JPS5988430A - Alkylation of compounds having ch- acid group under condition of gas liquid phase transferring catalyst - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the problem of providing a new process for alkylating CH-acid compounds, such as diethylmalonate, diethylacetoacetate and acetylacetone, in the gas/liquid phase.

In particular, the alkylation of compounds having active methylene groups, such as diethyl malonate and diethyl acetoacetate, is a synthetic technique widely used in the general chemical industry, the pharmaceutical industry, and the chemical community in general.

Usually strong bases Reaction with alcoholates usually yields reactive anions. Note that alcoholate is a reaction product of alcohol and sodium metal.

D, H, White (5ynth, Comm, 7,
559 (1977)) has recently proposed the use of weak bases such as 2CO3.

At this time, the operation is carried out in an azorotic solvent such as dimethylformamide.

Recently, the use of quaternary onium salts and ether-coulombic catalysts has also been proposed, which facilitates anionic activation under phase transfer conditions. It is something that makes you familiar. Brändström et al. describe the alkylation of acetylacetone with a conventional reagent in which the corresponding anion of the reagent forms the opposite moiety of the quaternary ammonium salt.

In order to use these catalysts in effective amounts for catalytic purposes, it is necessary to operate in the absence of water. This is because esters are hydrolyzed in basic media.

Akosude et al. (J, Org, Chem, 43',
4682 (1978) in the absence of water and in the presence of a catalytic amount (0.2 to 0.1 molar equivalents) of ammonium salt or ether-chlorine, diethylmalonate, ethylacetate, using 2CO3 as base. - Describes the alkyl-1-7, fillet method for various alkyl halogneeds of acetate and ethylmethylcyanoacetate.

A process for the alkylation of CH-acidic compounds under gas-liquid phase transfer conditions has now been found, which is the object of the present invention.

Catalytic methods for gas-liquid phase transfer are mainly used in other organic syntheses and Hibi-Penzurello Synthesis 952 (1979); , Chem, Commun
, 1127 (1980); (4) A survey;
Chi, Patsund and Böbenzühle, 7 o J, C
hem, Soc, Perkin I.

993 (1982) and other documents.

The process supports a phase transfer catalyst and operates without stirring in the absence of a solvent by passing the reactive compound continuously and in gaseous form through a fixed bed held in a cylindrical externally heated column. can do. The product is collected by condensation at the outlet. And because of the high reaction temperatures allowed and the absence of air, the reaction rate is high. 92 By adapting the outflow or passage of the reactive compounds to the amount of fixed bed in the column, the desired conversion rate is usually achieved. The purity of the product that can be obtained is increased.

Additionally, the present invention allows the effective use of otherwise less effective catalysts, such as polyethylene glycol (carbowax).

These catalysts are inexpensive, non-hazardous, remain active for long periods of time, and have economic advantages.

In this method, the reaction column is filled with an alkali carbonate or alkali bicarbonate which has adsorbed a phase transfer catalyst. The reaction temperature and reaction pressure are adjusted by suitable means to maintain the mixture of active compounds in gaseous form and are maintained between 150 and 200°C and between 0.013 and 0.04 bar (1
0 to 30 Torr; the reactive compounds are passed through the column by means of a pump, the value of which is between 1 and 5 ml per milliliter of column volume.

The molar ratio of base and CH-acidic compound is from the same to about 25
It is. Alkali halognides, on the other hand, are usually used in 50% excess.

The reaction product is collected by condensation at the outlet of the column using a cooling means.

The reaction mixture can be passed through the column repeatedly in a similar manner to increase the conversion to alkylated product.

Catalysts used with various activities and selectivities include phosphonium salts such as tetrabutylphosphonium bromide, e.g. 18-couronne-6
and etherchlornes such as dibenzo-18-chlorine-6 (
eters-couronnes) or polyethylene glycols such as Carbowax 6000.

Besides the classical substances such as malonic acid, acetoacetic acid, acetylacetone, etc. derivatives such as 1,3-cyclohexadione, dimedone, nitroalkanes and other commonly β
Other advantages of the invention include the absence of solvents, the ease of separation of the reaction products in high purity, and the carbonic acid of alkali metals. It consists in using weak acids such as salts and bicarbonates. In this way, the use of alkali metals for producing reactive anions can be avoided and the equipment set can be separated from the operating range, so that safety for installations on an industrial scale can be maintained very easily. Additionally, the catalysts that make such syntheses advantageous direct the reaction appropriately depending on whether a C-20- or di-alkylated product is desired; in particular carbowaxes are used as C-20- or di-alkylated products in the acetoacetate and acetylacetone synthesis. It shows remarkable selectivity towards alkylated products.

