KR810000612B1 - Process for preparing 2,p-dioxatricyclo(4,3,1,0 3,7)decanes - Google Patents

Abstract

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Description

Preparation of 2,9-dioxatricyclo- (4,3,1,03,7) -decane

The invention 2,9-dioxa-tricyclo-relates to a process for the preparation of decane - ^{(4,3,1,0, 3,7).}

Some of the many 2,9-dioxatricyclo- (4,3,1,0 ^{, 3,7} ) -decane compounds have a buffering effect, hypnosis, and neuropathy in the central economy. It has the effect of vasodilation. At the same time, some of the other compounds have obvious analgesic activity and can cause anorexia due to the gin.

The present invention is useful pharmacological and therapeutic properties with 2,9-dioxa-tricyclo-decane relates to - ^{(4,3,1,0, 3,7).}

It was surprisingly discovered that compounds with a basic substitution at the 3'-position not only significantly increased sleep but could also cause paradoxal sleep.

The present invention compound is 2,9-dioxa-tricyclo ^{(4,3,1,0, 3,7)} - decane general expression as follows.

Wherein R ₁ is a first, second or tertiary amine group, one of R ₂ and R ₃ is a hydrogen atom and the other is a hydroxyl group, acyloxy or carbamoyl oxy group, or R ₂ and R ₃ are Together are oxygen atoms, one of R ₄ and R ₅ is a hydrogen atom and the other is alkoxy and the 10,11-position can be hydrogenated.

The valuable action of the present compound 2,9-dioxatricyclo- (4,3,1,0 ^{, 3,7} ) -decane is its action on sleep and REM-sleep, resulting in less sedative and less toxic effects. In addition to the characteristics, the electrical nerve conduction method shown in the rat experiment has already been established to meet the requirements of recent studies on sleep.

There are currently no sleeping pills available that can extend REM-sleep, which is absolutely necessary for the recovery of living organisms.

The surprising effect of this product can be exemplified by considering the piperidino derivatives of formula (II).

The compound of formula (II) was observed pharmacologically as a hydrochloride salt, in the experiment indicated by the symbol 1973, and as hydrogen tartrate, as an experiment indicated by the experiment number 2661. When the compounds of formula (I) were assayed in rats, nucleobarbital was administered orally without the anticonvulsant effect caused by benzodiazepines or barbitrate, depending on the dose or dose, up to 10 mg per kilogram of body weight. The compound of formula (I) was easily recognizable because the compound of formula (II) induced the prolongation of sleep induced by.

In the exercise test, the ED ₅₀ for this inhibitory effect was 3 milligrams per kilogram of body weight when administered orally.

This sedative effect was confirmed when the compound was assayed in rats. In mice, new EEG effects were evident during sleep. When administered orally at a dose of 2.5 to 80 milligrams per kilogram of body weight, the length of the no-sleep period significantly increased REM sleep and sleep time without a significant decrease. This effect was confirmed at both 4 and 8 hours of observation.

The LD ₅₀ of the hydrochloride compound when injected intraperitoneally in mice is 406 mg / kg and 1136 mg / kg when administered orally. 10,11-dihydro form of structural formula (IIa) Similar characteristics are shown as in the morpholino compound of V).

And the other compounds are listed in the following Table 1 to 6 and all these compounds can be seen that the same action.

Compounds of the present invention substituted with tertiary amines at 3′-carbon atoms, in the presence of a catalyst of the halogen compound of the formula (VIII), suitably use an amine as a solvent or after dilution, neutral solvents such as dimethylformamide Can be produced by aminolysis. The amine compound thus produced can be reduced to 10,11-2, and converted to the desired salts by substituting a substituent on the carbon atom at the 4-position. (It will be explained in the embodiment.)

(R ₁₂ = hydroxy or acetoxy

R ₁₃ = alkyl or aralkyl

X = oxo, cancel or chlorine).

The primary amine derivative of formula (VI) can be synthesized via the azide of formula (IX) derived from the halide of formula (VIII). The method of reducing azide to a primary amine derivative may be carried out by contacting hydrogen, which is a known method, with Raney nickel, or with hydrazine. The secondary amine derivative of formula (VII) is obtained by addition-decomposable debenzylation of the tertiary benzylamine derivative of formula (X). Dimethylamine derivatives of formula (XI) are produced by formaldehyde reduction methylation of the primary amine derivative of formula (VI).

The present invention will be listed according to the following examples.

The luminous intensities shown in the following Table 1-6 are measured in water for salts and in methanol for organic substrates.

Example 1

-아세톡시-8-메틸렌-2,9-디옥사트리시클로-(4,3,1,0^,3,7)-데칸에 서부터 구조식(IIa)의 3-피페리디노메틸-4

-하이드록시-4-메톡시-10-메틸렌-2,9-디옥사트리시클로-(4,3,1,0^,3,7)-데칸의 제법][3-Iodomethyl-4 of Structural Formula (VIII)

-Acetoxy-8-methylene -2,9- dioxa-tricyclo ^{(4,3,1,0, 3,7)} - 3-piperidino-4 seobuteo of formula (IIa) in decane

-Hydroxy-4-methoxy-10-methylene -2,9- dioxa-tricyclo ^{(4,3,1,0, 3,7)} The preparation of decane;

(R ₁₂ = acetoxy, R ₁₃ = methyl).

