DE2560493C2 - 2,9-Dioxatricyclo [4,3,1,0 → 3 → →, → → 7 →] decane - Google Patents

Description

The invention relates to 2,9-dioxatricyclo [4,3,1, 0 ³ⁱ⁷ ] decanes of the general formula A
R ¹

CH ₂ -HaI

(A)

OCOCH ₃

in which Hal is chlorine, bromine or iodine, R ^{1 is} hydroxy and R ^{2 is} hydrogen or both together are oxo if X and Y together form a bond, or R ¹ and R ^{2 are} each hydrogen if X is bromine or iodine and Y is hydrogen mean.

These compounds are valuable intermediates for the preparation of 2,9-dioxatricyclo [4,3, 1,0 ^{3> 7} ] decanes of the general formula B

H ₃ C

CH ₃

(B)

in which one of the two radicals R ⁴ and R ^{5 is} hydrogen and the other is hydroxy, Cp to C ₇ acyloxy or N-methylcarbamoyloxy, or both radicals R ⁴ and R ⁵ together are oxygen.

These 2,9-dioxatricyclo [4,3, 1,0 ^{3> 7} ] decanes are distinguished by valuable pharmacological, in particular strong analgesic, effects.

In the production of these end products starting from extracts containing didrovaltratum or didrovaltratum or the 4> acetoxy-3-halomethyl-8-alkoxy or 8-aralkoxy-10-methylene-2,9-dioxatricyclot4,3 known from DE-OS 1961433 l, 0 ^3I7] decanes, 'drop the initially mentioned compounds as intermediates.

The process for preparing the end products using the intermediates according to the invention is characterized in that extracts containing didrovaltratum or didrovaltratum are reacted with hydrogen halide in acetic acid or alcohol, the 8-alkoxy obtained in the case of reaction in alcohols

or 8-aralkoxy compound converted into the corresponding 8-hydroxy compound by cleavage of the ether bond using nitric acid in glacial acetic acid, the S-hydroxy-S-halomethyl- ^ - acetoxy-10-methylene-2,9- obtained in both cases dioxatricyclo [4,3, l, 0 ³ ' ⁷ ] decane of the formula Π is oxidized to the lactone of the formula EI, the lactone hydrogenolytically with hydrogen on palladium / carbon to l-halomethyl ^ methyl-T-acetoxy-l-oxa-bicyclo [ 3.2, l] oct-3-en-8-carboxylic acid of the formula IV, the acid is reduced with metal hydrides to the primary alcohol of the formula V, the alcohol by oxidative ring closure by means of halogen in halogenated hydrocarbons into the 10-halogen-10- methyl-S-halogenmethyMjS-acetoxy ^ -dioxatricyclof ^^ jO ³ - ⁷ ] -decane, the halogens are split off with hydrogen on Raney nickel in the presence of a strong base, at the same time the ester is saponified, so that the 3.10 -Dimethyl-4 / ^ hydroxy-2,9-dioxairicyclo- [4,3, l, (r ^] decane of the formula VE is obtained, which is optionally mi Carboxylic acid anhydride or chloride or with alkyl isocyanates or carbamic acid esters converted into the acyloxy or carbamoyloxy compound, or optionally converted into the decanone of the formula VIII by oxidation of the 4-hydroxy group, this optionally with metaUhydrides to the 4ar-hydroxy -Decari of the formula IX, which is optionally converted into the acyloxy or carbamoyloxy compound with carboxylic acid anhydride or chloride or with alkyl isocyanates or carbamic acid esters.

The following reaction scheme illustrates the preparation of the compounds according to the invention by hand of the following examples.

Notwithstanding the reaction scheme, however, z. B. in the production of Π from DidrovaJtratum or Didrovaltratum containing extracts also used hydrochloric or hydrobromic acid instead of hydroiodic acid will.

Instead of the metal hydrides mentioned in the scheme in the reduction of the acid IV to alcohol V or des Decanons VIII to the hydroxy compound IX, other metal hydrides can also be used, provided they have the leave other functional groups of the molecule intact and also react sterically in the manner indicated.

Finally, the acid residues in the esters X and XIII can also consist of other saturated and unsaturated Carboxylic acids with 1 to 7 carbon atoms originate from the specified acetic acid.

