SU1711674A3 - Method for the synthesis of azonium spironortropanol ester - Google Patents

Abstract

The present invention provides a process for the preparation of partly novel azoniaspironortropanol esters of the general formula:- <IMAGE> useful for treating asthma and as broncholytics, are prepared by (a) demethylation of tropine to give nortropine, (b) reaction of nortropine with a dihalide to give a corresponding azonia compound, and (c) esterification of the azonia with an acyl imidazolide compound, using specified conditions in each step.

Description

The invention relates to a method for producing a new azonispironotropanol complex ef.ir, which has antispasmodic, asthma-therapeutic, and bronchodilatory activity.

 Azoniaspironotropanol ester has the general formula

 he0

OR,

 where R is an alkyl residue - (CH2) 4- or - CH2-CH CH-CH2-;

RI is hydrogen;

R2 is phenyl.

The purpose of the invention is to obtain new derivatives of nortropanol, which have pharmacological advantages over the known analogues of similar effect.

The goal is achieved by the fact that tropine formula. .

tjFVH (ii

 but

about 1

four

 00

enter into interaction with ethyl chloroformate in chloroform medium in the presence of an alkali metal bicarbonate, followed by hydrolysis of the obtained 8-alkoxycarbonylnortropin in an aqueous solution with a base, after which the resulting nortropine

NH

tH

. ABOUT)

HE

is introduced into the reaction with a dichloride of the formula Cb-R-CI, where R has the indicated values in dimethylformamide in the presence of diethylamine at a ratio of 1: 2: 4 nortropine: diethylamine: dichloride at room temperature for one to several days, after which time - learned compound of general formula

.

W

ct

at

s

HE

n

(9

where R has the indicated meanings, esterify to ester with imideaeolide of the general formula .30

HE

4 s-t-r "

About R

")

where RI and R2 have the indicated meanings in anhydrous acetonitrile in the presence of -4-N.N-dimethylaminopyridine as a catalyst.

PRI me R 1. For -benzyloxy-norropropan-8-spiro-1-pyrrolidinium chloride.

Stage A. Dimethylation of Tropine to Norgropine.

In a stirred reactor with a capacity of 300 l, with a fitted reflux condenser, 1.9 kg tropine (97%, respectively, 1.843 kg of pure substance, respectively, 13 mol) is dissolved in 240 l of chloroform and 5.7 kg of carbonate powder are mixed sodium and 5.3 liters of ethyl chloroformate (more than 98%, respectively 6.0 kg, i.e. 55.7 mmol-). Heat to boiling and then boil for the next 2 hours under reflux. The progress of the reaction is followed by thin layer chromatography (silica gel 60 - dimethylformamide; diethylamine: ethanol: ethyl acetate 5: 10: 30: 60). The still hot reaction mixture is filtered and the chloroform is distilled off. To the residue is added

50

five

0

five

0

5 0 5

a solution of 18 kg of potassium hydroxide (85%) in, 90 l of water. Heat to boiling and then for another 9 hours under reflux. The cooled solution is extracted on a Karr-column with chloroform. Extraction conditions. The stationary phase is the light phase (solution of caustic potash), which moves at a rate of about 14 l / h. The dispersed phase is the heavy phase (chloroform), which moves at a rate of about 35-40 liters / hr. Shaking frequency: 200 strokes / min. Temperature 26-28 ° C.

Thus, the formed notropin is approximately quantitatively extracted from a solution of caustic potash. After removing the solvent, the crude product is used in stage B without further purification.

1.876 kg of northropin are obtained with a content (high pressure liquid chromatography on a column / g-Bondapack C18. Eluent: methanol - water 1: 9 with P1C-B7) 87%. This corresponds to 1.632 kg of pure nortropin, respectively, a yield of 98%.

Stage B. .. t

3 # -Oxinortropan-8-spiro-1-pyrrolidinium-hrrrid.

The composition of the reaction mixture should be attributed to pure northropine. The molar ratio of northropine: diethylamine: 1,4-dichlorobutane should be exactly 1: 2; 4.

