CS216191B2 - Method of making the derivatives of the 2-+l oxazolinoazetidin-6-yl+p-3-methyl-2-or buten acids - Google Patents

Abstract

PURPOSE:To increase the S/N, by providing the threshold value set circuit producing the threshold value based on two signal levels outputted from the memory means of binary information, and by comparing its output with the read-in signal and outputting it. CONSTITUTION:When the sampling instruction pulse is given from the terminal 36 at time to, the level 42 of the read-in signal waveform 40 is sampled with the sampling hold circuit 31. When the sampling instruction pulse is given from the terminal 37 at time t1, the level 43 of the read-in signal waveform 41 is sampled at the sample hold circuit 22 and held. On the other hand, at the threshold value set circuit 33, the average value (Vo+V1)/2 between the level 42 of Vo held at the circuit 31 and the level 43 of V1 held at the sample hold circuit 42, is produced. This threshold value and the read-in signal are compared with the comparison circuit 34 and output is obtained, allowing to increase the S/N.

Description

The present invention relates to a process for the preparation of certain derivatives of thiophenitetic derivatives which are useful as intermediates for the preparation of anti-bacterial agents.

Accordingly, the present invention provides a process for the preparation of 2- (oxazolinoazetidin-6-yl) -3-methyl-2- or -3-butenoic acid derivatives of structurally different general formulas I and III

R

JZ-fjj н to to toe (II

where ¹

R represents a hydrogen atom, a phenyl group, optionally substituted by halogen, cyano, niitro, alkyl of 1 to 5 carbon atoms or alkoxy of 1 to 5 carbon atoms, phenylalkyl or phenoxyalkyl in which: the alkyl moiety always contains 1 to 5 carbon atoms,

B represents a hydroxyl group, a C 1 -C 5 alkoxy group, a benzyloxy group, a 2,2,2-tri group ^{, a} pnitro-benzyloxy group or a diphenylmethoxy group, and

X represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkyl group having 1 to 5 carbon atoms, an alkanoyloxy group having 1 to 5 carbon atoms, a trifluoroacetoxy group, a methyltetrazolylthio group, a phenylthio group or a phenylsulfinyl group;

in which

B ‘represents a hydroxyl group or a carboxyl-protecting group, preferably selected from the group consisting of C 1 -C 5 alkoxy, benzyloxy, p-nitrbininzyloxy and diphenylmethoxy,

R @ 1 and X @ 1 are as defined above, and the S @ 1 - and C @ 1 -CH2 bonds are cis to each other, preferably at a temperature of 80 DEG to 115 DEG C., optionally in the presence of a solvent and / or. the dehydraactive agent and the compound of formula I thus obtained are optionally converted by treatment with a base into the isomeric form of formula III, and / or the B-protecting group is optionally cleaved from the resulting product.

Protected carboxyl groups within the meaning of the COB 'group are the respective groups common in chemistry / lactams, which do not interfere with the reaction conditions of the process of the invention. Generally, ^one may be carboxy and carboxylic · · · contained in the group COB group protected in the form · napříkíad esters [such as the alkyl (e.g. methyl, ethyl or terc.butyleste · ether), aralkyl (e.g. benzylestoru, difenyhnethyleisteru or trityl) "aryl ester ( for example, a phenyl ester or an indane tester) or an ester containing an organometallic ester moiety (e.g., trimethylsilyl ester, ethoxydimethyl-tertiaryl), amide (e.g., diisopropylhydrazide) These protecting groups may be optionally substituted by electron withdrawing or providing substituents, in particular halogen atoms, hydroxy, acyloxy, alkoxy, oxo, acylamino, nitro, cyano or alkyl moieties and may include aryl groups thereof heteroaryl rings, these protecting groups are formed after completion The reactions according to the invention are usually eliminated and their structure is not important for the process according to the invention.

As mentioned above, compounds of formula I can be prepared from compounds of formula II by simultaneous ring opening and recycle reactions. The compounds of formula (II) may be obtained by methods analogous to those described in the Journal of the Chemic. Society, Perkin I, 1: 973, p. 932.

