KR820001220B1 - Process for preparing semi-synthetic 4-erythtomycin a derivative - Google Patents

Abstract

Title compds. [I(or II); Ac = R2 = C2-3 alkanoyl; R3 = H useful as fungicides, were prepd. by catalysis of triethylamine(>1 mole) and reaction product obtained from the reaction of I'(or II'), N-chlorosuccinimide and dimethylsulfide at 0-25≰C in the presence of inactive solvent. Thus, 4.0 g 2'-acetyl-4"-deoxy-4"-oxo-erythromycin A was dissolved in 75 ml methanol, stirred for 20 hr, and recrystallized with methylene chloride-hexane to give 3.44 g 4"-deoxy-4"-deoxy-4"-oxo-erythromycin A(m.p. 170.5-172.5≰C).

Description

Method for preparing semisynthetic 4 "-erythromycin A derivative

The present invention relates to a process for the preparation of the following novel compounds of formula (I) or (II) which are useful as intermediates for the preparation of 4 "-deoxy-4" -amino erythromycin A antibacterial agents.

Ac and R ₂ in the above formula are each alkanoyl of 2 to 3 carbon atoms

이다.R ₃ is hydrogen and R ₂ and R ₃ together

to be.

Erythromycin is an antibiotic that is formed during incubation of a strain of Streptomyces erythrois in a suitable medium, as described in US Pat. No. 2,653,899. Erythromycin is produced in two forms, A and B, and is represented by the following structural formula.

The structural formula shows that the antibiotic consists of three main parts: a sucrose fraction known as cladinose, a second sucrose site containing a basic amino substituent, known as desormine, and 14 known as erythrolide A or B. The number of the raw lactone ring, the macrolide ring, and the macrolide ring is just a number, the large source amine is represented by a prime ('), and the cladinose is represented by a double time (").

Many derivatives of erythromycin have been prepared for the purpose of improving biological and pharmaceutical properties.

US 3,417,077 describes reaction products of erythramycin and ethylene carbonate as excellent antimicrobials and US 3,884,903 describes 4 "-deoxy-4" -oxo-erythromycin A and B derivatives useful as antibiotics. .

Erythromylamine, a 9-amino derivative of erythromycin A, has been steadily studied (see, eg, British Patent No. 1,100,504, Tetrahedron Letters., 1645 (1967) and Croatica chemica Acta, 39, 273 (1967)) and its structure Has been debated. Tetrahedron Letters 157 (1970) and British Patent No. 1,341,022. Sulfonamide derivatives of erythromyylamine are useful as antimicrobial agents and are described in US Pat. No. 3,983,103. Other derivatives have also been reported to have antimicrobial activity in vivo and ex vivo. See, J. Med.chem., Ryden et al., 16, 1059 (1973) and J. Med. chem., 17, 105 (1974)]

The compound of the present invention used as an intermediate for preparing the 4 "-deoxy-4" -aminoerythromycin A antibacterial agent can be represented by the following general formulas (I) and (II).

이고 R₃는 수소이고 R₂및 R₃는 함께일 경우

이다.Wherein R ₁ is hydrogen or alkanoyl of 2 to 3 carbon atoms, R ₂ is alkanoyl of 2 to 3 carbon atoms, and Y is N-OH or

And R ₃ is hydrogen and R ₂ and R ₃ are together

to be.

Preferred of these compounds are those of the formula (I) and are particularly preferred when R ₁ is hydrogen or acetyl.

The second preferred compound is of formula (II) and is particularly preferred when R ₁ is hydrogen or R ₁ is acetyl.

The compound of formula (I) or (II) of the present invention is reacted with N-chlorosuccinimide and dimethyl at 0 to -25 ° C in the presence of a solvent inert to the reaction of the compound of formula (I ') or (II'). It is prepared by reacting with each mole of sulfide followed by contact with at least one mole of triethylamine.

이다.Wherein Ac and R ₂ are each alkanoyl having 2 to 3 carbon atoms, R ₃ is hydrogen and R ₂ and R ₃ are together

to be.

Preferred among the above reactions is the use of benzene and toluene as inert-reaction solvents.

Throughout the present invention, the chemical meaning of the sucrose and macrolide cyclic substituents is that of naturally occurring erythromycin (except epimerization at the 4 "-position).

Also included in the present invention are derivatives of erythromycin B, which are compatible with derivatives of formulas (I) and (II). Erythromycin B compounds are also useful as intermediates in the preparation of 4 "-deoxy-4" -amino erythromycin A antibacterial agents and are prepared by the same synthetic procedures as erythromycin A compounds.

