UA98280C2 - Process for the preparation of isothiochromene-4-one 2,2-dioxide - Google Patents

Abstract

The invention relates to the synthesis of 1H-isothiochromene-4(3H)-one 2,2-dioxide in order to enhance variety of compounds that can be used in medicine as compounds for the preparation of physiologically active substances. The technical result is in availability of initial compounds, high yield of desired product in three stages – 85%, short duration of reactions – minimum duration of each stage is 1 hour, ease separation of reaction products, extraction of spectroscopically pure compounds.

Description

This invention relates to the field of organic chemistry, in particular to the chemistry of heterocyclic compounds, namely to the method of obtaining isothiochroman-4-one 2,2-dioxide (1H-2-benzothiopyran-4(3H)-one 2,2-dioxide) of the general formula 1: 1 from which can be used as an intermediate compound for obtaining physiologically active substances in medicine |11.

The method for obtaining isothiochroman-4-one 2,2-dioxide 1 (2-31), according to which the process occurs in three stages (scheme 1): 1. Benzylthioacetic acid 4 was obtained by the interaction of benzyl hydrosulfide with a solution of chloroacetic acid Z in the presence of of sodium carbonate and sodium hydroxide when heated in a water bath for one hour (the yield is almost quantitative). 2. Compound 4 in benzene in the presence of P2O5 was converted into isothiochroman-4-one 5 (yield 37 Os) (21.

Another reference to the preparation of compound 5 with a yield of 60 95 was also found.

C. Compound 5 was converted into isothiochroman-4-one 2,2-dioxide 1 (yield 60 9b) in dichloromethane in the presence of m-chloroperbenzoic acid (MCPA).

СсИСН, СОоОНн зн

WITH

--- -y4--

Ma",so" 5. i7boH 2 4 (c)

R.O., RIN 5 itbOON MU-- 225252

WITH

4 5 o (c) sNn.si, ---zya

MOSRVA

5 To 5 (c) 1

Scheme 1

The disadvantage of this method is: low yield of the target reaction product in three stages, namely 36,905; long reaction time: third stage 20 hours; complications at the stage of product isolation 1, namely the need to observe anaerobic conditions for the reaction, time-consuming processes of washing, drying and evaporation of the organic phase of the reaction mixture, the need for additional purification of the product.

The invention is based on the task of creating a new, more convenient method of obtaining isothiochroman-4-one 2,2-dioxide, increasing the yield of the reaction product, reducing the complexity of product isolation, the time of the reaction itself, and increasing the safety of the synthesis.

The problem is solved by implementing a method for obtaining isothiochroman-4-one 2,2-dioxide 1 by the interaction of 2-(chloromethyl)benzonitrile 6 and thioglycolic acid ethyl ester 7 in the presence of a base in an organic solvent and oxidation of the obtained ethyl (2-cyanobenzyl)thioacetate 8 in ethyl(2-cyanobenzyl)usulfonyl|acetate 9 with an oxidant in an acidic environment with subsequent cyclization in an organic solvent in the presence of alkali metal alcoholates according to Scheme 2.

The first stage is carried out in acetonitrile at a temperature of approximately 10 to 81 2s, the reagents are taken in a stoichiometric ratio. After 1-5 hours, the precipitate is filtered. The filtrate is evaporated under reduced pressure and an oily liquid is obtained - compound 8. The second stage is carried out in acetic acid at a temperature from 0 to 70 "C with 33 96 hydrogen peroxide. Compound 9 is cyclized in ethyl alcohol in the presence of sodium ethylate at a temperature of 50-78 C, during 3 hours (third stage).

NZSNOSOE see

And S

--- SO! cm SNUSM, KoSO, Z 6 8

SM cm sov N.O,, NOAs

From 22220 in; in 9 cm about maogee ----»

S len EUN 9 rev (c) 1

HER scheme

The obtained product has sufficient purity for further use in the synthesis of other chemical compounds, including biologically active ones. However, if there is a need for additional purity of the product, the isothiochroman-4-one 2,2-dioxide obtained by the claimed method can be purified by well-known methods, such as crystallization. As a result, pure isothiochroman-4-one 2,2-dioxide is isolated with a yield of 93 95.