190 g of compound of formula (XIII) and 250 g of sodium bicarbonate are added to 500 ml of piperidine. The solution is vigorously stirred at 150 ° C. in an oil bath to reflux and then cooled to room temperature. 1.5 liters of ether are added to the mixture, followed by addition of a solution of 40% caustic soda in 1 liter of water. The ether layer is separated and the aqueous layer is extracted with 500 ml of ether each time. The ether extracts are combined and dried over sodium sulfate and cleaned with activated carbon. Filter through "neolith" with suction filter and wash with ether. The liquid is concentrated in a rotary evaporator, which is first concentrated to 50 ° C. in a vacuum of a water jet pump and then to 100 ° C., whereby 180 g of oily compound (IIa) is obtained. It does not refine | purify this and uses for manufacture of the following compound (II).

Experimental formula: C ₆ H ₂₅ NO ₄

Molecular Weight: 295.38

= +41.6℃(메탄올 중에서)

= +41.6 ° C (in methanol)

The same procedure as described in Example 1 was carried out to obtain a compound of the structural formula shown in the following table. (See Table 1).

3-morpholino-4-beta-hydroxy-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) - decane (XIII ).

3- (4-Methyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^3,7 ) -decane (XIV).

3-fatigue Li dino-4-beta-hydroxy-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) - decane (IV ).

3- (4-phenyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^3,7 ) -decane (XIV).

3- (4-hydroxyethyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1, 0, ^3,7 ) -decane (XVII).

3- (N, N ', N''-triethylethylenediaminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3 , 1,0, ^3,7 ) -decane (XVIII).

3- (N-benzyl-N-methylaminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^{3 , 7} ) -decane (XIX).

3- (N, N-Dibenzyliminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^{3 , 7} ) -decane (XX).

3- (hexamethyleneiminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^3,7 )- Deccan (XXI).

3- (1-Indolinomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^3,7 )- Decane (XXII).

3-piperidino-methyl-4-oxo-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) - decane (XXIII).

3- (N, N-dibutylaminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^{3, 7} ) -decane (XXIV).

3- [4- (2-pyridyl) -1-piperazinylmethyl] -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3 , 1,0, ^3,7 ) -decane (XXV).

TABLE 1

Example 2

[3-morpholinomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1) of formula (XIII) , 0, ^3,7 ) ^-making method of decane]

38 g of compound (VIII) and 50 g of sodium iodide are added to 100 ml of morpholine. The solution is refluxed for 3 hours and then cooled to room temperature. After evaporating the solvent, the mixture is treated with 200 ml of 2N hydrochloric acid and a small amount of methanol is added as solvent. In order to remove acidic and neutral impurities, the reaction solution is first extracted twice with 100 ml of ether each time to discard the ether layer. Add 2N caustic soda solution to the salt-saturated aqueous layer, and finally extract 5 times with 100 ml of ether. The basic ether extract is dried over sodium sulfate, washed with activated charcoal, and then suction filtered through “deo titite”. Concentration in vacuo afforded 17.92 g of 61% theoretical oily compound (XIII).

Experimental formula: C ₁₅ H ₂₃ NO ₅

Molecular Weight: 297.35

= +42° (메탄올)

= + 42 ° (methanol)

Example 3

[3- [4- (2-pyridyl) -1-piperazinylmethyl] -4-beta-hydroxy-8-methoxy-10-methylene-2 of formula (XXV) from compound (VIII), Preparation of 9-dioxatricyclo-((4,3,1, 0, ^3,7 ) -decane.]

38 g of Compound (VIII) and 49 g of 1- (2-pyridyl) piperazine and 50 g of carbon soda are taken up in 100 ml of dimethylformamide and refluxed for 8 hours. The mixture is filtered over ＂deolith＂, washed with methanol and the filtrate is concentrated in vacuo. The evaporated residue is dissolved in 200 ml methanol, and a solution of 8 g of caustic soda is added to 10 ml of water, and then the mixture is allowed to stand at room temperature for 10 minutes. After neutralization with dilute hydrochloric acid, the solvent is evaporated and the residue is made alkaline with 2N-caustic soda solution and extracted with chloroform. After treatment with sodium sulfate, treatment with activated carbon, and the chloroform layer is suction filtered with "deodorite". Evaporate with chloroform and evaporate the residue on silica gel with n-hexane and 50% ether chromatography on silica gel. The eluate is concentrated, the residue is dissolved in methanol and crystallized. After filtration over nutsche and washing with methanol, white crystals yield 29.0 g of a compound of the following structural formula 77.7% in white crystals.

Experimental formula: C ₂₀ H ₂₇ N ₃ O ₄

Molecular Weight: 373.45

Melting Point: 130-132 °

= 0°(메탄올)

= 0 ° (methanol)

Example 4

[3- (N, N-diethylaminomethyl) -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo of formula (XXVI) from the compound of formula (VIII) -((4,3,1,0, ^3,7 ) -Decane Preparation.]

