DE2336559A1 - 4A-ARYL-TRANS-DECAHYDROCHINOLINES AND THE METHOD FOR THEIR PRODUCTION - Google Patents

Description

godparents! 'lawyers

DR.-ING. BY KREISLER DR.-ING. SCHÖNWALD

DR.-ING. TH. MEYER DR.FUES DIPL-CHEM. ALEK VON KREISLER D1PL.-CHEM. CAROLA KELLER DR.-ING. KLOPSCH DIPL.-ING. SELTING

COLOGNE 1, DEICHMANNHAUS

Cologne, the 1o. July 19 73 AvK / Ax / IM

EGG. Du Pont de Nemours and Company, Wilmington, Del./V.St.A.

4a-aryl-trans-decahydroquinolines and process for their preparation

The invention relates to certain new 4a-aryl-trans-decahydroisoquinolines and methods of making them. These compounds are valuable as analgesics and / or antagonists of narcotics and intoxicants.

A closely related compound, N-methyl-4a-phenyl-cis-decahydroisoquinoline was described by Boekelheide and Schilling (J.Am.Chem.Soc. 72, 712 (195o)). They called this Compound "N-methyl-io-phenyldecahydroisochirdine" and stated that it had little analgesic effect.

The invention relates to compounds of the formula

wherein R ^{1 represents} hydrogen, Cj-Cg-alkyl, benzyl (-CH ₂ CgH ₅ ), phenylethyl (-CH ₂ CH ₂ C ₆ H ₅ ) or cycloalkylmethyl of the formula -CH ₉ CH <(CH-), in the η is an integer in the range from 2 to 5, R for divalent oxygen (= 0),

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^c "

OCCH ₃

Il

-2-

H CH ₃ '

\ 0H '\ 0CH3 P

'or

A for hydrogen or hydroxyl, Ar for

stands in which the radicals R, which are identical or different, represent hydrogen, hydroxyl, methoxyl or acetoxyl and the radicals R, which are identical or different, stand for hydroxyl, methoxyl or acetoxyl and in each case two

3 4
of the radicals R or R, which are on adjacent carbon atoms, can together form a divalent methylenedioxy radical (-OCH ₂ O-).

Representative for the radicals R are methyl, ethyl, propyl, butyl, hexyl, cyclopropylmethyl ^ -CH ₂ CH <(CH ₃ ) ₂ _ /, cyclobutylmethyl ^ ¹ CH ₂ CH <(CH ₂ ) ₃ _7 and cyclohexylmethyl / "- CIi ₂ CH <(CH ₂ J ₅ /.

Representative for the radicals Ar are phenyl, 3-hydroxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-acetoxyphenyl, 2,3-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4-

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Diacetoxyphenyl, 2-methyl-5-hydroxyphenyl, 3-methyl-5,6-dimethoxyphenyl, 3-hydroxy-4-methoxyphenyl, 2-methoxy-3-acetoxyphenyl and 3,4- (methylenedioxy) phenyl.

The 4a-aryl-trans-decahydroisoquinolines of the formula I include various stereochemical isomers derived from the substitution at the 6-position and from the optical Derive from asymmetry of the entire structure. If at the

2 6-position the monovalent substituents R different

(for example, when R is ^ H), require

^CH 3

spatial considerations the presence of axial and equatorial isomers. Require in the molecule as a whole spatial considerations the presence of d- and 1-optical isomers. The latter usually lie as racemic mixtures, which can be separated by known methods (Eliel, Stereochemistry of Carbon Compounds, McGrawHill, 1962, p. 31).

In the multi-stage process according to the invention of 2-cyano-3-aryl-3-carbalkoxymethylcyclohexenen, which can be prepared by processes that by Boekelheide and Schilling (loc.cit) in connection with ^ -Cyan-S-phenyl-S-carbäthoxymethylcyclohexen (see Example 1, Part A). The key stage in this process is the novel implementation of a 2-cyano - 3-aryl-3-carbalkoxymethylcyclohexene with hydrogen chloride in a lower alkanol, e.g. ethanol, to form a 4a-aryl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline (see example 1, part B). The new 1,3-diketo-1,2,3,4,4a, 5,6, T-octahydroisoquinolines have a matching arrangement of the condensed rings. This requires the formation of trans-decahydroisoquinoline structures, when the 8,8a double bond is converted to a single bond.

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The choice of specific manufacturing steps after the initial formation of a 1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline depends on the particular 4a - / \ ryl-trans-decahydroisoquinoline derivative desired. the Sequence comprises at least three stages, which can be represented as follows:

( ² O

B-2. (3)

Alles

0 -NR ¹

b ο

(5)

C-I. (4)

UAlH ₄

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C-2. (5)

In the above formulas (1) to (7) the radicals R 'have the meanings given above. R stands for

H H

CH H

or

OCH ₃

R ⁶ for C ₁ -C ₄ AlCyI, Ar ¹ for

OT _R 7,

or

7 8

where R is hydrogen or methoxy and R is meth

7 ο

oxy and two of the radicals R or R attached to adjacent C atoms are, together can form a divalent methylenedioxy radical.

In stage A, the reactant is R OH, the is at the same time the reaction medium, is generally used in excess. However, to achieve a maximum yield to ensure it should be in an amount of at least 1 mole per mole of cyano ester can be used. The reactant

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HCl can also be used in excess should however, present in an amount of at least 1 mole per mole of cyano ester to ensure maximum yield be. The reaction is carried out in the liquid phase under anhydrous conditions. The reaction temperature should be in the range of about 5o to 12o ° C. The reaction pressure is not critically important. Normally for the sake of simplicity, normal pressure is used, but the pressure should be reached when the said reaction temperature be consistent.

In stage B-1 corresponds to the hydrocarbon residue of the hydrocarbon bromide used as a reactant or iodides the radical R in the general formula I. These hydrocarbon bromides or iodides are readily available as the following table shows:

• R ¹ Table I. origin C ₁ -C ₆ alkyl available in the stores Cyclohexylmethyl dto. Benzyl dto. Phenylethyl dto. Cyclopropy! Methyl Kirmse u.Mitarb., Ber. 99 (1966), 2855

Cyclobutylmethyl Krug et al., J.Am.Chem.Soc.

T ±, (1954), 3222

Cyclopentylmethyl Smith et al., J.Org.Chem. ,

21: 1448 (1956)

To produce a 2-cyano-3-phenyl-3-carbalkoxymethylcyclohexene, the Boekelheide and Schilling basically assumed cyclohexanone as follows:

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a) cyclohexanone } 2-chlorocyclohexanone

(Homing, Organic Syntheses, Coll. Vol. Ill, 1955, P. 188)

b) 2-chlorocyclohexanone> 2-phenylcyclohexanone

(Newman et al. J. Am. Chem. Soc. £ 6 (1944), 1551)

c) 2-phenylcyclohexanone * 2-phenyl-2-carbethoxy-

cyclohexanone

(Newman and colleagues J. Am. Chem. Soc. £ 9_ (1947), 942)

d) 2-phenyl-2-carbethoxycyclohexanone »2-cyano-3-

phenyl-3-carbethoxycyclohexene

These precursors can lead to the formation of various equivalents caused by the different meanings of Ar and R defined in general formula I favor by appropriately substituted cyclohexanones in step (a) and of appropriately substituted aryl magnesium bromides as intermediates in the step (b) is assumed. So can 4-Methyicyclohexanone and 4-methoxycyclohexanone, which are commercially available as basic raw materials for the production of

2 compounds of the word I, in which R for, H or M

CH ₃ ^V ° ^CH 3 can be used.

