Method of producing derivatives of thioformamide

专利摘要:

公开号:SU1209029A3
申请号:SU823415750
申请日:1982-03-29
公开日:1986-01-30
发明作者:Алуп Жан-Клод；Бушодон Жан；Фарж Даниель；Жам Клод
申请人:Рон-Пуленк Санте (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new thioform-I amide derivatives of the general formula
 X / szshn
Cx
X Ret
R is C-C-alkyl;
Het - 3 pyridyl, 4-pyridyl,
3-pyridazinyl, 2-pyrazinyl, 2-quinol1 or 3-quinolyl; sulfur;
X y
- sulfur, oxygen, valentine
bond or methylene; or Het is 2-pyridyl;
X is sulfur,
Y is sulfur, oxygen or methylene or Het is 2-pyridyl;
X is oxygen;
Y is a valence bond that has pharmacological activity and can be used in medicine.
The aim of the invention is to develop a method for the preparation of new derivatives of thioformamide with high antiulcer and antihypertensive activity.
Example 1. To 300 cm of a 1.6 M solution of n-butyl lithium in hexane in an argon atmosphere at -60 ° C, 225 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran, taken in a ratio of 47:53 by volume, was added dropwise in 22 minutes. Then, a solution of 56 g of 2-z-pyridyl--1,3-dithian in 225 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) is introduced in 30 minutes. After stirring for 15 minutes, dry 15 minutes 31 g of methyl isr-thiocyanate solution in a 225 cm mixture of anhydrous.
hexamethylphosphorotriamide and tetrahydrofuran (47t53 by volume). The reaction mixture was stirred for 1 hour at - and then the temperature was gradually raised to 20 ° C for 1 hour. The reaction mixture was poured into a mixture of 1500 cm of distilled water and 1500 cm of ethyl acetate. After decantation, the aqueous solution is extracted twice with 2500 cm of ethyl acetate. The organic extracts are combined, washed three times with 4500 cm of distilled water, dried with anhydrous sodium sulfate, lit, and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) at 50 s.
0
five
0
five
0 5
0
The obtained substance (90 g) is dissolved in 600 cm of boiling ethanol, after which the solution is gradually cooled over 30 minutes to C. The crystals formed are separated by filtration, washed with 20 cm of ethanol, and then twice with 40 cm of isopropyl ether, after which they are dried under reduced pressure of 20 mm Hg. (2.7 kPa) at 20 s. The resulting substance (23.7 g) is combined with 0.7 g of the substance obtained under similar conditions during a similar operation, after which it is dissolved in 780 cm of boiling ethanol, 2.5 g of vegetable black is added to the solution, filtered on heat, then cooled for 1 h at. The crystals formed are separated by filtration, twice washed in 50 cm of ethanol, and then
about
in 25 cm of isopropyl ether and dried under reduced pressure of 20 mm Hg, (2.7 kPa) at. The resulting material (9 g) is dissolved in 600 cm of boiling ethanol; 5 g of vegetable black are added to the solution, lit up with heat, then cooled for 15 hours C. The crystals formed are separated by filtration, washed twice with 50 cm of ethanol, and then 25 cm of isopropyl ether, and the sulate is under reduced pressure of 1 mm Hg .st. (0.13 kPa) at 55 ° C. 15.9 g of N-methyl-2-2-pyridyl -1.3-dithian-2-carbothiamide are obtained, melting at 159 C.
Example 2. To 119 cm of a 1.6 M solution of n-butstlity in hexane under nitrogen and at -60 ° C, 70 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) are added dropwise for 15 minutes. Then a solution of 19.5 g is injected for 15 minutes.
2 pyrazinyl tetrahydrothiophene in
 3
70 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 in volume). After stirring for 15 minutes, a solution of 12.7 g of methyl isothiocyanate in 30 cm of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) is introduced in 15 minutes. The reaction mixture is stirred for 45 minutes at -65 C and then for 1 hour the temperature is gradually raised to l / 2O C. Then the mixture is poured into a mixture of 300 cm of ethyl acetate and 500 cm of distilled water.
After decantle1; and aqueous solution
about
extracted with 400 cm of ethyl acetate twice. The organic extracts are combined, washed three times with 1500 cm of distilled water, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure of 20 mm Hg. (2.7 kPa) at. The obtained substance (33.3 g) is subjected to chromatography on 330 g of gel of neutral silica, placed in a column with diameter A, 2 cm. The solution is washed successively.
about
a 4000 cm column of a mixture of cyclohexane-ethyl acetate (90:10 by volume), then 7000 cm of a mixture of cyclohexane-ethyl acetate (80:20 by volume), yielding 500 cm of fractions. Fractions 13-22 are combined and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) at 60 ° C. The resulting material (11 g) is dissolved in a 48 cm boiling mixture of propanol and isopropyl ether (75:25 by volume); 0.2 g of vegetable black is added to the solution, filtered, then cooled for 18 hours to 5 ° C. The crystals formed are separated by filtration, expanded into 10 cm of propanol-isopropyl ether mixture (75:25 by volume, and dried under reduced pressure of 1 mm Hg, (0.13 kPa) at 45 C. Obtain 4.9 g of N-methyl-2-pyrazinyl-2- -tetrahydrothiophenecarbrothioamide, melting at 127 ° C,