In fact, it is possible to produce products in which the carbon atoms are mono- or dialkylated. In the case of anions whose charges are dispersed in two positions, such as those obtained from acetylacetone and acetoacetone, it is possible to obtain a product in which the carbon and oxygen are dialkylated, or a product in which oxygen is alkylated. It is.

It is possible to direct the reaction to the desired product by appropriate selection of the base, catalyst and liberating group as known in the literature, and by the specific reagents used for the alkylation. In particular, Na HCO3 increases the C-alkylation rate. However, the rate of change is not significantly increased by the proportion of carbonates such as 2C05. On the other hand, since the reaction is not an equilibrium reaction, the rate of change can be controlled either by reducing the amount of the two reactive compounds passing through and, as a result, increasing the contact time, or by increasing the amount of solids in the column. can also be increased by passing the reaction mixture through the column several times. The dimensions of the tower play a fundamental role in that regard as well.

A very important factor in its selectivity is likewise that the catalyst is dispersed as a liquid film over the surface-enhanced spread of the base used, allowing the reaction to proceed and the diffusion of the reactive compounds in the gaseous state. Yosi.

The selection of catalysts is also based on the fact that they provide a medium that promotes the reaction by continuously transferring anions from the liquid phase to the solid phase and vice versa. For this reason, the catalysts used in GL-PjC are reactive anions (in the case of anions whose charges are distributed in two places) as well as for the direction of the reaction for C-alkylated or O-alkylated products. Appropriate attention is paid to both the stabilization of the product and the product.

In the total synthesis described, the effectiveness of the catalyst is expressed as a function of the conversion rate obtained and the dipenzo-18-reo y) B
u40+Br-Tom18-Cron-6>Carbowax They differ in rank.

The catalysts also differ in the ratio between C-alkylation and O-alkylation and in the formation of the anion of the C-alkylated product.

In particular, polyethylene glycol provides a highly polar medium compared to other catalysts governing the reaction to C-alkylated products. C2C-dialkylation and C20-dialkylation products do not occur due to the fact that this medium is also not in a state to form the anion of the C-alkyl product.

The etheric acid produces a polar medium in the protish as well as the medium provided by the carbowax, but the carbowax provides a C-alkylation as well as an O-alkylation.
Suitable for forming anions of alkyl products. The above-mentioned anion formation effect appears even more strongly when Bu4P Br- is used as a catalyst. And that is C
This is demonstrated by the excellent production of 3C-dialkylation (synthesis with malonic acid, acetoacetate and acetylacetone) and C,Q-dialkylation (synthesis with acetylacetone and acetoacetate).

The following examples illustrate the invention.

Example 1° a) Preparation of the catalyst bed
Dissolve I dibenzo-18-chlorine-6 and 649 g (5 weight strips) of Carbowax 6000) in methanol (carbowax and phosphonium salts) or methylene chloride. To the solution thus obtained is added 0.95 mol of 2CO3 or NaHCO3, previously dried in an oven at 120 DEG C. for 2 hours. The suspension obtained is evaporated under reduced pressure and the residue is dried in an oven at 120° C. for 3 hours.

b) Synthesis using malon ester, acetoacetate and hyacetylacetone la) in a horizontal glass tower with a height of 40 cm and a diameter of 2t7n.
(Depending on the bed thickness, 50 to 60 I
) The temperature regulated by the thermostat is brought to 170° C. under a pressure of 20.155 76 oPa. Using a pump, various amounts of a mixture of alkyl halognide and the compound to be alkylated in a molar ratio of 1.5:1.0 (containing base and active notylene groups, depending on the amount of base present in the column) are added. (so that the molar ratio of the compounds is 2.5) g
Introduce at a liquid outflow rate of Q mVh. This mixture passes through the column in vapor form. The gaseous products are condensed at the outlet using cooling means.

Qualitative and quantitative analysis of the reaction product mixture was carried out by gas chromatography in a Varapport column containing 5 parts of fiSE-30 (100-240%).
°C, 20 °C/m).

Example 2. Diethyl malonate noalkylation with 1-bromobutane Example 1. The influence of base, catalyst and their ratio in the reaction of diethyl malonate and 1-bromobutane under the conditions of b) was investigated. The conversion rates and relative percentages of hepnotic and di-alkylated products are listed in Table I. Rates of change are based on reacted diethylmalonate.

Table 1 Influence of alkylation of diethyl malonate with 1-brombutano base, catalyst and its % content a: alkylha, lognide: compound with active methylene group: base = 1.5: 1.0: 2.5 (m
:m) b: The catalyst content is expressed in weight in the case of carbowaxes, and in moles in the other cases.

c: T=180°C; alkyl halognide: malonate,
Base=3. O: 1.0: 6.0 (m: m)
Example 3 Alkylation of diethylmalonate and influence of groups removed Under the conditions of Example 1, the influence of groups liberated or removed during alkylation of diethylmalonate was investigated.