The compounds of the formula I in which R ₂ (R in the process description) stands for .H, can be used as intermediate

^0CH 3

rule products for compounds of formula I are used in

2
the R has other meanings. The following table II

gives the additional meanings for R and the known ones Methods by which they can be made.

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Table II
R ² . procedure

Demethylation of the methoxy compound OH

Acetylation of the hydroxy compound CCH ₀

Oxidation of the hydroxy compound

<"" · * Implementation of the oxo compound with

Lithium methyl

.CII3 / ^CH 3

Acetylation of the \ compound

OH 11 0

<H reaction of the hydroxy compound with

in a strong chlorinating agent, e.g.

Thionyl chloride

Conversion of the oxo compound with sulfur tetrafluoride (Martin and colleagues * _ _v J.Org.Chem. _2J7 (1962) 3164)

The use of appropriately substituted phenyl bromides in the preparation of the Grignard compound can also be used A'rylmagnesiümbromid in step (b) to the corresponding Ar residues (in the process description Ar ') in the Products of the formula I lead. In Table III below, suitable Ar * radicals are those defined above Substituents R? and called R.

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Table III

Ar

source

Bromides in which R is hydrogen or methoxyl and R ^{a is} hydrogen are commercially available. The bromide in which R is water ^a

substance and R ^a Methoxyl..ist is also available commercially. The bromide in which both R ^ and R are methoxy radicals is prepared by the method of Mason, J.Am. ChenuSoc. 69 (1947), 2241 can be produced.

The bromides in which R and R ^{a are} both

Are methoxyl and in which R ° is hydrogen

Q-,

and R are methoxyl are commercially available. The bromide in which R and R together form dioxymethylene is also commercially available.

3-Bromo-4-methylanisole is prepared by the method of Mueller et al., Ann. 645 (1961), 92 can be produced.

2-Bromo-4-methyl-6-methoxyphenol, which via methylation leads to the formation of 3-methyl-5,6-dimethoxyphenyl bromide can serve (see üeda and Miitarb., Chem.Abs. Ε> 8> (1963):. 3419)

Compounds in which Ar contains methoxyl substituents (as in Table III) can be used as intermediates for Compounds of the formula I are used in which Ar contains hydroxyl groups or acetoxy radicals as substituents, by applying techniques to transform the residues

as shown in Table II.

R ⁵ in REs te R ²

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Specific embodiments of the invention are shown in The following examples are described in which all parts are parts by weight, unless otherwise specified.

example 1

N-Methyl-4a-phenyl-trans-decahydroisoquinoline A. 2-Cyano-3-phenyl-3-carbethoxymethylcyclohexene

° 6 ^H 5 CO ₂ G ₂ H ₃ 2 *. POCl ^ Λ] CO ₂ G ₂ H ₃

90 g (0.346 mol) of 2-carbethyoxymethyl-2-phenylcyclohexanone (Boekelheide et al., See above), 200 ml of hydrogen cyanide and 12 drops of a saturated aqueous potassium cyanide solution are stirred ^{at 0 ° C. overnight.} After adding 15 drops of concentrated sulfuric acid, the excess hydrogen cyanide was evaporated. The crude cyanohydrin was taken up in ether and washed with cold 10% sulfuric acid solution, then _{dried with Na 2} SO 2 and evaporated. The oil which remained as a residue was dissolved in 500 ml of pyridine. 100 ml of phosphorus oxychloride were added to the solution. The reaction mixture was heated at the reflux condenser with stirring under nitrogen for 5 hours and then left to stand at 25 ° C. overnight. It was then carefully poured into a mixture of 2 l of ice water and 400 ml of concentrated hydrochloric acid and extracted with ether. The ether extract was washed with dilute hydrochloric acid, water and brine, then dried (Na ₂ SO.) And evaporated. The oil remaining as residue was distilled, 45 g of a pale yellow liquid having a boiling point of 135 ° C./0.2o mm Hg, which was identified as 2-cyano-3-phenyl-3-carbethoxymethylcyciohexene.
NMR (CDCl ₃ ) ⁽²⁾ : triplet at 64, 71, 78 Hz, 3H (-OCH ₂ CH ₃ );

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Methylene shell from 7o-15o Hz / ca 6H;

Singlet at 178 Hz, 2H (-6-CH ₂ -CO ₂ -); Quartet at 234, 242, 249, 256, 2H (-OCH ₂ CH ₃ );

Triplet at 4o6, 419, 414, 1H (tr

Singlet at 436 Hz, 5H (aromatic H)

(2) Peaks given in Hz from tetramethylsilane (TMS).

IR (without solvent): 4.5ou (C = N); 5.5 and 5.85 η (lactone as an impurity); 5.75 u (-CO ₂ ^- ).

B. 4a-Phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7- octahydroisoquinoline

HCl, CgH ₅ OH.

The product obtained in accordance with Section A and dissolved in the minimum amount of absolute ethanol (50 g) was added to 2> 5 liters of absolute ethanol which had previously been saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 48 hours. It was then cooled and concentrated to approximately 300 ml on a rotary evaporator. A white crystalline solid was precipitated by cooling, which was filtered off, washed with cold ethanol and dried, 25 g (56%) of the desired compound having a melting point of 241-243 ° C. being obtained.
Elemental analysis
calculated for C ₁₅ H ₁₅ NO ₂
found

C. , 65 H 6th , 26 N 81 74 , 67 6th , 25 5, 65 74 5.

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C. N-Methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline

1. NiiH, DMP

2. CH ₃ I.

7.2o g (29.9 mmol) of the product prepared according to Part B. in 5o ml of dry dimethylformamide were added to 1.58 g of a 55.5% suspension of sodium hydride in Mineral oil (36.5 mmol NaH) was added while the reaction mixture was kept at 70 ° C. under nitrogen. as the evolution of hydrogen ceased (about 1 hour), the reaction mixture was cooled to 25 ° C, whereupon a Solution of methyl iodide (8.52 g, 6o mmol) in 2o ml of dimethylformamide was added dropwise. The mixture was then heated to 90 to 100 ° C. for 2 hours and then cooled, in Poured ice water and extracted with ether. The ether was evaporated and the residue was recrystallized from ethanol, whereby 6.56 g (86%) of the desired product was obtained.

Elemental analysis: CH £ 1

for C ₁₆ H ₁₇ O ₂ N 75.27 6.71 5.49 found 75.22 6.71 5.71

In the same way, but using cyclohexylmethyl bromide instead of methyl iodide, N-cyclohexylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline was used manufactured. Likewise, using cyclopropylmethyl bromide and cyclobutylmethyl bromide instead of methyl iodide, N-cyclopropylmethyl-4a-phenyl-1,3, -diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline or N-cyclobutylmethyl-4a-phenyl-1,3-diket-1,2,3,4, 4a, 5,6,7-octahydroisochiiid.in produced.