2-Pyrazinyl tetrahydrothiophene was prepared as follows,
A solution of 59 g of (pyrazinylmethyl) - - (3-chloropropylsulfide) in 75 cm of anhydrous tetrahydrofuran is added dropwise for 15 minutes, maintaining the temperature above 30 ° C, to a solution of 51 g of potassium t-butylate in a mixture of 75 cm of anhydrous hexamethylphosphorotriamide and 400 cm anhydrous tetrahydrofuran. After stirring for 30 minutes at the same temperature, 10 g of potassium t-butoxide are introduced, followed by stirring for 30 minutes. The reaction mixture is drunk into a mixture of 800 cm of distilled water and 400 cm of ethyl ether. After decantation, the aqueous phase is extracted twice with 300 cm of ethyl ether. The organic extracts are combined, washed three times with 2400 cm of distilled water, dried with anhydrous
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sodium sulfate, filtered, and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) at 35 ° С. The obtained substance (30 g) 5 is subjected to chromatographic analysis for 100 g of neutral silica, placed in a column of
about
rum 3 cm; the column is washed with 750 cm of cyclohexane, then 2500 cm of the mixture
10 cyclohexane - ethyl acetate (90:10 by volume) and 500 cm of ethyl acetate, get 250 cm fractions. Fractions 4-15 are combined and concentrated to dryness under reduced pressure of 20 mm Hg.
15 (2.7 kPa) at give 19.5 g of 2-pyrazinyl tetrahydrothiophene as a brown oil.
Rf 0.52; chromatography is carried out on a thin layer of dioxide dioxide gel; solvent; cyclohexane - ethyl acetate (50:60 by volume).
Pyrazinylmethyl- (3-chloropropo1) sulfide is prepared as follows.
To a solution of 77.6 g of 2- (pyrazinylmethyl) isothiourea monochlorohydrate in
about
250 cm of distilled water drop by drop for 15 minutes with a nodule of 39 cm of aqueous 10 N sodium hydroxide solution. After heating for 30 minutes at 70 ° C, cooled to 15 seconds, after which 47 cm of aqueous 10 N sodium hydroxide solution are added, and then b6.5 g of 1-bromo-3-chloropropane and stirring is continued for 15 hours at 20 C. Reactionary
the mixture is then extracted three times
280 cm of methipenchloride. The organic extracts are combined, washed twice with 200 cm of distilled water, and dried with anhydrous sodium sulfate.
The resulting solution is drunk on 80 g of neutral silica gel, placed in a column with a diameter of 2.7 CMJ, 900 grams of methylene chloride are drunk on the column. The first fraction (300 cm)
removed, the second fraction (600 cm) is selected and concentrated to dryness under reduced pressure of 20 mm Hg (2.7 kPa) at 35 ° C. Get 59 g (pyrazinylmethyl) - (3-chloropropyl)
sulphide in the form of oil of yellow-orange color.
Rf 0.47; chromatography is carried out on a thin layer of silica gel; solvent; cyclohexane ethyl acetate (50:50 by volume).
2- (Pyrazinipmethyl) isothiourea hydrochloride is obtained as follows:
five
To a suspension of 68 g of thiourea in 370 cm of boiling ethanol a solution of 88 g of chlorine is added dropwise 15 minutes
q
methylpyrazine in 200 cm of ethanol. After stirring the reaction mixture at the boil for 1 h 30 MIN, the mixture is cooled for 15 h at 5 ° C. The crystals formed are filtered off, dusted twice in 120 cm of ethanol and dried under a reduced pressure of 20 mm Hg (2.7 kPa) with, 74 g of 2- (pyrazinylmethyl) hydrochloride is obtained from isocuria, melting at 183 ° C,
PRI me R 3. To 75 cm of a 1.6 M solution of n-butyl lithium in hexane under a nitrogen atmosphere at -60 ° C, 80 cm of a mixture of anhydrous hexamethylLoyforotriamide and tetrahydrofuran (47:53 by volume) are then added dropwise for 15 minutes, then 20 min. solution of 5 g 2-
- (2-pyridyl) tetrahydrofur in I 3 80 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume). After stirring for 30 minutes at the same temperature, a solution of 8.8 g of methyl hypothocyonate in 800 cm of anhydrous hexamethylphosphorotriamide and tetrahydrofuran mixture (47:53 by volume) was introduced into the indicated solution for 20 minutes :. The reaction mixture is stirred for 45 minutes at -60 ° C, and then the temperature is gradually raised to 20 ° C by f. The mixture obtained is drunk into a mixture of 600 cm of distilled water and 400 cm of ethyl acetate. After decantation, the aqueous solution is extracted twice with 800 cm of ethyl acetate. The organic extracts are combined, squandered three times in 1500 cm of distilled water,
one
