SU665803A3 - Method of producing imides of carbonic acids, their dextro- and levorotatory isomers or their salts - Google Patents

Description

(54) METHOD FOR OBTAINING CARBON IMAGES

ACIDS, THEIR RIGHT OR LEFT-ROTATING

ISOMERS OR THEIR SALTS

/ 7 about

V (

he hu i

- (SpN2p) -X.

where l, R4 and Rs have the indicated values, or its right-or levorotatory isomer. Acylate with the 3-indole carboxylic acid chloride of the formula

SOS1

/

in

where: Ri, R2, Ra and Re have the indicated values, in an organic solvent, at a temperature from room temperature to the boiling point of the mixture, followed by isolation of the target products in free form, in the form of their right or left rotation isomers, or their salts.

The acylation is usually carried out in benzene, toluene, xylene, pyridine, methylene chloride, or a mixture thereof.

Example 1. Getting bicyclo 2,2,1 heptane-endo-2,3-dicarboxy - 5 - endooxyu-lactone (11-a).

500 g of concentrated sulfuric acid are slowly added with vigorous stirring to a suspension of 164 g of endo anhydride ("c-bicyclo 2.2, -5-en-2,3 - dicarboxylic acid in 500-600 ml of water. The reaction is exothermic; the temperature rises to 80-90 ° C. To the reaction solution are added 2 L of boiling water and immediately filtered. After cooling the filtrate, colorless plates of Compound II crystallized out. At the end of the crystallization of the crystalline crystal, the tally is filtered, washed with cold water and 138 g of air-dried crystals are obtained. ; mp 200 ° C.

Example 2. Preparation of imides of 5-endooxy-M-amino (lower alkyl) -bicyclo 2,2.1 heptane-2,3-di-endo-carboxylic acid (I). . .

A mixture of 0.1 mol of lactone II in Example 1 and .50 ml of thionyl chloride is refluxed for 2 hours in a water bath. The excess thionyl chloride is removed in vacuo and the remaining oily residue is washed with w-hexane (or petroleum ether) and dissolved in 50 ml of anhydrous benzene. 0.9 mol of the corresponding amine, for example, M, M-dimethylaminopropylamine and 100 ml of anhydrous benzene are added to this solution with intermixane. The mixture is concentrated for 5 hours with a condenser and then concentrated under vacuum. The resulting brown syrupy substance is boiled for 5 hours under reflux in 300 ml of 50% aqueous ethanol containing 0.12 mol of potassium hydroxide. The solvents are removed under vacuum, a saturated solution of potassium carbonate is added and the resulting solution is re-extracted with ethyl acetate-benzene 1: 1. United Organic

the extracts are washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulphate. After filtration, the solution is concentrated in vacuo and the formula III product is recovered.

crystallization, chromatography, and / or vacuum distillation.

Example 3. Preparation of 5-endooxy-N-amino (lower) alkyl-bicyclo 2,2.1 heptane-2,3-di-endo-carboxylic acid amides.

A mixture of 0.1 mol of lactone primer 1 and 30 ml of PCL3 is boiled in a water bath for 2 hours with refluxing. The excess PCL3 is removed in vacuo, the oily residue is dissolved in 50 ml of chloroform or methylene chloride and a solution of 0.12 mol of the corresponding amine, for example, H, M-dimethylaminopropylamine dissolved in

100 ml of anhydrous chloroform or methylene chloride. Transfer for a further 2 hours, after which the mixture is warmed to room temperature and then refluxed for 15 minutes. Solution

washed with saturated potassium carbonate solution, cooled and separated. The separated organic phase is washed with a saturated solution of sodium chloride, dried over anhydrous sulfate.

sodium, filtered and concentrated under vacuum. In Examples 4-10, compounds 1Pa, 111g are obtained, which are presented in Table 1. Example I. Preparation of imides of (±) -5-endo-benzoyloxy N - amino (lower alkyl) -bicyclo1 2.2.1 heptane - 2,3-di - endocarboxylic acid

