is 3 or C-CH2R 'at 3 ° R is a hydrogen atom, a \ ch3' quaternary ammonium group or an organic, via O, N or S -

C

a group attached thereto, R is a methyl, phenyl, hydroxyphenyl, 2-cyclohexadienyl or thienyl group, and R and A are as defined above,

The particularly good properties of the compounds of the formula IV and their non-toxic salts are due to the part in the molecule: where R and A denote the above, The compounds of the formula I are thus quite useful intermediates for the preparation of the compounds of the formula IV and their acid addition salts. Particularly preferred are compounds of formula I wherein A is an ethylene group. The preparation of compounds of formula 1¾ from compounds of formula I is described in Finnish patent application 751 340, 3 62833

The compounds of general formula I are prepared as follows:

O O

A compound of general formula II; χ_ AN N-R1 (II) N- ^ R2 1 2 wherein R is a hydrogen atom or a protecting group, and R and A are as defined above, is reacted with a compound of general formula III which is phosgene, chloroformic acid trichloromethyl ester or a compound derived therefrom: X 1; -R 3 (m) 0 wherein X is halogen, and R 3 is halogen or an ester group, and the desired

where -C-R

0 is converted to another carboxyl group-containing reactive derivative by conventional methods.

In the above formulas, A is such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, dodecyl; allyl, cyclohexyl; phenyl or benzyl.

When A is present, it may be substituted with chlorine or an acetoxy group.

In the general formula I, the reactive derivative of the carboxyl group B is an acid halide, an acid anhydride, a mixed anhydride with organic or inorganic acids, an active ester, an active acid amide or an acid cyanide, etc. In particular, B is an acid chloride, a mixed anhydride or an active acid ester. Examples of mixed anhydrides include mixed anhydrides with substituted acetic acids, alkylcarboxylic acids, arylcarboxylic acids and aralkylcarboxylic acids; examples of active esters include cyanomethyl ester, trichloromethyl ester, trichloroethyl ester, substituted phenyl ester, substituted benzyl ester, substituted i · 4 62833 thienyl ester, etc., and examples of active acid amides are amides of amides of saccharines, imidazoles, benzoylamides, etc. with.

The protecting group labeled in the formula in general formula II is a group which is readily removed when the compound is reacted with a compound of formula IIImu. Examples of protecting groups include silyl groups such as those of formulas (CH3) 3Si, (CH3) 2Si2, (CH3O) Si, etc., and organic phosphorus groups such as those of the formulas ~ ° \ / “° \ P”> (ps ( C2H50) 2p, etc. groups.

- cr \ cr • 3

In the general formula III, the ester group R is one capable of reacting with the amino group of the acyl group of 6-aminoacylaminopenicillanic acid or 7-aminoacylaminocephalosporanic acid. Examples of preferred groups are substituted alkoxy groups such as trichloromethoxy or cyanomethoxy, etc.

A compound of formula II wherein R 1 is hydrogen, i. compound of formula II can be readily prepared by reacting an N-substituted ethylenediamine with an oxalic acid diester as described in the following literature reference: J.L. Riebsomer, J.Org.Chem. 15, 68-73 (1950).

Examples of compound II are given in Table 1 below:

Table 1 0 0 \ // / - \ (II) a-n 'nh 2

R

Compound 6.p. (crystallization I.R. (cm -1) solvent) _9 158 ° C (IPA) \) C = 0 1695 »1660 ...... / V,) nh 3220