anhydrous sodium sulfate, filtered and concentrated under reduced pressure of 20 mm Hg (kPa). at 45 ° C. The obtained substance (g is dissolved in 350 cm of boiling isopropyl ether; Oj5 g of vegetable black is added to the solution, the warm solution is filtered, then cooled for 30 minutes at 0 ° C. The crystals formed are separated by filtration twice in 10 cm of isopropyl ether and dried under reduced pressure of 20 mm Hg (2.1 kPa) at 20 s. The compound obtained (7.7 g) is combined with 0.8 g of the compound, similar conditions and
but
dissolved in 30 cm of boiling ethanol; add 0.2 g pot to the solution
12090296
vegetated soot, filtered to heat, then cooled for 1 hour at
from-
solution,
. Crystals formed
divided by filtration, twice npoNW-5, watered in 10 cm of ethanol and dried under reduced pressure of 1 mm Hg. (0.13 kPa) at 45 ° C. 6 g of M-methyl -2- (2-pyridp) -2-tetrahydrofurancarboamide, melted at 10 P5 ° C, are obtained.
2- (2-Pyridyl) -tetrahydrofuran was prepared as follows. one
A solution of 122 g of 4- (1 1 dimethyl-
propoxy) 1- (2-pyridyl) -1-butanol and 107.4 g of para-toluenesulfonic acid in
about
1000 cm of toluene is maintained at a boiling point of 28 hours so as to be removed by azeotropic distillation20
25
thirty
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water formed. After oh-
OQ
250 distilled water is added at 20 ° C. Organic
about
c1) the azu is decanted and washed with 50 cm of distilled water; the aqueous phases are combined and 49 g of sodium bicarbonate is neutralized. The mixture is thrice extra3
1500 cm of ethyl acetate; the organic extracts are combined, filtered and concentrated under reduced pressure of 2G mmHg (2.7 kPa) at 40 ° C. to obtain a first oil-containing fraction (30.8 g). The aqueous preceding phase is again extracted 5 times with 2500 cm of methylene chloride; the organic extracts are combined, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) at. A second oil fraction (11.2 g) is obtained. Both fractions obtained were combined (30.8 and 11.2 g), poured over 30 g onto 200 g of polyphosphoric acid at. After 10 minutes of stirring at this temperature, the mixture is cooled to 20 ° C. Poured into
3
400 cm of distilled water, a 450 cm of aqueous 10 N sodium hydroxide solution was added, and the temperature was kept below 20 ° C. The crystals formed were separated by filtration and washed with 500 cm of ethnyl acetate. After decanting the filtrate, the aqueous phase is extracted three times with 1500 cm of ethyl acetate. The organic extracts are combined, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure of 20 mm Hg.
(2.7 kPa) at 40 ° C., 26 g of 2- (2-pyrndyl) -tetrahydrofuran are obtained.
Rf 0.57; chromatography is carried out on a thin layer of silica gel; solvent: ethyl acetate.
Example 4. To 55 cm of a 1.6 M solution of n-butyl lithium in hexane under a nitrogen atmosphere at -60 ° C, 36 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofu were added dropwise for 15 minutes
wound (47:53 by volume). Then a solution of 9.7 g of 2- 3-pyridazin-J-tetrahydrothiophene in 36 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) is added in 20 minutes. After 15 minutes of stirring at this temperature, 6.4 g methyl isothiocyanate in solution in 36 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 in volume). The reaction mixture is stirred for 1 h at -65 s and then
1h gradually raise the temperature to -10 C. The reaction mixture is drunk
into a mixture of 350 cm of distilled water and 300 cm of ethyl acetate. After decantation, the aqueous solution is extracted with 200 cm of ethyl acetate. The organic extracts are combined, washed three times in 900 cm of distilled water,
dried with anhydrous sodium sulfate - I
It is filtered, and concentrated to dryness under reduced pressure of 20 mm Hg (2.7 kPa) at 55 C. The resulting substance is 12.4 g combined with 1 g of the substance obtained under similar conditions and subjected to chromatographic analysis of 154 g of a neutral silica gel placed on a 3.2 cm column. The column was washed with 500 cm of cyclohexane-ethyl acetate (90:10 by volume), 1000 cm of cyclohexane-ethyl acetate (80:20 by volume), 2250 cm of a mixture of cyclohexane - ethyl acetate (50:50 by volume), obtaining fractions in the amount of
   3
250 cm, Fractions 19-25 are combined and concentrated to dryness under reduced pressure of 20 mm Hg, st. (2.7 kPa) at 55 s. The obtained substance (2.4 rj is dissolved in 50 cm of boiling ethanol; 0.15 g of vegetable black is added to the solution and the warm solution is filtered, then cooled 30 minutes to O C, The crystals formed are separated by filtration, washed with water.
2 cm of ethanol, then twice - in
6 cm of isopropyl ether and dried
under reduced pressure of 1 mm Hg. (0.13 kPa) at 60 ° C, 0.8 g of N-methyl-2-3-pyridazinyl | -2- -tetrahydrothiophenecarbothioamide, melting at 199 ° C., is obtained.
2-z-pyridazinylP-tetrahydrothiophene is obtained in the following way.
