CS199586B2 - Process for preparing derivatives of 6,7-benzomorphanes - Google Patents

Abstract

Compounds of formula L <IMAGE> wherein the substituents are defined in Claim 1, are prepared from corresponding 9 alpha -hydroxy compounds, in which the 2'-hydroxy group and the amino group are protected, by treatment with a strong base and subsequent alkylation to give a 9-OR<5> compound or by treatment of the blocked compound with a diazo(lower)alkane or tri(lower)alkyloxonium fluoroborate and subsequent alkylation, resulting in 9-OR<5>-substituted compounds. After cleaving off the protective groups and conversion to the 2'-OR<2> and 2-R<1> group, the compounds L are obtained. Compounds L with R<2>=H are converted to compounds with R<2>=lower alkyl by etherification. The compounds prepared are used as analgesics and/or as antagonists of narcotics and are non-addictive.

Description

The present invention relates to a process for the preparation of novel derivatives of 6,7-benzomorphans, in particular. ^{2-cyclopropyl,} opylmethyl-2 '- hydiroxy-9a' - methoxy-'5 - methyl-6,7-benzomor ¢ anu that are effective as analgesics, and / or agents counteracting like- narcotics.

In particular, the invention relates to derivatives of 6,7-benzomorphans of the general formula L

carbon atoms or. (C 2 -C 6) alkenyl;

R 4 is hydrogen. or alkyl having 1 to 6 carbon atoms and

R5 represents an alkyl group having 1 to 5 carbon atoms; Or a pharmaceutically acceptable salt thereof. acid addition salts; or. their racemic mixtures or their optical isomers.

The invention also discloses a novel intermediate for the preparation of a compound of formula L having the general formula

where where

R 'represents a hydroxyl protecting group, preferably alkyl. a (C1 -C6) group, in particular a methyl group; '. .

R ³ . represents an alkyl group with. Or (C 1 -C 6) alkenyl; 6 carbon atoms,

R 1 represents a group of the formula

-CWjrO · - CWfO · l

R ² represents hydrogen or alkyl having 1 to 6 carbon atoms,

R 3 represents an alkyl group of 1 to 6

R ⁴ is hydrogen or C 1 -C 6 alkyl;

R ⁵ represents an alkyl group having 1 to 6 carbon atoms or an allyl group, as well as acid addition salts.

Drug abuse by young people who are eager to get excited, or by people seeking to escape the reality of everyday life, is becoming more common in today's American society. One group of widely abused drugs are narcotic analgesics, such as codeine, morphine, meperldine, etc. Due to the high additive potential of these substances, the pharmaceutical industry and government spend a lot of time and money trying to discover and develop new non-addictive analgesics and / or anti narcotic. Examples of efforts to solve this problem include:

(1) Everette May and Hiroshi Kugita, J. Org. Chem. 26, p. 188 (1961J), where they are described as mild to weak analgesics of the compound of the general formula

where

R is methyl or phenethyl;

R ¹ is methyl or hydrogen, and

R ³ is hydrogen, hydroxyl or methoxy; (4) Everette May, Colin Chignell and J. Harrison Ager, J. Med. Chem. 8, p. 235 (1985), which discloses compounds of the formula

where

R is methyl or phenethyl and

R ² represents hydrogen or a methyl group, (2) Everett May, James Murphy and J. Harrison Ager, J. Org. Chem., 25, 1396 (1960), where compounds of the formula are described as effective analgesics

where

R is methyl or phenethyl and

R ^z represents hydrogen or methyl, (3) May Everett, Hiroshi Kugita Harrison and J. Ager, J. Org. Chem. 26, pp. 16'21 (1961), which discloses analgesic inducing compounds of varying degrees, of the general formula:

R ¹ represents hydrogen or methyl and

R ² represents a methyl group having analgesic activity, (5) and Hiroshi Everett May Kugita, J. Org. Chem. 26, 1954 (1961), which discloses compounds of the general formula

R is methyl or phenethyl,

R ¹ represents hydrogen or methyl and

R ² is hydrogen or acetyl are analgetidkou efficiency, (6) and Everett May Selichi Sato, J. Org.

