KR940009527B1 - Process for preparing 2-£2'-aminothiazole-4'-yl|-2-(alkoxyimino) acetate - Google Patents

Abstract

The compound of fomula (1) is made by reaction of salt compound of fomula (5) and compound of fomula (7) with tetra-n-butyl ammonium bromide as catayst in a mixing solution of non polar solvent and NaOH solution. In fomula, R1 is hydrogen or C1-C4 alkyl and R2 is alkyl or carboxyl and R3 is alkyl, alkyl group. The compound of fomula (1) is useful as an intermediate of cephalosporin antibiotics.

Description

Method for preparing 2- (2'-aminothiazol-4'-yl) -2- (substituted oxyimino) acetate

The present invention relates to an improved process for the preparation of 2- (2'-aminothiazol-4'-yl) -2- (substitutedoxyamino) acetate derivatives having the following structural formula (I) useful as intermediates of cephalosporin antibiotics: will be.

Wherein R ¹ represents hydrogen, a C ₁ -C ₄ alkyl group, CH ₃ CO—, Cl ₃ CCH ₂ OOC—, ClCH ₂ CO— or Ph ₃ C, and R ² represents CH ₃ —, CH ₃ CH ₂ − , CH ₃ CH ₂ , CH _2- , HC≡CCH ₂ -,-CH ₂ COOH, -CH (CH ₃ ) COOH or -C (CH ₃ ) ₂ COOH, R ³ is CH _3- , CH ₃ CH _2- , allyl or tert-butyl.

The compound containing the structural unit of formula (1), an important cephalosporin antibiotic among those currently used as actual therapeutic agents, is Ceftazidime (formula 2) of the third generation and Cefpirom of the fourth generation ( Cefpirome (formula 3) is representative.

In addition to the two cephalosporin antibiotics currently being used as therapeutic agents, there are a number of compounds that include the structural unit of Structural Formula (1) that are currently under development, which cannot be enumerated (Pharm. Review 1991, Vol. 1). , No. 1, page 64, "Publishing a New Research Center for the Creation of New Materials by the Korea Research Institute of Chemical Technology". Therefore, the development of a simple, economical and general production method for the preparation of the compound of formula (1) is a very important problem in many related fields.

For example, the method for preparing the compound of formula (1) may be prepared by reacting a suitable base from a hydrochloride salt of an oxime ester compound of formula (5), which is commercially available, as shown in Scheme 1 below. The oxime ester of 6) and the compound of formula (7) (hereinafter referred to as "alkylating agent" for convenience) are reacted in dimethyl sulfoxide (DMSO) in the presence of a suitable base (Shinichi Kondo et al., The Journal of Antibiotics). , 1990, XLIII, No. 1, page 62, British Patent 2024808, Korean Patent Publication No. 91-7980).

Scheme 1

Wherein R ¹ , R ² , R ³ are as described above and X represents -Cl, -Br, -I, -OSO ₂ -CH ₃ or -O-SO ₂ -Ph.

The above known method is a representative simple method for preparing the compound of formula (1), but is known to have the following disadvantages.

First, for the O-substitution reaction of oxime (hereinafter referred to as "O-alkylation" for convenience), the salt form of formula (5) should be converted to the free form of formula (6), where formula (6) is ethyl acetate It has poor solubility in organic solvents such as, so it has to be extracted by using a large amount over several times (about 50 L of ethyl acetate per kg of compound of formula (6)). Therefore, the work is cumbersome and uneconomical.

Second, DMSO is used as a reaction solvent in the O-substitution reaction process. Since the boiling point is high and it is soluble in water, much energy is consumed for its recovery.

Third, when preparing an O-propazylated compound as shown in the following formula (8) according to the scheme of Scheme 1, the reaction proceeds smoothly to about 0.1 mole (based on the reactant (6)), but when the reaction degree increases The reaction is not complete. Therefore, separation of unreacted starting materials is essential for the purification of reaction products.

Fourth, reacting the reactant of formula (6) with a methylating agent (eg, CH ₃ I, CH ₃ OSO ₃ CH ₃ ) to make an O-methylated oxime derivative as shown in formula (9) A considerable amount of the methylated compound of the desired compound of formula (9) and the nitrogen atom of the thiazole ring of formula (10) is obtained and the reaction is very efficient (see Scheme 2).

Scheme 2

Therefore, since various problems arise due to the generation of side reactants such as formula (10), it has been proposed to prepare a desired formula (9) material by the method shown in Scheme 3 below (Korean Patent Publication No. 81-980). US Pat. No. 243,578, et al.).

Scheme 3

Example of another method for preparing O-methylated oxime ester derivative of formula (9)

However, the method according to Scheme 3 above can produce the compound of Structural Formula (9) to some extent, but there is a big problem that it must go through too many reaction processes.