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D. N-MethylMa-phenyl-l., 3-diketo-trans- decahydroisoquinine

A mixture of the product prepared in accordance with Section C. (2, ο g, 7.85 mmol), 175 ml of absolute ethanol and 3oo mg of 5% palladium-on-carbon was 24 hours under a hydrogen A pressure of 2.8 kg / cm was shaken. The catalyst was filtered off and the solvent was evaporated from the filtrate. By recrystallization of the residue from ethanol, 1.8 g (θο%) of the desired product were obtained from Melting point 151-153 ° C obtained.

Elementary analysis CHN

for C ₁₆ H ₁ QNO ₂ 74.66 7.44 5.44 found 74.74 7.66 5.33

In an analogous procedure, the reduction of the N-hydrocarbon-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinolines mentioned in Part C resulted N-Cyclohexylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline, N-Cyclopropylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline or N-cyclobutylmethyl-4a-phenyl-1, S-diketo-trans-decahydroisoquinoline.

E. N-Methy1-4a-phenyl-trans-decahydroisoquinoline

R ¹ «CH3

^X HA * = H

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The product prepared according to Section D (1.34 g, 5.2 mmole) in 40 ml of tetrahydrofuran which had been dried over sodium was treated with 1.34 g of lithium aluminum hydride under nitrogen. The mixture was refluxed for 24 hours, then cooled and deactivated by the sequential addition of 1.3 ml of water, 1.3 ml of 15% aqueous sodium hydroxide, and 3.9 ml of water. The inorganic salts were filtered off and washed with ether. The combined filtrates were dried (K ^ CO-j) and then evaporated to a clear oil. This oily residue was taken up in 10 ml of absolute ethanol and treated with 3o ml of saturated picric acid solution in ethanol. The precipitate formed in this way was filtered off and dried and then recrystallized from ethanol, 1.8 g of picrate having a melting point of 217.5 to 219.5 ° C. (corr.) Being obtained. Elemental analysis C H N

for ^C 22 ^H 26 ^N 4 ° 7 57.63 5.72 12.42 found 57.49 5.55 11.91

The picrate was chromatographed on a 2.54 × 15.2 cm column of neutral Woelm aluminum oxide I (packed in methylene chloride) and eluted first with methylene chloride and then with 5% ethanol-methylene chloride. The eluates consisted of 44o mg of a clear oil followed by 39o mg of a yellow-green material. The latter part was taken up in methylene chloride and washed with aqueous ammonium hydroxide, then dried (K ₂ CO ₃ ) and evaporated. The oil remaining as a residue was distilled with evaporation (boiling point 100 ° C./0.7 mm Hg), 300 mg of an oil being obtained which was combined with the part of 40 mg, so that a yield of 74o mg (62%) %, based on the imide) was obtained. This oil solidified on standing and formed white crystalline N-iMethyl-4aphenyl-trans-decahydroisoquinoline with a melting point of 72 to 73 ° C.

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Elemental analysis H ₂₃ N C. 77 H· N calculated for C _c
1 O 83, 76 1O / 6.11 I.
found 83, 1O | 5.84 r1O r23

LiAlH ₄ - In the same way, the N-hydrocarbon-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline N-cyclohexylmethyl- ^ a-phenyl-trans-decahydroisoquinoline, N-cyclopropylmethyl-4a, prepared according to section D was obtained by reduction -phenyl-trans-decahydroisoquinoline or N-cyclobutylmethyl-4a-phenyl-trans-decahydroisoquinoline obtained.

Example 2

1- and d-N-methyl-4a-phenyl-trans-decahydroisoquinoline

A. 1- and d-2-carboxymBthyl-2-phenylcyclohexanone — Λ -phenyl ethylamine salt ^ __ ^ _____

1. 2-carboxymethyl-2-phenylcyclohexanone (Boekelheide et al., See above) (40 g, o, 154 mol), prepared by alkaline hydrolysis of 2-carbethoxymethyl-2-phenylcyclohexanone, was dissolved in 14o ml of hot ethanol and mixed with 27 gi + J - ^ - phenylethylamine treated. The mixture was allowed to slowly crystallize, yielding 21.8 g of the 1-salt having a melting point of 130-132 ° C. / <= * _ 7 _D - 94. A second recrystallization from ethanol gave a material with a melting point of 137 to 139 ° C. l <* _ / -142 °. Further recrystallization did not change the optical rotation.

2. The mother liquors from the crystallizations mentioned above were taken up in 6N hydrochloric acid. The free Acid was extracted with ether. This material was

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dissolved in ethanol, with. (-) <A-phenylethylamine treated and left to slowly crystallize. The white, crystalline d-salt had a melting point of 136 to 137.5 ° C. ^ _7q ⁵ ° + 141 °.

B. 1- and d-2-carboxymethyl-2-pheny! Cyclohexanone

NH ₀ CHC ₆

CO ₂ H

1. A solution of the product prepared according to Section A-1 (15.9 g) in 250 ml of cold 6N hydrochloric acid was extracted with ether. The ether extracts were dried with anhydrous magnesium sulfate and filtered. The ether was evaporated, whereby 1o, og of the 1-keto acid with a melting point of 94 to 95 ° C. were obtained. £ λ_7 _η + 193 ° (C 1, o3, CHCl ₃ ).

2. A solution of 14.0 g of the product prepared according to Section A-2 in 250 ml of cold 6N hydrochloric acid was extracted with ether and worked up in the manner described above, 9.6 g of the d-keto acid having a melting point of 94 to 95.degree were obtained. ^ _7 ²⁵ -194 (c 1, o4, CHCl ₃ ). ⁿ

C. 1- and d-2-carbethoxymethyl-2-phenylcyclohexanone

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2336553

1. A solution of 28 g of the product prepared according to Section B-1 in 700 ml of ethanol which contained 3 ml of concentrated sulfuric acid was refluxed in a Soxhlet extraction apparatus whose sleeve was filled with a 3A * molecular sieve. After refluxing for 24 hours, excess potassium carbonate was added. The mixture was filtered and the solution evaporated. The residue was distilled, the 1-ketoester being obtained as a clear oil with a boiling point of 125 ° C./0.1 mm Hg. 1 ^ _7q -2o7 ° (c 1.5, CHCl ₃ ).

2. A solution of 4o. g of the product prepared according to Section B-2 in 1000 ml of ethanol, which contained 8 ml of concentrated sulfuric acid, was treated in the manner described above, after the distillation of the d-keto ester as a clear oil with a boiling point of 125 ° C / 0.1 mm Hg was obtained. / <* _ 7 _D ⁵ + 234 ° (c 1, oo, CHCl ₃ ).