Chem. 26, p. 4536 (1961), which discloses compounds having analgesic activity of the general formula

where

R ¹ represents a methyl or ethyl group,

R ² represents hydrogen or methyl,

R ³ represents a methyl or ethyl group and

R ⁴ represents hydrogen or acetyl group, and (7) NB Eddy EL overview published May 6,7-benzomorphan in the journal Synthetic Analgeticš Pergamon Press (1966).

The purpose of the invention was to discover new non-addictive analgesics and / or anti-narcotic agents.

Another object of the invention was to find a process for the synthesis of these novel compounds which would not be dependent on opium alkaloids as starting materials and yet would be commercially viable.

The purposes set out by the invention have been achieved by providing a process for the complete synthesis of compounds of formula L from the readily available 7-methoxy-3,4-dlhydiro-2 [1H] -naphthalenone (I) as a starting material.

The compounds prepared by the process of the invention have a basic benzomorphane core represented by a planar formula

Although there are three asymmetric carbons (designated -J-) in the benzomorphane molecule, only two racemic forms are possible, since the iminoethane group attached at positions 1 and 5 maintains a cis- (1,3-diaxial) arrangement for geometric reasons. Therefore, these racemates can only differ in configuration on carbon 9. The only variable will be the cis and trans position of the 9-alkoxy compound relative to the amino group. If it is present in the compounds obtained by the process according to the invention,

The 9-alkoxy group in the trans position relative to the iminoethane group will be 9α-alkoxybenzomorphanes. For N, R-alkoxybenzomorphanes, the 9-alkoxy group will be in the cis position relative to the iminoethane group.

As used herein, a graphical representation of benzomorphane is intended to include

199588

chemical mixture and its resolved d ischomers.

The compounds obtained by the process according to the invention, for example 9β-alkoxybenzoimorphans, can exist as two optical isomers, namely the levorotatory and dextrorotatory isomers. These optical isomers can be represented graphically as follows:

9i (β-methoxybenzomorphane:

The invention encompasses all of these isomers, including optical isomers, obtained by separation from each other.

The optical isomers may be separated and isolated by fractional crystallization of diastereoisomeric salts formed, for example, with d- or 1- tartaric acid or D - (.alpha.) - .alpha.-bromocapirsulfonic acid. Other acids commonly used for the separation of isomers may also be used.

The most preferred forms are the levorotatory isomers of the compounds obtained by the process of the invention.

As used herein, the term "alkyl" refers to an alkyl radical of 1 to 6 'carbon atoms, an "alkenyl group" of a hydrocarbon radical of 2 to 6 carbon atoms containing one double bond, an "alkanoyl" radical of an acyl radical of 2 to 6 atoms carbon, such as acetyl, propionyl, isobutyryl, etc. and the like. The term "pharmaceutically acceptable acid addition salt" includes all addition salts of the compounds prepared by the process of the invention with inorganic and organic acids, which are commonly used to produce relatively non-toxic salts of amine-containing drugs.

By way of example, salts formed by mixing compounds of the formula h with acids such as hydrochloric, sulfuric, nitric, phosphoric, phosphorous, hydrobromic, maleic, malic, ascorbic, citric, tartaric, lauric, stearic, palmitic, oleic, myristic, laurylsulfone, naphthalenesulfone, linoleic, linolene, fumaric, etc.

The compounds of the present invention are prepared by complete synthesis involving a variety of steps. Nevertheless, good yields are achieved by this synthesis, so it appears commercially viable. The process of the invention for producing these compounds is illustrated in Schemes I and II.