The crude northropine obtained in stage A (1.186 kg, respectively 1.632 kg of pure substance, respectively 12.85 mol) is dissolved in 52 liters of N.N-dimethylformamide and 2.6565 liters of diethylamine (1.876 kg; 25.7 mol) and 5.766 l 1,4-dichlorobutane (6.528 kg; 51.4 mol). The reaction mixture was allowed to stand for 18 days at room temperature. The crystals that have been isolated are sucked off, washed with a small amount of acetonitrile and dried in a vacuum oven at 50 ° C. 2.25 kg are obtained (80% based on the tropine used in the first stage) of the pure product with m.p. 250 ° C.

Stage B.

Tropinchloride: (3 a-benzyloxy-nortropan-8-spiro-1-pyrrolidinium) -chloride id.

a) Imidazolide benzyl acid.

With the exclusion of moisture, the heat of 1.944 kg M, 1M-carbonyldiimidazole (12 mol) is dissolved in 19.2 liters of anhydrous dichloromethane. With stirring at 15-20 ° C, 2.736 kg of anhydrous benzyl acid (12 mol) are added over 6 minutes. Stir for 1 h at room temperature. In this case, the benzyl acid is first dissolved, then soon the release of imidazolide benzyl acid in solid form begins. Sucked off and washed with 0.8 l of anhydrous dichloromethane. 2.4 kg of benzyl acid imidazolide are obtained.

b) Preparation of the target compound. - In a stirred reactor with a capacity of 30Q l, 1.3 kg of the absolute compound obtained in accordance with step B are suspended in 230 l of absolute acetonitrile and heated to 78 ° C. 74.0 g of 4- (dimethylamino) -pyridine in 2 liters of absolute acetonitrile is added to the suspension. Then, in three portions, in intervals of 30 minutes at 78 ° C, a supension of 2.086 kg of benzyl acid imidazolide in 9.0 l of absolute acetonitrile is added. Then it is stirred at 78 ° C until the first addition of imidazolide benzyl acid is reached from the first addition, the total reaction time is 4 hours. It is cooled to 20 ° C and stirred overnight. The resulting suspension is sucked off and washed with a small amount of acetonitrile. The residue, as well as the further product obtained (by concentration of the mother liquor) (total 2.14 kg), is recrystallized from isopropanl. Obtain 1.78 kg (70%) of the pure product with so pl. 63 ° C (decomposition) .I

FD-MS: m / e. 392 (molecular cat. He). . :. : ..U.-. .. h - .; ; :: /

IR (KBr) v, cm 1: 3150, 1735, 1498,1452,747.

PRI mme R 2. For -benzyloxy-north-panan-8-spiro-1- (3-pyrrolinium) -chloride.

Stage B ,.

Over -Oxo-nortropan-.8-spiro-1: - (3.-pyrroline) -chloride.

1.05 ml of diethylamine (10 mmol) and 1.05 ml (10 mmol) of cis-1,4-dichlorobutene-2 are mixed into a solution of 635 mg (5 mmol) of nortropin in 9.5 ml of N.N-dimethylformamide. After 1 h, the pure crystalline product is sucked off. The mother liquor is mixed with ethyl acetate until the beginning of the pi mist, in order to obtain further ripoi duct. The crystals are sucked off and washed with a small amount of acetone.

The output of 984 mg (91%), so pl. 204 ° C.

FD-MS: m / e 180 (molecular cation),

IR (KBr), v cm 1: 3250, 1621,

- NMR (90 MHz, D20) d (value: 1 s to TSP 0); 1.7-2.7 (8H, H-2, H-4, H-6, H-7); 3.92 (2H, H-1, H-5): 4.05 (1H, H-3), 4.14 and 4.31 (P2H; H-21 and H-51); 5.90 (2H; N-ЗГ.Н-ф ..

Stage B.

/, Z-Benzyloxy-nortropan-8-spiro-1- (3-pyrrolinium) -chloride.

530 mg (2.4 mmol) of 3ct-Oxy-Nortropan-8-spiro-11- {3-pyrroline) -chloride are suspended in 353 ml of absolute acetone and together with 14 ml (0.12 mmol), 4-dimethylamino-pyridine and 678 mg (2.4 mmol) of benzyl acid imidazolide are stirred in an autoclave at 70 ° C for 23 hours. The product crystallizes out of the reaction mixture while cooling to room temperature. It is sucked off and washed with a small amount of acetone.

Its output is 650 mg (62%), mp. 267 ° C.

FD-MS: m / e - 390 (molecular cation) ..

MK-cneKTptKBrJv.cM 1: 1722,1595,1490,

1,445,741.