38 g of compound (VIII) and 50 g of sodium bicarbonate were taken up in 200 ml of diethylamine, the solution was allowed to stand at 150 ° C. for 6 hours in a bomb tube in an oil bath, and 4 g of sodium hydroxide was dissolved in 10 ml of water. 100 ml of methanol is added. After standing at room temperature for 10 minutes, the mixture is treated with 6 ml acetic acid. After evaporating the solvent, 100 ml ether is added, the mixture is dissolved in 200 ml of water, 40 ml of 30% caustic soda solution is mixed and stirred. The ether layer is removed and the aqueous layer is extracted three times with 100 ml ether each time. The layers are combined, dried over sodium sulfate and bleached with activated charcoal. Suction filtration with “deodorite” and washing with ether, then concentrated the filtrate first at 50 ° C. in a vacuum of a water jet pump and then at 100 ° C. with an oil pump vacuum in a rotary evaporator. 32 g of an oily substance of the following structural formula (XXVI) are obtained.

Experimental formula: C ₁₅ H ₂₅ NO ₄

Molecular Weight: 283.37

= +48°(메탄올)

= + 48 ° (methanol)

By the same method as in Example 4, the following compounds were produced. 3-urethra-methyl-4-oxo-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) decane in formula 3- (N, N- diethylamino) -4-oxo-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) the preparation of decane.

Experimental formula: C ₁₅ H ₂₃ NO ₄

Molecular Weight: 281.34

3-methyl-4-urethral alpha-hydroxy-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^3,7) - decane-3-in ( N, N-diethylaminomethyl) -4-alpha-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo-((4,3,1,0, ^3,7 )- The preparation of decane (XXVIII).

Experimental formula: C ₁₅ H ₂₅ NO ₄

Molecular Weight: 283.36

Example 5

[Compound (IIa) 3- piperidino-4-beta-hydroxy-8-methoxy-10-methylene -2,9- dioxa-tricyclo - ((4,3,1,0, ^{3, 7} ) -The recipe of decane.]

Nitrogen is introduced into the hydrocracking system for the first 10 minutes and hydrogen is introduced for the next 10 minutes to fill with hydrogen.

100 g of damp Raney nickel is introduced into the hydrocracking flask of the device, washed with methanol and subjected to primary hydrocracking at a slight gauge pressure at room temperature with stirring for about 2 minutes. A solution in which 180 g of compound (IIa) in 250 ml of methanol was dissolved was introduced into a flask. A solution of 20 g of caustic soda in a small amount of water was added thereto, cooled to room temperature, diluted with methanol, and cooled to room temperature again. While stirring, the reaction urine is subjected to hydrolysis at room temperature for about 30 minutes under gauge pressure of a weak acid. As soon as the hydrogen uptake is over, the mixture is suction filtered on sdeortite and then washed with methanol. (Caution: Do not dry catalyst as it may cause burns.)

After addition of 30 ml of acetic acid, the mixture is evaporated at 60 ° C. and cooled to room temperature. The residue is taken up in ether, and paste into 250 ml of silica gel (particle size 0.2-0.5 mm).

After evaporating the solvent at 50 ° C., the residue is taken up in n-hexane and concentrated at 60 ° C. The residue is filtered in 500 g of silica gel column (particle size 0.2-0.5 mm), first with n-hexane (1 liter) and then with 1.5% diethylamine in n-hexane.

When the filtrate is evaporated at 60 ° C., 150 g of oily compound (II) is obtained.

Experimental formula: C ₁₆ H ₂₇ NO ₄

Molecular Weight: 297.399

= 0°(메탄올)

= 0 ° (methanol)

In the same manner as in the manufacturing method of Example 5, the compound described below was obtained. (See Table 2). 3-morpholinomethyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo-4,3,1,0, ^3,7 -decane (XXIX). (3- (4-methyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methox-2,9-dioxatricyclo-4,3,1,0, ^{3 , 7} -decane (XXX) 3-Pyridinomethyl-4-beta-hydroxy-8-alpha-methoxy-10-alpha-methyl-2,9-dioxatricyclo-4,3,1, 0, ^3,7 -decane (XXXI).

(3- (4-phenyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -Decan (XXXII)

(3- (4-hydroxyethyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-ethyl-2,9-dioxatricyclo- [4,3,1, 0, ^3,7 ] -Decane (XXXIII)

-3- (N, N ', N''-triethylethyleneaminomethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo-4,3,1 , 0, ^3,7 -decan (XXXIV)

3- (N-benzyl-N-methylaminomethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo-4,3,1,0, ^3,7 Deccan (XXXV)

3- (N, N-dibenzylaminoethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -Decan (XXXVI)

3-methylene filament butylimino-ethyl-4-beta-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] - decane (XXXVII )

3- (1-Indolinomethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (XXXVIII)

3-4- (2-pyridyl) -1-piperazinylmethyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1, 0, ^3,7 ] -Decan (XXXIX)

3-fatigue Li dino-4-beta-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] - decane (XL)

3 Pirelli dino-4-alpha-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] - decane (XLI)

3-Chloro-4-alpha-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] decane from.

