DE4138616A1 - Prepn. of acylated single carbon-hydrogen and cpds. - by acid deriv. in presence of calcium cpd., useful in prepn. of intermediates used in pharmaceuticals and plant protectives - Google Patents

Abstract

Prepn. of ketones of formula (III) comprises reating a C-H acid cpd. of formula (I) with an acid deriv. of formula R4COX (II) in presence of a Ca cpd. of formula Can(R6)m (V). In the formulae R1-R3 = COOR', COR' SO2R', CN, NO2, halo or H; R' = alkyl; R4 = opt. substd. alkyl, cycloalkyl, alkenyl, alkynyl, X = a leaving gp.; n = 1 or 3; m = 1 or 2; R6 = halo, NO2, NO3, CN, SO4, BF4, S, PO4, ClO4 or R4COO. USE/ADVANTAGE - (III) are useful in prepn. of intermediates for use in prodn. of pharmacueticals and plant protectants. Reaction is quick and uses cheap and readily accessible Ca cpds.. Reaction takes place at 500m temp. in acetone (which is practically non-toxicds

Description

The invention relates to a process for the acylation of C-H-acids Links. Acylated C-H-acidic compounds are valuable intermediates for active pharmaceutical ingredients.

The process is characterized in that C-H-acidic compounds of Formula I,

in which
R ¹ , R ² , R ^{3 may be the} same or different and mean COOR ', COR', SO ₂ R ', CN, NO ₂ , halogen or hydrogen and
R 'represents alkyl, in particular C ₁ -C ₆ alkyl,
with compounds of the formula (II),

R⁴-CO-X (II)

in which X represents a leaving group, preferably halogen, particularly preferably fluorine and chlorine, and
R ^{4 represents} optionally substituted, preferably halogen-substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heteroaryl, to the pharmaceutically valuable intermediates of the formula (III)

be implemented. The compounds of the formula (III) can be wholly or partly in the enol form if one of the substituents R ¹ , R ² or R ^{3 is} hydrogen.

The reaction is carried out in the presence of a tertiary base of the formula (IV)

N (R⁵) ³ (IV)

wherein R⁵ preferably alkyl, cycloalkyl, aryl or heteroaryl, especially preferably C₁-C₄-alkyl or cyclohexyl, the radicals R⁵ also can be different and in the presence of a compound of formula (V)

Ca _n (R⁶) _m (V)

wherein
R ^{6 can be the} same or different and represent halogen, NO ₂ , NO ₃ , CN, SO ₄ , BF ₄ , S, PO ₄ , ClO ₄ and R ₄ -COO and
n for 1 or 3 and
m represents 1 or 2, depending on the valence of R ⁶ ,
in the substantial absence of water, optionally in an inert solvent, preferably in acetone.

No component of the reaction mixture should have a water content greater than 2% by weight, preferably not more than 1.5% by weight, particularly preferably not more than 0.5% by weight.

CaCl ₂ is particularly preferably used in the commercial form customary for drying purposes.

The process is preferably carried out with compounds of the formulas (I) to (V) in which R ¹ COOR ⁴ or COR ⁴ are independent of one another
R ² COOR ⁴ or COR ⁴
R ³ H,
R ⁴ CH ₃ , C ₂ H ₅ , particularly preferably C ₂ H ₅ , aryl, particularly preferably halogen-substituted aryl and heteroaryl,
R ⁵ C ₂ H ₅ and
R ⁶ Cl
mean. The process according to the invention is particularly preferably used in the synthesis of the active compounds ciprofloxacin, enrofloxacin and the antifungal 2, as described in more detail below.

The compounds of formula I are usually equimolar to those of Formula II used. An excess of I can be beneficial in some cases, what can be determined by simple preliminary tests.

The calcium compound (V) is obtained in at least a stoichiometric amount on (I). An excess of 5-50 mol%, based on (I), favors the Amount of the yield and purity of the product (III), preferably (V) is used in 5 mol% excess, based on (I). The base (IV) is usually in double the molar amount of calcium compound (V) used.