RI

The 5-endo-hydroxy-L-1 amino (lower alkyl) bicyclo 2.2.1 heptane-2,3-di-endocarbric acid acid formula of formula III (0.01 mol) obtained in Example 2 is added to 50 ml a solution of pyridine-piperidine (100: 1) containing 0.012 mol of a suitable benzoyl halide, for example benzoyl chloride, during transferring. The resulting mixture is left to stand overnight in a refrigerator or heated in a water or oil bath. The mixture was poured into a mixture of ice water, saturated with sodium carbonate, and then extracted with a mixture of benzene-ethyl acetate (1: 1). The combined organic extracts are Washed With a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After filtering off and concentrating in, the desired product V is obtained. V6). A. Instead of a suitable benzoyl halide, take an equivalent amount of benzoyl chloride and, instead of the imide of dicarboxylic acid P1, take an equivalent amount of P1a and obtain the desired product as the hydrochloride salt. B. The free base is dissolved in almost boiling ethanol (700 ml) and 90 ml of ethanol saturated with hydrochloric acid is added. The solution is cooled with ice and after crystallization from a mixture of methanol-asheton, colorless plates of the V6 hydrochloride salt are obtained; m.p. 239 ° С (with decomposition). Yield 90%. Calculated,%: C 61.07; H 6.83; N 6.96. С2зН2704С1. 1/3 NgO Found,%: C 60.63; H 6.8-8; N 7.33. Example 13. Decomposition of e-hydrochloride imide (±) -5-endo-benzoyl-hydroxy-M (3-dimethylaminopropyl) -bicyclo 2,2.1 heptane-2,3-di-endo-carboxylic acid I. Preparation of (-) -enantiomer. A. Imide (-f) -5-endobenzoyloxy-S - (3Dmethylaminopropyl) - bicyclo 2,2.1 hectan-2, 3-di-endo-carboxylic acid (V6). A mixture of the V6 hydrochloride salt (South) in water (150 ml) and ether (200 ml) is neutralized with stirring by the addition of sodium carbonate. The aqueous layer was extracted with ether (2X200 ml). The combined ether extracts are washed with water, then with water, saturated with sodium chloride (3 times) and dried over sodium sulfate. After removal of the ether, colorless crystals of racemic V6 base (9.3 g) are obtained; m.p. 106-107.5 ° C. B. (+) - 10-salt of sulfonic acid of the imide (-) - 5-endo-benzoyl-hydroxy-M- (3-dimethylaminopropyl) -bicyclo 2,2.1 heptane-2, 3-di-endo-carboxylic acid. A hot solution of (4 -) - 10-sulfonic acid (276.5 g, 1.19 mol) in ethanol (1.1 l) is added to the racemic base W (441.1 g of 1.19 mol) in this nol (3.5 l) containing water (175 ml). The solution is heated to near boiling and is rapidly cooled to 20 ° C. After 3 hours at 20 ° C, colorless crystals obtained are collected, washed with cold ethanol (600 ml) and 325.3 g of the expected product are obtained; m.p. 221-226 ° C. The salt is recrystallized from acetonitrile and colorless needles are obtained (282.6 g) with an mp. 230-233C. The ethanol mother liquor is retained for the recovery of the (- | -) - isomer. B. Imide (-) - 5-endo-benzoyloxy-N- (3-dimethylaminopropyl) - bicyclo 2,2.1 heptane-2, 3 - di-endo-carboxylic acid ((-) - V6). The sulfonic acid salt from step B (282.6 g) is distributed between a stirred mixture of ethyl acetate (3.5 L) and water (3 L) containing sodium carbonate (150 g). The aqueous layer was extracted with ethyl acetate (600 ml). The combined ethyl acetate extracts are washed with water, saturated with sodium chloride (3 times) and dried over sodium sulfate. After the formation of ethyl acetate, the product remains in the form of colorless crystals (173.3 g); m.p. 131.5-132.5 ° C; 53 (with 4.26, ethanol). G. Hydrochloride IMID (-) -5-ENdo-benzoyloxy - N - (3-dimethylaminopropyl) -bicyclo 2,2,1 heptane-2,3 - di - endocarboxylic acid (V). To the almost boiling solution of the (-) - isomer (173.3 g, 0.468 mol) from stage B, 475 ml of 95% ethanol containing 0.468 mol HC1 was added in 95% standard (3.5 l). Coolant solution is placed in ice. Colorless crystals are collected, washed with cold 95% ethanol (600 ml), dried and the indicated product is obtained (182.6 g); m.p. 207-209 ° C; a -85.56 ° (1.5, water). After further recrystallization from & 5% ethanol, the melting point and rotation do not change significantly. Getting the (- +) - enantiomer. A. Vinnokisla imide salt (- | -) - 5-endoben-zoyyloxy-N - (3 - dimethylaminopropyl) bicyclo 2, 2.1 heptane, - 2,3 - di-endo-carboxylic acid. The ethanol mother liquor from stage 1B (see above) is stored at 0 ° C to obtain additional crystalline material (237.2 g), t. Pl. 183-186 ° C. The filtrate is concentrated and an additional portion of colorless crystals (119.9 g) are obtained; m.p. 168-177 ° C. Both portions are combined, distributed between ethyl acetate and an aqueous solution of sodium carbonate according to example 1B and a mixture of (-J-) and (-) - isomers (214 g) is obtained; m.p. 125-129 ° C. highly enriched (+) - enantiomer. (-) - Tartaric acid (89.6 g, 0.596 mol) is added to a hot stirred solution of an enriched (-f) isomer mixture (221.4 g, 0.596 mol) in ethanol (3.6 l) containing water ( 40 ml). Move the mixture to almost boil and then cool to 25 ° C for 4 hours. The colorless crystalline material is collected, washed with cold 95% ethanol (500 ml), dried and get tart (+) - enantiomer (291, 6g); m.p. 157-161 ° С (with decomposition).