3- (N, N- dibutylamino) -4-beta-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo -4,3,1,0, ^3,7- Deccan (XLII)

3- (N, N- diethylamino) -4-beta-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo -4,3,1,0, ^3,7- Deccan (XLIII)

TABLE 2

Example 6

[3- (N-methyl aminomethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo-4,3,1,0, ^3,7 -decane ( XLIV) recipe.]

16.9 g 3- (N-benzyl-N-methylaminoethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 , ^3,7 ] -decane (XXXV) is dissolved in ethanol and hydrolyzed with hydrogen for 2 hours in the presence of 5.0 g of palladium oxide. As soon as the hydrogen uptake is over, the mixture is suction filtered on sdeortite and washed with ethanol. The filtrate was concentrated and then crystallized with chloroform / ether to give 11 g of debenzylated compound corresponding to 84% of theory. The crystals are washed with ether and air dried.

Experimental formula: C ₁₂ H ₂₁ NO ₄ + H ₂ O

Molecular Weight: 261.30

Melting Point: 161-164 ℃

= 25°(메탄올)

= 25 ° (methanol)

Example 7

[3-Piperidinomethyl-4-beta-phenylcarbamoyloxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [46,3,1,0, from compound (II) ^3,7 ] -The preparation of decane (XLV).]

5.0 g of compound (II) is dissolved in 10 ml of methylene chloride, 3 ml of phenylisocyanate and 680 mg of phenylmercuric acetate are added as catalyst and the mixture is refluxed for 1-2 hours. After 5 ml of methanol is added, the mixture is concentrated. The residue is taken up in ether and treated with sodium sulfate and activated carbon.

After filtration, washing with ether and evaporation yielded 6.27 g of crystalline phenylcarbamate of the following structural formula (XVL), corresponding to 90% of theory.

Experimental formula: C ₂₃ H ₃₂ N ₂ O ₅

Molecular Weight: 416.52

Melting Point: 81-86 ℃

The following compound was obtained by operation in the same manner as in Example 7 (see Table 3).

3-hexamethyleneiminoethyl-4-beta-ethylcarbamoyloxy-8-methyl-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (XLVI)

3- [4- (P-chlorobenzohydryl) -1-pyrerazinylmethyl] -4-beta-ethylcarbamoyloxy-8-methyl-10-methylene-2,9-dioxatricyclo- [ 4,3,1,0, ^3,7 ] -decane (XLVII)

3- [4-methyl-1-pyrerazinylmethyl] -4-beta-phenylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1, 0, ^3,7 ] -decane (XLVIII)

3- [4- (2-ethylcarbamoyloxyethyl) -1-pyrerazinylmethyl] -4-beta-ethylcarbamoyloxy-8-methyl-10-methylene-2,9-dioxatricyclo - [4,3,1,0, ^3,7] - decane (XLIX)

3- [4 (-pyridyl-2) -1-pyrerazinylmethyl] -4-beta-ethylcarbamoyloxy-8-methyl-10-methylene-2,9-dioxatricyclo- [4, 3,1,0, ^3,7 ] -decane (L)

3- (4-methyl-1-pyrerazinylmethyl) -4-beta-ethylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1, 0, ^3,7 ] -decane (LI)

3- (N, N ', N''-triethylenediaminomethyl) -4-beta-ethylcarbamoyloxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4, 3,1,0, ^3,7 ] -decane (LII)

3-Pyridinomethyl-4-beta-isopropylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ]- Deccan (LIII)

3-piperidinomethyl-4-alpha-alkylcarbamoyloxy-4,8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] Deccan (LVI)

3-piperidinomethyl-4-alpha-isopropylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ]- Deccan (LV)

3-piperidinomethyl-4-beta-ethylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (LVI)

3-Pyridinomethyl-4-beta-isopropylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ]- Deccan (LVII)

3- (N, N-diethylaminoethyl) -4-beta-allylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (LVIII)

3-piperidinomethyl-4-beta-allylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (LIX)

TABLE 3

Example 8

[3-morpholinomethyl-4-beta-benzoyloxy-8-methoxy-10-methyl-2,9-dioxilicyclo of formula (LX) in formula (V), [4,3,1, 0, ^3,7 ] -Decane's recipe]

Dissolve 3.75 g of Compound (V) in 15 ml of pyridine and add ancillary benzoic enhancement. The mixture is refluxed for 2 hours, chloroform is added and then shaken with 2-N-caustic soda solution. The organic layer is washed once with water and the aqueous layer is extracted twice with chloroform each time. The organic extract is treated with sodium sulfate and activated charcoal and filtered over ＂deolite.

The filtrate is evaporated and the residue is column chromatographed with 50% ether-n-hexane as eluent in silica gel. Evaporation of the eluate and crystallization with isopropanol yields 2.9 g of structural (LX) benzoate.

57% theory

Experimental formula: C ₂₂ H ₂₉ NO ₆

Molecular Weight: 403.45

Melting Point: 120-121 ℃

= +60°(메탄올중)

= + 60 ° in methanol

The following compounds were obtained in the same manner as in Example 8.

