CS216193B2 - Method of making the 2-+l 7-oxo-2,6-diaza-4-oxabicyclo+l3,2,+p-hept-2-en-6-yl+p-4-halogenbuten acids - Google Patents

Description

The invention relates to a process for the preparation of oxazolinoazetidinylpentenoic acid derivatives, in particular 2- (7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-en-6-yl) -4-halobutenoic acids.

Oxazolinoazetidinylpentenoic acid derivatives of formulas II and IV in which:

R 'represents a hydrogen atom, an alkyl group, an aryloxyalkyl group, an aralkyl group or an aryl group,

Z 'represents the rest of the formula

N ^ O

R

N ^ Q

CH2 CH3

II I —CH — C— or - C = C—

COB 'COB' where

COB ´ means a carboxyl group or a protected carboxyl group,

Hal represents a halogen atom and

X represents a nucleophilic moiety, as described in U.S. Pat. No. 216191, wherein these compounds are prepared from 2-substituted-methyl-6α-amidopenamide derivatives by treatment with heat and preferably a desulfurizing agent such as triphenylphosphine.

However, the starting 6-epipenicillins containing a substituted methyl group on the penam nucleus are somewhat difficult to prepare, so this procedure is not very suitable in practice. To solve this problem, the inventors have chosen more straightforward procedures for the preparation of the above compounds by finding a new halogenation process and nucleophilic substitution resulting in the formation of the desired compounds in a more expedient manner than allowed by the earlier process.

These efforts result in the processes disclosed and protected both in this patent document describing halogenation and in our related U.S. Pat. No. 216192, which relates to the replacement of group Y by another nucleophilic group within the meaning of the symbol X.

The differences between the previous procedure and those of the two related publications result from the following reaction schemes:

(Previous procedure)

(Procedures according to the aforementioned related patents)

QOJ ndAT οη - r) AOJAJlB

000 ooBungoiBi)

The compounds of formulas (II) and (IV) above may also be prepared by another synthetic method, for example by treating triphenylphosphine with 6-epipenicillin-1-oxides bearing a nucleophilic group on the methyl group attached to the 2-position of the penam nucleus. However, the introduction of a suitable nucleophilic group on the methyl group at the 2-position of the penam core is generally difficult, and our two related Czechoslovak patents disclose a preferred alternative process for preparing the subject compounds.

The present invention provides a process for the preparation of 2- (7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-en-6-yl] -4-halobutenoic acids of formula II

± -N-Z-CH 3 H &

Oi y ^(II)

in which

Z represents a divalent radical of the formula

CH2 CH3

II I —CH — C— or - C = C—

AND

COB

COB where

COB represents a carboxyl group or a carboxyl group protected in the form of an ester, for example methyl ester, 2,2,2-trimethyl ester, tert-butyl ester or benzhydryl ester, and

R is phenyl, optionally substituted alkyl or alkoxy of 1 to 3 carbon atoms, nitro, cyano or halogen, phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety or phenoxyalkyl of 1 to 3 carbon atoms in the alkyl moiety, and

Hal represents a halogen atom, characterized in that it is a compound of the formula I

in which

R and Z are as defined above, acting as a halogen atom introducing a halogen atom in the meaning of the symbol Hal.

The protected carboxyl group in the meaning of the COB moiety can generally be any protected group commonly used in the chemistry of (3-lactams). In general, the carboxyl group in the COB moiety is ester protected, including an alkyl ester such as methyl, ethyl, tert-butyl or cyclopropyl ether, aralkyl ester such as benzyl ester, phenethyl ester, diphenylmethyl ester or trityl ester, aryl ester such as phenyl or indanyl ester, organometallic ester such as trimethylsilyl ester, ethoxydimethylhexylsilyl ester, or the like; This protecting moiety of B may contain other substituents, in particular halogen atoms, hydroxyl groups, acyloxy groups, oxo groups, acylamino groups, nitro groups, alkyl groups, carboxyl groups, alkoxycarbonyl groups, cyano groups, carbamoyl groups, acyl groups, and the aryl portion thereof includes heteroaromatic cyclic groups. The protecting group is generally cleaved by a subsequent reaction and its structure can be varied widely without departing from the spirit and scope of the invention.

However, in accordance with the invention, a preferred protected carboxyl group in the meaning of the COB moiety is a carboxy group protected in the form of an ester, for example an ester mentioned in the description of the meaning of the symbol COB under formula II.

If the COB moieties contain moieties subject to unwanted side reactions, such moieties may be protected before the reaction itself and deprotected after the reaction. This case is also within the scope of the invention.