 Recrystallization from acetonitrile gives 247.2 g of purified salt; m.p. 162-164 ° C.

B. Imide (- | -) - 5-endo-benzyloxn-.M- (3-dimethylaminopropyl) - bicycle 2,2,1 heptane 2, 3-di-endo-carboxylic acid ((+) - V6).

The tartaric acid mixture from stage A (247.2 g) was decomposed with an aqueous solution of sodium carbonate and the liberated (+) - enanthimer was extracted with ethyl acetate as in Example 16. After the removal of ethyl acetate, the (+) isomer (171.6 g) remained as colorless crystals; m.p. 131-133; 5 C; +77.74 (with 1.89, ethanol). .

B. Hydrochloride IMID (+) - 5-endobenzoyloxy-N - (3 - dimethylaminonrolyl) bicyclo 2, 2,1 heptane-2,3-di-endo - carboxylic acid (VI).

The (+) -enantiomer (171.6 g) from step B is treated with an equivalent of ethanolic hydrogen chloride as described for the (-) - enantiomer in 1G, and colorless hydrochloric (+) enantiomer (188.2 g) is obtained; m.p. 207-209 ° С and 25 + -85.88 (с 1.36, water).

Example 14. Preparation of imide 5-EN-dooxy-N - (4 - dimethylaminobutyl) bischislo 2,2,1 heptane-2,3-d-endo-carboxylic acid (P1k).

To a stirred mixture of 7-lactone-5-endo-hydroxy-bicyclo 2, 2.1 heptane — 2,3-di-endocarboxylic acid (15.2 g, 0.144 mol) in 100 ml of dry CHsCla is added thionyl chloride (25 ml ) and DMF (3 calli). The mixture was boiled under reflux with stirring for 3 hours. Then the resuscitating solution was cooled to 23 ° C and the diluent was distilled off under reduced dosing. The remaining yellow oil is dissolved in 50 ml of benzene and, after distillation under reduced pressure, a pale yellow solid is obtained. This substance was dissolved in 100 ml of CH2Cl2 and 4-dimethylaminobutylamine (20 g, 0.173 mol) dissolved in 50 ml of CH2Ci was added dropwise to it. After the addition is complete, the reaction mixture is stirred at 23 ° C for 2.5 hours. The reaction mixture is then treated with a saturated solution of CsCO3 and the phases are separated. The aqueous phase is built with 2X125 ml of CH2C8, these phases are combined, washed with a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and expelled under reduced pressure. Received

the pale yellow liquid is treated with boiling ethyl acetate, the decanted ethyl acetate solution is distilled off under reduced pressure and a pale yellow solid is obtained.