3- [4- (pyridyl-2) -1-pyrerazinylmethyl] -4-beta-benzoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- (4,3, 1,0, ^3,7 ) -decane (LXI)

Experimental formula: C ₂₇ H ₃₁ N ₃ O ₅

Molecular Weight: 477.54

3- (4-Methyl-1-pyrerazinylmethyl) -4-beta-benzoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- (4,3,1,0, ^{3 , 7} ) -decane (LXII)

Experimental formula: C ₂₃ H ₃₁ N ₂ O ₅

Molecular Weight: 416.09

Melting Point: 99-102 ℃

3- [4-methyl- (2-benzoyloxyethyl) -1-pyrerazinylmethyl) -4-beta-benzoyloxy-8-methoxy-10-methyl-2,9-dioxatricyclo- (4 , 3,1,0, ^3,7 ) -decane (LXIII)

Experimental formula: C ₃₁ H ₃₈ N ₂ O ₇

Molecular Weight: 550.63

Example 9

[3-hexamethyl-lean-imino-ethyl-4-beta-acetoxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] decane 3-hexamethyllinimino methyl-4-beta-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0,3 ^{, 7} ] -The recipe of decane.]

3 g of 3-hexamethyllinimino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane (XXXVII) is dissolved in 6 ml of acetic anhydride and the solution is left to stand at room temperature for 30 minutes. After adding chloroform, the mixture is stirred with 2N-caustic soda solution. The organic layer was washed once with water and the aqueous layer was extracted twice with chloroform. Organic extracts are combined and treated with sodium sulfate and activated carbon. Suction filtration and evaporation followed by ether only and finally with 10% methanol in ether. Concentration of the eluate gave 2.2 g of oily substance of the structural formula (LXIV) of 67.8% theory.

Experimental formula: C ₁₉ H ₃₁ NO ₅

Molecular Weight: 337.44

= 0°(메탄올중)

= 0 ° (in methanol)

Example 10

Of [3-hexamethyleneimino methyl-4-beta-propionyloxy-8-methoxy-10-methyl-2.9-dioxatricyclo- [4,3,1,0 ^3,7 ] decane (LXV) quite]

2.74 g of 3-hexamethyleneimino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] decane ( XXXVII) is dissolved in 6 ml of propionic anhydride and left at room temperature for 30 minutes. After adding chloroform, the mixture is stirred with 2N-caustic soda solution and the organic layer is treated with sodium sulfate and charcoal. The organic layer is filtered and concentrated, and this isopropanol is crystallized to give 950 g of propionate. 29.4% of theoretical amount

Experimental formula: C ₂₀ H ₃₃ NO ₅

Molecular Weight: 367.47

Melting Point: 52-54 ℃

= 0°(메탄올중에서)

= 0 ° (in methanol)

The following compound is produced by the same method described in Example 10.

3- [4- (P-chlorobenzhydryl) -1-piperazinyl methyl] -4-beta-propionioxy-8-methoxy-10-methylene-2,9-dioxatricyclo] 4, 3,1,0 ^3,7 ] -Decane (LXVI)

Experimental formula: C ₃₁ H ₃₇ N ₂ ClO ₅

Molecular Weight: 552.78

Example 11

Of [3-piperidino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane (LXVII) Hydrochloric acid method.]

This 5 g of Compound (II) is dissolved in 50 ml of ether and the dry hydrogen chloride gas is passed through the solution until precipitation is formed. The ether is decanted off and the precipitate is taken up and dissolved in ether free of hydrogen chloride. After suction filtration, washing with ether and drying, 5.4 g of crystalline hydrochloride is obtained. It corresponds to 97% of theoretical amount.

Experimental formula: C ₁₆ H ₂₈ NClO ₄

Molecular weight: 33.86

Melting Point: 188 ℃

= 0°(메탄올중)

= 0 ° (in methanol)

Operation in the same manner as described in Example 11 yields the following compounds (see Table 4).

3-Pyrrolidino Methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrochloride (LXVIII)

3-morpholino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrochloride ((LXIX )

3- (4-phenyl-1-piperazinyl methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -Decane dihydrochloride (LXX)

3-hexamethyleneimino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrochloride LXXI)

3-piperazinyl methyl-4-beta-phenylcarbamoyloxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] decane hydrochloride ( LXXII)

3-hexamethylene-butylimino-4-beta-hydroxy-8-methoxy-10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7] decane hydrochloride ( LXXIII)

3- (1-Indolinomethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ] -decane Hydrochloride (LXXIV)

3-Phenyl (1-indolino methyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0, ^3,7 ]- Decane Hydrochloride (LXXV)

3- [4- (P-chlorobenzhydryl) -1-piperazinylmethyl] -4-beta-ethylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0, ^3,7] decane dihydrochloride (LXXVI)

Example 12

[From the compound (IV) 3- fatigue Li dino-4-beta-hydroxy-8-methoxy -10-methyl -2,9- dioxa-tricyclo [4,3,1,0, ^3,7 ] -Preparation of Decane Hydrogen Maleate (LX XVII).]

3.3 g of the compound of formula (IV) are dissolved in 20 ml of ethyl, and a solution of 1.4 g of maleic acid in ether is added. After decanting the solvent, the residue is taken up in ethane and dissolved. After suction filtration, washing with ether, and drying, 4.4 g of maleate of the formula (LXXII) contained 90.2% of theoretical amount.