The halogenation of the present invention is illustrated by the following reaction scheme, and this halogenation consists in reacting a compound of formula I with a halogenating agent in an internal solvent at, for example, from -20 ° C to 100 ° C, for example from 0.5 to 24 hours. compounds of formula II.

In the formulas shown in this scheme, R, Z and Hal are as defined above.

The starting compounds of the formula I can be obtained by treating triphenylphosphine with the known 6-epipenicillin-1-oxide or with compounds closely related thereto at elevated temperature, as described in our above-mentioned Czechoslovak patent publication no. 218191. By treatment with a base such as triethylamine, it is possible to induce the migration of the double bond in residue Z.

Halogenating agents useful in this reaction are those capable of introducing a halogen atom into an allyl position. Typical examples include molecular halogens (e.g. chlorine, bromine, iodine, chloroiodine or chlorobromide), sulfur halides, hypohalogens (e.g. tert-butyl hypohalogens), copper halides (e.g. copper (I) bromide), selenium halide derivatives (e.g. selenium halides, phenylselenhalides, optionally selenium chloride), sulfuryl halides, thionyl halides, N-halides or N-halides (e.g. N-bromosuccinimide, N-chlorosuccinimide, N-bromoacetamide, N-chloroacetamide, N-chlorophthalimide, chloramine T or chloramine B), N-haloisocyanuric acid, arylsulfenyl halides , benzothiazol-2-ylsulfonyl halides, quinoline-2-sulfenyl halides or o-nitrophenylsulfenyl halides), iodobenzene dichloride, pyridine hydrohalide halides and the like. The above halogenating agents preferably contain chlorine or bromine as halogens, although iodine is also useful.

The reaction described above is preferably carried out in an inert solvent. Representative examples of suitable solvents include hydrocarbons (e.g. pentane, hexane, cyclohexane and benzene), halogenated hydrocarbons (e.g. methylene chloride, ethylene chloride, chloroform, carbon tetrachloride and chlorobenzene), carbon disulfide, ethers (e.g. diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and tetrahydrofuran). esters (e.g. methyl acetate, ethyl acetate, isopropyl acetate and methyl benzoate), nitriles (e.g. acetonitrile and benzonitrile), amides (e.g. dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide), carboxylic acids (e.g. formic acid and acetic acid), bases (e.g. pyridine and quinoline) , alcohols (e.g. methanol, ethanol and t-butanol) and other inert solvents used in organic reactions as well as water, and mixtures of these solvents.

The reaction temperature is generally from -20 ° C to 100 ° C, preferably from 20 ° C to 80 ° C, in which case the reaction is usually complete in 30 minutes to 24 hours. However, the above-mentioned reaction temperature and time values vary depending on the starting materials, reagents, concentration of the reactants, solvents and the reaction accelerator, if any.

If desired, free radical initiators (e.g. peroxides, peracids or azobisisobutyronitrile) light irradiation, hydrogen halide binding agents such as bases (e.g. pyridine, triethylamine, urea or alkaline earth oxides), epoxides (e.g. ethylene oxide, propylene oxide or cyclohexanoxide) or other reaction accelerators.

A preferred example of the halogenation described above is as follows:

A solution of 1 part of the starting material in 5 to 50 volumes of solvent is mixed with 1 to 2 equivalents of halogenating agent, usually heated to 80 ° C to 100 ° C, if necessary in an inert gas atmosphere (e.g. nitrogen or argon) and optionally in the presence a free radical initiator or a hydrogen halide binding agent, or under irradiation.

The products prepared by the above process may be isolated, for example, by concentration, extraction, washing or other conventional methods used to remove solvents, unreacted starting materials, by-products and other impurities, and then purified by reprecipitation, recrystallization, chromatography, adsorbent treatment or other conventional way.

Occasionally, double bond migration or isomerization may occur during the above-mentioned treatment. However, such cases are also within the scope of the invention.

The compounds of formula (II) obtained can be converted to actibacterially active by the procedure described in our related Czechoslovak patent specification 216 192

1-dethia-1-oxacephalosporins.

The invention is illustrated by the following non-limiting examples. In all schemes and individual residue patterns, Ph is phenyl.

The core structure, position numbering and nomenclature used for some of the compounds in the examples are based on the (1R, 5S) -7-oxo-4-oxa-2,6-diazabicyclo [3.2.9] hept-2-ene nucleus corresponding to the formula

Stereochemistry about carbon # 1 is identical to the stereochemistry of 6-epipenicillin at position 6, and stereochemistry about carbon # 5 is opposite to penicillins at position 5 and cephalosporins at position 6.