The invention is confirmed by the following examples, which illustrate, but do not limit the scope of this invention. 1. Method of synthesis of isothiochroman-4-one-2,2-dioxide

The first stage. Methodology of the synthesis of ethyl (2-cyanobenzyl)thio|)acetate 8.

A mixture of 100 mmol of 2-(chloromethyl)benzonitrile b and 100-105 mmol of thioglycolic acid ethyl ether 7 is dissolved in 750-900 mmol of acetonitrile. When stirring, add 50-100 mmol of potassium carbonate. Stir for 1-18 hours. Potassium carbonate is filtered. Evaporate the filtrate under reduced pressure. An oily liquid of ethyl (2-cyanobenzyl) thioacetate 8 is obtained.

Output 95 95. IR spectrum, U, cm"!: 2224.O8vsm, 1731.46bs-o; progo-1.5520; NMR spectrum "H (DMSO-av),

Magap Megsigu 400, 5, mch: 7.77 (1H, d, ZuUnene-8 Hz, AN), 7.67 (1H, t, ZUnana-7.6 Hz, Z)na-

Koo) n5-7.6 Hz, Ag"H), 7.57 (d, 1H, ZuOnz-at-7.6 Hz, AN), 7.48 (1H, t, ZOnv-at-7.6 Hz . (2Н, с, СН»), 1.29 (ЗН, и, Zunn-- 7.4,

Z)nn-7,4, СНз (ОБО); NMR "C, ppm: 14.54, 33.18, 34.62, 61.34, 112.81, 117.49, 128.43, 130.76, 133.30, 133.59, 141.78 , 169.67. Found, 95: M 5.58, C 58.92, H 5.576, 5 13.310.. C12H1izMO»5.

Calculated, 90: M 5.95, C 61.25, H 5.57, 5 13.63.

The second stage. The method of synthesis of ethyl((2-cyanobenzyl)sulfonyl|acetate 9.

Ethyl((2-cyanobenzyl)tide|acetate 8 (100 mmol) is dissolved in 700-800 mmol of acetic acid.

450-500 mmol of hydrogen peroxide is added to the cooling solution (0-10 72). The reaction mixture is kept for 1-12 hours at room temperature. The sediment is filtered, washed with water.

Output 96 95 (methanol), m.p. 75-77 C; IR spectrum, U, cm": 2229.69cm, 1742.65s-o, 1323.07o, (asym.) and 1155.24 zo, (sym.). NMR spectrum "H (DMSO-dv), Mapap Megsigu 400, b mch.: 7.84 (IN, d, 33-76 Hz, Ag9H), 7.73 (1H, t, Z)na-na-7.6 Hz, ZUna-nve-7.6 Hz , Ag"H), 7.64 (1H, d, 3)-7.6 Hz, AIZN), 7.60 (IN, t, Zunv-at-7.6 Hz, ZUnv-not-7.6 Hz , AN), 4.86 (2H, s, CH"), 4.46 (2H, s, AI-CH"), 4.26 (2H, sq,

З)нн-7.2 СНе (ОЭХ), 1.93 (ЗН, т, З)н-на- 7.2 Hz, З)н-нве-7.2 Hz, СН3 (ОЕО); NMR "C, ppm: 15.49, 57.74, 58.00, 62.41, 115.16, 117.47, 130.04, 130.99, 133.25, 133.44, 133 ,77, 163,21 Found, 90:

M 4.99, C 53.33, H 4.825, 5 11.801. С12Н13МО45. Calculated, 90: M 5.24, C 53.92, H 4.90, 5 12.00.

The third stage. Method of synthesis of isothiochroman-4-one 2,2-dioxide 1.