Detailed description of the preparation of the compounds of the invention used as intermediates for the preparation of 4 "-deoxy-4" -amino-erythromycin A is as follows: 2'-alkanoylerythromycin A, or derivatives thereof. Using as a starting material, it is prepared according to the following scheme.

이다)를 산화시켜 4"-데옥시-4"-옥소-에리트로마이신 A 화합물로 전화시키는 산화반응에 관한 것이다. 이 반응에서는 산화제로서 N-클로로석신이미드와 디메틸 설파이드의 사용하며 실제에서, 이들 두 반응물은 처음에 0℃ , 반응-불활성 용매에서 함께 혼합하고 10 내지 20분 후 온도를 0 내지 -25℃로 내리고 알콜물질(I') 또는 (II')를 첨가하며 상기 언급한 온도를 유지시킨다. 2 내지 4시간 반응시킨 후, 트리에틸아민 같은 3급 아민을 첨가하고 반응혼합물을 가수분해시킨 후 끝처리한다.This reaction is a 4 "-hydroxy substituent of the compounds of formulas (I ') and (II'), wherein Ac and R ₂ are each alkanoyl having 2 to 3 carbon atoms, R ₃ is hydrogen and R ₂ and R ₃ together Occation

Is converted to a 4 "-deoxy-4" -oxo-erythromycin A compound. In this reaction, N-chlorosuccinimide and dimethyl sulfide are used as oxidizing agents. In practice, these two reactants are initially mixed at 0 ° C., in a reaction-inert solvent, and after 10-20 minutes, the temperature is reduced to 0-25 ° C. Lower, add alcohol (I ') or (II') and maintain the above mentioned temperature. After reacting for 2 to 4 hours, tertiary amines such as triethylamine are added and the reaction mixture is hydrolyzed and finished.

For the amount of reactants, one mole of N-chlorosuccinimide and one dimethylsulfide per mole of alcohol used is required. Experimentally, in order to complete the reaction quickly, it is preferred to use succinimide and sulfad reactant in an excess of 1 to 20 times and the tertiary amine used must be compatible with the molar amount of succinimide used.

The reaction-inert solvent used in this reaction should be one that dissolves the reactants and does not react with the reactants or the formed product. Since the reaction is carried out at 0 to -25 ℃, it is preferable to use a solvent having the following freezing point in the reaction in addition to the above characteristics. Such solvents or mixtures thereof include toluene, ethyl acetate, chloroform, methylene chloride or tetrahydrofuran. Solvents that meet the above requirements but have a freezing point or higher can be used in small amounts by mixing with one or more of the preferred solvents. Particularly preferred solvent for this reaction is toluene-benzene.

Preferred compounds prepared by this reaction are 11,2'-diacetyl-4 "-deoxy-4" -oxo-erythromycin A 6,9-hemiketal, 2'-acetyl-4 "-deoxy-4 "-Oxo-erythromycin A 6,9-hechemical 11,12-carbonate ester and 2'-acetyl-4" -deoxy-4 "-oxo-erythromycin A.

The reaction time is not limited and depends on the concentration, the reaction temperature and the intrinsic reactivity of the reactants. When the reaction temperature is 0 to -25 ℃ reaction time is 2 to 4 hours.

In the order of addition of the reactants, as already mentioned, it is preferable to add the alcohol substance (I ') or (II') to the premixed succinimide derivative and dimethyl sulfide.

The 4 "-deoxy-4" -oxo compound of the following structural formula (II) of the present invention is prepared by treating the compound of the following structural formula (I) with alkanolic anhydride (R ₂ O) and pyridine.

Wherein R ₁ and R ₂ are each alkanoyl having 2 to 3 carbon atoms, R ₃ is hydrogen and Y is oxygen.

In practice, it is preferred to react ketone (I) with excess anhydride in a pyridine solvent and to use an excess of 4 times the anhydride in the reaction. The reaction is typically carried out at ambient temperature at which the reaction time is about 12 to 24 hours.

Removal of the alkanoyl site at the 2'-position of the intermediates, ketones (I) (Y = 0) and (II), involved 2'-alkanoyl-4 "-deoxy-4" -oxo-erythromycin A The compound is carried out in a solvolysis reaction with excess methanol and stirring overnight at room temperature. Methanol is removed and, if necessary, the residue is subsequently purified to yield compounds of formula (I) (Y = 0) and (II), wherein R ₁ is hydrogen.

As already mentioned, the ketones of formulas (I) (Y = 0) and (II) are useful intermediates for preparing 4 "-deoxy-4" -amino erythromycin A antimicrobials. Preferred compounds are 2'-acetyl-4 "-deoxy-4" -oxo-erythromycin A 6,9-hechemical 11,12-carbonate ester and 4 "-deoxy-4" -oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester.