A solution of 28.2 (3-pyridazinylmethyl) - (3-chloropropyl) sul4ide in 35 cm of anhydrous tetrahydrofuran is added dropwise over 15 minutes, maintaining the temperature at -20 ° C, and 24 g of tert-butylate potassium in a solution in a mixture of 35 cm of unheated hexamethylphosphorotriamide and 190 cm of anhydrous tetrahydrofuran. The reaction mixture is stirred for 1 hour 30 minutes at -40 ° C, after which it is extracted with a mixture of 500 cm of distilled water and 500 cm of ether, and the aqueous phase is extracted with 250 cm of ether. The ether extracts were combined, washed three times with 1500 cm of distilled water, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure of 20 mm Hg (2.7 kPa) at 30 ° C, yielding 10.5 g of 2- pyridazinyl1-tetrahydrothiophene in the form of a brown oil,
Rf 0.4; chromatography is carried out on a thin layer of silica gel; solvent: ethyl acetate,
(3-Pyridazinylmeett | - (3-chloroproI drank sulfide is obtained by pededued in a manner.
 i,
To a solution of 106 g of dichlorohydrate 2-
- (3-Pyr-aa-eninylmethyl) isothiourea in 220 cm of distilled water was added dropwise 10 minutes, maintaining the temperature above 18 ° C, 84 cm of aqueous 10 N sodium hydroxide solution. After heating for 20 minutes at 75 seconds and then cooled, 50 cm of an aqueous 10 N solution of sodium hydroxide and then 69 g of 1-bromo-3-chloropropane are introduced under stirring with stirring and then stirring is continued for 15 hours at 20 ° C . The reaction mixture is extracted three times with 340 cm of methylene chloride. The organic extracts are combined, washed in: 250 cm of distilled water and dried with anhydrous sodium sulfate. After grinding, the resulting solution is drunk on 80 g of Neutral Silica Gel placed on a 2.7 cm column; then the column is washed in
700 cm of methylene chloride. The first fraction (200 cm) is removed. The second fraction (500 cm) is taken, after which it is concentrated to dryness under reduced pressure of 20 mm Hg, (2.7 kPa) at 60 g (3 pyridazinyl-methyl) - (- 3-chloropropyl) sulfide in the form of oil is red,
Rf 0, lj chromatography is carried out on a thin layer of silica gel; solvent: cyclohexane - ethyl acetate (50:50 by volume).
Example 5, K 44 cm
1.6 M in
50 ml of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) are added dropwise for 10 minutes in a solution of n-butyl lithium in hexane under a nitrogen atmosphere at -70 ° C. Then, at the same temperature, a solution of 8.5 g of 2- (3-pyridyl1-1,3-oxathian in 50 cm of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) is introduced by 25 mi. After 15 minutes of stirring, add 15 minutes a solution of 5.4 g of methyl isothiocyanate in 50 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume). The reaction mixture is stirred for 45 minutes at -70 C. then I gradually increase the temperature to 20 ° C. The mixture is poured into a stirred a mixture of 300 cm of distilled water and 240 cm of ethyl acetate. After decanting, the aqueous phase 400 ml of ethyl acetate are extracted.
20 (2.7 kPa) at 20 ° C. The obtained substance (4.4 g) is subjected to chromatographic analysis on a 40 g gel of neutral silica placed in a column with a diameter of 2.6 cm. Then the column is washed with 2000 cm of a mixture of cyclohexane - ethyl acetate (40:60 by volume), 800 cm of ethyl acetate, collecting fractions in the amount of 200 cm.
The organic phases are combined, washed three times with 600 cm of distilled water, dried with anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure of 20 mm Hg, st. (2.7 kPa) at 50 ° C. The resulting compound is stirred in a solution of 70 cm of a mixture of isopropyl ether and ethyl acetate (90:10 by volume) and the resulting crystals are separated by filtration, washed twice with 20 cm of isopropyl. ether, dried with understanding of mercury, art.
Fractions 4-14 are combined and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) at 50 ° C. The obtained substance (3.9 g) is dissolved in 45 cm of boiling acetonitral. After adding 0.2 g of vegetable carbon black, the solution is filtered warm, left for 1 hour at the formed crystals.
twice and
talts are filtered, washed with 10 cm of acetonitrile
five
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five
reactionary
750 cm water
dried under reduced pressure of 1 mm 1 mercury, st. (0.13 kPa) at 6P ° C, 2.9 g of N-methyl-2- (3-pyridyl - -1,3-oxathian-2-carbothioamide, melting at 194 ° C.) are obtained.
2- (3-pyridyl) -1,3-oxathian prepared as follows.