D. 1- and d-2-cyano-3-phenyl-3-carbethoxymethylcyclohexene

1. The product prepared according to Section C-1 (36 g, 0.138 mol), 200 ml of hydrogen cyanide and 12 drops of a saturated aqueous potassium cyanide solution were stirred ^{at 0 ° C. overnight.} After adding concentrated sulfuric acid, the excess hydrogen cyanide was evaporated. The residue was taken up in ether, washed with 0.1 N sulfuric acid and then with brine, dried (Na ₂ SQ,) and evaporated. The oily residue was dissolved in 250 ml of pyridine. 50 ml of phosphorus oxychloride were added to the solution. The reaction table was refluxed with stirring and under nitrogen for 5 hours and then left to stand at 25 ° C. overnight. He was then in a mixture of 1 1 ice water and 2oo ml

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Poured concentrated hydrochloric acid. The mixture was extracted with ether. The ether extract was diluted with Washed hydrochloric acid, water and brine, dried (Na ^ SO,) and evaporated. That remaining as residue Oil was distilled, 28 g of the 1-cyano ester having a boiling point of 130 ° C. / 0.1 mm Hg being obtained.

2. The product manufactured in accordance with Section C-2 (35 g, o, 134 mol) was treated in the manner described above, 25 of the α-cyano ester having a boiling point of 130 ° C. / 0.1 mm Hg were obtained.

4,

E. d- and 1-4a-Phenyl-1,3-diketo-1,2,3,4a, 5,6,7-octahydroisoquinoline

O ₂ C ₂ H ₅

HOl.

1. A solution of 28 g of the prepared according to Section D-1 Product in 50 ml of absolute ethanol was added to 6oo ml of absolute ethanol that had previously been mixed with anhydrous Hydrogen chloride had become saturated. The solution was refluxed under nitrogen for 48 hours and then chilled and evaporated. A white crystalline solid was precipitated out and filtered off and then recrystallized from ethanol to obtain 12.0 g of the unsaturated d-imide.

- -25 ° η
^ ok_ / £ + 219 ° (c 1, oo, CHCl ₃ ).

2. The product obtained according to Section D-2 (17 g) in 40 ml of absolute ethanol became 400 ml of absolute Given ethanol which had previously been saturated with anhydrous hydrogen chloride and then in the one described above Treated manner, whereby 8.9 g of the unsaturated 1-imide of melting point 169 to 170 ° C were obtained.

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-2o8 ° (c 1.2o, CHCl3).

In this example, the sign of the rotation changes in the ring closure reactions.

F. d- and l-N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline

1. NaH, DMF

2-

1. The product prepared in accordance with Section E-1 (7.2 g, 29.9 m> lol) in 50 ml of dry dimethylformamide was added to 1.58 g of a 55.5% strength suspension of sodium hydride in mineral oil (36.5 mmol NaH) in 50 ml of dimethylformamide, while the reaction mixture was kept at 70 ° C under nitrogen. After the addition, the mixture was stirred at 70 ° for one hour and then cooled, whereupon 8.5 g of methyl iodide in 20 ml of dimethylformamide were added dropwise. The mixture was heated to 90 ° C. for 30 minutes and then allowed to stand at 25 ° C. overnight. It was poured into ice water and extracted with ether. The ether extracts were dried (Na ₇ SO ₄ ) and evaporated. The residue was recrystallized from ethanol, 6.17 g of the unsaturated dN-methylimide vom

O
Melting point 156 to 158 ° C were obtained.

+ 245 ° (c 1.25, CHCl ₃ ).

- -25®

2. The product prepared according to Section E-2 (8.94 g, 37.1 mmol) in 60 ml of dimethylformamide became 1.96 g of a 55.5% strength suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide in the above given way. After recrystallization from ethanol 6.0 g of the unsaturated 1-N-methylimide with a melting point of 149 ° to 153 ° C. were obtained. foS / ^ ° -258 °.

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-2ο-

G. d- and IN-methyl-4ä-phenyl-1,3-diketo-trans-deca hydroisoquinoline

H,

1. A mixture of the product prepared according to Section F-1 (6.1 g, 23.9 mmol), 100 ml of glacial acetic acid and 2 g of 5% palladium-on-carbon was shaken for 24 hours under a hydrogen pressure of 2.8 kg / cm. The catalyst was filtered off and the solvent was evaporated, the residue from ethanol gave Umkristallisätion of 3.7 g of trans-saturated dN-Methylimids melting °

point 189 to 191 ° C.

+81 '

2. The according to section F-2 product produced (6, ο g, 23.5 mmol) was treated in the manner described above, wherein 4, o g of saturated trans-1-N-xMethylimids was obtained of melting point 159 to 16ooc .

~ ⁷²

CHCl ₃ )

H. 1- and dN-methyl ^ a-phenyl-trans-decahydroisoquinoline

1. The product manufactured in accordance with Section G-1 (3.5 g, 13.6 mmol) in 5o ml of tetrahydrofuran, which is dried over sodium was treated with 4.0 g of lithium aluminum hydride under nitrogen. The mixture was Heated for 24 hours on the reflux condenser, then cooled and by successive addition of 4, ο ml of water, 4, ο

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watery
ml of 15% sodium hydroxide and 12.0 ml of deactivated water. The inorganic salts were filtered off and washed with ether. The combined filtrates were dried (K ₂ CO ₃ ) and evaporated to give 2.75 g of a clear oil. Purification via the picrate (melting point 186.5 to 188 ° C.) gave white crystalline IN-methyl-4a-phenyl-trans-decahydroisoquinoline with a melting point of 6.7.2 bi
CHCl ₃ ), fiJlH "3 °,

Melting point 6.7.2 to 67.6 ⁰ C. 1 \ 7q ⁵ ° + 2 ° (G 1,1o,

2. The product prepared according to Section G-2 (3.43 g _f 13.3 mmol) was treated in the manner described above, 2.6 g of dN-Methy ^ a-phenyl-trans-decahydroisoquinoline of melting point 66, 5 to 67 ° C was obtained. ° °

0 °, & Jll ° ₆ +1.3, frJlH +6.3 , (Zg \ l _s +17.5

It should be noted that in this experiment, too, the sign of the rotation changes during the reduction Lithium aluminum hydride changes.

Example 3 N-methyl-4a- (m-methoxyphenyl) -trans-decahydroisoquinoline

A. 2-cyano-3-carbäthoxymethyl-3- (m-methoxyphenyl) -cyclo hexen

A. HCN 2.

CO ₂ C ₂ H ₅

A mixture of 25 g (86.3 mmol) of 2-carbethoxymethyl-2- (m-methoxyphenyl) cyclohexanone (Langlois et al., Tetrahedron 27, (1971) 5641), 100 ml of hydrogen cyanide and 4 drops of saturated aqueous Potassium cyanide solution was ^{stirred at 0} ° C. under nitrogen for 24 hours. After this time 5 drops of concentrated sulfuric acid were added

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sets, whereupon the excess hydrogen cyanide was evaporated. The oil remaining as residue was taken up in ether and washed with 10% sulfuric acid and then with brine and dried (MgSO ₄ ). The ether was evaporated. The crude cyanohydrin thus obtained was taken up in 175 ml of pyridine. To the mixture, 35 ml of phosphorus oxychloride was added. The solution was refluxed under nitrogen for 3 hours. It was then cooled and poured into a mixture of 500 ml of ice water and 100 ml of concentrated hydrochloric acid. The resulting mixture was extracted with ether. The ether extract was washed with brine, dried and concentrated, 22 g of crude product being obtained. This product was distilled in a short-path distillation, 16 g of product having a boiling point of 166 ° C./0.5 mm Hg being obtained. The infrared spectrum of this material indicated that it consisted of 2-cyano-3-carbethoxymethyl-3- (m-methoxyphenyl) cyclohexene with a small amount of impurity, probably a lactone, with bands at 5.5o and 5.85µ. This material was considered sufficiently pure to be used in the next stage.