1H-NMR (900 MHz, DaO) d (values refer to TSP 0): 1.3-2.8 (8H; H-2. H-4, H-6, H-7); 3.85 (2H, H-1, H-5); 4.09 nv4.37 (2H; H-2 and H-5); 5.24 (1H, H-3); 5.95 (2H, H-3J H-4), 7.44 (YUN, aromatic protons of benzyl acid).

Stage G,

Conversion of Za-benzoyloxy-northropan-8-spiro-1- (3-pyrrhenium) -chloride to 3-benzyloyloxy-north. Propane: 8-spiro-1 pyrrolidinium-chloride.

500 mg of Z.sg-Benzyloxy-nortropan-in-spiro-11- (31-pyrrolynium) -chloride are dissolved in 15 ml of methanol and after the addition of platinum dioxide at the tip of the spatula, it is hydrogenated at normal pressure and at 25 ° C until absorption ceases hydrogen. The hydrogenation is carried out in standard equipment. After filtration, platinum is concentrated under vacuum to dryness. According to 1H-NMR spectroscopy, the conversion is quantitative. Recrystallization is carried out as shown in Example 1, Step B.

PRI me R 3.

3 a -Benzyloxy-nortropan-8-epiro-2-yzo-innon chloride.

a) Za-hydroxy-nortropan-8-spiro-2-isoin-lobarium.

1.27 g (10 mmol) of northropin is dissolved in 7 ml of chloroform and mixed with 1.46 g (20 mmol) of diethylamine and 7 g (40 mmol) of 1,2-bis (chloromethyl) benzene. The clear reaction solution was left to stand closed for 24 hours at room temperature. It is then concentrated in wine, wine and -mixed with ethyl acetate to start crystallization. The crystals are filtered off with suction and recrystallized from a mixture of isopropanol with ethyl acetate.

Yield 1 g (38%), so pl. 245-247 ° C.

he)

FD-MS: m / e 230 (molecular CAT spectrum (KBr) 3168, 757, 742.

1H-NMR (250 MHz, D20) d (values refer to TSP-0): 2.09 (2H, H-ba. H-7a); 2.40-2.67 (4H, H-2, H-4); 2.59 (2H, H-6l, H-76); 4.03 (2H, H-1, H-5); 4.24 (1H, H-3); 4, 82 and 4.99 (4H, H-1 and H-3); 7.47 (4H, H-4 + H-7J.

b) For -Benzyloxy-nortropan-8-spiro-21-isoindolinium-chloride.

A TC3 g (5 mmol) 3 a-hydroxy-nor trrpan-8-spiro-1-isoindolinium chloride is suspended in 210 ml of absolute acetonitrile and heated to 78 ° C. With stirring, first mix 62 mg (0.5).

Example 4.

, 3 a-Benzyloxy-nortropan-8-spiro-4-morpholinium chloride. ,

a) Over-Oxy-nortropan-8-spiro-4-morpholini-chloride.

11, 8 ml (113.2 mmol) of diethylamine and 26.6 ml (226.5 mmol) of 2,21-dichlorodiethyl ether are mixed into a solution of 7.2 g (56.6 mmol) of nortropin in 70 ml of chloroform. The clear reaction solution is kept closed at room temperature for three days. The separated mixture (oil crystals) was homogenized and left to crystallize overnight at 0 ° C. The crystals are filtered off with suction, washed with a small amount of chloroform and dried for 2 hours in vacuum at 40 ° C. By concentrating the mother liquor and treatments with ethyl acetate, an additional substance is obtained.

Exit 12.5 g (95%), so pl. 274-276 ° C (decomposition).

FD-MS: m / e 198 (molecular cation).

PC spectrum (KBG) V,. 3320-892.

1H-Ya MR (250 m Hz, D20) b (meaning and related to TSP 0): 2.00 (2H H-ba, H-7a); 2.22- 2.62 G6N. H-2, H-4, N-bv, H-7c); 3.50 and 3.65 (4H, H21 and H61); 4.01 and 4.08 (4H, H-21 and H61);

4.18 (1H, H-3); 4.22 (2H, H-1 and H-5).

 a-Benzyloxy-nortropan-y-spiro-4-morpholinium chloride.