A solution of 16 g of 3-pyridinecarboxaldehyde, 48 g of 3-mercapto-1-propanol and 2.25 g of para-toluenesulfonic acid in 1500 cm of 1,2-dichloroethane are boiled for 15 hours in order to remove the water formed by using an distillation nitrogen . After cooling to 20.degree. C., the mixture is washed three times with 5 N sodium hydroxide solution, then washed three times in 1500 cm of distilled water. The organic phase is dried with anhydrous sodium sulfate, filtered and concentrated to dryness under reduced length of 20 mm Hg (2.7 kPa) at 50 ° C. The resulting compound (15.6 g) is chromatographed on a 200 g gel of neutral silica placed in a column 3.7 cm in diameter. The column was successively washed with 600 cm of a mixture of cyclohexane-ethyl acetate (80:20 by volume), 2700 cm of a mixture of cyclohexane-ethyl acetate (70:30 by volume), obtaining fractions in an amount of 300 cm, Fractions 5-1I combined and concentrated to dryness under reduced pressure of 20 mm Hg, st, (2.7 kPa) at 8.6 g of 2- (3- pyridyl) -1,3-oksatiana in the form of a yellow oil,
Rf 0.6; chromatography is carried out on a thin layer of silica gel; solvent: ethyl acetate,
- Example 6, K 625 cm of a 1.6 M solution of n-butyl lithium in hexane under a nitrogen atmosphere cooled to -60 ° C, injecting 10 g of a solution of 101 g of diisopropylamine in 225 cm of a mixture of anhydrous hexamethylphosphoric triamide and tetrahydrofuran (47:53 by volume). After a 10-minute break
,
a solution of 84 g of (3-pyridylmethyl) - (4-chlorobutyl) sulfide in
about
300 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume). The reaction mixture is stirred for 1 hour at, and then a solution of 117 g of methyl isothiocyanate in 225 cm of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) mixture is drunk for 20 minutes at this temperature. Then the mixture is stirred for 30 minutes and then the temperature is gradually increased for 1 hour. to 10 ° C. After adding 1 liter of distilled water, the mixture is extracted 6 times in 5 l of ethyl acetate. The organic extracts are combined, washed 5 times with 5 liters of distilled water, dried with anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure of 30 mm Hg (4 kPa) and temperature. The obtained substances (167 g) are subjected to chromatographic analysis for 1500 g of gel of neutral silica;
Stake with a diameter of 7.4 cm. I
The impurities are removed by washing approximately 50 liters of a mixture of cyclohexane and ethyl acetate, in which the ethyl acetate content gradually changes from 0 to 30%, washed with pure ethyl acetate to obtain 3 fractions in an amount of 1 l, then 8 fractions in an amount of 0.7 l The last 8 fractions are combined and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) and a temperature of 60 C. The resulting substance (20 g)
but
dissolved in a boiling mixture of 80 cm
q
isopropyl ether and 40 cm of ethanol. After cooling for 1 hour at 0 ° C, the formed crystals are separated by filtration, washed with 25 cm of isopropyl ether and dried under reduced pressure with 20 mm Hg. (2.7 kPa) and a temperature of 20 ° C. The resulting substance (14.2 g) is dissolved
 3
43 cm of boiling acetonitrile; after adding 0.8 g of vegetable black, the solution is filtered warm and condensed after cooling for 45 minutes at 5 ° C. The crystals formed are separated by filtration, washed with 4 cm of acetonitrile, then washed twice with 8 cm of isopropyl alcohol.
go ether. After drying at reduced, with at 212 C.
55 (2.7 kPa) and they give 173 g of d / dylmethyl) iso
20902912
pressure of 1 mm Hg (0.13 kPa) and a temperature of 60 ° C., 10.6 g of N-methyl-2-3-pyridyl -2-tetrahydrothiopyrancarbotriamide are obtained, melting
at
5 at 131 C.
(3-Pyridylmethyl) - (4-chlorobutyl) sulfide was prepared as follows.
To a solution of 173 g of 2- (3-pyridylmethyl) isothi6urea dichlorohydrate
10 330 cm of distilled water cooled to 4 ° C added yutpo drops 25 minutes, maintaining the temperature above 12 ° C, 144 cm of aqueous 10 N sodium hydroxide solution. After heating for 5 min at 70 ° C and then cooled to 11 ° C, 89 cm of 10 N aqueous sodium hydroxide solution are added with stirring, and then 123.5 g of 1-bromo-4-chlorobut 20, then stirring is continued for 15 h. at 20 C. Reactivity
g
the mixture is extracted 4 times with 560 cm of methylene chloride; the organic extracts are combined, washed twice with 25 BOO cm of distilled water, dried with anhydrous sodium sulfate and filtered. The solution is drunk on 150 g of gel of neutral silica, placed in a column with a diameter of
with at 212 C.
Q 3.7 cm; the column is washed with 2500 cm of methylene chloride. The first fraction (600 cm) is removed, the second fraction (2500 cm) is concentrated to dryness under reduced pressure of 25 mm Hg. (3.4 kPa) and a temperature not higher than 30 ° C, 3 g-pyridyl methyl) - (4-chlorobutyl) sulfide is obtained in PO,
Rf 0.31; chromatography is carried out on a thin layer of silica gel; solventglyclohexane - etcpacetate (50:50 by volume).
2- (3-nridklmethyl) isothiourea dihydrochloride is prepared as follows
in a way.
To pafcTBopy 91 g of thiourea in
5 510 cm of boiling ethanol is added dropwise in 20 minutes 164 g of 3-chloromethylpyridine hydrochloride in a solution in 510 cm of ethanol at 50 ° C. The reaction mixture is stirred for 3 hours and 50 minutes