The reactions according to the invention can be carried out simply by heating as described in the examples (for example refluxing in a mixture of benzene and N, N-dimethylacetamide (3: 2)), which means that in theory no specific use is required. reagent.

The reactions of the invention involve first the formation of sulfenic acid derivatives from the compounds of formula II and subsequent de-sulfurization. The former can be carried out under the conditions used to prepare the deacetoxycephalosporanic acids, the latter can be accelerated by the addition of a desulfurizing agent. The desulfurizing agent may be a trivalent phosphorus derivative (e.g., triarylphosphine, trialkylphosphine, or trialkoxyphosphine), a sulfur compound (e.g., sulfenic acid, sulfinic acid, or sulfite), a halogen derivative (e.g., molecular halogen, N-halamide or N-halimide), acid (e.g. organic or inorganic acid), acid anhydride or other compound and sufficient affinity for the sulfur atom.

Water is formed during the reaction, which is preferably removed by the addition of a molecular sieve. to the reaction mixture or by azeotropic drying of the reaction mixture by refluxing. cooler. However, this drying is not necessarily necessary when operating in accordance with the process of the invention.

The process of the invention is preferably carried out in a solvent. Representative examples of suitable solvents include hydrocarbons (e.g. benzene, toluene or hexane), halogenated hydrocarbons (e.g. methylene chloride, dichloroethane, trichloroethane or chlorobenzene J), ethers (e.g. ethyl ether of diethylene glycol, dioxane or tetrahydrofuran), amides (e.g. triamide), esters (for example ethyl acetate or amyl acetate), alcohols (for example ethanol, butanol or tert-butanol) and other inert solvents.

The reaction temperature may conveniently be from 70 ° C to 1.30 ° C. At temperatures below 70 ° C, the reaction proceeds slowly, at temperatures above 130 ° C, a large amount of degradation products is formed. The reaction of the invention takes place at a higher temperature in a few minutes, at a lower temperature in a few hours.

A preferred example of the process of the invention is the following:

part of the starting material is dissolved in a mixture of 7 to 15 parts by volume of a hydrocarbon solvent (for example benzene or toluene) and 7 to 15 parts by volume of a halogenated hydrocarbon solvent (for example dichloroethane or trichloroethane), mixed. with 5 to 2 mol equivalents (particularly 1.0 to 1.5 moles of desulfurizing agent (especially trimethylphosphite or triphenylphosphine)) and 1 to 5 parts by weight (especially 1.5 to 2 parts by weight) of a molecular sieve, and the mixture is heated under reflux for 10 minutes to 15 hours (most commonly 2 to 5 hours), optionally under azeotropic distillation of water, the water being removed either continuously or occasionally.

The compounds of formula (I) thus prepared can be worked up, isolated and purified by conventional methods, for example by filtering off the molecular sieves used, washing with water, drying, concentrating, crystallizing and, optionally, purifying by chromatography. silica gel.

The compounds of the formula I thus obtained are useful as intermediates for the preparation of antibacterially active substances. In accordance with the invention, the compounds of formula (I) by treatment with a base give the corresponding isomeric compound of formula (III), according to the following reaction scheme, wherein COB, R and X are as defined above:

(AND)

COB

This reaction can also be carried out in an inert solvent in the presence of an organic base (e.g., alkylamine or aralkylamine) or an inorganic base (e.g., alkali metal hydroxide or carbonate), at a temperature of, for example, from 0 ° C to 70 ° C for minutes to 5 hours.

An important radical in the meaning of R in the compounds of formula III is one of the above-defined aryl groups, which sometimes favorably affects further conversions of the compounds of formula III.

Thus, for example, treatment of compounds of formula III with propargyl alcohol, hydration, side chain cleavage at the 1-position by ozone, reduction, halogen substitution, triphenylphosphine to form a Wittig reagent, and recycle yield some known antibacterially active agents belonging to the 1- oxadethiacefalosporinům.