Therefore, the present inventors have diligently studied these problems, and thus solved only the above-mentioned problems because the compound of formula (5) used as a starting material can be purchased in large quantities at a relatively low price and the reaction step is very simple in two steps. It has been found that the known production process represented by Scheme 1, if already mentioned, can be improved in a very ideal way.

In addition, it was found that these problems can be easily solved by carrying out the reaction by applying the method of Scheme 1 in a reaction system composed of a mixed solvent composed of an aqueous NaOH solution and a nonpolar organic solvent and a phase transfer catalyst. That is, the salt form of formula (5) is naturally converted to the free form of formula (6) during the reaction because the first excess of base is used, and the O-alkylation reaction of oxime is moved by the phase transfer catalyst in the nonpolar organic solvent. Since the activated oxime O-anions attack the alkylating agent of formula (7) and react directly, the efficiency is at least equal to or better than that in the DMSO solvent used in Scheme 1 [TH Lowry, K.S. Richardson; "Mechanism and Theory in Organic Chemistry", 2nd Ed., Harper & Row, New York, 1981 p. 127].

The present invention is characterized by reacting the hydrochloride of the oxime ester compound of formula (5) and the compound of formula (7) in the presence of a phase transfer catalyst in a mixed solvent of NaOH aqueous solution of a nonpolar organic solvent. An improved process for preparing 2- (2'-aminothiazol-4'-yl) -2- (althoxyamino) acetate.

Wherein R ¹ represents hydrogen, a C ₁ -C ₄ alkyl group, CH ₃ CO—, Cl ₃ CCH ₂ OOC—, ClCH ₂ CO— or Ph ₃ C, and R ² represents CH ₃ —, CH ₃ CH ₂ − , CH ₃ CH ₂ CH _2- , HC≡CCH ₂ , -CH ₂ COOH, -CH (CH ₃ ) COOH or -C (CH ₃ ) ₂ COOH, R ³ is CH _3- , CH ₃ CH _2- , Allyl or tert-butyl, and X represents Cl, Br, I, -OSO ₂ CH ₃ or -OSO ₂ Ph.

The present invention is described in more detail as follows. An oxime compound of formula (5) in a suitable organic solvent (e.g., Cl ₂ CH ₂ , ClCH ₂ CH ₂ Cl, CHCl ₃ , CCl ₄ , C ₆ H ₆ , C ₆ H ₅ CH ₃ ), a phase transfer catalyst, and The temperature of the mixture consisting of the compound of formula (7) is maintained between 0 ° C. and room temperature, to which a NaOH aqueous solution is slowly added over 30 minutes to 2.5 hours at a temperature of 5 ° C. to room temperature and the reaction solution is kept at room temperature for 5 minutes to After stirring for 1.5 hours, the organic layer was separated from the water layer, the water layer was washed three times using the above organic solvent, the organic layers were collected, and the organic solvent was evaporated under reduced pressure to obtain the compound of formula (1).

A phase-transfer catalyst to be used in the present invention include ^{_{(CH 3) 4 N + Y}} -, (CH 3 CH 2) 4 N + Y -, (CH 3 CH 2 CH 2) 4 N + Y -, (CH 3 CH ^{_{2 CH 2) 4 N + Y}} -, (n- _{^{octyl) 4 N + Y -, (}} CH 3 CH 2) 3 PhCH 2 N + Y -, C 16 H 33 (CH 3 CH 2 CH 2 CH 2) 3 _{^{N + Y -, C 16 H}} 33 (CH 3) 3 N + Y -, C 16 H 33 (CH 3 CH 2) 3 N + Y -, Ph 3 MeP + Y -, (C 8 H 17) 3 EtP ^{+ Y -, (n-Bu} ) P + Y - ( wherein, Y represents a -Cl, -Br, -I or -HSO ₄₎ is, and its amount is 0.03 equivalents relative to compound of formula (5) 0.20 equivalent is preferred.

The preferred amount of the compound of formula (7) is 1 to 10 equivalents based on the compound of formula (5), which varies slightly depending on the type of alkylating agent, but the compound of formula (1) can be obtained in the best yield when using 5 equivalents. In addition, it is preferable to use the NaOH aqueous solution in an amount of 10 to 50% in an amount of 3 to 8 equivalents of pure NaOH based on the compound of formula (5).

The method of the present invention has the following advantages over the existing method.

First, in the known method of Scheme (1), the free form of Structural Formula (6) prepared from the salt form of Structural Formula (5) is used, whereas the salt form of Structural Formula (5) can be used directly in the method of the present invention. This can shorten the process by one step.

Secondly, since the reaction is carried out in the presence of water, it is not necessary to dry the reaction vessel and the reagents, so the operation is easy and economical (the known method requires a container and reagents in a fairly dry state).