Experimental formula: C ₁₉ H ₂₇ NO ₈

Molecular Weight: 397.43

Melting Point: 155-157 ℃

= +8°(메탄올중)

= + 8 ° (in methanol)

Operation in the same manner as described in Example 12 yields the following compounds. (See Table 5)

3- (4-methyl-1-piperazinylmethyl) -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- (4,3,1,0 ^{3, 7} ) -decane di (hydrogen maleate) (LXXVIII)

3-pyrrolidino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- (4,3,1,0 ^3,7 ) -decane hydromaleate ( LXXIX)

3- [4 (P-chlorobenzhydryl) -1-piperazinylmethyl] -4-beta-ethylcarbamoyloxy-8-methoxy-methylene-2,9-dioxy-tricyclo- (4 , 3,1,0 ^3,7 ) -decane di (hydrogen maleate) (LXXX)

3- (4-Methyl-1-piperazinyl methyl) -4-beta-phenyl carbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- (4,3,1, 0 ^3,7 ) -decane di (hydrogen maleate) (LXXXI)

3- [4- (2-hydroxyethyl) -1-piperazinylmethyl] -4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- (4,3 , 1,0 ^3,7 ) -decane di (hydrogen maleate) (LXXII)

TABLE 4

Example 13

3-Piperidino methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- (4,3,1 of formula (LXXXIII) from compound (II) , 0 ^3,7 ) ^{-Decanhydrogen Tartrate} Preparation.]

150 g of compound (II) is dissolved in 150 ml of alcohol and 75.0 g of L (+)-tartrate solution, previously dissolved in 525.35 ml of ethanol at about 60 ° C., is added.

The solution was evaporated at 60 ° C. to give a transparent solution for the first time to obtain hydrogen tartrate crystal of formula (II).

After concentration, the crystals are taken up in ethyl, suction filtered and washed with ether.

After vacuum drying at 50 ° C., 203.6 g of white crystalline hydrogen tartrate of formula (LXXXIII) are obtained. 91% theory

Experimental formula: Molecular weight: 447.46

= -5.4°(물중)Melting Point: 178 ℃ (Kepler, No Compensation)

= -5.4 ° (under water)

In the same manner as in Example 13, the following compound was obtained. (See Table 6)

3- [4- (P-chlorobenz hydryl) -1-piperazinyl methyl] -4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4, 3,1,0 ^3,7 ] -decane (hydrogen tartrate) (LXXXIV)

3- (4- (P-chlorobenz hydryl) -1-piperazinyl methyl) -4-beta-ethylcarbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (hydrogen tartrate) (LXXXV)

3- (4- (P-chlorobenzhydryl) -1-piperazinyl methyl) -4-beta-propionyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- (4 , 3,1,0 ^3,7 ) -decane (hydrogen tartrate) (LXXXVI)

3- (4- (2-pyridyl) -1-piperazinyl methyl) -4-beta-benzoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- (4,3, 1,0 ^3,7 ) -decantry (hydroben tartrate) (LXXXVII)

3- (4-Methyl-1-piperazinyl methyl) -4-beta-benzoyl-oxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^{3 , 7} ] -decane (hydrogen tartrate) (LXX XVIII)

3- (4- (2-ethylcarbamoyloxyethyl) -1-piperazinyl-methyl) -4-beta-carbamoyloxy-8-methoxy-10-methylene-2,9-dioxatri Cyclo- [4,3,1,0 ^3,7 ] -decane (hydrogen tartrate) (LXXXIX)

3- (N, N ', N'-triethyl-ethylenediamino methyl) -4-beta-ethylcarbamoyloxyca-8-methoxy-10-methyl-2,9-dioxa tricyclo- [ 4,3,1,0 ^3,7 ] -decanedi (hydrogen tartrate) (XC)

3-Pipemadanomethyl-4-alta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane di (hydrogen Tartrate) (XCI)

3-piperidino methyl-4-alpha-isopropyl carbamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane Di (hydroben tartrate) (XCI I)

3-N, N-dimethylamino methyl-4-alpha-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane di (Hydrogen tartrate) (XCIII)

3-piperidano methyl-4-alpha-allylcarbamoyloxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydride Rosen tartrate (XCIV)

3-N, N-diethylaminomethyl-4-alpha-allyl carovamoyloxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -Decane Hydrogen Tartrate (XCV))

3-N, N-diethylamino methyl-4-oxo-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrogentart Rate (XCVI)

3-morpholinomethyl-4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrogen tartrate (XCVII)

3-piperidino methyl-4-beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrogen tartrate (XCVIII)

3-pyrrolidano methyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane hydrogen tartrate (XCIX)

3-N, N-dibutylaminomethyl-4-beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane Hydrogentartrate (c)

TABLE 5

TABLE 6

Example 14

In 3-iodomethyl-4-beta-acetoxy-8-methoxy-10-methylene-2, 9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane of formula (VIII) Preparation of 3-aminomethyl-4-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane of formula (CIII).]

a) 3-ureomethyl-4-beta-acetoxy-8-methoxy-10-methylene-2,9-dioxa tricyclo [4,3,1,0 ^3,7 ] -decane of formula (VIII) 3-Azidomethyl-4-beta-acetoxy-8-methylcy-10-methylene-2,9-dioxatricyclo-4,3,1,0 ^3,7 ]- Deccan Recipe

14 g of the compound of formula (VIII) is dissolved in 10 ml of hexamethyl phosphate amide and 30 g of sodium azide are added. The mixture is heated to 100 ° C. for 4 hours with vigorous stirring. 600 ml of ether are added and the organic layer is washed five times with 150 ml of water each time. The aqueous layers are combined, shaken with ether, the organic layers combined, and dried over sodium sulfate.