199588

СЦ0

O (I)

Scheme I

ExampleLAd-X

CH ₃ O

O

Ы'кШ a

CH

^ -CH ₃

B> r Θ (Va) (IIIa) oxatite

O

CH ₃ O (V <sol

O

СНзр

M / a)

N - CH _b , H Bh

CH $ 'TLkled 5? N (.K.a.d & NH • OHpYk? H

CHb

-PruktA-d. to

O (Vtá

CH ₃

N-CH3

H '

OP

CH _b O

O

N-CH 2 -O och->

H S ^CH IX / a) t tfiLkUd

HIM

O (XI lac

N ~ CH2-O

СН _Ъ ^oc * _f Va. ) 'PŽikLa.d. bH

Scheme II? X / KLa.d. 43 ccp

ch1 (Vir), pLklbd S1

O

CH) (XX)

N-COC.H _P * ₃

OC-CH 2 - (XX 1) -CH ₂ PiXkIDide Soi ™ CH-O

(XHr)

Compounds of Formula XII

where

R1 is --CH2 --CH.dbd.CH2,

_-СН Л -О I <0 wherein or a pharmaceutically acceptable salt · adlční acids are particularly preferred agon-istickými / antagonist agents · v · narcotics.

All of the compounds of the preferred composition disclosed herein are novel and valuable for their properties as analgesics and / or antagonists against narcotics, or as intermediates in the preparation. compounds having these biological activities.

The compounds of formula XII have very desirable properties, i.e. properties as analgesics and / or as narcotic antagonists. In addition, some of the compounds are generic. of formula XII also active against. cough, which property usually performs analgesic efficacy.

The most potent and most preferred compounds that can be prepared by the process of the invention are:. are compounds of formula (XII). wherein R ⁴ is 9 H -hydrogen. and OR 5 represents a 9α-alkoxy group. This is surprising. Whereas, in the corresponding series of compounds in which the OR5 represents an OH group, the most active and the most preferred compounds in the position usually bound. OH and in the 9a position, hydrogen or R 3 represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having up to 6 carbon atoms. carbon atoms,

R 4 represents hydrogen or an alkyl group having 1 to 6 carbon atoms and

R ⁵ represents an alkyl group having 1 to ⁵ carbon atoms. C 6 -C 6 alkyl or allyl, C 1 -C 6 alkyl. .

It is known in the art of narcotic analgesics that it is possible for certain compounds to possess both agonist and antagonist properties. An agonist is a compound that mimics narcotic analgesics and has analgesic properties. The antagonist is a compound that counteracts the analgesic and euphoric properties of the narcotic or analgesic. The same compound may have both properties. A good example of such a compound is cyclazocine.

The discovery of compounds having the right agonist to antagonist potency ratio is critical to commercial success. Compounds having too much antagonistic activity tend to produce undesirable psychotomimetic effects (hallucinations), making these compounds unsuitable for clinical use.

Various in vivo assays have been performed with the individual compounds prepared by the method of the invention (in the form of their soluble salts) to determine their agonist and / or antagonist properties. Table I shows the results of these descriptions. The numbers given in Table I refer to the number of milligrams of compound per 1 kg body weight, whose subcutaneous administration elicits an agonistic or antagonistic effect in 50% of the experimental mice and rats (ED 50).

Table I

ED 50 '(mg / kg) ⁵ )

Agonist efficacy of writhing induced by phenylchi. nonem ¹ ) Test mouse rat compound

dl-XIIa 0,087 0,034 1-XIIa 0,053 0,021 dl-XIIb 1,25 not tested dl-XIIc 2.18 not tested d1-XII-e 5.30 not tested d1-XII-d 0.33 not tested dl-XIIr 1,8 not tested dl-XIIv 0.19 not tested pentazocine 4.9 not tested nalorphine 0.77 not tested levallorfan 26.3 (weak reaction) not tested cyclazocine 0,047 not tested naloxone 40 not tested dl-XII-m 0,026 not tested dl-XIIn 0.200 not tested · dl-XIIt ~ 20 not tested ·

Antagonistic efficacy in the Straub test using oxymorphone2) oxymorphone-induced anesthesia3) on the analgesic effect of morpholine. · Rat tail flick ⁴ ) 0.24 0.04 0.06 0.10 0.017 0.019 0.16 ~ 0.017 0.011 1,25 not tested not tested oo0,63 not tested not tested 0.32 not tested 0,029 3.5 not tested not tested 7.5 not tested not tested 12.0 10.1 12.1 1.14 0.58 ‘0.38 0.29 0.32 0,086 ' 0.81 0.12 0.040 0.17 0.02 0.010 not tested not tested 0,046 not tested not tested 0,033 cc7 not tested 0.18

X) 50% reduction in writhing induced by phenylquinone [E. S. Siegmund et al., Proc. Soc. Biol. and Med. 95, p. 729, (1957)].