Third, since a non-polar organic solvent having a low boiling point and no mixing with water is used, almost all of the solvent used can be recovered by simple distillation, which is economical, and at the same time, it is easy to purify the product (the known method uses DMSO. Pointed out problems can be caused)

Fourth, the selectivity of the alkylation reaction is very high. Therefore, unlike the above-described examples, since the production of by-products is little when preparing the compound of formula (9), it is possible to synthesize O-methylated derivatives of formula (9) with high yield and high purity.

Fifth, since there is almost no restriction on the reaction scale according to the kind of the target compound, compounds such as O-propazylated derivatives of the structural formula (8) can be synthesized with good yield even at large reaction scale.

Hereinafter, the present invention will be described in more detail with reference to Examples, but these Examples do not limit the scope of the present invention.

Example 1

Preparation of ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-propazyloxyamino acetate (11)

Ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-hydroxyimino acetate hydrochloride (5 ') (321.12 g, 0.65 mole), tetra-n-butylammonium bromide in a 5 L reaction vessel (31.43 g, 0.097 mole), propazyl chloride (484.31 g, 6.5 mole) and 1.3 L of dichloromethane were added thereto, and 10% aqueous 10% sodium hydroxide solution (1625 ml) was slowly added for 1.5 hours while stirring at room temperature.

The reaction mixture was further stirred for 5 minutes and then left for 30 minutes to separate the organic layer. The progress of the reaction was confirmed by thin layer chromatography, and a mixed solvent of ethyl acetate: normal-hexane = 1: 3 was used as the developing solvent (Rf ₅ = 0.09, Rf ₁₁ = 0.45). 1 liter of dichloromethane and 50 g of celite were added to the aqueous layer from which the organic layer was separated. The mixture was stirred for 15 minutes, filtered, and the organic layer of the filtrate was separated. Each organic layer was combined and washed twice with 500 ml of aqueous solution. The organic layer was dried over 50 g of magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. The residue was recrystallized from 1100 ml of ethanol to give 289.74 g (yield = 90%) of the title compound (11).

¹ H-NMR (CDCl ₃ ): δ = 7.29 (15H, s), 6.96 (1H, s), 6.54 (1H, s), 4.82 (2H, d, J = 2.44 Hz), 4.38 (2H, t, J = 7.32 Hz), 2.47 (1H, t, J = 2.44 Hz), 1.35 (3H, t, J = 7.32 Hz).

Example 2

Preparation of ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-ethoxyamino acetate (12)

Ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-hydroxyimino acetate hydrochloride (321.12 g, 0.65 mole), tetra-n-butylammonium bromide (31.43 g, 0.097 mole) Ethyl bromide (708.31 g, 6.5 mol) and dichloromethane (1300 ml) were placed in a 5 L reaction vessel and 10% aqueous 10% sodium hydroxide solution (1625 ml) was slowly added for 2 hours while stirring at room temperature. The reaction mixture was further stirred for 10 minutes and then left for 30 minutes. The progress of the reaction was confirmed by thin layer chromatography, and the developing solvent was a mixed solvent of ethyl acetate: normal-hexane = 1: 3 (Rf ₅ = 0.09, Rf ₁₂ = 0.45).

The organic layer of the reaction mixture was separated, 50 g of celite was added to the aqueous solution layer, the mixture was stirred for 20 minutes, and the celite was filtered off. The organic layer in the filtrate was separated, and the aqueous layer was extracted and separated with 500 ml of dichloromethane. The combined organic layers were washed three times with 700 ml of water and twice with 500 ml of saturated ammonium chloride. The organic layer was dried over 31 g of magnesium sulfate, filtered and the solvent was distilled off under reduced pressure to obtain the title compound (12) quantitatively.

¹ H-NMR (CDCl ₃ ): δ = 7.30 (15H, s), 6.96 (1H, s), 6.78 (1H, s), 4.38 (2H, q, J = 7.32 Hz), 4.33 (2H, q, J = 7.32 Hz), 1.35 (3H, t, J = 7.32 Hz), 1.30 (3H, t, J = 7.32 Hz).

IR (KBr): 3400-3200 cm (-NH) 1739.8 cm (-C = 0, VS).

Example 3

Preparation of ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-methoxyimino acetate (13)

Ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-hydroxyamino acetate hydrochloride (5) (24.70 g, 0.05 mole), tetra-n-butylammonium bromide in 500 ml reaction vessel (2.42 g, 7.5 mmol), 10% aqueous sodium hydroxide solution (125 ml) and dichloromethane (100 ml) were added thereto, and methyl iodine (70.97 g, 0.5 mol) was slowly added at room temperature for 30 minutes while stirring.

After stirring the reaction mixture for 30 minutes at room temperature, 4 g of celite was added and stirred for 20 minutes, and the celite was filtered out. The organic layer of the filtrate was separated, and then the aqueous layer was extracted with 50 ml of dichloromethane and separated. The combined organic layers were washed twice with 100 ml of water, washed twice with 100 ml of saturated aqueous ammonium chloride solution, dried over magnesium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain 21.22 g (yield = 90%) of the title compound (13).