After filtration, the residue was washed with ether and concentrated to 50 ° C. in a filtrate rotary bed degasser to yield 11.5 g of a colorless oily substance of formula (CI).

Experimental formula: C ₁₃ H ₁₇ O ₅ N ₃

Molecular Weight: 295.33

= -57°(메탄올)

= -57 ° (methanol)

b) 3-azidomethyl-4beta-acetoxy-8-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane of formula (CI) 3-azidomethyl-4meth-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of the formula (CII) in Recipe

10.55 g of 3-azido methyl-4beta-acetoxy-8-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane 250 ml of ethyl Is dissolved in and a solution of 1.5 g caustic soda in 70 ml of methanol is added. The mixed solution is stirred at room temperature for 1 hour and then adjusted to pH 7 with glacial acetic acid and concentrated in vacuo on a water jet pump. The combined organic layers were dried over sodium sulfate, filtered and concentrated to 50 ° C. on a rotary evaporator to yield 7.9 g of a colorless oily substance of formula (II), corresponding to 87.2% of theory.

Experimental formula: C ₁₁ H ₁₅ N ₃ O ₄

Molecular Weight: 253.26

= +10°(메탄올)

= + 10 ° (methanol)

c) 3-azidomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane of formula (CII) Of 3-aminomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of formula (CII) quite

3-Azido methyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] -decane 17.7 g of formula (CII) Is dissolved in 700 ml of methanol and 35 ml of 80% hydrazine hydrate is added.

About 1 g of Raney Nickel is introduced and the mixture is allowed to stand at room temperature for 1 hour. The catalyst is separated on asbestos and the filtrate is concentrated in vacuo at a water jet pump at 50 ° C. The residue is taken up in benzene, filtered and the solvent is evaporated off and reconstituted with ethyl to give 15.3 g, which is 94.6% of theory.

Example 15

[Formula (VI) in 3-Udomethyl-4 beta-acetoxy-8-methoxy-10-methylene-2,9- [4,3,1,0 ^3,7 ] -decane of formula (VIII) Preparation of 3-Aminomethyl-4meth-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane.]

a) in 3-iodomethyl-4 beta-acetoxy-8-methoxy-10-methylene-2,9-diotritricyclo- [4,3,1,0 ^3,7 ] -decane of formula (VIII) Preparation of 3-iodomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo [4,3,1,0 ^3,7 ] decane of formula (CIV).

A solution in which 38.0 g of compound (VIII) was dissolved in 250 ml of methanol was added to a solution of 4.0 g of caustic soda in 50 ml of methanol, and the mixture was stirred at room temperature for 30 minutes. 500 ml of water is added and then neutralized with glacial acetic acid. Ammonia sulfate is added, saturated and extracted with ether. After drying over sodium sulfate, the residue was washed with ether and the oily layers were combined and concentrated to 50 ° C. in vacuo to give 36.64 g of a colorless oil. Theoretical 94.5%

b) 3-iodomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of formula (CIV) 3-Iodomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of formula (CV) Recipe.

3-Iodomethyl-4beta-hydroxy-8-methoxy-10-methylene-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ]-of formula (CIV) in 250 ml of ethanol. To a 75 g solution of decane, a 6 g solution of pulatin (IV) oxide in 100 ml of ethanol was added and hydrolyzed at room temperature (5 L of hydrogen uptake). The catalyst is separated off and concentrated to 50 ° C. on a rotary evaporator. The residue is purified by n-hexane-ether on silica gel and then recrystallized from n-hexane-ether. Yield: 69.9 g, 92.8% of theory

c) 3-iodomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of formula (CV) 3-Iomethyl-4-meth-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of formula (CVI) in Recipe

20 g of ³ -yodomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of the formula (CV) Dissolve in 20 ml pyridine and 10 ml acetic anhydride and stop at room temperature for one hour. The reaction mixture is repeatedly evaporated with ethanol until dry. Purification with n-nucleic acid-ether on silica gel yields 15.4 g of the target compound (CVI). 68.5% theoretical

d) 3- in 3-iodomethyl-4beta-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (CVI) Preparation of azidomethyl-4beta-acetoxy-8-methoxy-10-methyl-2,6-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (CVII)

15.4 g in 3-iodomethyl-4-beta-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [7,3,1,, 0 ^3,7 ] decane (CVI) Is dissolved in 100 ml of nucleated methylphosphate triamide and 31 g of sodium azide are added.

The mixture is stirred for one hour at 100 ° C., 600 ml of ether are introduced and extracted five times with 150 ml of ether each time. The aqueous layer was extracted twice with ether, and the aqueous layer was collected, dried over sodium sulfate, filtered and reduced to 50 ° C in vacuo. 12.0 g of colorless oil (CVII) are obtained. 100% of theoretical amount.

e) 3-azidomethyl-4beta-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ]-of the formula (CVII)- 3-azidomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ]-of the formula (CVIII) in decane. Deccan recipe.