7.5 g (32 mmol) of -Oxy-nortropan-8-spiro-4-morpholinium chloride are suspended in 650 ml of absolute acetonitrile and mixed with 0.587 g (4.8 mmol) of 4- (dimethylamino) -pioidine. At 79 ° C and with stirring, 26 g (92.8 mmol) of benzyl acid imidazolide are added in portions over 3 hours. The reaction mixture is left to stand for seven days at room temperature and then the pure crystalline product is sucked off. The crystals are dried for 2 hours at 40 ° C under vacuum. Yield 8.4 g (60%), m.p. 225 ° C (decomposition).

FD-MS: m / e 408 (molecular cation).

PC Spectrum (KBG), vcM 1: 3410,3183.1731,

1492,703.

1H-NMR (250 MHz, D20) (values refer to KtSP -O): 1.51 (2H, H-ba. H-7a); 2.00 (4H, H-2a, H-4a, H-bv, H-7c); 2.63 (2H, H-2 v, H-4c); 3.38 &3; 64 (4H, H-21 and H-61); 3.99 and 4.04 (4H, H-3 and H-5); 4.09 (2H, H-1, H-5); 5.30 F, H-3); 7.46 (YUN, aromatic protons of benzyl acid).

PRI me R 5.

3 a-Benzyloxy-nortropan-8-spiro-1-pyrrolidino- (3, 4-b) quinoxalinium-bromide,

a) 3 a-Oxy-north-6-pan-8-spiro-11-pyrroidino- (3 4-b) -quinoxalinium-bromide. , To a solution of 5.57 g (43.6 mmol) of nortropin in 100 ml of chloroform, 54.8 ml (43.6 mmol) of diethylamine and 13.85 g (4; 3.6 mmol) of 2.3-; (brommetyl) -quinoxaline. The heated reaction mixture is cooled to 20 ° C, and the product is isolated in crystalline form. It is filtered off with suction, washed with chloroform, and dried under vacuum at 55 ° C for 22 h.

Output 1.1.1 g (71 ° / 0), so pl. 283 ° C (decomposition).

FD-MS: m / e 282 (molecular cation).

IR spectrum (KBG) v, 3345, 1504, .773.

1 H-NMR (250 MHz, DaO) d (value relative to tsp 0): 2.21 (2H, H-ba, H-7a); 2.53-2; 89 (6H, H-2, H-8, H-6b, H-7v); 4.29 (2H, H-1 and H-5); 4.31 (1H, H-3); 5.21 and 5.4 (2H; H-2 and H-5); 7.94-8.05 (2H. Quinoxaline-o-protons); 8.11-8.22 (2H, quinoxaline-m-protons). b) 3 a-Benzyloxy-nortropan-8-spiro-11-pyrrolidino- (31, 41-в) -quinoxalinium- bromide.

5 g (1.39 mmol) of 3 a-hydroxy-nortropan-8-spiro-1-pyrrolidino- (31, 41-b) -quinoxalinium-bromide are suspended in 130 ml of anhydrous dimethyl sulfoxide and 100 ml of anhydrous acetonitrile. After the addition of 0.26 g (2.09 mmol) of 4-dimethylaminopyridine, it is heated to 78 ° C. With vigorous stirring at intervals of 30 minutes, 7.74 g (27.8 mmol) of benzyl acid imidazolide was added in three portions. Stir for the next 2.5 hours at 78 ° C. The reaction mixture is cooled to 20 ° C and filtered. The residue on the filter is discarded. The filtrate is concentrated to dryness at a pressure of about 0.2 mb. The residue is extracted with 500 ml of boiling isopropanol and filtered hot. The residue on the filter is discarded.

763.

The filtrate is concentrated to 20 ml. The product crystallizes at room temperature overnight. It is filtered off with suction, washed with cold isopropanol, and dried for 2 hours at 55 ° C in vacuo. Yield 3.5 g (44%), m.p. 205 ° C (decomposition).

FD-MS: m / e 492 (molecular cation).

IR spectrum (3375, 1730, 1504,

.-

1H-NMR (250 MHz, CDCl3 / CD3OD - 3: 1) 5 (values refer to TMS - 0): 1.78 (2H, H-ba, H-7a); 2.08 (2H, H-2a, H-4a); 2.20 (2H, N-bv, H-7b); 2.85 (2H, H-2v ,, H-4b); 4.23 (2H, H-1, I-5); 4.62 (4H, H-2, H-5); 5.35 (1H, H-3); 7.30-7.48 (YUN; protons of benzyl acid); 7.84-7.97 (2H, o-protons of quinoxaline); 8.07-8.22 (2H, m-protons of quinoxaline).