X OJ_

X U O U JO

O O

X U

δ ζ χ

O O U

X U

O O

χ υ

U O O

χ υ ο ο υ

χ υ χ υ

2 X

Examples example 1

Production of 4-acetoxy-8-hydroxy-3-iodomethyl-10-methylene-2,9-dioxatricyclo [4,3, 1,0 ³ "] decane (II) from a 66% didrovaltrate extract

425 g of extract were dissolved in one liter of acetic acid at 60 ⁰ C, then the solution was added a mixture of 130 ml of hydriodic acid (57%) and 1 liter of water added and the batch with occasional stirring for 2 hours at 60 ° was allowed to stand, to

Reconditioning

After adding 100 g of activated charcoal, it was suctioned off through Theorit and washed thoroughly with 4 liters of ether. 3 liters of water were added to the filtrate, the mixture was shaken well and the ether phase was separated off. This then became Washed alkaline once with 2 liters of water and once with soda solution (1.5 kg of sodium carbonate in 8 liters of water). The three water phases were then individually extracted 3 times with 2 liters of ether each. The combined ether phases were dried over 1 kg of sodium sulfate, treated with 100 g of activated charcoal, suctioned off over Theorit and then in a p.and flask with the addition of 18 m! Water evaporated at 30-40 ⁰ C under vacuum to give crystallized II. After trituration with ether and suction through a suction filter, the following were obtained: 170 g of raw Kri stallisat, that's 70% of theory.

O HO-

CH ₂

CH ₂ J (Π)

OCOCH ₃

3j Molecular formula: Ci ₂ Hi ₅ O ₅ J Molecular weight: 366.14 Fp .: 152-156 ⁰ C (Kotier, uncorrected) [a] i ⁿ ° ^c : + 142 ° (methanol)

Example 2 Preparation of (Π) of 4-acetoxy-3-iodomethyl-10-methylene-8-methoxy-2,9-dioxatricyclo [4,3, l, 0 ^{3 '7]} decane.

760 g of 4-acetoxy-3-jodmelhyl-10-methylene-6-methoxy-2,9-dioxatricyclo [4,3, l, 0 ^{3> 7]} decane were dissolved at 60 ⁰ C in 2 liters of glacial acetic acid and then tie solution at room temperature with a mixture of 180 ml of 64% nitric acid and 2 liters of water. The batch remained under stirring at room temperature for 2 hours.

Reconditioning

8 liters of ether and 6 liters of water were added to the reaction mixture and the mixture was shaken well. The ether phase was separated off and once with 4 liters of water and then with soda solution (2 kg of sodium carbonate in 6 liters of water). The two water phases and the soda solution were then used individually 3 times each 4 liters of ether extracted. The combined ether phases were dried over 2 kg of sodium sulfate and mixed with 200 g of activated charcoal were then treated with suction via Theorit and washed thoroughly with ether. The filtrate was in a flask under addition of 36 ml of water in vacuo at 30-40 ⁰ C Derhierbei crystallizing residue concentrated was taken up in ether, filtered off over a frit, and 1 times washed well with ether.

Yield: 660 g (H), that is 90.2% of theory. Example 3

Preparation of 4-acetoxy-3-iodomethyl-10-methylen-8-oxo-2 ^ -dioxatricyclo [4 _r 3, l, 0 ³ⁱ⁷ ] decane (JID from (Π). 366 g (U) were in 20 liters of ether taken up at room temperature, 1250 ml of oxidizing reagent were added dropwise with vigorous stirring and the mixture was then stirred for a further 30 minutes

Preparation of the oxidation reagent

500 g Na ₂ Cr ₂ O ₇ · 2 H ₂ O were added to 375.2 ml of 97% H ₂ SO ₄ at zero ⁰ C and under stirring with cold water initially to about 2400 ml and then at room temperature to exactly 2500 ml filled up.

Working up the oxidation batch

The reaction mixture was admixed with 5 liters of H ₂ O and shaken. The ether phase was separated off and washed once with 1 kg of sodium carbonate in 5 liters of water. The water phase and the soda solution were extracted 3 times individually with 3 liters of chloroform each time. The ether and chloroform phases were dried over sodium sulfate, treated with activated charcoal and then filtered off with suction over theorite, washed with chloroform and evaporated in vacuo. The evaporation residue was taken up with ether, during which (III) crystallized. It was suctioned off and washed once with ether.

Yield: 310 g (III), that is 86% of theory.