Elemental analysis CHN

calcd for C ₁₈ H ₂₁ O ₃ N 72.2o 7, o7 4.68 found 72.22 7.13 4.1o

B. 4a- (m-Methoxyphenyl) -1,3-diketo-1,2,3,4,4a, 5,6,7-octa hydroisoquinoline

309885 / U32

A solution of 16 g (53.5 mmol) of the product prepared according to Section A in absolute methanol was added to 1.5 l of absolute ethanol which had previously been saturated with anhydrous hydrogen chloride. The solution was refluxed under nitrogen for 48 hours and then left to stand at 25 ° C. for 24 hours. It was concentrated to about 500 ml on a rotary evaporator and cooled in ice. The crystalline precipitate formed in this way was filtered off, with 8.0 g (55%) of the desired product having a melting point of 23o to 232 ° C. being obtained.

Elemental analysis C. H N calculated for C ₁ , -H ₁ ^ NO- j 7o, 83 6.31 5.16 found 7o, 97 6.33 5.59

In the same way, various 1,3-diketo compounds were made from the corresponding 3-carbethoxymethyl-2-cyancyclohexenes mentioned in the table below manufactured. This table also includes the sub-

2
stituent Ar and the radicals R are indicated in each pair.

Table IV pair Ar R

1 3-methoxyphenyl

2 2-methoxyphenyl

3 2-methoxyphenyl

4 4-I ethoxyphenyl µ

Sat

5 U-methoxyphenyl ^ \\ ■ 3 09885 / U32

2,3-dimethoxyphenyi

2,3-dimethoxyphenyl

8 2,4-dimethoxyphenyl

3,4-dimethoxyphenyl

10 3,4- (methylenedioxy) phenyl

/H

11 5, h- (methylerdioxy) phenyl '/ H

12 2-methyl-5-methoxyphenyl ^H

2-methyl ~ 5-methoxyphenyl

2 _i 3-di-methoxy-5-methylphenyl

15 2 _i 3-dimethoxy-5-methylphenyl

^{16 phenyl} 17 3-methoxyphenyl 18 2-methoxyphenyl

• 3 09885 / U32

Pair Ar R

4-methoxyphenyl ^ H

20 2,3-dimethoxyphenyi

21 x 5,4-dimethoxyphenyi

22 3 * ^ - (methylene dioxy) phenyl

2-methyl-5-methoxyphenyl / H

^ CH ₃

2,3-Dimethoxy-5- ' ^I- ethylphenyl> * "H

\ c

CH ₂ .

C. N-methyl-4a- (m-methoxyphenyl) -1,3-diketo-1, 2, 3,4,4a, 5, 6,7, -octahydroisochinolin

CH <

2. CH ₃ I.

The product manufactured in accordance with Section B (4, o7 g, ituMol) in 15 ml of dry dimethyl formamide was taken under Nitrogen from a mixture of 79o mg of a 55% suspension of sodium hydride (18.1 mmol NaH) in mineral oil added to 25 ml of dimethylformamide, while the temperature of the reaction mixture was kept at 6o to 7o ° C. After the addition, the reaction mixture was held at 90 ° C. for 2 hours. At that point the development had stopped by hydrogen. It was then cooled to 3o ° C, whereupon a solution of 4.25 g (3o mmol) of methyl

309885 / U3 2

C. 54 6th H 4th N 71 58 6th , 71 4th .91 71 , 93 .94

iodide in Io ml of dimethylformamide was added dropwise. That The mixture was heated to 90 to 100 ° C. for 2 hours, then cooled, poured into ice water and extracted with ether. the Ether extracts were washed with water, dried (magnesium sulfate) and evaporated. The residue was recrystallized from ethanol, the desired crystalline Product (3.8 g, 89%) obtained with a melting point of 139 to 141 ° C became.

Elemental analysis calculated for C ₁₇ H ₁₉ NO ₃ found

By using phenethyl bromide, cyclohexylmethyl bromide, Cyclopropylmethyl bromide and cyclobutylmethyl bromide instead of methyl iodide in the experiment described above, the corresponding N-phenylethyl, N-Cyclohexylmethyl-, N-Cyclopropylmethyl- or N-cyclobutylmethyl-4a- (m-methoxyphenyl) -i , 3-diketo-i, 2,3,4,4a, 5,6,7-octahydroisoquinolines were obtained. Likewise are through Replacement of 4a- (m-iMethoxyphenyl) -i, 3-diketo-1,2,3,4,4a, 5, 6,7-octahydroisoquinoline by the 4a-aryl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline described in Section B, 4a-Aryl-6-methoxy-1,3-diketo-1,2,3,4,4a, 5,6-7-octahydroisoquinoline or 4a-aryl-6-methyl-1,3-diketo-1, 2,3,4,4a, 5,6,7-octahydroisoquinoline the corresponding N-hydrocarbon-4a-aryl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinolines, N-hydrocarbyl-4a-aryl-6-methoxy-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinolines and N-hydrocarbyl-4a-aryl-6-methyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinolines, respectively obtain *

D, N-methyl-4a- (m-methoxyphenyl) -1,3-diketo-trans-decahydroisochirtiine

309885 / U32

. -27 "

CH ₃

CH ₃

, 'H ₃ , Pd / c

I ₃ . ·

HO

The product prepared according to Section C (3.2 g, 11.21 mmol), 100 ml of glacial acetic acid, 50 ml of dioxane and 7oo mg 5% palladium-carbon was shaken for 24 hours under a hydrogen pressure of 2.8 kg / cm. The catalyst was then filtered off and washed well with dioxane. The combined filtrates were evaporated to a clear oil. The amount of product was 3.2 g (99.4%). The product consisted of pure N-methyl-4a- (m-methoxyphenyl) -1,3-diketo-trans-decahydroisoquinoline, determined by thin layer chromatography (20% ether-benzene on silica gel plates) and the nuclear magnetic resonance spectrum. NMR (CDCIo): complex multiplet at 50 to 150 Hz

TMS (9H, -CH ₂ - and -CH); Quartet

148, 163, 173, 189 Hz (2H, -CH ₂ -CO-); Singlet at 180 Hz (3H, NCH ₃ ); Singlet

at 220 Hz (3H, OCH ₃ ); Multiplet at 397

up to 42o Hz (4H, Ar-H).