This substance was recrystallized from ethyl acetate to obtain light yellow crystals of P1k (13.3 g, 33, O%; mp, 108-109 ° C). Calculated,%: C 64.26; H 63; N 9.9.

C, 5H24N203

Found,%: C 64.21; H 8.46; N 10.02. (adjusted for 1.61% H2O). Example 15. Preparation of imides 5-endo (3-indolcar-bonyloxy) -N-amino (lower a kil) bicyclo | 2,2,1 heptane - 2,3-diene carboxylic acid. (I).

Imide (+) - 5-endo-hydroxy-N- {amino (lower alkyl) - bicyclo1, 2,2,1Theptan-2,3-di-endocarboxylic acid (1P) (0.01 mol) is added With stirring to a dry solution substituted indole-3carboxylic acid chloride (0.011 mol), for example indole-3-carbonyl chloride, in methylene chloride containing about 1 ml of pyridine. The resulting mixture is left to stand overnight in a refrigerator or heated in a water or oil bath. Then GMetb- is poured into ice, water, saturated

sodium carbonate and extracted with chloroform or a 1: 1 mixture of benzene-ethyl acetate. The combined organic extracts are washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate. After concentration of the filtered solution in vacuum, obtain the target product (1).

Example 16. Preparation of hydrochloride imide 5-endo- (3-indolcarbonyl) hydroxy-N- (3-dimethylaminopropyl) - bicyclo {2.2.1 heptane-2,3-di-endo-carboxylic acid (+) - la.

To the suspension of indole-3-carboxylic acid

(6.44 g, 0.04 mol) in 100 ml of dry ether was added 3.6 ml (0.05 mol) of thionyl chloride and the mixture was stirred under anhydrous conditions for 2 hours. The solvent and thionyl chloride were removed by evaporation under

reduced pressure at 25-30 ° C and the resulting oil is treated with donol-. with a solid volume of dry ether, which is then removed as described above, and a solid is obtained, the infrared spectrum

which corresponds to the target indole-3carbonyl chloride.

This chloric acid anhydride (7.16. G, 0.04 mol) is dissolved in 100 ml of dry OH, containing 13 drops of dry pyridine in it, alcohol (±) 1Pa (5.32 g, 0.02 mol) is added and the mixture is stirred at 25 ° G. After 5 minutes, a solid is precipitated and 20 ml of dry niridine are added to dissolve. After kiping the mixture under reflux

eleven

within 10 minutes the product precipitates from solution.

After cooling and filtration, 7.6 g (yield 86%) of the crude title compound are obtained, which is purified by recrystallization from a mixture of 20: 1 ethyl and methyl alcohols; m.p. 25b ° C

Calculated,%: C 62.09; H 6.12; N 9.44; € 1 7.97.

S2zN27Mz04 -NS

Found,%: C 62.27; H 6.19; N 9.36; CI 7.95.

Examples 17-20. In example 16, indole-3-carbonyl chloride is replaced with an equimolar amount of 2-methylindole-3-carbonyl chloride or 2-bromo-indole-3-carbonyl chloride, respectively, to obtain 5-endo-2-methyl-3-indole-2-methyl-3-indolecarbonyloxy-N - (3 - dimethylaminopropyl) -bicyclo 2,2.1 het1-ethyl - 2,3 - di-endocarboxylic acid (+) - 1c, to the hydrochloride imide 5-endo- (2-bromo-3-indolcarbonyloxy) - N - (W -dimethylaminopropyl) -bicyclo 2,2.1 heptane-2,3-di-endocarboxylic acid (- | -) - 1 s, and the replacement in example 15 of the imide of dicarboxylic acid 1P with equivalent amounts Shh and P1v gives, respectively, the imide of b-endo (3-indolcarbonyloxy) -M- (3-morpholylpropyl) bicyclo-2.2.1 heptane - 2,3 - di12

endo-carboxylic acid (+) - 1 and imide 5-endo (3 - indolocarbonyloxy) - M- (3-piperidinopropyl) - bicyclo 2,2,1 - heptyl2, 3-di-endo-carboxylic acid (la).