BuCl, BuBr, and BI were commercially available.

n-butylmedile), BuOMs are U, C,
5ekera etcol, u, A%, Cher
t, Soc, 55, 343 (1933). The results are shown in the following table ■.

The catalyst used is 5% polyethylene glycol (Carbowax 6000).

Table ■ Examples of alkylation of diethylmalonate using various reagents 4 Example of alkylation of ethyl acetoacetate using Aprompukun 1. Under the conditions of b), the effects of the base, catalyst, and their content on the reaction between ethyl acetoacetate and 1-bromobutane (commercially available product) were investigated. This rate of change and the relative content of mono- and dialkylated products and 〇- and C,O-alkylated products are shown in Table 2. This rate of change is based on 1·1 of ethyl acetoacetate reacted.

Example 5 Alkylation of ethyl acetoacetate. Example of influence of removed groups 1. The influence of the butyl-releasing group was investigated by the method of Example 3 under the same conditions as b). As in Example 3, the reaction rate is I-
”=Ms:) Br >> CI, its influence on the direction of the C- or 0-alkylation reaction is the same, consistent with the literature. The results are listed in the following table ing.

Table■ 2CO3 + 5 layers of Carbowax 6000
Catalyst Bed Example 6 Alkylation of Acetylacetone with 1-Bromobutane The alkylation of acetylacetone with 1-bromobutane was studied under the conditions of Example 1 b) and in the presence of various catalyst beds.

Table V lists the results obtained.

Example 7゜Alkylation of acetylacetone. Influence of the groups removed Table 1 lists the conversion rates and the proportions of C-alkylated and 0-alkylated products and of C3C-dialkylated and C10-dialkylated products. In this case, acetylacetone is added in Example 1 in the presence of butyl chloride, butyl bromide and butyl iodide. It was placed under the condition of b). The composition of the catalyst bed was 2Co, + yN-lyethylene glycol (5 parts by weight of Calgowanox 6000).

EXAMPLE 8゜NaHCO3+ 5% by weight of diethyl phthyl malonate (227 mol) obtained in the reaction of Example 2 using a catalyst bed consisting of carbowax in an amount of 5% by weight to the same catalyst bed. I passed it for the second time. The conditions at that time are Example 1. It was b). In this way C
- An increase in the products of alkylation was achieved (the original value of 22.7% rose to a factor of 385). Further, the amount of C,C-dialkylation product was very small.

Example 9 Example 1. Under the conditions of b), the conversion of ethyl acetoacetate to butyl-ethyl acetoacetate using 1-bromobutane was investigated, and the ratio of base and catalyst used was varied depending on the number of moles of reactive raw material compounds in the column. I let it happen. Example 1・a
), tetrabutylphosphonium bromide,
18-Clone-6 adsorbed on polyethylene glycol (Carbowax 6000) and 2CO3 was used. Ester and 1-bromobutane (1/1.5 m/
m) was continuously introduced into the column. Then various fractions of the reaction mixture were obtained. This mixture was analyzed and shown in the attached drawing as the molar ratio of the introduced ester/the molar ratio of the base most present in the rice grains.

[Brief explanation of the drawing]

The drawings are explanatory diagrams of the present invention. Agent: Patent attorney, Sunagawa Department 5 (1 other person)

Claims (1)

[Scope of Claims] (1) A catalyst bed consisting of an alkali carbonate or alkali bicarbonate on which a mixture of a compound containing all CH-acid groups and an alkyl halide, an alkyl mesylate, or an alkyl tosylate is completely adsorbed as a phase transfer catalyst in a gaseous state. Continuous alkylation method of a compound containing a CH-acid group with an alkyl logenide, alkyl dimedylate or alkyl tosylate (2) The compound having a CH-and group is a diester of malonic acid, Claims (1) and (2) characterized in that the phase transfer catalyst is tetrabutylphosphonium bromide. Process (4) according to claim 1, characterized in that the phase transfer catalyst is polyethylene glycol, especially Carbowax 6000 (
Processes (5) of 1) and (2), characterized in that the phase transfer catalyst is nityl-chlorine, in particular 18-chlorine-6 or dibenzo-18-chlorine-6. ) Method (6) The molar ratio of the base to the compound containing the cn-acid group is about 25:1, and the molar ratio of the alkyl halide, alkyl mesylate or alkyl tosylate to the compound containing the CH acid group is the same. The method of claims (1) to (5) is characterized in that the reaction acid product is about 15 to 1. Method (9) of Claims (1), characterized in that it is condensed and collected at the outlet; Claims (1) to (8) characterized in that KCO3 or NaHCO3 is used as a carrier for the base and catalyst; Method.