In the same way, the catalytic editing results of the analogous products from section C the corresponding N-hydrocarbon-4a-aryl-1,3-diketo-trans-decahydroisoquinolinij N-hydrocarbon-4a-aryl-6-methoxy-1, 3r diketo-trans-decahydroisoquinoline and N-hydrocarbon-4a-aryl-6-methyl-1,3-diketo-trans-decahydroisoquinoline &

E. N-Methyl-4a (m-methoxyphenyl) -trans-decahydroisoquinoline

CH ₃

LAIi, TIfl * v.

3 0 9-8 85 / U32.

NCH ₃

OCH-

Ar

The product prepared according to Section D (3.2 g, 11.2 mmol) in 75 ml of tetrahydrofuran which had been dried over sodium was treated with 3.2 g (84.2 mmol) of lithium aluminum hydride. The reaction mixture was refluxed under nitrogen for 20 hours. It was then left to cool to 25 ° C. and treated successively with 3.2 ml of water, 3.2 ml of 15% aqueous sodium hydroxide and 9.6 ml of water. The precipitated inorganic salts were filtered off and washed well with ether. The combined filtrates were dried over anhydrous potassium carbonate and evaporated to an oil. This oil was distilled with evaporation, whereupon 2.0 g (69%) of the desired product were obtained as a clear oil with a boiling point of 116 ° C./0.7 mm Hg. Elemental analysis CM ü

Calcd for C ₁₇ H ₂₅ NO 78.71 9.71 5.4o found 78.14.9.08

In the same way, reduction of the analogous products of Section D with lithium aluminum hydride gives the corresponding N-hydrocarbon-4a-aryl-trans-decahydroisoquinoline, N-hydrocarbon-4a-aryl-6-methoxytrans-decahydroisoquinolines and N-hydrocarbyl-4aaryl-6-methyl-trans-decahydroisoquinolines.

Example 4 N-MethyiHa- (m-hydroxyphenyl) -trans-decahydroisoquinoline

OCn ₃

IiCU ₃

3Bi "

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A solution of 800 mg of N-methyl-4a- (m-methoxyphenyl) -trans-decahydroisoquinoline (3.09 mmol) in 3o ml of methylene chloride was added in portions to a solution, cooled with ice, of 0.59 ml (1.55 g, 6.18 mmol) of boron tribromide in 15 ml of methylene chloride added. The solution, protected under nitrogen, was kept at 25 ° C overnight. To Addition of 5 ml of methanol, the solution was evaporated. The residue was washed with 15 ml of aqueous 5N sodium hydroxide treated and the mixture stirred for 15 hours. After adding 50 ml of ether, the two-layer mixture became Stirred for 2 hours. The aqueous layer and the ether layer were then separated and the aqueous one Partly saturated with carbon dioxide. The solid precipitate formed was extracted with ether and the extract evaporated, 680 mg of the desired compound having a melting point of 195 to 2o5 ° C were obtained.

NMR (CDCl3): methylene envelope from 60 to 160 Hz from TMS;

Singlet at 127 Hz (3H, NCH ₃ ); Multiplet at 127 Hz (3H, NCH ₃ ); Multiplet at 383-432 Hz (4H, Ar-H).

Elemental analysis C. 9 H 5 N calculated for C ₁₆ H ₃₃ NO 78.3o 9 , 44 5 found 78> o5 , 47 , 65

In the same way, analogous methoxy-substituted products based on those described in Example 3, Part E. Were prepared manner, are demethylated to corresponding hydroxy-substituted products.

In the table below, the substituents Ar and

2
Called R of these pairs.

309885 / U32

-30-Table V

Pair of methoxy compound Ar

Hydroxy compound Ar

2-Methoxyphcny1

2-hydroxyphenyl

2 2-methoxyphenyl Λ \ 2-hydroxyphenyl

.OCK ₃

4-methoxyphenyl

4-mathoxyphenyl

2,3-dimethoxy

phenyl

2,3-dimethoxy

phenyl

3,4-dimethoxy

phenyl

δ -3,4-dimethoxyphenyl

.9 2-Methyl-5-methoxyphenyl

.10 2-Methyl-5-methoxyphenyl

2,3-dimethoxy-5-

methylphenyl

2,3-dimethoxy-5-

methylphynyl

3-methoxyphenyl

2-methoxyphenyl

4-methoxyphenyl

2,3-di-methoxy

phenyl

OCH ₃ 4-hydroxyphenyl 4-hydroxyphenyl 2,3-dihydroxyphenyl 2,3-dihydroxyphenyl 3,4-dihydroxyphenyl 3 * 4-dihydroxyphenyl

2-methyl-5-hydroxyphynyl

H 2-methyl-5-hydroxy

OCH ₃ phenyl

<s 2,3-dihydroxy-5-methylphenyl

2,3-dihydroxy-5-methylphenyl

3-hydroxyphenyl, 2-hydroxyphenyl, 4-hydroxyphenyl 2,3-dihydroxyphenyl

CH ₃

309885 / U32

Table V continued

Pair of methoxy compound

Ar

Hydroxy compound Ar

17 3, H-Dlmethoxy-

phenyl ^ CH ₃

oxyphenyl

19 2,5-DimGthoxy-5-mcthyiphcny

3, ty-Dihyaroxyphenyi

2-methyl-5-hydroxyphynyl

2,5 ~ dihyaroxy-5-methyl'phenyl

CH ₃

^ CH ₅

Example 5 N-methyl-4a-phenyl ~ 8a-hydroxy-trans-decahydroisoquinoline

A. N-Methyl-4a-phenyl-1, S-diketo-S / ea-epoxydecahydroisoquinoline

0 0

A solution of 1, og (3.92 mmol) of N-methyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline in 10 ml of chloroform was with a Treated solution of 746 mg of 85% m-chloroperbenzoic acid in 12 ml of chloroform. The reaction mixture was refluxed for 36 hours and then poured into 5N sodium hydroxide. The aqueous phase was extracted twice with chloroform. The combined organic layers were washed well with water and then with brine. By drying with sodium sulfate and evaporating the solvent, 0.7 g of the desired compound with a melting point of 135 ° to 140 ° C. were obtained as a white solid.

In the same way, analogous products that have been prepared according to Example 3, Part C, are made with m-chloroperbenzoic acid into the corresponding N-hydrocarbon

309885/1432

4a-aryl-1, S-diketo-S ^ a-epoxy-decahydroisoquinoline, N-hydrocarbon-4a-aryl-1,3-diketo-6-methoxy-8,8aepoxy-decahydroisoquinoline and N-hydrocarbon-4aaryl-1 , S-diketo-ö-methyl-e ^ a-epoxy-decahydroisoquinoline converted.