In accordance with this process, the corresponding 1-oxadelthiac efalphorosporins can be prepared in high yield with fewer side reactions as compared to the process described in Japanese Patent Application Publication No. 135 800/1976.

The compound of formula I can be treated with osmium tetroxide to convert the exomethylene bond to the diol moiety, cyclize boron trifluoride and dehydrate to provide 1-oxadethium cephalosporins more easily than known methods.

As mentioned above, the invention describes useful intermediates and an efficient and economical process for their production.

The invention is illustrated by the following non-limiting examples. The cyclic nuclei and compounds in these examples correspond to the formula

This nucleus is named as [ββ, δβΗor (1R, 5S)] -7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] hept-2-ene. Stereochemistry at carbon atom 1 is identical to the stereochemistry of carbon at position 6 of 6-epipenicillin and stereochemistry at carbon atom 5 is opposite to penicillins and cephalisporins at position 5 or 6. Experimental errors in IR spectra are around +10 cm ¹ , in the case of NMR spectra in the range of +0.2, 2 ppm. The COB group in the compounds of formulas I and II generally has the R configuration, but the invention is not limited to the starting materials and the resulting products with this stereochemistry.

Example 1

Preparation of oxazolinoazetidine compounds (I) from penicillin-1 oxides (II)

The reaction conditions of the aforementioned concurrent ring opening and recycling reactions are given in Table I below.

Table II shows the physical constants of the products.

J ed é not if the man nose DETAILED IPU lac ei chandeliers embodiment described below, the reaction and workup, ja'k ¹ was performed in the reaction no. 10 in Table I.

A solution of 38.01 g of diphenylmethyl-6α-benzamidoipenicillanate-1-oxide and 22.11 g of triphenylphosphine in a mixture of 308 ml of toluene and 303 ml. The 1,2-dichloroethane was refluxed for 3-5 hours with removal of water using a Dean-Stark trap containing a molecular sieve (5 x ¹⁰ -10 m). After cooling, the reaction mixture was concentrated to a volume of 150 ml and purified by chromatography on 500 g of inactivated 10% water silica gel, using benzene / ethyl acetate (19: 1) and benzene / ethyl acetate (4: 1) as eluents. The desired product contained in the eluate afforded 26.15 g (81.2%) of diphenylmethyl- (2R) -3-methyl-2 - [(1R, 5S) -3-phenyl-7-oxo-4] crystallized from ether. oxa-2,6-diazabicyclo [3.2.0] -2-hepten-6-yl] -3-butenoate, m.p. 116-118 ° C.

In the following tables, each general symbol has the following meanings:

DMA = N, N-dimethylacetamide Ph = phenyl · refl. = reflux h = hours m = minutes ds = dried · using a Dean-Stark type water separator

for NMR spectra, the abbreviations have the following meanings:

values in Hz = coupling constants s = singlet d = doublet t = triplet q = quartet m = multiplet ws = broad singlet w = broad signal

A molecular sieve of 5 * 10 < ^-1 > m is always used.

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Table (Part 1)

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Table (Part 2)

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T a b u 1 к а I (part 3)

To a solution of 1 part by weight of the compound of formula (II), wherein each of the symbols is as defined below, in 10 parts (v / v) of 1,2-dichloireithane is added 1.2 moles equivalent (based on compound of formula ( ¹ )) of triphenylphosphine and 2 parts. 5 parts by weight of the molecular sieve and the mixture is heated to reflux until the maximum amount of product is obtained (4 to 10 hours). The reaction mixture is treated as in the case of Compound No. 10 in Table I [Part 1) to give the corresponding compound of formula I, wherein the individual symbols have the meanings given below:

number R ¹ R ² X 1 —Ph —H —H 0 —Pil —СНз —Br 3 —Ph —CH2CCI3 —Br 4 —Ph —CHaPh —Cl 5 —Pii —CHaPh —Br 6 —Ph —CHaPh -AND 7 —Ph —CHaPh -OII 8 —Ph —Cl 9 —Ph —ВГ 10 —Ph - CHPh2 —Cl 11 —Ph -OHPh2 —Br 12, —Ph —СЙР112 -AND 13 —Ph —CHPha —OH 14 —Ph —CHPha —OCCF3 II II 0 15 Dec —Ph ·> ;! —CHPha CH, N-N -> v 16 —Ph —CHPh2 —SPh 17 —Ph —CHPha —SC6H4CH3 — p 18 —CHaPh —C4H9 — t —Cl 19 Dec -CHaPh —C4H9 — t -AND 20 May —CHaPh —C4H9 — t —OH 21 —CHaPh —C4H9 — t —ОСНЗ 212 —CHaPh —CHaPh —Cl 23 —CHaPh —CHaPh -AND 24 —CHaPh —CHaPh —OH 25 —CHaPh —CHPha —Cl 26 —CHaPh —CHPha -AND 27 Mar: —CHaPh —CHPha —OH 28 —CHaPh —CHPha —ОСНЗ 29 —CHaOPh —CHPha —OH 30 —CHžOPh —CHPha —OCHO 31 —СбШС’Нз — p —CHPha -Cl 32 —СбШСНз — p —CHPh2 -AND 33 —СбШСНз — p —CHPha —OH 34 —C6H4NO2 — p —CHPha —Cl 35 —C6H4NO2 — p —CHPha -AND 36 —C6H4NO2 — p —CHPha —OH 3 (7 —C6H4CN — p —CHPha —Cl 38 —C6H4CN — p —CHPha -AND 39 —C6H4CN — p -CHPh2 —OH 40 —C6H4Cl — p —CHPha —Cl 41 —C6H4Cl — p —CHPha -AND 42 —C6H4Cl — p —CHPha —OH

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Ж

Table II (Part 1) Physical constants of products of general formula

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1788, 1748, 1647, 1172 1.73 bs 3H, 3.60 s 2H, 4.73 s 1H, 4.98 bs 1H, 5.10 bs 1H, 5.12. with 2H, 5.09 (3.8 Hz) 1H,

5.73 d (3.8 Hz) 1H, 7.27-7.33 m 10 H

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the physical constants of the products of the general formula

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1745 5.29 d (3 Hz) 1H, 5.48 s 1H, 5.98 d (3 Hz)

1H, 6.98 with 1H, 6.8 - 7.7 m 15H см

СО СП см см number R ¹ R ² X melting point _ CHCl 3 NMR: occcis [Hz = interaction (° C) ^{IC: υ} (cm ¹ ) constant) max —C6H4NO2 — p - CHPh2 —Cl 163-165 1790, 1748, 1640 4.15 with 2H, 5.30 with 1H, 5.40 d (3 Hz) 1H,

5.40 d (26 Hz) 2H, 6.03 d [3 Hz) 1H,

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1600 5.57 s 1H, 5.93 d (3 Hz) 1H, 6.87 s 1H,

7.2-7.5 m 12H, 4.67 d (9 Hz) 2H

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The relationships between the numerical designations of the individual compounds in Tables I and II are

listed in the following overview: Table I Table II part compound number part compound number 1 1 1 2 1 2 - 6 1 3 1 7 - 8 1 4 1 9 - 15 1 5 1 16 - 17 1 7 1 18 - 23 1 8 1 24 - 25 1 - 1 26 1 9 1 27 Mar: 1 - 1 28 1 10 1 29 1 11 1 30 1 12 1 31 1 13 1 32 1 14 1 33 1 6 2 1 2 26 2 2 2 27 Mar: 2 3 2 28 3 1 1 1 3 2 2 1 3 3 2 2 3 4 2 3 3 5 2 4 3 6 2 5 3 7 2 6 3 8 2 15 Dec 3 9 2 16 3 10 2 7 3 11 2 8 3 12 2 9 3 13 2 10 3 14 2 11 3 15 Dec 2 14 3 16 2 12 3 17 2 - 3 18 2 17 3 19 Dec 2 18 3 20 May 2 19 Dec 3 21 2 - 3 22nd 2 20 May 3 23 2 21 3 24 2 22nd 3 25 2 23 3 26 2 24 3 27 Mar: 2 25 3 28 2 - 3 29 2 29 3 30 2 30 3 31 2 34 3 32 2 35 3 33 2 36 3 34 2 31 3 35 2 32 3 36 2 33 3 37 2 37 3 38 2 38 3 39 2 39 3 40 2 40 3 41 2 41 3 42 2 42