CH3 N

· '' I 'f * t 5 62833

Table 1 (continued) 0. 0 / \ CH3COOCH2CH2-N NH oily Ό C = 0 1730'1550 \ _ / ς) ΝΗ 330 ° -3200 0. 0 y — f CH3CH2> N / NH 124 ° C (j Ί) ^ C0 1580 * 1650 \ -f ^ 0 ^ 'JNH 3250 0. 0 \\ # / - <CH3CH2CH2-N NH 98-100 ° C (f) l? C = 0 1680> 1650 \ _ / ^ o ^ i ) NH 3200.3100 0 0 / \ CHo (CH2) 2CH2-N NH 111-113 ° (CCl4) 1 ^ C = 0 169551670 \ _ / 1> NH 3240'3150 O o \\ / / - \ CCH3) 2CH -N NH 166-167 ° C) 0 C = 0 1650 J ^ wj) nh 3300-3200 O 0 ^ // / - CH (CH2) 3CH -N NH 104-106 ° C (IPE) i) c = 0 1700.1660 \ ------ / l) NH 3200.3100 ° \ / ° / - \ CH3 (CH2) 4CH2-N NH 111-115 ° C (IPE) l) C = 0 1700> 1880 \ / 3200,3100 oo 6 62833 3 _ / ΚΗ 112-115 ° (IPs) v> c_0 1700.1660 l) NH 3200.3100

0 / O

V / CH 3 (CV 6 CNV / NH 116-120 ° C (IPE) J C = O 1700.1660]) m 3225.3100

O O

W / / —v CH, = CHCH.-N mu 2 W 136-137 ° C Casetone) y) c = 0 1680 »1655 y) NH 3200.3100 O 0 W / / ΥΛ-Ν ^ ΝΗ

Mp / 202-204 ° C (IPA) i) c = 0 1690.1645

On 3260 O 0 Yj C1CH9CH „-N ^ 'mu \ _ / 128-129 ° C (EtOH) \) c = 0 17 ° 0" 165θ y) NH 3200-3100

o O

\ / - - \ ch9ch9-n n nh „.

2 / 127-128 c CAcOEt) Yeah 1660 J NH 3200.3080 CH3

O O

\ ~ f / \ CHq ~ N 'nh V_y 1 · * 6-1 «° 0 (O) ^ 0 = 0« 60' CH ° JNH 6706,3100 7

Note IPA = (CH3) 2CHOH 62 83 3 IPE = (CH _) - CHOCH (CH_) 3 2 3 2

AcOET = CH3COOCH2CH3

EtOH = CH3CH2OH

A compound of formula II wherein R 1 - is a protecting group may be prepared, for example, by reacting a compound of formula II with a silylation or phosphorylating agent, optionally an acid scavenger, for example a nitrogenous organic base such as triethylamine, tributylarino, N-methylpiperidine, N-methylmorpholine, in the presence of pyridine, diazobicycloundecene, etc.,

The following describes the operation of the method in more detail,

In the process, a compound of formula II is reacted with a compound of formula III in an inert solvent or solvent mixture, optionally in the presence of an acid scavenger. Suitable solvents include, for example, methylene chloride, chloroform, tetrahydrofuran, dioxane, acetonitrile, methyl acetate, acetone, methyl ethyl ketone, 1,2-dimethoxyethane, benzene, etc. Examples of acid scavengers include nitrogen-containing organic bases such as triethylamine, triethylamine, tributylamine, tributylamine -methylmorpholine, pyridine, diazabicycloundecene, etc. The reaction is usually carried out at a temperature in the range of 6060 ° C to + 50 ° C, and the reaction time is usually 30 minutes to 4 hours. After the reaction, the desired product can be easily isolated from the reaction solution by conventional methods. The obtained product can be recrystallized from a solvent or washed as a solvent, if necessary, to obtain a pure product. Suitable solvents include acetone, isopropyl alcohol, methylene chloride, ethyl ether, etc.

Other reactive derivatives of the carboxylic acid can be easily prepared from the compound obtained above by conventional methods,

Compounds of formula I in which B is a reactive derivative of a carboxyl group may be prepared by conventional methods from compounds of formula I in which B is a carboxyl group or a salt thereof,

Examples of compounds of formula I are the following (Table 2); 62833

Table 2 8 ..