2) Oxymorphine-induced (2 mg / kg subcutaneously) induced tail response of the test animal in 50% of mice in the Straub test;

3) Antagonism · on -oxymorphone-induced flush reflex loss (1.5 mg / / kg subcutaneously) in 50% of rats,

4) 50% reduction in the analgesic effect of morphine (15 mg / kg subcutaneously) in the rat tail flick test [L. S, Harrls and A.

Pierson, K., Plianmacol, and Expt. Therap., 143, p. 141 (1964)],

5) All weights are converted to the free base.

From the results of the tests shown in Table I, it can be seen that the compounds produced by the process of the invention have potent agonist and antagonist activity. The range of normal parental doses of these compounds in an adult human is about 0.25-10 mg mg three to four times daily. Orally, the dose ranges from about 1 to 50 mg mg four times a day.

It has been reported in the literature that haloperidol, i.e. 4- [4- (p-chlorophenyl) -4-dihydroxypiperidinoyl-4'-fluorobutyrophenone (Mark Index 8th edition ^ p. 515) has been used experimentally to alleviate in several cases · Lung symptoms when taking narcotics. It is therefore an advantageous variation of the use of the compounds according to the invention to combine haloperidol with narcotic antagonists to obtain a method according to the invention to obtain compositions which not only prevent narcotic abuse but also simultaneously. enables successful opioid-free therapy.

Haloperidol is usually administered orally at a dose of 0.5 to 5.0 mg two to three times daily depending on the severity of the case. A dose of haloperidol in this range would be administered concurrently with a dose of the narcotic antagonist obtained by the method of the invention, which is suitable to produce the desired result.

Other means; described by the invention include the narcotic antagonist obtained by the method of the invention in combination with an anxiety agent such as. is, for example, chlordiazepoxide or diazepam, or with phenothiazine, such as chlorpromazine, promazine or methotrimeptrazine.

Compounds of formula XII 'are readily converted to compounds of formula L. Esters and ethers of compounds of formula XII may in some cases be particularly advantageous for increased solubility, reduced solubility, ease of crystallization, not because they have no unpleasant taste. etc., but these are all side advantages over the major physiological effect of free phenol, which does not depend on the nature of the residue used in the preparation. ester or ether.

Another preferred compound prepared by the process of the invention is the compound o-.

of the general formula L , XX . R * O f < ^RIT '1 and (L) where

R 1 represents one of the groups of formulas —CH 2 —CH = CH 2, -CH 3 T -O

R2 represents hydrogen or an alkyl group of 1 to 6 carbon atoms,

R 3 represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms,

R ⁴ represents an alkyl group. Having 1 to 6 carbon atoms or

R @ 5 represents an alkyl group having from 1 to 6. Or a pharmaceutically acceptable acid addition salt thereof.

More preferred is a compound of formula XXXX

where

R 1 represents one of the groups of formulas —CH2 — CH = CH2,

R2 represents hydrogen or an alkyl group having 1 to 6 carbon atoms,

R ³ represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms,

R 4 represents hydrogen · or an alkyl group having 1 to 6 carbon atoms and

R 5 represents an alkyl group having 1 to 6 carbon atoms or an alkyl group, or a pharmaceutically acceptable acid addition salt thereof.

Another preferred variant is a compound of formula XXXX, wherein R 1 is a group of formula —CH2-CH — CH2,

-сн ^ - <1 «« δ © -CH ^ - <Q>

R2 is hydrogen or methyl,

R3 is methyl, ethyl,. for-. a pollen or allyl group,

R 4 is hydrogen and

R 5 represents a methyl, ethyl, propyl or allyl group, or a pharmaceutically acceptable acid addition salt thereof.

Another preferred variation is a compound of general formula. XXXX, where 1

R1 is --CH2 --CH.dbd.CH2;

-CHt .--- <1 ⁿ ' ^b ° ^-CHfc -

R2 is hydrogen,

R3 represents a methyl group,

R 4 is hydrogen and

R 5 represents a methyl, ethyl, propyl, or allyl group, or a pharmaceutically acceptable acid addition salt thereof.