Example

Za-Benzyloxy-nortropan-8-spiro-21- {21-aza-ZN-phenalenium) -bromide.

a) 1.33 ml (12.7 mmol) of diethylamine and 4 g (12.7 mmol) 1 are mixed with a solution of 1.62 g (12.7 mmol) of norropropine and 75 ml of NN-dimethylformamide 8 bis- (brommethyl) naphthalene. The product is crystallized from the reaction solution which remains slightly warm for 2 hours. It is filtered off with suction, washed with a small amount of N, N-dimethylformamide and dried for 2 hours in vacuum at 55 ° C.

Yield 3.5 g (76%), m.p. ZSORS (decomposition),

FD-MS: m / e 280 (molecular cation).

IR (KBr) v, cm 1: 3410,1604,15.12. H-NMR (250 MHz &apos; CDCIs / CDsOD - 3: 1) 5 (values refer to TMS 0): 2.02 (2H, H-ba, n-7a); 2.39-2.85 (6Н, Н-2, Н-4, Н-бв, Н-7в); 3.92 (2H, H-1, H-5); 4.28 (1H, H-3); 5.01, and 5.16 (4H H-1 and H-3); 7.51-7.64 (4H, H-8); 7.93 (2H,).

b) 3 a-Benzyloxy-nortropan-8-spiro-2CH2-aza-ZN-phenolenium.) - bromide.

2.95 g (8.2 mmol) of 3 a-hydroxy-nortropan-8-spiro-2: (2-aza-3H-phenolenium) -bromidaeus are pendated into 1660 ml of anhydrous acetonitrile and 160 ml of anhydrous s, M-di- methylformamide. After the addition of 152 mg (1.2 mmol) of 4-dimethylaminopyridine, it is heated to 78 ° C. With vigorous stirring at intervals of 30 minutes, 4.56 g (16.4 mmol) of a bisyl imidazolide acid are added in three portions. Stir for an additional 2.5 hours at 78 ° C and thereafter the reaction mixture is concentrated to half. The precipitated crude product is sucked off at 20 ° C and suspended in methanol. The undissolved portion in methanol is filtered off and discarded. The filtrate is concentrated until the beginning of the crystallization of the product. After crystallization overnight at room temperature, it is filtered off with suction and dried under vacuum at 55 ° C for 2 hours.

Yield 2.1 g (42%), m.p. 322 ° C (decomposition).

FD-MS: m / e 490 (molecular cation).

IR (KBg) V, cm 1: 3428, 3240.1738, 1603, 1497.

1H-NMR (250 MHz, COCl3 / SOzOO - 3: 1) (values refer to TMS 0): 1.75 (2H, H-ba, H-7a); 1.94 (2H. H-2a, H-4a); 2.20 (2H, N-bv, H-7b); 2.80 (2H, H-2b, H-4b); 3.85 (2H, H-1, H-5); 4.93 and 5.1.9 (2H, H-1 and HZ); 5.45 (1 H, H-3); 7.31-6.46 (YUN, proton of benzyl acid); 7.47-747 (4H, H-5, Hb, H-7T H-8); 7.93 (2H, H H-9).

PRI me R 7.

3 cc-Benzyloxy-nortropan-8-spiro- 1- (4-methyl) -piperidinium chloride. /

a) Over-Oxy-nortropan-8-spiro-1 (4-methyl) -piperidinium chloride.

7.62 g (0.06 mmol) of nortropin is dissolved in 200 ml of absolute N.N-dimethylformamide. After stirring 8.76 g (0.12 mol) of diethylamine and 37.18 g (0.24 mol) of 1,5-dichloro-3-methylp ntan, the reaction mixture was allowed to stand closed at room temperature for 18 days. The crystals that have been isolated are sucked off, washed with a small amount of acetonitrile and dried in a vacuum oven at 50 ° C. Obtain 7.84 g (53%) of the pure product, so pl. 290 ° C (decomposition).

FD-MS: m / e 210 (molecular cation).

IR spectrum (KBr) v, 3190.