12 g 3-azidomethyl-4beta-acetoxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1 in 1.5 g caustic soda in 20 ml of methanol , 0 ^3,7 ] -decane (CVII) is added to the solution. The mixed solution is stirred at room temperature for 10 minutes, introduced into 200 ml of ice water, neutralized with glacial acetic acid and saturated with ammonia sulfate. After extraction with ether, the organic layers are combined, dried over sodium sulfate, filtered and concentrated in vacuo. 10.7 g of colorless oil (CVIII) corresponding to a theoretical amount of 100% is obtained.

f) in 3-azidomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (CVIII) Preparation of 3-Aminomethyl-4beta-hydroxy-8-methylcy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (VI).

32 ml of haadazine hydrate (approximately 80%) was added to 10.7 g of 3-azidomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1 , 0 ^3,7 ] -decane (CVIII) is added to the solution.

After adding about 1 g of Raney nickel solution in 100 ml methanol, the mixture was stirred at room temperature for 1 hour. The catalyst is filtered off and concentrated in vacuo until the filtrate is solid. The residue is taken up in water and made alkaline with caustic soda before extraction with ether, the ether layers combined, dried over sodium sulfate, filtered and concentrated in vacuo at 40 ° C. to give 9.1 g of colorless oil (VI). 94.3% theory

Example 16

3-N of [3-aminomethyl-4beta-hydroxy-8-methoxy-10-methyl-2, 9-dioxatricyclo- [4,3,1,0 ^3,7 ]-(VI) , N, Dimethylaminomethyl-4meth-hydroxy-8-methylcy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (XI) .]

5 ml (37%) formalin solution was added with 800 mg of 3-aminomethyl-4beta-hydroxy-8-methoxy-10-methyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] 5 ml methanol solution of decane (VI) is added and stirred at room temperature for 10 minutes. A small amount of Ranickel is added and then hydrocracked at room temperature. As soon as hydrogen absorption is complete, the catalyst is filtered off and the filtrate is dried. Purification with chloroform-methanol on silica gel yields 780 mg of compound (XI). Theoretical amount: 86.9%

Example 17

Structural formula in [ ³ -iodomethyl-4beta-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (VII) CXI) 3- [1-azabicyclo (3,2,2,)-nonanyl] -methyl-4beta-hydroxy-8-methylcy-10-methyl-2,9-dioxatricyclo- [4 , 3,1,0 ^3,7 ] -Decane Hydrogen Tartrate Preparation.]

7.6 g of compound (VIII) and 10 g of sodium bicarbonate are taken up in 10 ml of dimethyl formamide and 7,5 g of 3-azabicyclo- (3,2,2) nonane are added. The mixture is boiled to 170 ° C. in an oil bath and cooled to room temperature. After concentration, 40 ml of water and 8 ml of 30% caustic soda solution are added to the residue and extracted three times with 20 ml of ether each time. Concentration of the ether extract yields 5.8 g of 3- [1-azabicyclo- (3,2,2,)-nonanyl] -methyl-4beta-hydroxy-8-methoxy-10-methyl-2,9- Dioxatricyclo- [4,3,1,0 ^3,7 ] -decane (CIX) is obtained. Dissolve 5.8 g of compound (CIX) in methanol, add 4.0 g of Raney nickel and 0.8 g of caustic soda and hydrodecompose with hydrogen. Immediately after hydrogen sorption, the mixture is filtered over ＂deolite and washed with methanol.

After 1.2 ml of acetic acid was added to the filtrate, the solution was concentrated and the residue was taken up in ether, and purified by column chromatography on silica gel (minus size 0.2-0.5 mm). Elution solvents are suitable for n-hexane and 1.5% diethylamine. Concentrate the eluate and 4.4 g of crystalline 3- [1-azabicyclo- (3,2,2,)-nonanyl) methyl-4beta-hydroxy-8-methylcy-10-methyl-2,9-di Oxatricyclo- [4,3,1,0 ^3,7 ] -decane (CXI) is obtained.

4 g of compound (CX) is dissolved in 8 ml of ether and added to a 13.6 ml ethanol solution of 1.94 g of L (+)-tartrate.

Claims (1)

Reacting 3-halomethyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of the general formula (VIII) with a first or second Production of 3-aminomethyl-2,9-dioxatricyclo- [4,3,1,0 ^3,7 ] -decane of the general formula (I)

Wherein R ₁ is a first, second or tertiary amine group, one of R ₂ and R ₃ is a hydrogen atom and the other is a hydroxyl group, acyloxy or carbamoyloxy group, or R ₂ and R ₃ together with one another An oxygen atom and one of R ₄ and R ₅ is a hydrogen atom, the other is C ₁ -C ₆ alkoxy or benzyloxy and the 10,11-position may be hydrogenated. R ₁₂ is a hydroxy or acetoxy group, R ₁₃ is a C ₁ -C ₆ alkyl or benzyl group and X is oxo, cancel or chlorine.