DD251357A5 - METHOD FOR PRODUCING CYCLODEXTRIN INCLUSION COMPLEXES - Google Patents

Abstract

The invention relates to a process for the preparation of novel cyclodextrin inclusion complexes consisting of a calcium bis-O-methyl (2,2-dichlorovinyl) phosphate and 2 molecules of 0,0-dimethyl-O- (2,2-dichlorovinyl ) phosphate formed complex and cyclodextrin.

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of cyclodextrin inclusion complexes of the formula I in which CD is a group which can be eliminated by removing Vn hydroxyl radicals from the cyclodextrin molecule, preferably from / 3-cyclodextrin, and where η is a value between 0.2 and 0.3 prepared from a complex formed from the calcium bis-O-methyl-O- (2,2-dichlorovinyl) -phosphate and 2 molecules of 0,0-dimethyl-O- (2,2-dichlorovinyl) -phosphate (hereinafter Called Dankyl) and cyclodextrin - preferably ^ -Cyclodextrin - exist.

Characteristic of the known technical solutions

It is known that the 0,0-dimethyl-O- (2,2-dichlorovinyl) phosphate (hereinafter called DDVP) is a very strong pesticide. Several patents describe the preparation of metal-containing phosphate complexes and their use.

GB-PS 1108467 and NL-PS 6508497 describe the insecticidal and acaricidal activity of the metal-containing complexes of organic phosphorus compounds.

One of these metal complexes is the complex of formula (II) consisting of calcium bis-0-methyl-O- (2,2-dichlorovinyl) -phosphate and 2 molecules of 0,0-dimethyl-O- (2,2-dichlorovinyl ! -phosphate (Dankyl).

The preparation of the metal complexes of formula (II) was first performed by Mippon Kagaku Zasaki 91, 657-663 / 1970. No./ (Munekata and Enomoto) and in GB-PS 1108467. The above compounds have been found to be insecticidal and acaricidal.

The DDVP prepared earlier than the complexes of formula (II) forms a stable crystalline inclusion complex with β-cyclodextrin in which, at a molar ratio of 1: 1, the DDVP content is 16.2%. From this inclusion complex, the DDVP does not escape in the dry state at all; the active ingredient only releases when the complex comes into contact with water. The preparation, properties and uses of this complex are described in several publications (Migamoto, S., Mifune, A., Okada, Y., Yoenda, T. Ger., Open, 2422316 [1974]; Szente, Szejtli, J., et al .: Acta Chim. A. Sei. Hung, 107, 195 [1981]).

The insecticides or acaricidal 0.0-dialkyl-O- (2,2-dichlorovinyl) phosphate preparations proved to be compounds with a very short duration of action because of their instability.

The DDVP-cyclodextrin inclusion complex has advantageous properties, namely its instability is significantly reduced compared to the active substances used per se.

Object of the invention

With the invention, improved active ingredients of the aforementioned type are to be provided.

Explanation of the essence of the invention

The invention is based on the object, a process for the preparation of cyclodextrin inclusion complexes of the formula I.

provide.

According to the invention the object is achieved in that

a) a compound of formula I! or their saturated CI_ ₄ alkanolic solution with an aqueous solution or suspension is added of cyclodextrin or

b) a saturated C _1. * alkanolic solution of the compound of formula II is kneaded with cyclodextrin. Preferably, the caclodextrin is based on -1 mol of cyclodextrin - added 0.2-0.3 mol of the compound of formula II.

Achieved thereby is an extension of the active ingredient range of Dankyl with more advantageous properties than the DDVP by including the active ingredient in a complex. In this sense, test and structural studies were carried out on Dankyl-Wirkstöff and the novel Dankyl-jS-cyclodextrin inclusion complex according to the invention of the formula

(I) produced.

The DDVP-β-cyclodextrin inclusion complex is one arising from typical apolar-apolar interactions

Inclusion.

The Dankyl, however, clearly belongs to the coordination metal complexes. In the literature so far no evidence has been found that the coordination metal complexes can also form inclusion complexes. In view of the dimensions of the Dankyl molecule, the formation of such a complex is by no means self-evident. The DDVP molecule fits into the cavity of the jS-cyclodextrin but the four-molecule, cross-shaped coordination metal complex with a calcium ion in the center can not fit into a caclodextrin molecule. In order to achieve that the DDVP "branches" of the molecule of this cross-shaped coordination metal complex with ^ -cyclodextrin can be brought into an inclusion complex, a / 3-cyclodextrin arrangement with a specific, spatially crowded structure must be created in the crystal lattice, which is actually difficult to imagine is.