1H-NMR (250 MHz, O20) 5 (values vm.d, refer to TSP 0): 1.01 (multiplet, 3N, CH 3); 1.37-2.02 (multiplet, 7H, H-7a, H-ba, H-3, H-4G 2.20-2.52 (multiplet, 5H. H-2a, H-4a, H-bv , Н-7в, ОН); 2.60 and 2.67 (2 х triplet; 2Н, Н-2в and Н-4в); 3,10, 3,20, 3,63 and 3,74 (4 х multiplet ; 4H; H-2 and H-6); 3.76 and 4.24 (2 x multiplet; 2H; H-1 and H-5); 4.19 (triplet, 1H, H-3).

b) 3 a-Benzyloxy-nortropan-8-spiro-1- (4-methyl) -piperidinium chloride.

7.37 g (30 mmol) For -Oxy-Nortropan-8- spiro-1- (4-methyl) -piperidinium-chloride is suspended in 650 ml of absolute acetonitrile and heated to 78 ° C with stirring. At this temperature, - First, 587 mg (4.8 mmol) of 4- (dimethyl-amino) -pyridine are sewn, then for 2 hours

13.35 g (48 mmol) of benzyl acid imidazolide, approximately 4 servings. Stir additionally for an additional 1 5 5 h at 78 ° C, and then the reaction mixture is cooled overnight without stirring to room temperature. The crystalline product is filtered off with suction and washed with a small amount of acetone. The crude crystallisate is recrystallized from anhydrous isopropanol. Pure crystals are dried for 2 hours at 40 ° C under vacuum. The yield of 9.56 g (70%) in the form of a 1: 1 mixed crystallisate with isopropanol ,. mp 256-259 ° C.

FD-MS: m / e 420 (molecular cation). . . ...- ..,:.;.

IR spectrum (KBr) v 1735.

1H-NMR (250 MHz, LaO) 3 (values in ppm; refer to TSP 0): 0.98 (multiplet, MN (/ CH3); 1.30-1.65 (multiplet, 4H, AND -7а, Н-За, Н-5а); 1.65-2.03 (multiplet, 7Н, Н-2а, Н-4в, Н-бв, Н-7а, Н-Sv, Н-4 Н-5в ); 2.52 and 2.72 (multiplet, 2H, H-2v; H-4v); 3.02,3,19,3,47, 3.72 (triolet, triplet, doublet, doublet; 4H; H -2 and H-6); 3.62 and 4.10 (multiplet, multiplet; 2M, H-1 and H-5); 5.30 (triplet, 1H, H-3); 7.40-7 , 50 (multiplet, YUN, aromatic protons).

Example 8. Za- (4,4-difluoro) -benzyl-yloxynortropan-8-spiro-1-pyrrolidine-chloride.

2.17 g (0.01 mol) of Za-Oxy-nortropan-8-spiro-1-pyrrolidinium chloride together with 2.02 g (0.01 mol) of sodium heptane-1-sulfonate is dissolved in 500 ml with heating. absolute acetonitrile. After cooling to 25-27 ° C with the exclusion of moisture, the sodium chloride precipitate is removed from the precipitate. The solution, mixed with 0.125 g of 4- (dimethyl-amino) -pyridine, is transferred to a reaction vessel, which is connected to a flask with a stirrer, in which 4,4-difluoro-benzyl acid imidazolide is obtained. This flask with stirrer is equipped with two dropping funnels. 2.64 g (0.01 mol) of 4.41-difluorobenzyl acid (prepared in a manner similar to Dt.OL 2, 034 943 from 14.) dissolved in 100 ml of absolute acetonitrile are added to one dropping funnel. A solution of 2.43 g (0.015 mol) of M.M-carbonyl-diimidazole is placed in another 150 ml of absolute acetonitrile in another dropping funnel. Approximately 1/4 volume of each of both solutions was simultaneously poured into the flask with stirring, then stirred for an additional 15 minutes, and the resulting solution of imidazolide, with careful exclusion of moisture, was transferred into a reaction vessel, in which the solution of 3-hydroxy-northropane-8 was stirred -spiro-1-pyrrolidinium-heptane sulfonate at room temperature. This process is repeated three more times until all reagents are combined. After this, it is barely boiled for 2 hours with a reflux condenser, then cooled overnight to room temperature.