The following examples illustrate the invention in detail and thereby do not limit the scope of the invention.

Example 1

4 "-deoxy-4" -oxo-erythromycin A

Dissolve 4.0 g of 2'-acetyl-4 "-deoxy-4" -oxo-erythromycin A in 75 ml of methanol, stir at ambient temperature for 20 hours, remove the solvent under vacuum, and remove the resulting white foamy material. Recrystallization with chloride-hexane affords 3.44 g of the title compound having a melting point of 170.5 ° to 172.5 °.

NMR (δCDCl ₃ ): 3.36 (3H) s and 2.33 (6H) s.

Such products are isolated when 2'-propionyl-4 "-deoxy-4" -oxo-erythromycin A is treated with ethanol at room temperature.

Example 2

2'-acetyl-4 "-deoxy-4" -oxo-erythromycin A

13.7 g of 4 "-deoxy-4" -oxo-erythromycin A is dissolved in 100 ml of ethyl acetate and 2.3 ml of acetic anhydride is added to the stirred solution, and the resulting reaction mixture is stirred at room temperature for 2 hours. The solution is added to 100 ml of water and the pH of the aqueous phase is raised to 9.5 by adding 6N sodium hydroxide solution, the organic layer is separated, dehydrated over sodium sulfate, concentrated and recrystallized with methylene chloride-hexane to give 14.5 g of white foamy material. .

Example 3

2'-Acetyl-4 "-deoxy-4" -oxo-erythromycin A 6,9-hechemal 11,12-carbonate ester

4.46 ml of dimethylsulfide are added to a suspension of 6.19 g of N-chlorosuccinimide suspended in 150 ml of toluene and 50 ml of benzene, cooled to -5 ° C. After stirring for 20 minutes, the resulting suspension is cooled to -25 [deg.] C. and 12.4 g of 2'-acetalerythromycin A 6,9-hemiketal 11,12-carbonate ester partially dissolved in 80 ml of toluene is added dropwise. During the addition the temperature is maintained at -19 to -25 ° C and then at -25 ° C for 2 hours. Add 6.79 ml of triethylamine all at once, remove the cooling bath and raise to -10 ° C. The reaction mixture is poured into water and the pH of the aqueous phase is adjusted to 8.4 to 9.0. The organic layer is separated, dehydrated over sodium sulfate and concentrated in vacuo to yield 14.0 g of a white foamy material. Treatment of the residue with diethyl ether crystallizes the foamy material which is filtered and dried to yield 11.3 g of a hard material having a melting point of 212 to 213.5 ° C.

NMR (δCDCl ₃ ): 5.26 (1H) t, 3.36 (3H) s, 2.30 (6H) s, 2.13 (3H) s, 1.63 (3H) s and 1.50 (3H) s.

In a similar manner, 2'-propionyl-4 "-deoxy-4" using the same amount of 2'-propionyl-erythromycin A 6,9-hemictal 11, 12-carbonate ester instead of 2'-acetylester -Oxo-erythromycin A 6,9-hemical 11,12-carbonate ester is obtained.

Example 4

4 "-deoxy-4" -oxy-erythromycin A 6,9-hechemal 11,12-carbonate ester

42.9 g of 2'-acetyl-4 "-deoxy-4" -oxo-erythromycin A 6,9-hemiketal 11, 12-carbonate ester was added to 800 ml of methanol and the resulting solution was stirred at room temperature for 72 hours. The solvent is then removed in vacuo to yield 41 g of white foamy material. The residue is dissolved in 100 ml of acetone and water is added carefully until it precipitates. The resulting crystalline solid was stirred for 40 minutes, filtered and dried to give 34.2 g of the desired product having a melting point of 186.5 to 188 ° C.

NMR (δCDCl ₃ ): 5.66 (1H) t, 3.35 (3H) s, 2.35 (6H) s, 1.65 (3H) s and 1.51 (3H) s.

In a similar manner, the same product is obtained using 2'-propionyl-4 "-deoxy-4" -oxo-erythromycin A 6,9-hemiketal 11,12-carbonate ester instead of 2'-acetylester. .

Claims (1)

The compound of formula (I ') or (II') is then reacted with each mole of N-chlorosuccinimide and dimethylsulfide at 0-25 ° C. in the presence of an inert solvent, and then the reaction mixture is at least 1 mole triethyl. Characterized by contacting with an amine to prepare a compound of formula (I) or (II).

In the regular formula Ac and R2 are each alkanoyl having 2 to 3 carbon atoms, and R3 is hydrogen; R2 and R3 together

Indicates.