0 at boiling, then cooled to 26 ° C. The formed crystals are separated by filtration, washed twice with 400 cm of ethanol and dried under reduced pressure of 25 mm Hg,
5 (2.7 kPa) and temperature, get 173 g of 2- (3-pyridylmethyl) isothiourea dichlorohydrate, melting
Example 7: A solution of 9.6 g of diisopropylamine in a 22 cm mixture of anhydrous hexamethylphosphorotriamide is added dropwise 11 min to 59 cm, 6 M solution of n-butyl lithium in hexane under a nitrogen atmosphere and at -50 ° C. and tetrahydrofuran (47:53 by volume). Then a solution of 9.2 g of (3-quinolylmethyl) - (3-chloropropyl) sulphide in 28 cm of anhydrous mixture of hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) is added at a temperature of approximately -60 ° C for 20 minutes. The reaction mixture stirred for 30 minutes at the same temperature, then a solution of 11.1 g of methyl isothiocyanate in 22 cm of a mixture of anhydrous hexamethylphosphorotriamide and tetrahydrofuran (47:53 by volume) was poured over 15 minutes. The mixture is stirred for another 25 minutes at -65 ° C, and then the temperature is gradually increased to 0 0 ° C for 30 minutes. After adding 100 cm of distilled water, the mixture is extracted three times with 300 cm of ethyl acetate. The organic extracts are combined, 5 times about 500 cm of distilled water are dried, dried with anhydrous sodium sulfate, and concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) and a temperature of 60 C. The resulting substance (20 g) is chromatographed on 30 g of gel of neutral silica placed in a column with a diameter of 3.8 cm.
The column is sequentially washed.
Q
200 cm of a mixture of cyclohexane and ethyl acetate, in which the ethyl acetate content gradually changes from 0 to 0%, 2400 cm of a mixture of cyclohexane and ethyl acetate (90:10 by volume), 1080 cm of a mixture of cyclohexane and ethyl acetate (85:15 by volume), 1080 cm of a mixture of cyclohexane-ethyl acetate (80:20 by volume and 1440 cm of a mixture of cyclohexane-ethyl acetate (70:30 by volume), obtaining fractions in an amount of 120 cm. Fractions 51-53 are combined and concentrated to dryness under reduced pressure 20 mm Hg (2.7 kPa) and a temperature of 55 ° C. The obtained substance (1.3 g) is dissolved in 17 cm of boiling ethanol solution after adding 0.4 g of vegetable black is filtered warm and left for 3 hours at 5 ° C. The crystals formed are separated by filtration, washed with 1 cm of ethanol and 2 times with 2 cm of isopropyl ether. After drying under reduced pressure
090291
 mm Hg, (0.13 kPa) and temperature, 0.8 g of N-methyl-2- (3- -quinolyl) -2-tetrahydrothiophenicarbothiamide, melting at 159 C., is obtained.
5 (3-Quinolmethyl) - (3-chloropropyl) sulfide was prepared as follows. To a solution cooled to consisting of 59.2 g of dichlorohydrate- -2- (3-quinolmethyl) isothiourea
 About 100 cm of distilled water, add 9 minutes, raising the temperature to 10 ° C, 40.8 cm of aqueous 10 N sodium hydroxide solution. After heating for 20 minutes at 70 ° C and then cooling to 12 C dropwise
about
5 min-25 cm of aqueous 10 N sodium hydroxide solution are added. Then, 33.6 g of 1-bromo-3-chloropropane are added and the stripping is continued for 20 hours, 0 at 20 ° C. The reaction mixture is extracted three times with 400 cm of methylene chloride. The organic extracts are combined,
q
washed with 100 cm of distilled water, dried with anhydrous sodium sulfate pH 25 and concentrated under reduced pressure of 20 mm Hg. (2.7 kPa) at up to a volume of 100 cm. The solution obtained is subjected to chromatography on 250 g of a gel of neutral dioxide.
30 silicon placed in a column with a diameter of 3.8 cm. The column was washed with 1500 cm of methylene chloride to obtain a fraction of 600 cm and a fraction of
in the amount of 900 cm, the last
The 35th fraction is concentrated to dryness under reduced pressure of 20 mm Hg. (2.7 kPa) and a temperature of 35 ° C., 9.2 g (3-quinolylmethyl-3-chloropropyl j sulfide in the form of an oil of yellow
40 colors.
Rf 0.6; chromatography is carried out on a thin layer of silica gel; solvent: ethyl acetate,
2- (3-quinolylmethyl) dihydrochloride
45 isothioureas should be followed in one way. I.
To 19.7 g of thiourea in the form of a suspension in MO cm of boiling ethanol 10.4 minutes 46.4 g of chlorine hydrate of 3-chloromethylquinoline in a solution of 160 cm of ethanol are added dropwise in 70 min. The reaction mixture is stirred for 1 h 30 min at boiling and then cooled to, the crystals formed are separated by filtration, washed twice with 100 cm of ethanol and dried under reduced pressure of 20 mm Hg. (2.7 kPa) and temperature 20 С, floor 15
59.3 g of 2- (3-quinolylmethyl) isothiourea, melting at 226-228 ° P, are used.
Under the conditions of Example G., the following compounds are prepared.