Example 21. Preparation of imide 5-endo (3-indole-carbonyloxy.) - H - (2-dimethylaminoethyl) -bicyclo 2,2.1 heptane - 2,3-di-endocarboxylic acid (±) -1L. Indole-3-carboxylic acid (4.52 g, 28 mol) is converted to the acid chloride in the usual way. The acid chloride is dissolved in dry GH2C12 (100 ml) and alcohol P1 (4.8 g, 19 mol) and dry α-pyridine (1 ml) are added during transport. After 70 minutes of refluxing, the product precipitates as a white solid (6.7 g, 81.6%). A sample for analysis is obtained by recrystallization from a mixture of isopropyl alcohol-methyl alcohol 2: 1; m.p. 259-261 ° С (with decomposition).

Calculated,%: C, 61.8; H 6.07; N 9.73.

С22Н25НзН4 «С1

Found,%: C 61.53; H 6.10; N 9.85.

Examples 22-30. In Examples 16 and 21, the corresponding imides of 5-endo (substituted 3-and " dolcarbonyloxy) - N- (3.-Dimethylaminopropyl) - bicyclo 2,2.1 heptane-2, 3-di-endo-carboxylic acid are obtained, details about which are presented in Table. 2

Table 2

Example 31. Hydrochloride imide (+) -5 - endo - (Z-indolocarbonyloxy) -M (3 - dimethylaminopropyl) - bicyclo 2,2.1 heptane-2,3-di - endo-carboxylic acid

(+) - 1a.

A. Imide (+) - 5-endo-hydroxy-H- (3-dimethylaminoproyl) - bicyclo 2,2.1 heptane-2,3di-EN-carboxylic acid (+) - 1 Pa.

Hydrochloride imide (- | -) - 5-endoox-M- (3-dimethylaminopropyl) -bicyclo 2,2.1 heptane-2,3-di-endo-carboxylic acid (3.65 g, 0.0086 mol) ( (B) -V0 are suspended in 18.8 ml. 1 N NaOH, heated with stirring for 45 minutes in an oil bath at 120-125 ° C. Then the solution is cooled, filtered, evaporated under reduced pressure and get a white solid. The solid is then treated in three, 80 ml portions of hot ethyl acetate. The combined portions are evaporated and an oil is obtained which is solidified upon cooling. The solid is then re-suspended in 100 ml of cyclohexane and 15 ml of ethyl acetate.

and yagreyut reflux. The filtered hot solution after cooling to 20 ° C gives a crystalline solid (1.53 g, yield 67%, mp. 121 - 122 ° C), defined as (+) - 1 Pa.

B. Hydrochloride imide (+) - b-endo (3-indolcarbonyloxy) -Y - (3-dimethylaminopropyl) - bicyclo 2,2.1 heptane-2,3-di-endo-carboxylic acid (+) - la.

To a stirred mixture of indole-3-carboxylic acid (2.6 g, 0.015 mol) and ethyl ether (40 ml1, add 3.0 ml of thionyl chloride and 1 drop of anhydrous dimethylformamide. After stirring for 3 hours at 23 ° C, blend filter, distill off the reagent and solvent to remove the filtrate, chlorine anhydride (2.6 g) as a dark semi-solid syrup. 40 ml of dry CH2Cl2 are removed, 5 drops of pyridine are added and then alcohol (-f) -P1a (2.0 g, 0.075 mol). The mixture is stirred at reflux 2 hours under anhydrous conditions, then the solvents are distilled off under reduced pressure. The dark residue is chromatographed on an aluminum oxide column (100 g), the product is eluted with CHCH, CH 2 CH 2 O and CH 2 OH 45:45: 10. the yellowish-brown oil obtained is dissolved in a mixture of ethyl ether and ethyl alcohol (75:25) saturated with hydrochloric gas. After removing the solvent and recrystallizing solid vegetation from ethyl alcohol and drying, under high vacuum, a pure hydrochloride is obtained one salt (0.921 g, yield 27.6%, T; square 193-195 ° C).