The reaction mixture is evaporated to dryness on a rotary evaporator under vacuum. The residue is purified by chromatography on a silica gel column (silica gel 60, 0.083 0.200 mm, Merk N2 7734). Mobile phase 1,2-dichloride: acetic acid: meta; Noldodaoda 57: 23: 13: 7 (by volume). Yield, mg (14%) of 3 a- (4.4-difluoro) -benzyloylok e nortropen-8-alcohol o-1-pyrrolidinium-heptusulfonate. After passing through a column that is filled with a strongly basic ion® by exchange in a chloride form (for example, Levatite @ MP5000), the desired compound is obtained. The crude product is recrystallized from isopropanol. washed with ethyl acetate and dried under vacuum until constant weight at 40 ° C. Yield 470 mg as a 1: 1 mixed crystallized with isog propanol, mp; 242-245 ° C.

FD-MS m / e 428 (molecular cation) ./

IR (KBr), v cm 1: 1508,1603,1733.

1H-NMR (250 MHz, D20) d (values in ppm, refer to K-TSP O): 1.44-1.57 (multiplet, 2H, H-ba, H-7a); 2.00-2.20 Duplicates, 8H, H-4a, H-2a, 7-6v, H-З H-4); 2.57 and 2.64 (2 x multiplet; 2H, H-2b and); 3.38 and 3.60 (2 x multiplet, 4H, H-2 H-5); 3.73 (multiplet; 5 2H, H-1, H-5); 5.27 (triplet. 1H, H-3); 7.19 and 7.42 (2 x multiplet, 8H, aromatic protons). ,

PRI me R 9. 3 a- (4,4-dimethyl) -benzyloyl-oxynortropan-8-spiro-1-pyrrolidium-chloride.

Proceed according to example 8, however, instead of 4,4-difluorobenzyl acid, 4,4-dimethylbenzyl acid is used as the starting material (obtaining analogous. Cannon: J. Org. Chem25, 959-962,1960). The output of 1.68 g, so pl. 275 ° C. FD-MS: m / e 420 (molecular cation).

IR (KBg) v, 1508, 1612 (weak). 1718.

H-NMR (250 MHz, D20) d (values in ppm refer to TSP 0): 1.47-1.51 (multiplet, 2H, H-ba, H-7a); 1.79-2.2 (multiplet, 8Н, Н-2а, Н-4а, Н-бв. Н-7в, Н-ЗГН-4); 2.33 (sing- 5 years, 6H, 2 x CH3); 2.48-2.66 (multiplet, 2H, - H-2b, H-4b); 3.34 and 3.58 (2x multiplet, 4H, H-2 and H-5J; 3.67 (multiplet, 2H, H-1, H-5); 5.23 (triplet, 1H, H-3); 7.20-7.31 (multiplet, 8H, aromatic protons).

five

0

five

0

0

five

0

PRI me R 10.

Za-di-n-butyloxybenzyloxy) - nortropan-8-spiro-1-pyrrolidinium-chloride.

Proceed according to example B, but instead of 4,4-difluorobenzyl acid, 4,4-di-n-butyloxybenzyl acid is used as the starting material (preparation is analogous to I. G. Cannon. J. org. Chem. 25, 959-962,1960).

Yield 240 mg, crystals spreading out at room temperature.

FDHVIS: m / e 536 (molecular cation).

IR (KBg) y, 1508, 1580 (weak). 1608, 1734.

TH-NMR (250 MHz, COClS) (values in ppm, refer to): 0.96 (triplet, 6H, 2 x CH3 from n-butyl-coli); 1.47 (triplet, quadruplet, 4H, 2 x CH3 from n-butyloxy); 1.53-1.63 (multiplet, 2H, H-ba, H-7a); 1.76 (triplet, triplet, 4H, 2 x CH2 from n-butyloxy); 1.80-2.30 (multiplet, 8H, H-2a, H-4a, H-bv, H-7b, H-31, H-4); 2.62-2.77 (multiplet, 2H, H-2b, H-4b); 3.65 and 3.99 (2 x multiplet, 4H, H-2 and H-5); 3.94 (triplet, 4H, 2 x CH2 from n-butyloxy); 4.10 (multiplet, 2H, H-1, H-5); 5.28 (triplet, 1H, H-3); 6.84 and 7.25 (2 x doublet, 8H, aromatic protons). Prim, er 11.

Za- (4-n-butyloxybenzylloyloxy) -nortropan-8-spiro-11-pyrrolidinium chloride.