The stereochemistry around the α-carbon associated with the COB moiety is usually the same as that of penicillins, but the invention is not limited to this arrangement.

In the tables, the abbreviations and symbols have the following meanings:

Ac = acetyl

An = acetone

Ph = phenyl and q = aqueous —C 6 H 4 - = phenylene

DMSO = dimethylsulfoxide

DMF-N, N-dimethylformamide

Et - ethyl h - hour (s) i— = iso— min = minute (s)

9 10 Am - overnight with = singlet refl. = reflux d = doublet tm = room temperature t = triplet t— - tertiary q - quartet Ts = p — CH3C6H4SO2— m = multiplet

w = wide signal

For NMR spectra, the abbreviations have the following meanings: Example I-1

Ph.

ί'ΓΟ

.....

0 ^with nchcch ₃

C00 / ‘‘ π;

Above \ _l CH ³ I * _ ^ -NC CCD ₂ = Br

CH,

Ph.

(3)

COOR

R1 = a) -CHPhz, bj-CH3, cj- ^{CH2-, NO2} 'dj-CH2Cl3, ej-CH2Ph.

aj Suspension 500 mg diphenylmethyl- (2R, 3-methyl-2- (1R, 5S-3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-) en-6-yl-3-butenoate (1a. R ¹ - CHPhzl, 238 mg of N-bromosuccinimide and 25 mg of azobisisobutyronitrile in 40 ml of carbon tetrachloride are refluxed under nitrogen for about 1 hour. The mixture was refluxed for a further 30 minutes, poured into ice water and extracted with methylene chloride, washed with water, cold aqueous sodium bicarbonate solution and water again, dried over sodium sulfate and evaporated. The residue (650 mg) yields four major spots on thin-layer silica gel chromatography in a benzene-ethyl acetate (20: 1) solvent system, which is chromatographed on 16 g of inactivated 10% water silica. 1) wash the following product those in the following order:

Dibromo first (4a, R = ¹ · -CHPhz) in a yield of 23 mg (3.5%)

Monobromderivátu second mixture of (3a R ¹ - = -CHPhzj and dibrominated (4a, R ¹ - = CHPhz) yield 153 mg (23%);

3. monobromo derivative (3a, R ¹ - —CHPhz) in 140 mg (26.4%) yield (mixture of geometric isomers);

Monobromderivát fourth (2a, R = ¹ - CHPhz) yield 144 mg (19%]

5. A mixture of the starting material (Ia, R ¹ = -CHPhz) and monobromderivátu (2AJ yield 44 mg

6. Starting material (1a, R ¹ = —CHPh 2 O in 57 mg (11%)).

bj analogous to that described above by reacting the starting material (lb, ^R1 - - -CH 3) (870 mg), 611 mg of N-bromosuccinimide and 57 mg of azobisisobutyronitrile in 36 ml of carbon tetrachloride affords the corresponding bromo derivative, which was chromatographed on silica gel deactivated with 10% water . Elution with benzene / ethyl acetate (2: 1) elutes the following products in the order shown below:

Dibromo first (4b, R ¹ = - CH 3) Yield 144 mg (12.3%);

The second mixture of dibromo (4b, R ¹ = -CH 3) and monobromderivátu (3b, R ¹ = - CH 3) Yield 253 mg,

Monobromderivát third (3b, R ¹ = CH3) with a yield of 95 mg (10.3%);

4. The mixture of two kinds monobromderivátů (3b and 2b, ^R1 = CH3) with a yield of 163 mg.

Monobromderivát fifth (2b, R ¹ = - CH 3) Yield 325 mg (31.0%);

6. a mixture of the starting material (1b, R ¹ = —CH 3) and the monobromo derivative (2b, R ¹ = —CH 3) in a yield of 67 mg,

7. Starting material (1b, R ¹ = —CH 3) in a yield of 22 mg.

c) By analogy to the above, the corresponding starting material is obtained from the corresponding starting material

4c _/ R =)

The R-values of compounds (4c), (3c), (2c), and (1c) ^{R = -CH} 2 - ( ^No 2).

thin layer chromatography on silica gel in benzene-ethyl acetate (2: 1) amounts to about 0.49, 0.42, 0.35 and 0.31, and these compounds are formed in a quantitative ratio of 1: 2: 2: 1.

dj Using an analogous procedure to the above, 91.7 mg of N-bromosuccinimide are added to a solution of the starting material (1d, R ¹ = —CH 2 Cl 3) in 3.92 ml of carbon tetrachloride and