B. N-methyl-1-phenyl-Sa-hydroxy-trans-decahydroisoquinoline

C ₆ H ₅ Y <· " ^{5 Rl} -""3"

' ^{r2 =} <H

^ilCIb A - OH

'/ Tv - OH

⁰ O Ar = C ₆ H ₅

A mixture of ο.6 g of N-methyl-4a-phenyl-1,3-diketo-δ, 8aepoxydecahydroisoquinoline and 1, og lithium aluminum hydride in 25 ml of tetrahydrofuran was refluxed overnight. The reaction mixture was cooled, whereupon 1 ml of water, 1 ml of 15% aqueous sodium hydroxide and finally 3 ml of water were added in succession. The mixture was diluted with 25 ml of ether and filtered to remove inorganic salts. The filtrate was concentrated by evaporating the solvents. The residue was taken up in ether and the ether solution was dried (K ₂ CO ^). Evaporation of the dried solution and trituration of the residue with ethanol gave a white crystalline compound with a melting point of 84 to 87 ° C., which was identified as the desired product. NMR (CDCl ₃ ): methylene envelope over 55-16o Hz from TMS (12H, -CH ₀ -); Singlet at 132 Hz (3H, NCH ₁ ); AB-quartet at 14o, 15o, 171, 182 Hz (211, -C-CH ₂ -N-); broad singlet at 261 Hz (1H, 0H); complex multiplet at 427 - 459 Hz (5H, ArH). Elemental analysis: CHN

for C ₁₆ H ₂₃ NO 78.3o 9.44 5.71 found 78.27 9.57 5.48

• 3 09885 / U32

In the same way, those according to the preceding Section A produced analogous products treated with lithium aluminum hydride, with the corresponding N-hydrocarbon ^ a-aryl-ea-hydroxy-trans-decahydroisoquinoline, N-hydrocarbyl-4a-aryl-6-methoxy-8a-hydroxy-trans-decahydroisoquinoline and N-hydrocarbon-4aary1-6-methyl-ea-hydroxy-trans-decahydroisoquinoline was obtained.

Example 6 N-Cyclohexylmethyl ^ a-phenyl-trans-decahydro! Soquinoline

A. N-Cyclohexylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline

QfcHs

Close

rim r- \ (V- 0 \ /

CH ₂ Br

A solution of 4a- (phenyl) -1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline (2, ο g, 8.3o mi «lol) in 15 ml of dry Dimethylformamide was added dropwise to 395 mg of a 55% suspension of sodium hydride in mineral oil in 15 ml of dimethylformamide given at 7o C. The reaction mixture was held at 70 ° C for 1 hour and then cooled to 25 ° C. Cyclohexylmethyl bromide (1.62 g) in 15 ml of dimethylformamide were added dropwise and the mixture was stirred at 25 ° C. overnight. To It was refluxed for 1 hour and poured into water and extracted with ether. The Crude product was triturated with ethanol to give 65o mg of a solid. The mother liquor was then chromatographed on 100 g of "Florisil" and eluted with mixtures of 4% acetone-hexane, with a further 825 mg with a melting point of 111 to 113 ° C. The product was found to be N-cyclohexylmethyl-4a-phenyl-1,3-diketo-1,2,3,4,4a, 5,6,7-octahydroisoquinoline identified.

3 09885 / U32

Elemental analysis calculated found

calculated for ^C ₂ 2 ^H 27 ^NO 2

C. 28 .- 8th H 4, N 78 o3 7th , 06 4, 15th 78 , 80 1o

B. N-Cyclohexylmethyl-4a-phenyl-1,3-diketo-trans-decahydroisoquinoline

C ₆ H ₅ Ha, Pd / C

A mixture of the product prepared according to Section A (858 mg), 75 ml of glacial acetic acid and 2oo mg of 5% palladium carbon was under a hydrogen pressure for 24 hours

shaken by 2.8 kg / cm. The catalyst was filtered off and the solvent evaporated to give the crude N-cyclohexylmethylimide. IR: 5.8o and 5.96 u (imide C = O); 6.25, 6.35 η (Ar C = C).

C. N-Cyclohexylmethyl-a-phenyl-trans-decahydroisoquinoline

The crude product prepared according to Section B (860 mg) was taken up in 50 ml of anhydrous tetrahydrofuran. Lithium aluminum hydride was added and the mixture was refluxed under nitrogen overnight. It was left to cool and then successively with 0.9 ml of water, 0.9 ml of 15% aqueous! Sodium hydroxide and treated 2.7 ml of water. The precipitated inorganic salts were filtered off and washed well with ether. The combined filtrates were dried over anhydrous potassium carbonate and evaporated. That as

309885/1432

The oil remaining was distilled; Boiling point 110 ° C / 0.04 mm Hg. The product was identified as fi-Cyclohexylmethyl-4a-phenyl-trans-decahydroisoquinoline. Elemental analysis CM £ 1

Calcd for C ₂₂ H ₃₃ N 84.83 1o, 68 4.5o found 84.85 1o, o3 4.74

Example 7 N-phenethyl-4a- (m-methoxyphenyl) -trans-decahydroisoquinoline

A. N-Phenethyl-4a- (m-methoxyphenyl) -1,3-diketo-1,2,3,4,4a- 5,6,7-octahydroisoquinoline

OCH:

Close

C ₆ H ₅ CH ₂ CH ₂ Br 1 ^ 1 / NCH ₂ CH ₂ C ₆ H ₅

a ■

A solution of 4a- (m-methoxyphenyl) -1,3-diketo-1,2,3,4,4a, 5,6,7-oetahydroisoquinoline (2.2 g, 8.12 mmol) in 15 ml of dry dimethylformamide was added dropwise to 386 mg of a 55% suspension of sodium hydride in mineral oil in 15 ml of dimethylformamide at 70 ° C. The reaction mixture was kept for 1 hour at 7o ° C and then cooled to 0 ⁰ C, were followed by 1.65 g Phenyläthylbromid in 15 ml of dimethylformamide was added. The mixture was stirred at 25 ° C. for hours and then poured into water and extracted with ether, 2.32 g of the desired product having a melting point of 134 to 135 ° C. being obtained after trituration with ethanol.

Elemental analysis CHN

calculated for ^C ₂ 4 ^II 25 ^NO 3 76.76 6.71 3.73

found 75.94 6.60 3.73

75.97 6.53 3.72

309885/1432

B. N-phenethyl-4a- (m-methoxypheny.l) -1, 3-diketo-transdecahydroisoquinoline

CH ₃

OCH ₃

Hg, Pd / C _v

A mixture of the product obtained in Section A (2.3 g) with 100 ml of glacial acetic acid and 600 mg of 5% palladium-carbon was shaken for 18 hours under a hydrogen pressure of 2.8 kg / cm ² . The catalyst was filtered off and the filtrate evaporated to give a crystalline solid melting at 119-122 ° C which was identified as the desired product

C. N-Phenethyl-4a- (m-methoxyphenyl) -trans-decahydroisoquinoline

CH ₃

H ~ cP,

LiAlH ₄ f ^^ H

The product prepared according to Section B was taken up in 1oo ml of dry diethylene glycol dimethyl ether. After adding 2.64 g of lithium aluminum hydride, the mixture was held at 110 to 120 ° C. for 48 hours. It was cooled to 0 C and then treated in succession with 3.0 ml of water, 3. O ml of 15% aqueous sodium hydroxide and then with 9.0 ml of water. The inorganic salts were filtered off and the filtrate was evaporated. The residue was taken up in ether and dried _{with K 2} CO _3. The solvent was evaporated. The residue was distilled with evaporation (boiling point 18o ° C / o, oo4 mm Ug),

309885/1 432

whereby 1.6 g of the desired product were obtained. NMR (COCl ₃ ): methylene envelope over 40 to 180 Hz from TMS;

Singlet at 227 Hz (OCH ₃ ); complex multiplatt centered at 431 Hz (ArH).