Example 2

Preparation of compounds of formula III from compounds of formula I (these starting and resulting compounds differ in the position of the double bond) (1) to a solution of 281 mg of p-nitrobenzyl- (2R) -3-methyl-2 - [(IR, 5S) -3 phenyl-7-oxo-4-oxa-2,6-diazabicyclo [3.2.0] -2-hepten-6-yl] -3-butenoate in 2 ml of methylene chloride is added 48 μΐ of triethylamine, the reaction mixture is left After standing for 15 minutes at room temperature, it was evaporated under reduced pressure to give 278 mg of foamy p-nitrobenzyl- (2R) -3-methyl-2 - [(1R, 5S) -3-phenyl-7-oxo-4-]. oxa-2,6-diazabicyclo (3,2,0] -2-hepten-6-yl] -2-butenoate.

NMR: δ CDCLs 1.96 with 3H, 2.30 with 3H,

5.05 with 1H, 5.18 with 1H,

5.48 d (3 Hz) 1H,

6.17 d (3 Hz) 1H,

7,3-8,4 m.

(2) In analogy to (1) above, a solution of 75 mg of diphenylmethyl- (2R) -3-methyl-2 - [(1R, 5S) -3-benzyl-7-oxo-4-oxa- 2,6-diabicyclo [3,2.0] -2-hepten-6-yl) -3-butenoate in 5 ml of methylene chloride was stirred at room temperature for 1 hour in the presence of 0.03 ml of triethylamine, yielding 95% yield. diphenylmethyl- (2R) -3-methyl-2 - [(IR,

5S) -3-Benzyl-7-oxo-4-oxo-2,6-diazabicyclo (3.2.0) -2-hepten-6-yl) -2-butenoate, m.p. 104.5-106 ° C C.

The physical constants of the compounds of formula (III) prepared as described above are shown in Table III, in which all the general symbols have the meanings given above.

The pairs of compounds Nos. 1 and 2, 3 and 4, 5 and 6, 8 and 9, 11 and 12 and 13 and 14 in this table represent geometric isomers.

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the physical constants of the compounds of the general formula

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PQ

О я ω о

Р ÍXi сч 42 ÍX см Р (X см См яР (Х | см 42 ÍX со 42 (X см 42 04 / см яЙ С4 X к я к К Ж X X no о no ω О О О

гр ЯЙ гР & яР яР Д2 42 Л ем νΗ & 1 Р-1 1 CU 1 Й4 1 G4 1 Рн 1 Р-1 1 Рм 1 Ж ω 1 О Г — 4 со CD о гЧ см со Ю со СО \ г-4 гЧ гЧ гЧ гЧ гЧ гЧ гЧ

Example 3

Preparation of starting material (part 1)

G

(H) (C 1 -CONH 2 O-H)

O;

COOCH (CH _£ ) _Z (2)

C _f H _F OCH2 CONf

O '(1)

N

S ~ S ~ ^ ^<S C ^* CH-CH ₂ I ² and

I С'Н ₃

COOCH (C & _S ) ₂

CHCOCH.CONH-.

& 5 / (2)

COOC.fi (CH ..)

Vj V ·> rX = СНзСОО—

X = Cl - (A) A solution of 3.63 g of compound (1) and 1.14 g of 2-mercaptobenzothiazole in toluene was refluxed for 45 minutes and then concentrated. The residue was dissolved in a small amount of methylene chloride and the solution was diluted with petroleum ether until crystallization. 2.90 g of compound (2), m.p. 83-86 ° C, is obtained.