15th

CH ₂ J

OCOCH ₃

Molecular formula: C ₁₂ Hi ₄ OsJ Molecular weight: 365.139 Fp .: 163-168 ° C (Kofler, uncorrected) ^20c : + 114 ° (methanol)

(IH)

Example 4

Preparation of l-iodomethyl-4-methyl-7-acetoxy-2-oxa-bicyclo [3.2, l] oct-3-en-8-carboxylic acid (IV) from (III).

100 g of palladium-charcoal (5%) were placed in a 2 liter Erlenmeyer flask, then with 1 liter of ethanol Suspended (absolute) under nitrogen and immediately with stirring at room temperature and normal temperature Pre-hydrogenated for 5 minutes (approx. 1300 ml of hydrogen were taken up). Then there was 182.5 g of (III) in 1.5 liters Dissolved absolute ethanol, added, and the approach about 2 hours until the hydrogen uptake ceases hydrogenated.

Hydrogen consumption: 11200 ml.

Reconditioning

20th

25th

30th

35

40

45

The catalyst was filtered off over Theorit, washed with absolute ethanol and the filtrate at about 30 ⁰ C and evaporated in vacuo The residue crystallized once; it was rubbed with ether, sucked off, washed with ether and dried

Yield: 180 g (IV), that is 98.2% of theory.

(TV)

COCH ₃

55

60

65

Molecular formula: C12H15O5J Molecular weight: 366.15

Mp .: 150-155 ° C (Kofler, uncorrected)
runs ²⁰ ° ^c : + 110 ° (methanol)

Example 5

Preparation of l-iodomethyl-4-methyl-7-acetoxy-8-hydroxymethyl-2-oxa-bicyclo [3.2.1] cct-3-ene (V) from (SV).

73.2 g (IV) were dissolved in 200 ml of tetrahydrofuran and the solution added slowly with stirring under nitrogen at -25 ° C with 1 liter Borwasserstoffin tetrahydrofuran (l% strength) Then, at +10 ⁰ C was allowed to stand for 2 hours.

Reconditioning

With stirring under nitrogen slowly added 30 ml of triethylamine were initially at -25 ° C was added and then the mixture with 80 ml of water dropwise slowly and the mixture evaporated at 30-40 ⁰ C. The residue was taken up in ether, 2 times with 700 ml of water and Washed 1 time with 90% saturated soda solution. The 3 aqueous phases were individually re-extracted 3 times with ether. The combined ether phases were treated with sodium sulfate and activated charcoal, filtered off with suction through Theorit and then evaporated at 30-40 ° C. Yield: 153 g of oily crude product (V). This was used for the preparation of (YI) without further purification.

CHiJ

(V)

OCOCH ₃

Molecular formula: Ci ₂ H _n JO ₄
Molecular weight: 352.17

Example 6

Preparation of 4-acetoxy-10-bromo-3-iodomethyl-10-methyl-2,9-dioxatricyclo [4,3, l, 0 ^{3 '7]} decane (VI) from (V).

153 g (V) (crude product) were dissolved in 1100 ml of methylene chloride in a brown round bottom flask and under vigorous stirring at -75 ° C with a mixture of 53 ml of bromine and 110 ml of methylene chloride, which was previously added -75 ° C were cooled, slowly added.

Reconditioning

After the end of the addition of bromine, the mixture was slowly neutralized immediately with a mixture of 168 ml of triethylamine and 110 ml of methylene chloride, _{washed once with water, with saturated Na 2} S ₂ Os-LOSUUg and potassium carbonate solution. The three aqueous phases were individually back-extracted three times with methylene chloride. The combined methylene chloride phases were treated with sodium sulfate and activated carbon, filtered with suction through Theorit and evaporated at 30 ⁰ C in a brown round bottom flask.

Yield: 186 g of oily crude product
O

CH ₂ J (VT)

OCOCH ₃

Molecular formula: Cj ₂ H ₁₆ BrJO ₄
Molecular weight: 431.07

Find examples of the further processing of the intermediate (VI) to the end products of the formula (B) in patent specification 2547205.

Br

Claims (1)

Claim: 2,9-DioxatricycIo [4,3, l, 0 ^{3 '7} Jdecane the general formula A
R ¹ CH ₂ -HaI (A) OCOCH ₃ in the Hai means chlorine, bromine or iodine. R ^{1 is} hydroxy and R ^{2 is} hydrogen or both together are oxo if X and Y together form a bond, or
R ¹ and R ² each signify hydrogen if X signifies bromine or iodine and Y signifies hydrogen.