It is extremely surprising that compounds of the Formula (V) activate the reactants in such a way that the reaction proceeds. Without No reaction takes place when the compounds of the formula (V) are added. In the chemical literature there is no evidence that calcium compounds have a have such a reaction-promoting effect.

Compounds of the formula (V) in which R ⁶ denotes halo are preferably used, and CaCl ₂ is particularly preferred.

It is known that anhydrous magnesium chloride for the acylation of malonic esters and acetoacetic esters was used (M.W. Rathke and P.J. Cowan, J. Org. Chem. 50, 2622 (1985). This publication also describes a number of metal chlorides mentioned that do not produce these effects; among them are divalent metals like Zinc and copper. The prejudice is built up that other than magnesium divalent metals have no reaction-promoting effect. All the more astonishing is that calcium compounds are excellent, which are in the present Perform acylation reactions described in the application.

Compared to the prior art, which the exclusive suitability of Teaches magnesium compounds, the present method has the following advantages:

1. Anhydrous calcium compounds are in contrast to the corresponding ones anhydrous magnesium compounds very accessible and economical  advantageous. For example, water is used in practically every chemical laboratory free calcium chloride used for drying. Already the quality of this Calcium compound is ideally suited for the acylamine reaction.

In contrast, anhydrous magnesium chloride cannot easily pass through Dehydration of the hydrate can be made because of decomposition to the basic Chloride occurs. It is only with additional, complex measures possible to produce anhydrous magnesium chloride. Furthermore, anhydrous magnesium chloride only with technical effort Synthesis can be obtained from magnesium oxide, chlorine and coke (textbook the inorganic Chemistry, Hollemann-Wilberg, 81.-90. Edition, p. 683 and 686-687). Anhydrous magnesium chloride is therefore relatively expensive and large technical quantities difficult to obtain.

The reaction can be carried out in acetone. Acetone is cheap, non-toxic and environmentally friendly. In contrast, the publication of Rathke et al. Acetonitrile and methylene chloride used. Is acetonitrile, compared to acetone, to be described as extremely handy; it is also expensive. Methylene chloride is also toxic; it is compared to acetone to designate environmentally harmful.

The reaction can be carried out at room temperature. In contrast to the reaction with MgCl ₂ according to the prior art, it is not necessary to use lower temperatures. In any case, low temperatures mean higher energy consumption.

The response time is very short. The reaction is over after two hours Room temperature expired virtually quantitatively. According to the state of the art the response time may be 12 hours.

In summary, it can be said that acylation reactions of CH-acidic compounds can now be carried out in the presence of readily accessible and inexpensive calcium compounds in practically non-toxic acetone at room temperature in a very short time. The pharmaceutical active ingredients which can be prepared by the present process are e.g. B. the anti-infectives ciprofloxacin (1a) and enrofloxacin (1b) as well as the antimycotic known from EP-A-03 65 915 ( 2 )

The synthetic route of 1a, b begins with that described in EP-A-01 14 604 Acid chloride 3, which is converted to 4 by the present process.

4 is then further converted to 1a or 1b as described in EP-A-00 78 362.  

Compound 2 is obtained starting from the acid chloride 5 which is converted to 6 according to the invention:

The compound 2 described in EP-A-3 65 915 can be produced from 6 in the following way:

As already mentioned above, the production of these two active pharmaceutical ingredients is to be regarded as exemplary. In the same way from the acylated CH-acidic compounds by partial saponification and decarboxylation, β-keto esters or by complete saponification and decarboxylation, ketones can be prepared which are important intermediates for e.g. B. are pesticides.

example 1 2-bromobenzoylmalonic acid diethyl ester

To a suspension of 186.5 parts by weight. anhydrous calcium chloride and 269.1 parts by weight Diethyl malonate in 1600 parts by volume. Be acetone 340 parts by weight Triethylamine dropped. After briefly stirring Room temperature 351.2 parts by weight 2-bromobenzoyl chloride within 45 minutes dripped. After stirring for 45 min, a mixture of 400 parts by volume. conc. Salt acid and 1200 parts by volume Water added. The phases are separated, the organic phase is concentrated. One obtains in almost quantitative yield 2-bromobenzoyl malonic acid diethyl ester.