Proceed according to Example 8, however, instead of 4,4-difluorobenzyl acid, 4-n-butyloxybenzyl acid is used as starting compound (preparation is similar to 75; 2654-2657, 1953). Exit 250 mg, mp. 206 ° C.

FD-MS: m / e 464 (molecular cation).

IR spectrum (KBr) v 1512, 1609, 1742.

1 H-NMR (250 MHz, CDCIs) d (values in ppm, relative to TMS 0): 0.97 (triplet, 3N, CH 3 n-butyloxy); 1.50 (triplet, quadruplet, 2H, CH2 from n-butyloxy); 1.56-1.64 (multiplet, 2H, H-6a, H-7a); 1.77 (triplet, triplet, 2H, СНа from n-butyloxy); 1.84-2.45 (multiplet, 8H, H-2a, H-4a, H-2v, H-7v, H-3 H-4); 2.65-2.85 (multiplet, 2H, H-2b, H-4b); 3.58 and 3.95 (2 x multiplet, 4H, H-2 and H-5); 3.95 (triplet, 2H, CH2 from n-butyloxy); 4.08. (multiplet, 2H, H-1 and H-5); 5.30 (triplet, 1H, H-3); 6.84 (doublet) and 7.26-7.37 (multiplet, 9H, aromatic protons).

PRI me R 12.

Stage: Oxidative dimethyl-. nia tropin to nortropin.

In a stirring pot containing a reflux condenser installed on it

30 kg of tropine (I) are dissolved in 300 l of water, after which 3 l of chloroform is dispersed and then 75 kg of solid sodium hydroxide are mixed in portions. Temperature

it should not exceed 40 ° C. At a temperature of 20-22 ° C, with vigorous stirring, a solution of potassium hexacyanoferrate (III) in 1 liter of water is added over 1.5-2 hours. Insofar as

the reaction is weakly exothermic, then cooling is necessary. The reaction mixture is stirred at 20-25 ° C until it turns orange in color (after 2-3 hours). The next day, stirring is continued without cooling. The precipitated salts are filtered off with suction and the filtrate is extracted in a column Tsil (Zlel scher Kolonne, 0-150 mm, flow rate 250 l / h) with chloroform in countercurrent. Chloroform phase

dried under vacuum, and the residue is further dried under vacuum at 40 ° C

Yield 81% of theory (analysis using gas chromatography).

Similar results are obtained and

when using 7.5 liters and 15 liters of chloroform.

These compounds have valuable pharmacological properties, namely, they have a pronounced bronchodilator effect. This has been demonstrated on awake guinea pigs. The animals were given intraperitoneally test compounds and then acetyl-ub-methyl-choline chloride as an aerosol to relieve bronchospasm. The average effective concentration (ECso) of acetyl / 3-methylcholine chloride, which is needed to relieve bronchospasm, was determined. The lower the average effective concentration, the better the bronchodilator

test compound effect. The following results were obtained.

Connection example 2 (stage G): ECso 0,00173.

Atropine: EbO 0; 0140.

 Connection example 1: ECso 0,002. LDso 700 mg / kg (oral, mouse). It can be seen that the target compounds have a significantly better effect than atropine, and are superior to compounds

described in the Federal Republic of Germany application No. 2605728, since

the latter do not have a better effect than atropine.

Claims (1)

The invention of the method for the preparation of azonium spironortropanol ester of the general formula C with, e  P he   m-, ... .OR, where Ri is an alkylene residue - (CH2) 4- or -CH2CHH-CH2-; Ri is hydrogen; R2 is phenyl, characterized in that the trope of formula CHj are introduced into interaction with ethyl chloroformate in chloroform medium in the presence of an alkali metal bicarbonate, followed by hydrolysis of the obtained 8-alkoxycarbonylnortropin in an aqueous solution with a base, after which the resulting northropine of the formula NH introduced into the interaction with the dichloride of the formula CI-R-GI, where R has the specified values in dimethylformamide in the presence of diethylamine with a ratio of nortropine: diethylamine: dichloride 1: 2: 4 at room temperature for one to several days, after which the resulting compound of the general formula J -Ns 0 xrti where R has the indicated meanings, esterify to ester with an imidazolide of the general formula. 20 HE D-rf About Rt where RI and Ra are the indicated values, 25 in anhydrous acetonitrile in the presence of 4-M, N-dimethylaminopyridine as a catalyst.