CHCls

IR: 3430, 3005, 1785, 1745, 1700 cm @ -1;

max

NMR: CDCl3 1.92 bs 3H, 4.47 s 2H, 5.01 s 1H,

4.9-5.3 m 3H, 5.17 d (2 Hz)

1H, 6.93 with 1H, 6.8-8.1 m of 15H.

(B) A solution of 1.36 g of (2) 400 mg of silver acetate and 1 ml of acetic acid in 21 ml of ethyl acetate was stirred at room temperature for 3 hours, after which the insoluble matter was filtered off. The filtrate is concentrated and the residue is chromatographed on 15 g of deactivated 10% water. Elution with a mixture of benzene and ethyl acetate (95: 5) gave 460 mg of compound (3) wherein X - CH 3 COO-.

__ cucis

IR ^: 344 ^, 3005 ^, 1785 ^, 1745 ^, 1696 ^,

HliiX

1600 cm -1;

NMR: CDCl3 1.21 with 3H, 2.10 with 3H, 3.84 d (11.5 Hz) IH, 4.26 d (11.5 Hz) IH, 4.53 with 2H, 4.88 with IH 5.23 double d (9.2 Hz) IH, 5.38 d (2 Hz) IH, 6.98 s IH, 6.8 - 7.8 m 15 H.

(C) 1.4 ml of a solution of 760 mg of iodobenzene dichloride in pyridine in 1.4 ml of pyridine containing 20% water are added to a solution of 785 mg of compound (3), where X = СНзСОО—, and the mixture is stirred at a temperature of 1.5 hours 50 ml of ethyl acetate. The insoluble material was separated, the filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using a 1: 1 mixture of benzene and ethyl acetate as eluent. 409 mg of compound (4) is obtained, where X = СНзСОО—.

CHC13

IR: at 3420, 3010, 1795, 1750, 1700,

1600 cm ^-1 ;

NMR: δ CDCl 3 1.09 with 3H, 2.13 with 3H, 4.33 bs 2H, 4.56 with 2H, 5.01 d (2.3 Hz) IH, 5.62 double d (2.3; 9) 1H, 6.99 s IH, 6.9-7.7 m 15H, 7.89 d (9 Hz) IH.

(D) A solution of 66 g of compound (2) and 3.33 g of copper (I) chloride in 100 ml of methylene chloride was stirred at room temperature for 3 hours, then the insoluble matter was filtered off and the filtrate was evaporated under reduced pressure. Purification of the residue by chromatography on silica gel inactivated with 10% water gave 2.72 g (yield 50%) of compound (3), where X = Cl.

CHC13

IR: 3415, 1790, 1750, 1700, 1605 ^cm-1; max

NMR: CDCl3 1.27 with 3H, 3.47 with 2H, 4.43 with 2H,

5.10 with IH, 5.12 double d (8; 1.5 Hz) IH, 5.28 d (1.5 Hz) IH, 6.83 with IH, 6.5 - 7.5 m 15H 7, 54 d (8 Hz) IH.

(Ε) К solution of 2.45 g of compound (3) where X = Cl in 4.5 ml of pyridine containing 20 v _/ water was added 4.5 ml of a solution 2.45 g jodbenzendichloridu pyridine. The mixture was cooled with ice during the addition. The reaction mixture was stirred at room temperature for 1 hour, then diluted with 200 mL of ethyl acetate and the insoluble material was filtered off. The residue is chromatographed on 45 g of inactivated 10% water in silica gel. Elution with a 4: 1 mixture of benzene and ethyl acetate gave 1.23 g of compound (4) wherein X-Cl. Yield 49%.

CHC13

IR: ν 3415, 1795, 1755, 1600 cm ^-1 ; max

NHR: CDCl3 1.07 with 3H, 3.70 with 2H, 4.47 with 2H, 4.90 with IH, 5.00 with IH, 5.48 with 8 Hz, 6.97 with IH, 6 , 8 - - 7.5 m 15H, 8.00 wd (8 Hz) IH.