Example 8. N-Methyl-2- (3-pyridyl) -tetrahydrothiophene carbioamide-2, T.Sh1. 133 C,
PRI me R 9. N-Methyl-2- (4-pyridyl) ttetrahydrothiophenecarbothioamide-2, so pl. 178 ° C.
Example 10. N-Methyl-2 (2-quinolyl) -tetrahydrothiophene carbothioamide-2, t.p. .
Example II N-Metsh1-2- (2-pyridyl) -tetrahydrothiopyrancarbothioamide-2, so pl. 153 ° C.
Example 12. K-Methyl-2- (2-pyridyl) -, 3-oxathianicarbothioamide 2, m.p. 157 ° C.
Data on the biological activity of the new compounds are as follows.
A. Antinuclear action by technologists Shay 17 h).
i Female rats of average weight of about 170 g, which were isolated and subjected to food starvation for 24 hours (drinking water as desired), were orally administered the test compound at a dose of 30 mg / kg. After 1 h after administration of the compound, a ligature of the pylor was performed under anesthesia with ether.
After 17 h after the ligature of the pylorus, the animal was released and its stomach was analyzed. Venturious formation of spots was noted in some cases in animals that received the test compound, as well as in animals for comparison.
1 2 3
Atoxic 900 About 900 Over 900
sixteen
0
five
0
five
0
five
Eight rats were taken for a single dose of the compound. The compounds were regarded as active in the case when in the group of treated animals at least one animal is protected from all gastrointestinal manifestations.
B. Antihypertensive effect. The antihypertensive effect was determined on rats whose blood pressure increased as a result of a sudden awakening.
The systolic blood pressure was measured by the bloodless method at the level of the tail in an awakened animal by the sphygnomanometric method.
The test substance (as an aqueous solution or 10% suspension of gum arabic in an aqueous solution) was administered orally.
Each substance was investigated in 2,3 or 4 doses at the rate of A-8 rats per dose.
The blood pressure of each rat was measured before the administration of the medicine, and then 1, 3 and 6 hours after the administration of the substance.
The active dose (DA, o) was determined graphically as the dose causing a decrease in systolic blood pressure of 30 mm Hg, compared with its initial value. Toxicity.
The dose of the substance (DLyp) which, when orally administered to mice, causes the death of 50% of the animals, is determined.
The results of biological tests of compounds of general formula I and known compounds (la) -2-pyridi-cyclopentacarbothiamide and LS-2-β-carbothiamide methyl-3-methylthioethylpyridine are presented in the table.
Between 5 and 10 100
3/8
four
five
6
7
eight
9 10 11 12
connection 1a connection 1
300 - 900 Atoxic 900 More than 900 More than 900 Atoxic 900 More than 900 Atoxic 300 Atoxic 900
450
Atoxic 900 Atoxic 900
Note. In the experiments, 48 control animals were identified.
(all animals had a stomach sound), the test substance was administered orally.
and 1 per 100 per 100
1/8 4/8 2/8 8/8
3/8
0/8
0/8