Example 2 2,4-dichloro-5-fluorobenzoyl malonic acid diethyl ester

2,4-dichloro-5-fluorobenzoyl chloride is reacted as in Example 1. You get in almost quantitative yield of 2,4-dichloro-5-fluoro-benzoylmalonic acid diethyl ester.

Example 3 Pivaloyl-malonic acid dimethyl ester

To a suspension of 17.5 parts by weight. anhydrous calcium chloride and 20.8 g Parts by weight Malonic acid dimethyl ester in 150 parts by volume. Acetone are 31.8 parts by weight. Triethylamine dropped. After briefly stirring, within 45 min 18.1 parts by weight Pivalic acid chloride was added dropwise at room temperature. After 2 hours A mixture of 38 parts by volume is stirred. conc. Hydrochloric acid and 113 parts by volume water dripped. The phases are separated, the aqueous phase is repeated several times Toluene extracted. The combined organic phases are combined with little Washed water, dried over sodium sulfate and concentrated. You get in almost quantitative yield of dimethyl pivaloyl malonate. The connection is identical to authentic material.  

Examples 4-9

As described in Example 3, the verbin listed in the table manufactured. They are in different proportions in the keto and Enol form (only the keto form is listed here for the sake of simplicity). All ver bindings are identical to authentic material.

Example 10 Phthalidylidenmalonsäuredimethylester (3-oxo-3H-isobenzofuran-1-ylidene) malonic acid dimethyl ester)

To a suspension of 35.0 parts by weight. anhydrous calcium chloride and 21.8 g Parts by weight Malonic acid dimethyl ester in 150 parts by volume. Acetone are 46.9 parts by weight. Triethylamine dropped. After briefly stirring, within 45 min 30.5 parts by weight Phthalic acid dichloride was added dropwise, the reaction mixture passing through Cooling is kept at room temperature. After stirring for 2 hours, a mixture from 38 parts by volume conc. Hydrochloric acid and 113 parts by volume Water dropped. The phases are separated, the organic phase is concentrated. 35.0 parts by weight are obtained. (89.1% of theory) Phthalidylidenmalonsäuredimethylester, which from toluene can be crystallized.

Claims (4)

1. Process for the preparation of compounds of formula (III) by reacting CH-acidic compounds of the formula (I) with compounds of the formula (II) R⁴-CO-X (II) in which
R ¹ , R ² , R ^{3 may be the} same or different and mean COOR ', COR', SO ₂ R ', CN, NO ₂ , halogen or hydrogen and
R ′ represents alkyl,
R ^{4 represents} optionally substituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl or heteroaryl and
X represents a leaving group,
in the presence of a tertiary base, characterized in that the reaction is carried out in the presence of a compound of the formula (V) Ca _n (R⁶) _m (V) in which, depending on the valence of R ⁶
n for 1 or 3 and
m represents 1 or 2 and
R ^{6 can be the} same or different and represent halogen, NO ₂ , NO ₃ , CN, SO ₄ , BF ₄ , S, PO ₄ , ClO ₄ and R ⁴ -COO. 2. The method according to claim 1, characterized in that it is in the Compound of formula (V) is calcium chloride. 3. The method according to claims 1 and 2, characterized in that it is in the compound of formula (II) around 2,4-dichloro-5-fluoro-benzoic acid chloride is concerned. 4. The method according to claims 1 and 2, characterized in that it is the compound of formula (II) is 2-bromobenzoic acid chloride.