UA30387U - Process for 3-phosphorylation of indoles with free nh-function - Google Patents

Abstract

A process for phosphorylation of indole of formula (I):wherein indole is treated with phosphorus trihalide (РНаl), where Hal is halogen atom, in the presence of base with the preparation of 3-phosphorylated indole of formula (II):.

Description

Description of the invention

A useful model concerns the mode of 3-phosphorylation of indoles with a free MH function. 2 Indole can rightly be called a unique compound and it can be stated with certainty that no other compound has been devoted to so many publications (ХОХ, 1969, 23, 360; ХОХ, 1970, 40, 498; ХОХ, 1974, 44, 2668;

ZHOH, 1976, 26, 2204). The indole system is part of many biologically important compounds. As an example, we can mention an irreplaceable amino acid - tryptophan, a plant growth stimulator - indoleacetic acid, one of the mediators in the transmission of nerve impulses - serotonin, a large group of indole alkaloids, a number of 70 antibiotics (for example, indolmycin, pimrin). In medical practice, synthetic indole preparations with a diverse spectrum of action are used: mexamine (for the prevention of radiation damage), indopan (an antidepressant), indomethacin (an anti-inflammatory drug) and others.

The high biological activity of organophosphorus compounds is well known, among which highly effective pesticides, compounds with anticholinesterase activity, antiviral and antimicrobial effects are found. 12 It is obvious that the combination of indole and phosphorus fragments in one molecule allows us to expect from phosphorus-containing indoles the manifestation of certain useful properties, primarily biological activity. An example of such a combination can be a natural compound - psilocybin (dimethyltryptamine 4-phosphate) - the active substance of "Mexican mushrooms" with a high hallucinogenic effect (ХОХ, 1975, 45, 2338). 7 cook nal b

N Z

Psilocybin

Therefore, it was interesting to obtain phosphorylated indoles with a free MH function, which can be used for various chemical transformations to obtain new phosphorylated indoles with new biological properties. -

Several examples of the synthesis of phosphorylated indoles with a free MH function are described in the literature. Thus, the authors of Irobit Sag7.Spit.a!., 1930, 60, 144 and ZhOH, 1974, 44, 2587) mention the method of indole phosphorylation using organomagnesium compounds, as a result of which phosphines are formed, which are unsuitable for further SU chemical transformations, and as well as reactions of indoles with amidophosphites or amidophosphates, in which a primary attack on the nitrogen atom occurs and M-P-derivatives are formed, which are then rearranged into 3-phosphorylated indoles. at

But amidophosphites and amidophosphates are not substances suitable for further chemical transformations, therefore, the application of this method is quite limited.

Therefore, the task of a useful model is to develop a simple and general method of 3-phosphorylation of indoles with a free MH function. "

The problem is solved by the method of indole phosphorylation of the formula (1): still "-c", in which the indole is treated with a phosphorus trihalide (PnNaII 5), where Na! means a halogen atom, in the presence of a base to obtain the 3-phosphorylated indole of the formula (I):

РНЯ з о оз n «0

In a preferred embodiment of the utility model, Nai means an atom of SI, Vg, and I. More preferably, Nai means an atom of SI. Phosphorylation described above is carried out in a solvent in the presence of a base in an inert atmosphere. Any suitable organic solvent that does not react with the reagents used, for example, methylene chloride, methylene bromide, chloroform, carbon tetrachloride, etc., can be used as a solvent. As a base, any suitable base that does not react with the reagents used can be used, for example, organic bases such as pyridine, triethylamine, triisopropylamine, M-methylmorpholine, etc. are preferred. The base is used in this method to bind the hydrogen halide released as a result of the reaction. To create an inert atmosphere, any inert gas that creates favorable conditions for the target reaction can be used, for example, argon. It will be apparent to one skilled in the art that the base can be used as a solvent when used in the appropriate proportion.

In a preferred embodiment of the utility model, methylene chloride is used as the solvent and pyridine is used as the base.

The temperature of the reaction lies in a fairly wide range and depends on the reactivity b5 of the reagents used. Usually, the reaction is carried out at a temperature from -102C to the boiling point of the solvent used. A temperature of 02 to room temperature is most preferred.