权利要求:
Claims (1)
[1]
METHOD FOR PRODUCING THIOFORMAMIDE DERIVATIVES OF THE GENERAL FORMULA / —Y.CSNHR ^ -xnet where R — C, —C ₄ -alkyl 'Het - 3-pyridyl, 4-pyridyl, 3-pyridine zinyl, 2-pyrazinyl, 2-quinolyl or 3 quinolyl;
X is sulfur;
Y is sulfur, oxygen, valence bond or methylene;
or
Het - 2-pyridyl;
X is sulfur;
Y is sulfur, oxygen or methylene; or
Het - 2 pyridyl;
X is oxygen;
Y is a valence bond, characterized in that. compound of the general formula
SU „„ 1209029 where Het, X and Y have the indicated meanings, in a mixture of anhydrous hexamethylphosphorothiamide and tetrahydrofuran at (-70 C) - (-60 C), they are treated with butyllithium in a solution of hexane and then with an isothiocyanate of the formula
R is N 'C "S, where R has the indicated meanings.

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EP0077083B1|1985-08-07|

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KR830006277A|1983-09-20|

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引用文献:

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IT1056205B|1970-07-30|1982-01-30|Fujisawa Pharmaceutical Co|COMPOUND PASTE OF TIOA CETAMID DERIVATIVES AND THEIR SALTS PROCEDURE FOR ITS OBTAINING AND COMPOSITIONS CONTAINING IT|

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DK627174A|1974-01-17|1975-09-08|Ciba Geigy Ag|

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FR2452488B1|1979-03-30|1982-06-18|Rhone Poulenc Ind|

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FR2528849B1|1982-06-17|1985-06-21|Rhone Poulenc Sante|NEW THIOFORMAMIDE DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM|

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FR2573428B1|1984-11-20|1987-01-30|Rhone Poulenc Sante|NEW THIOFORMAMIDE DERIVATIVES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM|

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FR2653770B1|1989-10-31|1992-01-03|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF-2 TETRAHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXYDES-1- , LES-2 TETRHYDROTHIOPYRANNECARBOTHIOAMIDE-2-OXYDES-2-OXYDES PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.|

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JPH04211048A|1990-03-05|1992-08-03|Mitsubishi Kasei Corp|Thiocarbamoylacetonitrile derivative|

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US5625068A|1995-06-05|1997-04-29|American Cyanamid Company|Substituted quinoline herbicide intermediates and process|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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FR8018035A|FR2488609B1|1980-08-18|1980-08-18|

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