Precisely for this reason, during our own experiments, the surprising finding was made that the Dankyl forms stable inclusion complexes with cyclodextrin, which are very favorable from the point of view of the formulation of pesticides

Own properties.

Upon contact with water, the complex allows a constant release of the Dankyl, thus creating the possibility of producing preparations with long-lasting insecticides, acaricidal and anthelmintic effect.

The following are comparisons of the insecticidal activity and the duration of action of Dankyl and Dankyl-jS-cyclodextrin.

Inclusion complex described.

The test object was the WHO normal house fly sensitivity (Musca domestica). As a method of investigation, the "Tarsale Kontäkttest" was applied, the essence of which is that the animals get on a poisoned glass surface, which is covered with a Petri dish with a diameter of 9 mm. It was on the 1st, 2nd and 4th. Day-showing mortality in% (Table 1) and the time course of knock-down effectiveness (%) (Table 2) were measured

Form, the standard applied in acetone solution. - -

Table 1

Mortality in% at the house fly

insecticide Time after the dose * Treatment in days / xg / Petri dish 3 10 Mortality 44 26 30 Dankyl Dankyl / 3-CD complex 1 0 0 38 53 61 79 Dankyl Dankyl-ß-CD complex 2 0 0 0 23 62 76 Dankyl Dankyl-ß-CD complex 4 0 0 31 80

based on the pure active substance content of the complexes.

Table 2

Knock-down effect in% Exp. Time

JDankyL

Dankyl-.beta.-cyclodextrin complex

1 day 2 days 4 days 1 day 2 days 4 days 30 0 0 0 0 0 0 60 0 0 0 0 0 0 90 0 0 0 0 0 0 120 0 0 0 10 0 0 150 0 0 0 35 30 32 180 6 0 0 35 41 34 320 20 15 0 63 65 52

The data prove that the duration of action of Dankyl in complex form increases. At the highest dose (3 (Vg), the effectiveness of Dankyl decreases by half on the 4th day after treatment of the glass surfaces, while the effectiveness of the Dankyl / 3-cyclodextrin complex remains unchanged.

The stable Dankyl-jS cyclodextrin inclusion complex can be formulated mixed with commonly used carrier, adhesive and other excipients known in the formulation of pesticidal preparations.

embodiments

Further details of the invention will be apparent from the following embodiments.

example 1

Preparation of the Dankyl-β-Cyclodextrin Inclusion Complex

57.5 g (0.05 Mql) ^ -cyclodextrin are dissolved at 63 ° C in 500 ml of distilled water.

11 g (0.012 mol) of Dankyl are dissolved in 250 ml of 96 vol .-% ethanol and slowly added dropwise under stirring with the / 3-cyclodextrin solution.

The reaction mixture was cooled after the addition of Dankyls with constant stirring over 4 hours to room temperature, then for 12 hours (at +4 ⁰ C) kept on ice. The precipitation of the crystalline complex begins at 42 to 45 ° C.

The crystalline product is isolated by filtration and dried at room temperature over phosphorus pentoxide to constant weight.

Weight of white crystalline product: 43g.

The Dankyl content of the product was determined by elemental analysis. The chlorine content of the products was determined by elemental analysis and used to calculate the Dankyl content. The same procedure was followed in the following examples. Chlorine content: measured: 3.78%

calculated: 5.42%

Dankyl content: 11.6% yield on / 3-cyclodextrin: 66.1% on Dankyl: 45.4%.

Melting point: not characteristic, the substance turns brown at a temperature of 280-300 ⁰ C, then chars.

Example 2

57.5 g (0.05 mol) / 3-cyclodextrin are kneaded at 22 ° C for one hour with a solution of 11g Dankyl in 20 ml 96vol .-% ethanol until a nearly powdery product is obtained. The crystalline material is dried to constant weight under an infrared lamp. Weight of the product (white microcrystalline powder): 67.0 g Chlorine content: measured: 5.31%

calculated: 5.23%

Dankyl content: 15.5%

Yield on ^ -cyclodextrin: 98.4% on Dankyl: 94.4%

The thermal stability of the product thus obtained is lower than that of the product according to Example because of the surface-absorbed Dankyl (a few%). An advantage of the kneading method is undoubtedly the considerable improvement in the yield and elimination of treatment with mother liquor.

Example 3

57.5 g (0.05 mol) of ^ -cyclodextrin are allowed to mix at room temperature with TOOmI water.

A solution of 11 g (0.012 mol) of Dankyl in 250 ml of 96% ethanol is added dropwise with constant stirring to the aqueous suspension of / 3-cyclodextrin.

After addition of the Dankyl, the suspension is stirred at room temperature until, on microscopic examination, the Dankyl oil droplets next to the complex crystals are discolored. (This can be achieved after 48 hours of stirring.)