¹ H-NMR (CDCl ₃ ): δ = 7.30 (15H, s), 7.01 (1H, s), 6.48 (1H, s), 4.38 (2H, q, J = 7.32Hz), 4.04 (3H, s) , 1.35 (3H, t, J = 7.32 Hz).

Example 4

Preparation of Allyl-2- (2'-tritylaminothiazol-4'-yl) -2- [2 ''-P-methoxybenzyloxycarbonyl) ethoxyamino] acetate (14)

Allyl 2- (2'-tritylaminothiazol-4'-yl) -2-hydroxyimino acetate (6) (458 mg, 1 mmol), tetra-n-butylammonium bromide (48 ml, 0.15) in a 10 ml reaction vessel. Mmol), para-methoxybenzyl 2-chloropropionate (1.063 g, 5 mmol) and 3 ml of dichloromethane were added and stirred at room temperature.

2.5 ml of 10% aqueous sodium hydroxide solution was added to the reaction mixture for 5 minutes, and the reaction progress was confirmed by thin layer chromatography while stirring at room temperature. The developing solvent was a mixed solvent of acyl acetate: normal-hexane = 1: 1: 3. (Rf ₆ = 0.08, Rf ₁₄ = 0.31).

After 5 hours, the reaction mixture was diluted with 10 ml of dichloromethane, 2 g of celite was added thereto, stirred for 10 minutes, and filtered to remove celite. The organic layer of the filtrate was separated, and the aqueous layer was extracted and separated twice with 5 ml of dichloromethane, and each organic layer was combined and extracted twice with 5 ml of distilled water and twice with 5 ml of saturated ammonium chloride. The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent, and then the residue was separated by glass column chromatography (developing solvent = methyl acetate: normal-hexane = 1: 5) to give 340 mg of the title compound (yield). = 54%).

¹ H-NMR (CDCl ₃ ): δ = 7.30 (1H, s), 6.84 (2H, d, J = 9.14 Hz), 6.51 (1H, s), 5.92 (1H, m), 5.40 (1H, d, J = 17.01 Hz), 5.24 (1H, d, J = 10.99 Hz), 5.10 (2H, q, J ₁ = 11.60 Hz, J ₂ = 21.96 Hz), 4.95 (1H, q, J = 7.32 Hz), 4.79 (2H, d, J = 5.50 Hz), 3.78 (3H, s), 1.48 (3H, d, J = 7.32 Hz).

Claims (7)

A hydrochloride of an oxime ester compound of formula (5) and a compound of formula (7) are reacted in the presence of a phase transfer catalyst in a mixed solvent of a NaOH aqueous solution of a nonpolar organic solvent, and is represented by the following formula (1) To prepare 2- (2'-aminothiazol-4'-yl) -2- (substitutedoxyimino) acetate. Wherein R ¹ represents hydrogen, a C ₁ -C ₄ alkyl group, CH ₃ CO—, Cl ₃ CCH ₂ OOC—, ClCH ₂ CO— or Ph ₃ C, and R ² represents CH ₃ —, CH ₃ CH ₂ − , CH ₃ CH ₂ CH _2- , HC≡CCH ₂ , -CH ₂ COOH, -CH (CH ₃ ) COOH or -C (CH ₃ ) ₂ COOH, R ³ is CH _3- , CH ₃ CH _2- , Allyl or tert-butyl, and X represents Cl, Br or I. The method of claim 1, wherein the phase transfer catalyst is tetra-n-butylammonium bromide. The process according to claim 1 or 2, wherein the catalyst is used in an amount of 0.03 to 0.2 equivalents based on the oxime compound of formula (5). 2. Process according to claim 1, characterized in that the alkylating agent of formula (7) is used in the amount of 1 to 10 equivalents based on the compound of formula (5). The method of claim 1 wherein the nonpolar organic solvent is Cl ₂ CH ₂ , ClCH ₂ CH ₂ Cl, CHCl ₃ , CCl ₄ , C ₆ H ₆ , or C ₆ H ₅ CH ₃ . The method according to claim 1, wherein the amount of NaOH solution used is such that the amount of pure NaOH is 3 to 8 equivalents based on the compound of formula (5). The compound of formula (1) according to claim 1, wherein the compound of formula (1) prepared is ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-propazyloxyamino acetate, ethyl 2- (2'-tri Tylaminothiazol-4'-yl) -2-ethoxyimino acetate, ethyl 2- (2'-tritylaminothiazol-4'-yl) -2-methoxyimino acetate or allyl-2- (2 '-Tritylaminothiazol-4'-yl) -2- [2' '-(carboxy) ethoxyimino] acetate.