Yet another preferred variation is the compound of formula XXXX wherein

R 1 is a group of the formula ^{s /} - * ^{or c} H - CH = CN 1

II

R ² represents hydrogen or methyl.

R ³ represents a methyl group and

R ⁴ is hydrogen, or a pharmaceutically acceptable acid addition salt thereof.

The most preferred variations are:

A) (+) -2-cyclopropylmethyl-2'-hydroxy-9a-methoxy, 5-methyl-6,7-benzomorphane or an acid addition salt thereof,

(B) (-) -2-cyclopropylmethyl-2'-hydroxy-9a-methyl-5-methyl-6,7-benzomorphine or its hydrochloride, fumarate or tartrate,

C) (±) -2-cyclobutylime ^| thyl-2'-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphane or an acid addition salt thereof,

D) (-) -2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-5-methyl-6,7-beta-isomorphane or its hydrochloride, fumarate or tartrate,

E) (±) -2-allyl-2'-hydroxy-9'-methoxy-h-methyl-6,7-benzomorphane or an acid addition salt thereof,

F) (-) -2-allyl-2'-hydroxy-9a-methoxy-5-methyl-6,7-benzomorphane or its Oydrochloride, fumarate or tartrate,

G) (+) - 4-Cyclopropylmethyl-D 6 -ethoxy-2'-hydroxy-5-methyl-6,7-benzoforphan or a pharmaceutically acceptable acid addition salt thereof,

H) (-) -2-cyclopropylmethyl-9a'-2H-hydroxy-5-methyl-6,7-benzomorphane or is 10 hydrochloride, fumarate or tartrate,

(I) (±) -2-cyclopropyl-2-oxyl-4- (4-methoxy-5-allyl-6,7-benzofuran) or an acid addition salt thereof,

j) - (-) -2-cyclopropylmethyl-2H-hydroxy-9H-methooy-5-allyl-6,7-benzomorphane or its hydrochloride, fumarate or tartrate

K) (±) -2-cyclobutylmethyl-2H-Oydroxy-9H-methoxy-h-allyl-6,7-benzomorphane or an acid addition salt thereof,

L) (-) - 2-cyklobuitylmetOyl ^{Oydroxy-2'-methyl-9a-d} tOoxy-5-allyl-6,7-benzomorphan and its hydrochloride, fumarate or tartrate,

M) (±) -2-Cyclopropyl-thyl-2'-hydroxy-9'-methoxy-5-propyl-6,7-benzomorphane or its acid addition salt,

N) (-) -2-cyclopropylmethyl-2'-hydroxy-4-oxonyloxy-5-propyl-1-beoromorphane, or - its hydrochloride, fumarate or tartrate,

O) -O-2-yl-but-butyl-2'-hydroxy-9a-methoxy-h-propyl-6,7-benzomorphane or an acid addition salt thereof,

P) (E-Z-cyclobutylmethyl) -hydroxy-9a, 9H, 9H, 11H, 11H (5H-5-propyl-6,7-benzomorphane or its hydrochloride, fumarate or tartrate),

Q) (-) -h-allyl-2-cyclobutylmethyl-2'-hydroxy-9, α-methoxy-9β-methyl-6,7-benzomorphane or its hydrochloride, tartrate or fumarate,

R) (-) ^{2-cyclobutylmethyl-2-hydroxy-9a-9-metOoxy} $ -metOyl HN-propyl-6,7-benzomorphan or- its hydrochloride, tartrate or - ,, fumarate

S) (- - 5-allyl-2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-QS - ((1 - 6) - (1-6) - (b) isomorphane or -) OydrocOloride, tartrate or fumarate,

T) (-) - 2-Cycloprop-p-methyl-2'-hydroxy-9'-N-methoxy-9'-methyl-h-n-propyl-56,7-benzomorphane or its hydrochloride, tartrate or fumarate.