100 mmol of ethyl(2-cyanobenzyl)sulfonyl|acetate 9 is added to a solution of 200 mmol of sodium in 4200-4500 absolute ethyl alcohol. The reaction mixture is boiled for 1-3 hours. The solvent is evaporated under reduced pressure. Acidify with diluted mineral acid to an acidic reaction. The precipitate is filtered. Output 93 95 (benzene). IR spectrum, U, cm": 1689.51s-o, 1317.76 59" (asym.) and 1119.7599" (sym.); mp - 157-158 "С; NMR spectrum "H (DMSO-de), Mayap Megsigu 400, 5, m.h: 8.07 (1Н, d, З)na-nu-7.6 Hz, AIZN), 7.70 (1Н, t, ZUne-nu-7.2. Hz, ZOne-nu-7.2 Hz, AgH), 7.51-7.56 (2H, m, AgI"H, AgH) 4.85 (2H, s, C" Н2), 4.56 (2Н, с, СН2); .56, 135.57, 186.53. Found, 90: C 55.71, H 4.275, δ 16.37. CeNeOz5. Calculated, 90: C 55.09, H 4.11, 5 16.34. 2. Method of synthesis of isothiochroman-4-one 2,2-dioxide 1

The first stage. Methodology of the synthesis of ethyl (2-cyanobenzyl)thio|)acetate 8.

A mixture of 100 mmol of 2-(chloromethyl)benzonitrile b and 100-105 mmol of thioglycolic acid ethyl ether 7 is dissolved in 750-900 mmol of acetone. When stirring, add 50-100 mmol of sodium carbonate. Stir for 1-5 hours. Sodium carbonate is filtered. Evaporate the filtrate under reduced pressure. A clear oily liquid is obtained.

Output 88 95. IR spectrum, U, cm": 2224.08cm, 1731.46bs-o; pogo-1.5520; NMR spectrum "H (DMSO-dv),

Ko) Mapap Megsigu 400, b mch 7.77 (IN, d, Zunen-8 Hz, AN), 7.67 (1Н, t, ZUna-na-7.6 Hz, Zuna- n5-7.6 Hz, Ag"H), 7.57 (d, 1H, ZUNaz-at-7.6 Hz, AIZN), 7.48 (1H, t, ZOn-at-7.6 Hz, ZUn5-nve-8.0 Hz . 29 (ZN, t,

ЗОнн- 7.4 ЗОня 7.4, SNz (OB); NMR "ZS, ppm: 14.54, 33.18, 34.62, 61.34, 112.81, 117.49, 128.43, 130.76, 133.30, 133.59, 141 .78, 169.67. Found, 95: M 5.58, C 58.92, H 5.576, 5 13.310.

С1и2НизМО»5. Calculated, 90: M 5.95, C 61.25, H 5.57, 5 13.63.

The second stage. The method of synthesis of ethyl((2-cyanobenzyl)sulfonyl|acetate 9.

Ethyl(2-cyanobenzyl)thioacetate 8 (100 mmol) is dissolved in 700-800 mmol of acetic acid.

450-500 mmol of hydrogen peroxide is added to the solution. The reaction mixture is kept for 1-12 hours at room temperature. The sediment is filtered, washed with water. Output 82 95 (methanol), m.p. 400 75-77 2C; IR spectrum, U, cm": 2229.69cm, 1742.65s-o, 1323.0729" (asym.) and 1155.2490" (sym).

NMR spectrum of "H (DMSO-av), Magap Megsigu 400, b.m.h.: 7.84 (1H, d, 3)-7.6 Hz, AGeH), 7.73 (1H, t,

З) na-na-7.6 Hz, ZOna-n-7.6 Hz, AN), 7.64 (1H, d, 392-7.6 Hz, AIZN), 7.60 (1H, t, Z )nv-at-7.6 Hz, ZUnv- ne-7.6 Hz, Ag"H), 4.86 (2H, s, CH"), 4.46 (2H, s, AgheSNe"), 4, NMR "ZS, m.ch.: 15.49, 57.74, 58.00, 62.41, 115.16, 117.47, 130.04, 130.99, 133.25, 133.44, 133, 77, 163.21. Found, 9: M 4.99, C 53.33, H 4.825, 5 11.801. C12Niz3MO»5. Calculated, 90: M 5.24, C 53.92, H 4.90, 5 12.00.

The third stage. Method of synthesis of isothiochroman-4-one 2,2-dioxide 1.