The product is isolated by filtration and dried at room temperature over phosphorus pentoxide to constant weight. Weight of the product: 62.0 g

Chlorine content: measured: 4.41%

calculated: 4.88%

Dankyl content: 14.8%

Yield on ^ -cyclodextrin: 91.8% on Dankyl: 83.4%

Example 4

11.35 g (10 mol) / 3-cyclodextrin are dissolved at 68 ° C in 100 ml of water, whereupon 2.2 g (2mMol) are added to 45-5O ⁰ C preheated Dankyl with intensive stirring.

After the disappearance of the solid or oily Dankyls the temperature of the reaction mixture is maintained at 68 ⁰ C for 30 minutes, then the resulting solution is cooled with constant stirring, within about four hours at 22 ⁰ C. The reaction mixture is maintained at a temperature between 0 and +5 ⁰ C for 18 hours, then the crystalline inclusion complex is isolated by filtration. It is then dried in air at room temperature to constant weight. Yield: 9.8 g of white crystalline inclusion complex

Chlorine content: measured: Dankylgehalt: 2.97% calculated Yield on / 3-cyclodextrin: 2.99% on Dankyl: 10.1% 77.6% 45.6%

Example 5 X-ray diffraction studies

The results of the X-ray diffraction powder diagram of the Dankyl-.beta.-cyclodextrin crystalline complex prepared according to Example 1 and the 'empty' .gamma.-cyclodextrin are shown in Table 3. Since the guest molecule is not crystalline, the presence of the complex is in the crystalline state showed significant deviations in the diffraction diagrams of the Dankyl-0-cyclodextrin complex and the similarly crystallized "empty" ^ -cyclodextrin.

Table 3

Characteristic diffraction peaks (2O ⁰ C)

^ cyclodextrin Dankyl-j 4.7 +++ 6 + 9.0 +++ 11.8 ++ 12.5 ++ + 12.5+ + 13.6 +++ 17,5 + 14.6 ++ 18.0 + 15.3+ + 21.0 + 18.2 + + 19.0 +++ 21.2 +++ 22.8 27.5

Dankyl-.beta.-cyclodextrin complex

Example 6 Thermoanalytical investigations

During the investigations, it was found that the thermostability of the included in the 0-cyclodextrin Dankyls increased significantly compared to that of the pure drug. The Dankylwirkstoff produced according to Example 3 shows when heated at a temperature of 141 ⁰ C, a maximum in the delivery of organic substances (measurement by the TEA method [Thermal Evolution Analysis]). If the Dankyl-jS-cyclodextrin inclusion complex is heated, a clear maximum can still be observed at 195 ° C, which results from the decomposition of the complex. At this temperature, no organic material is released from the Dankyl jS cyclodextrin inclusion complex. In the DTA curves (differential thermogravimetric analysis) characteristic differences between the Dankyl, the mixture of Dankyl and / 3-cyclodextrin and the Dankyl-β-cyclodextrin inclusion complex can also be observed.

Cl.

CH ₃ O

Cl

CH ₃ O / I

P-O-CH

CH ₁ O

0) _N ! / 0 _v 0CH-C.

ρ.

^cl

Cl

) -CH

CH ₃ O

CH ₃ O

^ P-O-CH = C Cl Cl

(I)

chjo

CH ₃ O / j

P - O - CH = CCl ₂

0 Ca ''

Cl ₂ C = CH-O '

- 'η

0-CH = CCl ₂ O-CH ₃

CH ₃ O

CH ₃ O

PO-CH = CCl ₂ (I)

12.1Z86- 394105

Claims (2)

1. A process for the preparation of cyclodextrin inclusion complexes of the formula (I), in which CD is a group which can be eliminated by removal of Vn hydroxyl radicals from the cyclodextrin molecule, preferably from β- cyclodextrin, and η is a value between 0.2 and 0.3, which consists of a complex formed from calcium-bis-O-methyl- {2,2-dichlorovinyl} -phosphate and 2 molecules of 0,0-dimethyl-O- (2,2-dichloro-vinyl-D-phosphate and cyclodextrin - preferably / 3 Cyclodextrin - consist, characterized in that a) adding a compound of formula (II) or its saturated C ₁ alkanolic solution with an aqueous solution or suspension of cyclodextrin, followed by isolation of the resulting crystalline substance, or b) a saturated C ₁ ^ ₁ alkanolic solution of the compound of formula (II) is kneaded with cyclodextrin. 2. The method according to claim 1, characterized in that the cyclodextrin - with respect to 1 mol of cyclodextrin - 0.2 to 0.3 mol of the compound of formula (II) is added.