Another preferred variation is the compound of formula XXXXI.

where

R 1 represents a group of the formula —ch2 —ch = ch2 -,

- <*, .— 0 ^nib ° ^-CH <- <Q>

R2 is hydrogen or (C1-C6) alkyl;

R 3 represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms,

R ⁴ is hydrogen or alkyl of 1 to 6 carbon atoms and

Rh represents an alkyl group having 1 to 6 carbon atoms or an allyl group, or a pharmaceutically acceptable acid addition salt thereof.

A more preferred variation is a compound of formula - XXXXI, - wherein R 1 is a group of formula --CH 2 --CH = CH 2,

-CH— <Н'Ь'-СЦ, '- <Q>

R2 is hydrogen,

R 3 represents a methyl, ethyl, propyl or allyl group, or

R 4 is hydrogen and

R 5 - represents a methyl, ethyl, propyl or allyl group or a pharmaceutically acceptable acid addition salt thereof;

199586 15 18 nou. Other · the general formula XLI, wherein the variation is more preferred compound R1 is a group of formula CH = -CHCH _from .mbo-ζ ^ -C j

R ² represents hydrogen or a methyl group, ·,

R? represents a methyl group,

R 4 is hydrogen and

R 5 represents a methyl, ethyl, propyl, or allyl group, or a pharmaceutically acceptable acid addition salt thereof.

Another more preferred variation is a compound of formula XXXXI wherein.

R ¹ represents a group of the formula

-CH ^g —0 »-CWj— <2> ^ Ьо-СН-СН = СН _л

R ² represents hydrogen or methyl, ·,

R ³ represents a methyl group,

R 4 is hydrogen and

R ⁵ represents a methyl group, or a pharmaceutically acceptable acid addition salt thereof.

The most advantageous variations are:

A) (+) -5-allyl-2-cyclobutylmethyl-2H-hydroxy-9H-methoxy-6,7-benzomorphane or a pharmaceutically acceptable acid addition salt thereof,

B) (-) -5-Jallyl-2- [3- (4-methyl-2'-hydroxy-2-methoxy-6,7-benzo) -morphane; its hydrochloride, fumarate or tartrate,

C) (+) -5-allyl-2-cyclobutyl-2'-hydroxy-9'-methoxy-or-methyl-6,7-berole ^: zonofuran or a pharmaceutically acceptable acid addition salt thereof,

DJ (-) -5-allyl-2-cylobutylmethyl-2‘-hydroxy-N-hydroxy-9α-methyl-6 ', 7-benzomorphane or its hydrochloride, fumarate or tartrate.

Accordingly, the present invention provides a process for the preparation of 6,7-benzomorphanes derivatives of formula (L)

R2 represents hydrogen or an alkyl group having 1 to 6 carbon atoms,

R3 represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms,

R 4 is hydrogen or C 1 -C 6 alkyl;

R 5 is a fused alkyl group. C 1 -C 6; allyl, or a pharmaceutically acceptable acid addition salt thereof or a racemic mixture thereof, or. their optical isomers, which method is characterized by:. the compound of formula (VII):

where where

R represents a protecting group. Hydroxyl groups, preferably an alkyl group having 1 to 6 carbon atoms,. and

R3 and ^R4 are as defined above, is to establish the protecting group on the ring nitrogen atom · react with a compound of formula ..

R ¹ represents a group of the formula

Х-ОО-ф хсо- <Э .-. '~ * CO-CF _t X-CO-OR' (b) the thus protected compound with pUbi alkali metal hydride, preferably sodium hydride, and the resulting compound was then. alkylated to prepare a compound of formula VII *.

where

X stands for. chlorine, bromine or iodine; and

R 10 represents an alkyl group having 1 to 6 carbon atoms, optionally with a compound of formula X-CN, wherein X is as defined above,

where

R, R ³ , R ⁴ and R 5 are as defined above, t (c) and optionally, when the electron-withdrawing protecting group attached to the ring nitrogen atom is a group of the formula —CO — O — R ¹⁰ , —CO— CF 3 or —CN where

R ¹⁰ has the abovementioned meaning, this protecting group is removed by methods known per se, - in the resulting compounds of general formula VII 'wherein R 3, R 4 -A R ⁵ have the abovementioned meanings, is acylated or alkylated NH group, whereby to give a compound of the formula

where

R, R 3, R 4 - and R 5 are as defined above and

R ⁸ represents a group of the formula

--CO - <, - (-) - CH = CH3 (d) and - represents a R ⁶ radical containing a carbonyl group, this carbonyl group is reduced to the methylene group by treatment with a reducing agent, preferably lithium aluminum hydride, to obtain the compound of formula XI

рЗ (XI) where.