100 mmol of ethyl(2-cyanobenzyl)sulfonyl|acetate 9 is added to a solution of 200 mmol of sodium in 3100-3300 isopropyl alcohol. The reaction mixture is boiled for 1-3 hours.

The solvent is evaporated under reduced pressure. Water is added to the residue. Acidify with diluted mineral acid where there is an acidic reaction. The precipitate is filtered. Output 87 95 (benzene). IR spectrum, U, cm": 1689.51 c-o, 1317.76 o, (asym.) and 1119.757 72 (sym.); mp - 157-158 C; Spectrum

NMR "H (DMSO-dv), Mapap Megsigu 400, 5 m.h: 8.07 (1H, d, Z)na-nu-7.6 Hz, AN), 7.70 (1H, t, ZOne- nv-7.2 Hz, Une-n-7.2 Hz, AgH), 7.51-7.56 (2H, m, Ag"H, AgH), 4.85 (2H, s, С"H» ), 4.56 (2Н, с, СеН»);

NMR "C, mp: 55.32, 62.17, 129.71, 129.78, 130.56, 130.73, 132.56, 135.57, 186.53. Found, 90:

C 55.71, H 4.275, 5 16.37. CeNeOz5. Calculated, 95: C 55.09, H 4.11.5 16.34.

Thus, the result of the invention is a simplification of the synthesis of isothiochroman-4(ZH)-one 2,2-dioxide of formula 1 and an increase in the yield of the product due to the use of a new technique.

Sources of information: 1. Rai. В 1 259 415 // IvoOtiosptotap sagrokhatidev5// СО7О 65/14; ABIK 27/00. 2.). Spent Bosieiu A. K. Kiapd apa ER. with. Mapp // Tne Bigisiyge apa Rgorepiev oi Sepaip

Roiususiis Ipdoio-apa Optsipoiipo-degimaymev5. Rai IM. Oegimaimev oi I-Tpiospgotap-4-ope apa oi 2-

Tpiospgotap-4-ope. // 1951, R. 1909-1914. 3. U. Ateg. Spent Zosieiu S. S. Rgise, M. Nogi, T. Ragazagap and M. Roik // Tpiarepepez.IM. 1- apa 2-Tniaparpina!ev apa 10-Tniaapingasepevz. Emidepse og susiis Sopiidaiiop // 1963, 85, R. 2278. 4. Sap. U. Spet. I. MU. U. BIJ apa 0. K. T. M/ivop // a-Okhovitev: geasiyuope m/yp aiKepe5 apa aiKupez /1992, M 70, R. 964-973.

Claims (6)

FORMULA OF THE INVENTION 1. The method of obtaining isothiochroman-4-one 2,2-dioxide 1 in three stages ! . | (c) 1, which differs in that mixing 2-(chloromethyl)/benzonitrile b and ethyl thioglycolic acid ester 7 in the presence of a base in an organic solvent, oxidizing the obtained ethyl(2-cyanobenzyl)tide|acetate 8 into ethyl|( 2-cyanobenzyl)sulfonyl|acetate 9 with an oxidant in an acidic medium, cyclize it in an organic solvent in the presence of alkali metal alcoholates, and isolate the target product by a known method: Fa. in Na! 50, SO» NeSNSO»E! with. side cm 2002 i a 6 7 8 9 2. The method according to claim 1, which differs in that the reaction is carried out in a stoichiometric ratio of reagents. Q. The method according to claim 1, which differs in that acetonitrile is used as an organic solvent. 4. The method according to claim 1, which differs in that ethanol is used as an organic solvent. 5. The method according to claim 1, which is distinguished by the fact that sodium ethylate is used as an alcoholate of alkali metals. 6. The method according to claim 1, which differs in that acetic acid is used as an acid. 000 KomputernaverstkaL.Tsikhanovska.dD (00000000 State Intellectual Property Service of Ukraine, 45 Urytskogo St., Kyiv, MSP, 03680, Ukraine SE "Ukrainian Institute of Industrial Property", Glazunova St., 1, Kyiv - 42, 01601