Compound Physical Properties I.R. (Cm-1)

0 0 sp. 94-95 ° C

% f (CH 2 Cl 2 -Et 2 O) CH, N / N-COCl (decomposes) C = 0 1790/1680

\ S

/ - \ CH-, COOCH-CH, -N N-COCl 10 C = 0 1790 '1720 \ _ / oily 1670

O O

CH3CH2 N'N-COCl m.p. 95-96 ° C (AcOBu) ^ OO 1780 '1660' - '(decomposes)

O O

Va ch, .ch9ch9-n ', N-COCl v) c = 0 1780' \ _ / oily 1710-1640

O O

\\ / CH3 (CH2) 2CH2-N N-COCl \) c = 0 1780 '1660 ^ -f oily

O O

(CH3), CH-N N-COCl v) C = 0 1780 '1660 / m.p. 130-131 ° C (decomposes) CH, CH 2 -n'N-COOCC 1, m.p. 115-117 ° C) C-0 1810 '1710 ^ (decomposes) 1675 9 62833 O o y _ // CH-. (CH9) -CH, -N N-COCl oily 1) C = 0 1790 'J z J ^ \ _ / 1720-1665

O O

CH-5 (CH,) „CH, -N N-COCl oily 0 C = 0 1780 '3 2 4 2 \ _ / 1720-1640

O O

V- (CH ·, (CH,) cCH9-N N-COCl oily 0 C = 0 1780 'N_ / 1720-1640

O O

\ / CHo (CH0), CH0-N N-COCl oily l) C = 0 1780 7 3 2 6 2 \ _ / 1720-1640

O O

y_s CH2 = CHCH2-N N-COCl m.p. 70-74 ° C JC = 0 1775 'N_ / ·. 1660-1620 (najoaa)

O O

\ / / () S-N N-COC1 crystalline \) C = 0 1785 '\ W / \ _ / 1720-1650

O O

^ ^ C1CH2CH2-N N-COCl m.p. 85-90 ° C J C = 0 1790 '1730 W (decomposes) 1680 10 ° 62833 Y_ / CH 3 CH 2 -N N-COCl 1 m.p. 65-70 ° C l) C = 0 1785 '1680 ^ (decomposes) CH3 (Γγ \ - CHo-N N-COCl crystalline C = 0 1790' Y ^ J \ _ / 1720-1650 0 0 w / CH CH0-N N-CON, mp 191-193 ° C l) N_ 2150 -3 z ^ J 3 (decomposes) j 1750> 1655

Note: Et 2 O = CH 3 CH 2 OCH 2 CH 3

AcOBu = CH3COO (CH2) 3CH3

The following examples illustrate the preparation of the compounds of the invention:

Example 1 1) To a mixture of 8 g of diethyl ester of oxalic acid and 8 ml of ethanol was added dropwise 4.4 g of N-ethylethylenediamine at room temperature. The mixture was allowed to react for 3 hours, then heated to remove ethanol. The residue was crystallized from 10 ml of dioxane to give 5.4 g of 1-ethyl-2,3-dioxopiperazine, m.p. 124 ° C, yield 76.0%, 2) 0.71 g of 1-ethyl-2,3-dioxopiperazine was suspended in 15 ml of anhydrous dioxane, and 0.70 g of trimethylsilyl chloride and 0.83 ml of triethylamine were added to the suspension with stirring. Stirring was continued at room temperature for 20 hours, during which time triethylamine hydrochloride precipitated. It was removed by filtration, the filtrate was added dropwise at 5-10 ° C to a solution of phosgene in 10 ml of anhydrous tetrahydrofuran. The mixture was allowed to react at 5-10 ° C for 30 minutes and then at room temperature for 2 hours, then the solvent was removed by distillation under reduced pressure to give 1.0 g of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride as pale yellow crystals.

I1 62833 IR (KBr) cm-1: 1) C = 0 1780, 1660 Using the compound of formula II shown in Table 3 and repeating the above procedure, the compounds shown in the following Table 3 were obtained:

Table 3

Compound of Formula II Prepared compound I.R. (cm ”*) 0 0 0„ 0 J_❖ ♦ _ * CH-jN NH CH ^ -N N-COC1 l) C = 0 1790 '1680 3 \ _ / 3 v_y

mp. (decomposes) 94-95 ° C

0 0 0 0 W // \ '' / / “\ / \. 1780 CH3CH2CH2-N NH CH3CH2CH2-N N-COCl3) C = 0, L / ou ^ / 'v / 1710-1640 CH3 (CH2) 2CH2-N ^ _ ^ NH CH3 (CH2) 2CH2-N2- ^ N-COC1 i) C = 0 1780, 1660 oily 0 0 0 0 \ 1 \ t (CH-JOCH-N NH (CH-) OCH-N N-COCl JC = 0 178 ° '1660 3 2 \ _ / 3 2 \ _f mp (decomposes) 130-131 ° C 0 0 0 0 \ // \ // / \ / \ 1 17Q0 1720 CH3COOCH2CH2-N NH CH3COOCH2CH2-N N-COCl C = 0

Ns- ^ ^^ 1670 oily

Table 3 (continued) 12 62833 0 0 0 0 \ // \ // CH2 = CHCH2- n NH CH2 = CHCH2-N N-COCl1) c = 0 1775 '^ ^' 1660-1620

mp. (decomposes) 70-74 ° C

0 0 0 0 W // W // NH ^ N-COCl) c = 0 1785 'N ^ ^' - / 1720-1650

Crystalline 0 0 0 0 \\ // W // / \ / \ C1CH2CH2-N NH C1CH2CH2-N N-COCl1) C = 0 1790 '1720

^ n 1680 sp. (decomposes) 85-90 ° C

CH3CH2-N NH CH3CH2-N N-COCl3) C = 0 1785 '1680 (CH3 CH3 m.p. (decomposes) 65-70 ° C, 0 0 0 0 W // W / / CH3 (CH2) 3CH2-N NH CH3 (CH2) 3CH2-N_ ^ N-COCl v) C-0 1790 1720-1665 oily 62833

Table 3 (continued) 13 0 0 0 0-Q »®-.Κ-ο = ο.

mp, (decomposes) I30 ^ i33 ° c

Example '2 «...,. n ... x n v ^, L, v

To a solution of 3.56 g of l-n, N-2,3-n-dioxopiperazine in 25 ml of methylene chloride was added dropwise 3.27 g of trimethylsilyl chloride and 3 g of triethylamine at 5 ° C to -10 ° C. The mixture was allowed to react at the same temperature for 30 minutes, then the mixture was cooled to 20 ° C, then 15 ml of a methylene chloride solution of phosgene (3g) was added to the reaction mixture, and the mixture was allowed to stand at room temperature for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, 30 ml of tetrahydrofuran was added to the residue to precipitate triethylamine hydrochloride, which was removed by filtration. Tetrahydrofuran was removed by distillation under reduced pressure to give 4.6 g of 4-ethyl 90-05 ° C (decomposes), yield 90%. Recrystallization from butyl acetate gave the product, m.p. 95-96 ° C (decomposes).

XR (KBr) cm-1; C0178Q, 1660 Using a compound of formula II and repeating the procedure described above 14 62833, the compounds shown in the following Table 4 were obtained:

Table 4

Compound of Formula III Prepared compound I.R. (cm-1) 0 0 0 0 \\ // ^ // CH3 (CH2) 4CH2-N NH CH3 (CH2) 4CH2-N N-COCl Jc = o 1780 '^ ^ ^ 1720-1640 oily 0 0 0 0 CH2 (CH2) 5CH2-N2-CH3 CH3 (CH2) 5CH2-N2-N-COCl () C = 0 1780 1720-1640 oily 0 0 0 0 \ s \ // CH3 (CH2) 6CH2-N2- ^ NH CH3 (CH2) 6CH2-N N-COCl3) c = 0 1780 '1720-1640 oily 0 0 0 0 \ w / w / Q \ -CH2-N NH \ 0 / “CH2-N N-COCl 10 C = 0 1790 '' - '^^ ^ f 1720-1650 crystalline is 62 83 3

Example 3

To a solution of 3.56 g of 1-ethyl-2,3-dioxopiperazine in 34 ml of methylene chloride was added dropwise 3.27 g of trimethylsilyl chloride and 3 g of triethylamine at -5 to -10 ° C. The mixture was allowed to stand at the same temperature for 30 minutes, then cooled to -20 to 30 ° C. To the reaction mixture was then added 2.98 g of chloroformic acid trichloromethyl ester, and it was allowed to react at the same temperature for one hour. The temperature of the reaction mixture was then raised to room temperature for one hour. Further work-up was carried out as in Example 2 to give 4.6 g of 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride, m.p. 90-95 ° C (decomposes), yield 90%.