Example 4

Preparation of starting materials (Part 2)

(6)

CFLOCOCH.

соосн

C _& H _S OCH, CONH (A) In analogy to Example 3 (A), refluxing a solution of 1.02 g of compound [5] and 0.35 g of 2-mercaptobenzothiazole in 30 ml of toluene affords compound (6). .

NMR: CDCl3 1.97 with 3H, 4.47 with 2H, 4.80-5.25m 6H, 5.43d (1Hz) 1H, 6.80-7.92m 12H, 8.10d (4Hz) 2H.

(B) The reaction mixture prepared in (A) above was mixed with 5 ml of acetic acid and 0.7 g of silver acetate and worked up in an analogous manner to Example 3 (B). A mixture of 0.54 g of compound (7) and 0.18 g of p-nitrobenzyl-7α-phenoxyacetamido-3-methyl-3-acetoxycepham-4-carboxylate is obtained.

NMR: 5CDCl3 1.38 s, 1.83 s, 1.93 s, 3.43 d (2 Hz), 3.67 d + 4.23 d ABq (6 Hz), 4.50 s, 4.87 s, 5.30 s, 5.07 - 5.40 m, 6.83 - 7.73 m,

8.30 d (4 Hz).

(C) In a manner analogous to Example 3 (C), a solution of 0.45 g of compound (7) in a mixture of 2 ml of pyridine and 0.4 ml of water was mixed with 1.5 ml of a solution of 520 mg of iodobenzene dichloride in pyridine and After stirring at room temperature for one hour, 0.39 g of compound (8) was obtained as a foam.

CHC1-.

IR: ν 1800, 1755, 1700 cm -1;

max

NMR: 5CDCl3 1.33 with 3H, 2.10 with 3H, 4.10 with 2H, 4.57 with 2H, 4.87 with 1H, 5.05 d (1 Hz) 1H, 5.33 double d (1 H); 4Hz) 1H, 6.83-7.42m 5H, 7.62d + 8.27d ABq (4Hz) 4H, 7.93d (4Hz) 1H.

Claims (3)

SUBJECT OF THE INVENTION 1. Process for the preparation of 2- (oxazolinoazetidin-6-yl) -3-methyl-2- or -3-butenoic acid derivatives of structurally different formulas I and III cr | * cos where R is hydrogen, phenyl optionally substituted by halogen, cyano, nitro, C 1 -C 5 alkyl or C 1 -C 5 alkoxy, phenylalkyl or phenoxyalkyl in which the alkyl moiety each contains 1 to 5 carbon atoms , V is hydroxyl, C 1 -C 5 alkoxy, benzyloxy, 2,2,2-trichloroethoxy, p-nitrobenzyloxy or diphenylmethoxy; and X is hydrogen, halogen, hydroxyl, C 1 -C 5 alkyl, C 1 -C 5 alkanoyloxy, trifluoroacetoxy, methyltetrazolylthio, phenylthio or phenylsulfinyl, wherein the compound of formula II is reacted in which B 'represents a hydroxy or carboxyl-protecting group, preferably selected from the group consisting of C 1 -C 5 alkoxy, benzyloxy, 2,2,2-trichloroethoxy, p-nitrobenzyloxy and diphenylmethoxy, R and X are as defined above, and the bonds S -> O and C - N 2 are in a cis configuration, preferably at a temperature of 80 to 115 ° C, optionally in the presence of a solvent and / or a dehydrating agent, and thus the compound of formula (I) obtained is optionally converted by treatment with a base into the isomeric form of formula (III) and / or the protecting group B 'is optionally cleaved from the resulting product. 2. The process according to claim 1, wherein the reaction is carried out in the presence of a desulfurizing agent, for example triarylphosphine. 3. The process according to claim 1, wherein the reaction is carried out in the presence of a dehydrating agent, for example a molecular sieve.