CzsHsrNsOi HC1

Calculated,%: C, 61.95; H 6.33; N 9.42; C1 7.95.

Found (corrected for 1.65% HgO),%: C 62.45; H 6.41; N 9.74; C1 8.13.

a | 9- + 57.8 (, 069,).

Example 32. Hydrochloride imide (-) - 5 - endo- (3-indolcarbonyloxy) -Y-1 3-dimethylaminopropyl 2, 2,1 - heptane - 2,3-di-endo-carboxylic acid (-) - P1a.

A. Imide (-) - 5-endo - hydroxy - N - (3-dimethylaminopropyl) - bicycle 0 2.2.1 heptane-2, 3-di-endo-carboxylic acid (/ - / - P1a).

Replacing in example 31A of the compound (+) - V with an equimolar amount of the compound (-) - Ve gives the compound (-) - Ilia; mp 119-120 ° C.

B. Hydrochloride imide of (-) - 5-endo (Z-indolocarb-onyloxy) -M - (3 - dimethylaminopropyl) - bicyclo | 2,2,1 heptane - 2,3 di-endo-carboxylic acid.

Indole-3-carboxylic acid (2.6 g, 0.015 mol) is converted into crude acid chloride by the software using 31B. Treatment with alcohol (-) - 1Pa (2.0 g,

0.0075 mol) in a mixture of CHgCY - pyridine is carried out according to Example 31B for the compound (+) - la and the crude product is obtained. Chromatographing it in a column with alumina (100 g) after elution with a mixture of CHCl3 (CH3CH2) Oa and CH2OH 33: 12: 55 gives a purified free base. From the fractions containing the product, the solvent is distilled off, the residual oil is extracted with a mixture of ethyl ether - methyl

alcohol 75: 25 and treated with hydrochloric gas. After removing the solvent, the hydrochloride salt is obtained as a brown solid. Two recrystallizations from ethyl alcohol,

treating with hot ethyl acetate and drying at 78 ° C over pH in high vacuum yields the desired product (1.47 g, 44% yield, mp 172-174 ° C).

Calculated,%: C, 61.95; H 6.33; N 9.42;

C1 7.95.

C23H27N304 HC1

Found (adjusted for 5.02% water):

C, 62.01; H 6.07; N 9.52; C1 3.22. -58.2 (c 0.052, H2O)

Example 33. Ethanol solvate of hydrochloride imide 5-endo (indole-3carbonyloxy) -Y - (2 - dimethylaminopropyl) - bicyclo 2.2.1 | heptane-2,3-di - endocarboxylic acid.

Lactonic acid On (8.0 g, 44 mol), SOC12 (12 ml) and dry dimethylformamide (20 drops) are suspended in dry CH2Cl2

(200 ml) and the mixture is stirred at reflux for 1.5 h. The normally isolated crude acid chloride is redissolved in dry CHaCla (150 ml). Then, with stirring, a solution of 2-dimethylamino-n-propylamine (6.74 g, 66 mmol) in 50 ml of dry CH2Cl2 is added over 10 minutes. The mixture was heated under reflux for 3 hours and stirred for 16 hours at and then the solution was washed with a 5% solution of Na2CO3 and a saturated saline solution, dried over MgSO4 and the solvent was removed. The 5-endo-hydroxy-M- (2-dimethylaminopropyl) -bicyclo-2,2,1 heptane-2,3-di-endo-carboxylic acid (III) imide is obtained as a crude yellow oil. Solids are removed by treatment with Skellisolve B and ethyl acetate and filtration. Refined oil III (II, 4 g, 42.8 mmol, yield 97.4%) was added to indole-3-carbonyl chloride (from 10.0 g, 62 mmol of indole-3-COOH in the usual way), in dry CH2Cl2 (200 ml) containing pyridine (2 ml), as

described in example 20. The product is separated from