8.8 mg of azobisisobutyronitrile, the mixture was heated under reflux for 2 hours, then diluted with ethyl acetate, washed with aqueous sodium thiosulfate solution, aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated. The 110 mg residue was subjected to column chromatography (Prepacked column A - Merck Co.). Elution of the column with benzene / ethyl acetate (4: 1) gave the following products:

1. monobromo derivatives (3d, R ¹ = —CH 2 Cl 3) in a yield of 25 mg (23%) (mixture of geometric isomers in a ratio of about 2: 1),

Monobromderivát second (2d, R ¹ = -CH2CCl3) yield 15 mg (14%);

3. Starting material (1d, R ¹ = - CH 2 Cl 3) in a yield of 34 mg (35%).

Example 1-2

To a solution of 113 mg of p-nitrobenzyl- (2R) -3-methyl-2- (1R, 5S) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept- 2-en-6-yl-3-butenoate (1c) in 2.2 ml of benzene is added 1 mg of dibenzoyl peroxide, a small amount of molecular sieve and 23 μΐ of sulfuryl chloride, stirred at room temperature for 2.5 hours, then poured out The extract was washed with water, dried and evaporated, and the residue was chromatographed on 5.5 g of deactivated 10% water with 19 mg of p-nitrobenzyl- (2R) - (1R, 5S). 3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-en-6-yl) -3-chloromethyl-3-butenoate.

~ f -NCHCCH,

I ° t00CPtPh. _of (1a)

0 '

Example I - 3

Pii

N ^ O

PkCONrl

SiO ₂ nelx; C $ H _S N! 59.3%

Cl;

Ph

N ^ O

Cl

CHz

-HCHCCH2 Cl {

COOCHPI2 _Z (6)

CH _Z ^ CHCCH _from Cl ^{1 0} COOCHPh?

(7)

a) To a solution of 4.525 g of diphenylmethyl- (2R) -3-methyl-2 - ((1R, 5S) -3-phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept 2-en-6-yl) -3-butehoate (1a) in 68 ml of methylene chloride was added dropwise over 30 minutes with 9.0 ml of a 1.66N chlorine in carbon tetrachloride solution under stirring under nitrogen. After 25 minutes, the reaction mixture was concentrated under reduced pressure at 20 ° C. The remainder is diphenylmethyl (2R) -2- (3H-benzamido-2-oxo-4-chlorazetidin-1-yl) -3-chloromethyl-3-butenoate (6).

NMR (CDCl3):

4.15 d + 4.45 d ABq (12 Hz) 2H, 4.8-5.0 m 1H, 5.17 s 1H, 5.50 s 1H, 6.17 d (1 Hz) 1H, 7, 00 with 1H, 7.2 - 8.0 m 15M.

This residue is chromatographed on 135 g of inactivated 10% water silica gel. Elution with a 6: 1 mixture of benzene and ethyl acetate gave 2.888 g (59.3% yield) of diphenylmethyl- (2R) -2 - ((1R, 5S) -3-phenyl-7-oxo-4-oxa-2, 6-Diazabicyclo [3.2.0] hept-2-en-6-yl) -3-chloromethyl-3-butenoate (7), m.p.

104.5-106 ° C.

b) A solution of 2.0 mol equivalents of chlorine in carbon tetrachloride was added to a solution of 100 mg of compound (Ia) in ethyl acetate at room temperature. The product obtained is treated with 1.2 equivalents of pyridine under ice-cooling for 45 minutes instead of silica gel chromatography to give 110 mg of compound (7).

c) To a solution of 1 g of compound (Ia) in 30 ml of ethyl acetate is added 3.3 ml of a 1.66 N solution of chlorine in carbon tetrachloride, the mixture is allowed to react at room temperature for 10 minutes, then 0.21 ml of pyridine are added. The resulting product was purified by silica gel chromatography to give 454 mg of compound (7) and compound (8) as a by-product.

d) To a solution of 100 mg of compound (Ia) in 3 ml of methylene chloride was added 0.2 ml of a 1.66N solution of chlorine in carbon tetrachloride under stirring at 38 ° C under nitrogen. Chromatography on silica gel yields compound (7).

e) Compound (7) is obtained even when the reaction is carried out at -20 ° C.

f) To a solution of 100 mg of compound (Ia) in 3 ml of chloroform was added 73 ml of iodobenzene dichloride (under a nitrogen atmosphere) and the mixture was allowed to stand overnight at room temperature. Compound (6) is obtained, which is then treated with pyridine to give compound (7).