Element ar analysis CM £ 1

for C ₂₄ H ₃₁ NO 82.47 8.94 4.00 found 81.92 8.99 3.75

Example 8 N-phenethyl-4a- (m-hydroxyphenyl) -trans-decahydroisoquinoline

A solution of 1.25 g (3.58 mmol) of the product prepared according to Example 7, Part C, in 30 ml of methylene chloride was converted into a solution of 0.7 ml (7.2 nmoles) of boron tribromide in 15 ml within 20 minutes Given methylene chloride at O ^{0 C.} The mixture was ^{stirred at 0} ° C. for 2 hours and then at 25 ° C. overnight. The reaction mixture was worked up in the manner described in Example 4, an oil having a boiling point of 220 ° C./0.03 mm Hg being obtained after distillation with evaporation. This oil was triturated with ether to give a crystalline solid melting at 184 ° to 190 ° C. which was identified as the desired product. NMR (CDCl ₃ ): The lack of that in the product of Part C of

Example 7 singlets present at 227 Hz (OCH ₃ ) indicated that the methyl ether had been demethylated.

The new 4a-aryl-trans-decahydroisoquinolines of the formula I are generally valuable as anaigetics that are based on any Ways in which the compound is delivered to the site of action in the body of warm-blooded animals can. Parenteral administration is suitable (subcutaneous, intravenous, intramuscular or intraperitoneal) and oral administration (as an alternative to or simultaneously with parenteral administration). The analgesic The effect of these compounds is determined by those in the

309885 / U32

The experiments described in the following examples illustrate

,,,,. female

light, the nut / white mice using N-methyl-4a-phenyl-trans-decahydroisoquinoline (Example 1, Part E and Example 2, Part H), N-methyl-4a- (m-methoxyphenyl) -trans-decahydroisoquinoline (Example 3, Part E) and N-Methyl4a- (m-hydroxyphenylj-trans-decahydroisoquinoline (Example 4). Example A

In a modified standard mouse test according to Siegmund et al. (Proc.Soc.Exp.Biol. Med. 95 (1957), 729) the test compound suspended in 1% Methocel was administered orally to female white mice which had been deprived of food for 17-21 hours. 5 to 20 animals were used per double-blind test. Aqueous 0.1% phenylp-benzoquinone (phenylquinone) was injected intraperitoneally 23 or 30 minutes later, 0.25 ml / mouse being used. Beginning 30 minutes and 37 minutes after oral administration of the test compound, respectively, the mice were observed for 10 minutes for a characteristic stretching syndrome, which is indicative of the pain produced by the phenylquinone. The effective analgesic dose for 50% of the mice (ED ^) was calculated using the moving average method of Weil (Biometrics Q (1952) 249). The following table shows the oral ED _5Q doses of the test compounds.

Compound ' Dosage (mg / kg)

Example 1-E. 1o

Example 3-E 3

Example 4 2.3

309885 / U32

Example B.

The optical isomers of N-methyl-4a-phenyl-transdecahydroisoquinoline (products of Example 6H, Part 1 and Part 2) were tested for their analgesic effect according to the phenylquinone test described in Example A. The following ED _5Q dosages show that the left-hand and right-hand forms are both effective, but that the right-hand form is significantly more effective than the left-hand form.

Isomer dosage (mg / kg)

clockwise (example 6 H-2) 3.5 counterclockwise (example 6 H-1) 23.0.

The other new products according to the invention are the 1,3-diketo compounds of formulas 2, 3, 4 and 5. How the description of the processes and the examples show that these products are all chemical intermediates suitable for the preparation of the new analgesics according to the invention.

309Ö85 / U32

Claims (12)

Claims 1. Compounds of the formula in which R stands for hydrogen, Cj-Cg-alkyl, benzyl, phenyl ethyl or cycloalkylmethyl of the formula -CH ₉ CH < (CH ₉ ), £ £ Ti in which η is an integer from 2 to 5, R for divalent oxygen (= 0) OCH- "" 0CCH ^J Il OH CH Il or Cl A for hydrogen or hydroxyl Ar for ■ IT or CH ₃ R ' ■ 3098 85 / U is where R is hydrogen, hydroxyl, methoxyl or acetoxyl and R is hydroxyl, methoxyl or acetoxyl, 3 4 and two of the radicals R or R, which are on adjacent carbon atoms, can together form a divalent methylenedioxy radical (-OCH ₂ O-). 2. The dextrorotatory isomers of the compounds according to claim 1. 3. The levorotatory isomers of the compounds according to Claim 1. 4. N-methyl-1-phenyl-trans-decahydroisoquinoline. 5. The levorotatory isomer of the compound of claim 4. 6. The dextrorotatory isomer of the compound of claim 4. 7. N-Methy1-4a (m-methoxypheny1) -trans-decahydroisoquinoline. 8. N-Methyl-4a- (m-hydroxyphenyl) -trans-decahydroisoquinoline. 9. N-methyl ^ a-phenyl-ea-hydroxy-trans-decahydroisoquinoline. 10. N-Cyclohexylmethyl-a-phenyl-trans-decahydroisoquinoline. 11. N-phenethyl-4a- (m-metnoxyphenyl) -trans-decahydroisoquinoline. 12. N-phenethyl-4a- (m-hydroxyphenyl) -trans-decahydroisoquinine. 30988 5 / U.3 2 Analgesic pharmaceutical preparation containing a compound according to Claims 1 to 12 as active ingredient and a pharmaceutically acceptable carrier. Process for the preparation of compounds of the formula in which R ^{1 is} hydrogen, Cj-Cg-alkyl, benzyl, phenylethyl or cycloalkylmethyl of the formula -CH ₂ CH <(CH ₂ ) _n , in which η is an integer from 2 to 5, and R and Ar are the abovementioned Have meanings, characterized in that one after the other a) a compound of the formula with an anhydrous alcohol of the formula R OH, in which Br is an alkyl radical having 1 to 4 carbon atoms, in the presence of anhydrous HCl under inert, anhydrous conditions at a temperature in the range from 5o to 12ooc to the corresponding diketo derivative of the formula 309888/1432 implements, b) the diketo derivative from step (a) with sodium hydride and a halide R Br or R I to the corresponding • N-substituted derivative of the formula implements, c) the N-substituted derivative from step (b) with hydrogen in the presence of a reducing catalyst to the corresponding trans-diketo derivative of the formula implements and then d) the trans derivative from step (c) is heated with lithium aluminum hydride in a reflux condenser. Process for the preparation of compounds of formula in which R, R ⁵ and Ar have the abovementioned meanings, characterized in that a) compounds of the formula 309885/1432 in which R , R and Ar have the meanings given above, heated with chloroperbenzoic acid and thereby an epoxy compound of the formula forms, in which the members have the meanings given above and b) the epoxy compound from step (a) with lithium aluminum hydride heated. 30988B / 1AJ2