IR (KBr) cm-1: ^ c = 0 1780, 1660.

Example 4 5 g of 1-ethyl-2,3-dioxopiperazine were dissolved in a solvent mixture of 0.2 ml of methanol and 50 ml of methylene chloride. 4.6 g of trimethylsilyl chloride were added dropwise to the mixture at> -10 ° C, and 4.3 g of triethylamine at -25 to -30 ° C over 15 minutes.

The mixture was allowed to react at the same temperature for 30 minutes, then 4.2 g of chloroformic acid trichloromethyl ester was added dropwise thereto, and the reaction was carried out at -40 to -50 ° C for 30 minutes. The temperature of the reaction mixture was raised to 0 ° C for 1 hour, and the solvent was removed by distillation under reduced pressure to give 4-ethyl-2,3-dioxo-1-piperazinecarbonyl chloride, 4-ethyl-1-trichloromethoxycarbonyl-2,3-dioxopiperazine and triethyl. -amine hydrochloride mixture. The mixture was poured into ice water, the precipitated crystals were filtered, washed with water and dried to give 5.7 g of 4-ethyl-1-trichloromethoxycarbonyl-2,3-dioxopiperazine, m.p. 113-114 ° C (decomposes), yield 53.5%. Recrystallization from acetone gave flaky crystals, m.p. 115-117 ° C (decomposes).

IR (KBr) cm -1: ν max = 0 1810, 1710, 1675.

Example 5 1.63 g of sodium nitride was dissolved in 20 ml of water, the resulting solution was diluted with 20 ml of acetone and cooled to 0 ° C. To the solution was added 9.3 g (purity 55% w / w) of 4-ethyl-2,3-dioxo-1-piperazinylcarbonyl chloride over 10 minutes to maintain the temperature of the solution at 0-5 ° C. At the end of the addition, the solution was stirred. at the same temperature for another 30 minutes. The separated crystals were filtered, washed with 5 ml of ice-cold water and then with 10 ml of acetone, dried to give 4.2 g (79.5%) of 4-ethyl-2,3-> syloxo-1-piperazinecarbonyl azide, m.p. 191-193 ° C (decomposes).

IR (KBr) cm-1! Y N, 2150 V c = 0 1750 '1655

Claims (2)

17 6 2 83 3 1. 2,3-Dioxopiperazine derivatives of the general formula used as intermediates in the preparation of antibacterial penicillin and Cephalosporin derivatives; r ° A_ N 'N _ B I 2 wherein R 2 is a hydrogen atom or a methyl group; A is a C 1-4 alkyl group which may be substituted by chlorine or acetoxy, or an allyl, C 1-6 cycloalkyl, phenyl or benzyl group; and B is a reactive derivative of a carboxyl group, A process for preparing a compound of claim 1 having the general formula; 0 0 X A - N N - B I 2 R 2 2 wherein R is a hydrogen atom or a methyl group; A is a C 1-6 alkyl group which may be substituted by chlorine or acetoxy, or an allyl, C 1-6 cycloalkyl, phenyl or benzyl group; and B is a reactive derivative of a carboxyl group, characterized in that the compound of general formula; 1. wherein R is a hydrogen atom or a protecting group, and R and A are as defined above, is reacted with phosgene or chloroformic acid trichloromethyl ester or a compound derived therefrom having a general formula (III); XC-R3, f III 0 wherein X is a halogen tower, and B3 is a halogen atom or ester group, in an inert solvent optionally in the presence of an acid scavenger at a temperature between-^ 60 ° C and + 50 ° C, and then, if desired, the reactive derivative of the carboxyl group is converted to another reactive derivative way.