(g) When the same reaction is carried out under irradiation with light, the product (6) is also obtained, but a large amount of a chlorine-saturated double bond is also produced as a by-product.

The above by-product (8) corresponds to the formula

(81

NMR (per deuterodimethylsulfoxide, δ values):

(1.39 s + 1.70 s) 3H, [(3.82 d + 4.05

d) ABq (11 Hz) + 4.12 s] 2H, 5.55 s 1H, [5.88 d (3 Hz) + 5.65 d (3 Hz)] 1H, 6.44 d (3 Hz) 1H, 7.4-8.2 m 5H;

max

IC: at 1845, 1790, 1635 cmi.

CHCb

Example 1-4

O

Pk

N? O i i F ^Hs

J_4 = CCH ₂ COOCHP k ^ (9)

Pk

Pk \ z

CH _Z

-dCHCCH ₂ Cl ⁰ COOCHPk _of (7)

0 '

CH _? CÍ I nchcch ^ coo (7)

To a solution of 753 mg of compound (Ia) in 20 ml of benzene was added at room temperature

1.86 g of powdered calcium oxide and 0.268 ml of sulfuryl chloride were stirred under nitrogen for 1 hour. After completion of the reaction, the insoluble material was filtered off and the filtrate was evaporated at room temperature under reduced pressure. The residue was dissolved in benzene, the solution was washed with 5% aqueous sodium bicarbonate solution and water, dried over magnesium sulfate and evaporated. The residue was chromatographed on a silica gel column using benzene / ethyl acetate (4: 1) as the eluent to give 117 mg (14.5 g) of compound (9), 394 mg (48.8% yield) of (7) and 98. mg (yield 18.4%) of compound (8).

As acid acceptors in this reaction, propylene oxide (10 mol), calcium oxide (0.5 to 20 mol), pyridine (1 mol), silica gel, urea (1 mol) and the like can be used. Benzene and methylene chloride may be used as solvents. If the reaction is carried out at 0 to 90 ° C, it takes 10 to 100 minutes to complete.

Example 1-5

Pk

COOCH _from Pk (1e)

Pk

(77)

18

A solution of chlorine in carbon tetrachloride (1.5 mol / liter, 1.7 equivalents) was added dropwise over 21 minutes to a solution of 6.00 g of the starting material (1e, R ¹ = —CH 2 Ph) in 180 ml of ethyl acetate. After 15 minutes, the reaction mixture is stirred with 180 ml of a solution of 3.53 g of sodium hydrogen carbonate and 5.90 g of sodium thiosulfate pentahydrate in water, diluted with 180 ml of acetone, stirred for 2 hours and then extracted with ethyl acetate. The extract was dried (MgSO4) and evaporated. The residue (7.58 g) was subjected to column chromatography (Prepacked column C - Merck A).

G.). The column was eluted with a 2: 1 mixture of benzene and ethyl acetate to give the following compounds:

1. a mixture (1: 1) of the geometric isomers of compound (10) and a mixture of the starting material and the corresponding chlorine addition product in a yield of 1,688 g (16% w / w);

2. Compound (11) in a yield of 5.026 g (75.8 Vo), which upon crystallization from ether gave 3.72 g (yield 55.8%) of the corresponding pure product, m.p. 68.5-69 ° C.

3. starting material (chlorohydrin derivative) in a yield of 82 mg.

Further halogenations are summarized in Table I below.

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Claims (2)

Process for the preparation of 2- (7-oxo-2,6-diaza-4-oxabicyclo [3.2.0] hept-2-en-6-yl) -4-halobutenoic acids of the general formula II R Z is a divalent radical of the formula methyl, tert-butyl, benzyl, p-nitrobenzyl or benzhydryl; and R represents a phenyl group optionally substituted by an alkyl or alkoxy group containing from 1 to 3 carbon atoms, a nitro group, a cyano group or a halogen atom, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety or a phenoxyalkyl group having 1 to 3 carbon atoms in the alkyl moiety; Hal represents a halogen atom, characterized in that it is a compound of the formula I CH 2 —CH — C— or AND COB (Π CHs I — C = C— AND COB where COB means a carboxyl group or a carboxyl group protected in the form of an ester, for example the methyl ester, 2,2,2-trimethyl, wherein R and Z are as defined above, acting with a halogen atom introducing a halogen atom in the meaning of Hal, in an inert solvent at a temperature of -20 to 77 ° C for 15 minutes to 2.5 hours. 2. A process according to claim 1, wherein the halogenating agent is a molecular halogen.