One of the features of the proposed method is that, first, phosphorylation occurs on the nitrogen atom of indole with the formation of an M-phosphorylated derivative, and then, upon aging, the resulting

M-phosphorylated derivative in solution at room temperature undergoes migration of the dichlorophosphino group

From the position of the indole cycle, i.e., rearrangement occurs according to the following scheme:

Hn

SO SO what s vnytna

I am for us, tanperatuty N vs

Esh "shi Esh nd dO shi.

Such rearrangement was not known before and allows to obtain many 3-phosphorylated indoles with 79 free MH function.

Compounds (II) and (I) were not isolated from the reaction mixture due to their instability, while their formation was recorded by NMR spectra on 3D.

The obtained compound of formula (I) can be converted into stable compounds, for example, by treatment with suitable reagents, for example, alcohols, thiols, amines, etc., and by parallel oxidation to obtain the corresponding phosphonic acid derivatives.

For example, morpholine and elemental sulfur were used to stabilize the compound of formula (II). By boiling the compound of formula (I), morpholine and elemental sulfur for 30 minutes, the compound of formula (IM) was obtained:

With c With 2 so and (ge) "in

The reaction was carried out in the same reaction mixture containing the dichlorophosphinoindole of formula (II) and the resulting derivative of formula (II) was isolated in the usual way and the structure was confirmed using physical methods such as

NMR for UR, "H and "ZS, chromatographic separation with mass spectrometric detection.

From the above, it is clear that the proposed method of C-phosphorylation of indoles with free o

The MH function allows to obtain 3-phosphorylated MH-indoles containing a highly reactive dichlorophosphino group in the 3-position. By carrying out chemical transformations on this group, many new derivatives can be obtained. In addition, it is possible to modify the molecule according to the MH function. That is, C3-phosphorylated MH-indoles with a dichlorophosphino group are key starting compounds for the synthesis of a number of new phosphorylated indoles - C 70 potentially biologically active substances. c The possibility of implementing a useful model is confirmed by the following example. from Example 1 1H-indol-3-yl(4-morpholyl)|-phosphinosulfide

0.0 imol of phosphorus trichloride was added to a solution of 0.01 mol of indole and 0.01 pyridine in bOml of methylene chloride in an atmosphere of dry argon while cooling with ice at 15 °C and stirring. The reaction mixture was kept at room temperature for 4 days (NMR ZR d -158.2 m.h4.). Then 0.04 mol of morpholine and 0.01 mol of elemental sulfur were added to the reaction mixture and refluxed for 30 minutes. c It was cooled, the precipitate of salts was filtered off, the filtrate was evaporated and the residue was extracted with a mixture of hexane:diethyl ether 1:1. Crystallized from acetonitrile. Exit 53905. so Tpl.-131-13296. "h with NMR (DMSO-AIV) 869.00. "IN NMR (DMSO-adv): 82.99 (m, 8H, O-CH"); 3.56 (m, 8H, M-CH"); 7.15 (m, 2H, Ag); 7, 47 (d1H, dnn-b Hz, Ag); 7.8 (w s, 1H, H»); 7.92 (d, 1H, Unn-e Hz, Ag); 11.84 (w s, 1H, M-N). 59 t/2351|MI". c Calculated, 90: C46No»oMa3OoR Z (351): C 54.69; H 6.31; M 11.96. Found, 9o: C 54.52; H 6.18; M7,11.

Claims (8)

The formula of the invention 1. The method of indole phosphorylation of formula (1): b5 | "ShSH in which indole is treated with phosphorus trihalide (Rnai| z), where Na! means a halogen atom, in the presence of a base with the production of 3-phosphorylated indole of formula (II): Na, -. . (at 70 2. The method according to claim 1, where Na! means SI, Vg or I. 3. The method according to claim 1, where phosphorus trichloride is used as RNa!z. 4. The method according to claim 1, where pyridine is used as a base. 5. The method according to claim 1, where the phosphorylation reaction is carried out in a solvent such as methylene chloride. 6. The method according to claim 1, where the phosphorylation reaction is carried out in an inert atmosphere. 7. The method according to claim 1, where the phosphorylation reaction is carried out at a temperature from 02C to room temperature for up to 4 days. 8. The method according to claim 1, where the obtained compound of the formula (I) is treated in a reaction mixture with morpholine and elemental sulfur to obtain the compound of the formula (IM): oh shk; at. 4 v -o M n ' Na che Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated circuit microcircuits", 2008, M 4, 25.10.2008. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. о со - с з з о з со с 60 b5