R, R1, - - ^R2, R3, R4 and R5 have the above · - defined, followed by (e) the trade - R hydroxyl SKU pins cleaved - known methods, to yield a compound of Formula L, wherein R2 is - hydrogen - and R1, R3, R4 and R5 are as defined above, (f) optionally converting the hydroxyl group at the -2 'position to the -OR2 group, wherein R2 is an alkyl group having from 1 to 6 atoms (g) - if the compound of formula (L) is a racemic mixture, it is optionally resolved into its optical isomers, (h) if the acid addition salt of the compound of formula (L) is to be prepared, reacting with a pharmaceutically acceptable acid.

In step (a), a compound of formula (VII), wherein R, R3 and R4 are as defined above, is reacted to a nitrogen atom of the ring with a compound of formula to attach a protecting group, an electron withdrawing group,

X-O- ^O , X-COX-CO-CF 3, and X-CO-OR ⁴⁰ , wherein

X is chlorine, bromine or iodine;

R 10 represents a C 1 -C 6 alkyl group, optionally with a compound of formula X-CN, wherein X is as defined above, or with a functional equivalent thereof such as anhydride and the like. The reaction is preferably carried out in a solvent inert to reactants such as benzene, xylene, chloroform, methylene chloride, ether, etc., optionally with heating.

In step (b), the nitrogen-protected compound in the ring is preferably treated with an alkali metal hydride, preferably sodium hydride, in a molar ratio of 1 to 1.1 moles of base per mole of nitrogen-protected compound, in an inert solvent. against reactants such as dimethylform 19

1995 amide, dimethylacetamide, tetrahydrofuran, hexamethylphosphoramide, benzene, toluene, diethyl ether and the like, followed by addition of an excess of lower dialkyl sulfate, lower alkyl tosylate, lower alkyl halide or allyl halide, wherein the halogen is bromine, chlorine or iodine, but preferably methyl iodide. to obtain the —OR ⁵ group at the 9-position wherein R ⁵ represents an alkyl group having from 1 to 6 carbon atoms or an allyl group, or - alternatively, an excess of the nitrogen-protected compound in kiruh is treated with an excess lower diazoalkane or lower trialkoxonium fluorobo. %, preferably with an excess of palzomethane, to give the -OR 5 group in the -9 position, wherein - - R ⁵ represents an alkyl group having 1 to - 6 - carbon atoms. .

In step (c), the nitrogen protecting group in the rings, if other than desired, is removed by methods known per se. For example, when the protecting group is an alkoxycarbonyl- or trifluoroacetyl group, the compound is preferably hydrolyzed with a strong alkali metal base, preferably potassium hydroxide, in a lower alkanol, preferably at 95 percent. ethanol, to give the - liberated - secondary -amine forming part of the ring. - As a cyano protecting group, the compound is preferably treated with lithium aluminum hydride in tetrahydrofuran - while heating under reflux, - whereupon - The mixture is treated with water and sodium hydroxide to give the liberated secondary amine.

After removal of the nitrogen protecting group in the ring, the secondary amine compound is acylated, preferably by an acid halide, an anhydride, or a mixed anhydride, a compound of the group consisting of compounds of the formulas

O O

A HO - C - in an organic solvent, inert to reagents such as methylene chloride, chloroform, diethyl ether and the like, optionally with heating in the presence of a tertiary amine; or the secondary amine is preferably alkylated with a compound of the formula

X — CH2 —CH = CH2, where,

X is chlorine, bromine or iodine, in an organic solvent, inert to the reactants, preferably in a lower alkanol, to give a compound of formula X.

In step - (d), if R ⁸ contains a carbonyl group residue, this carbonyl group is preferably reduced in the methylene group by treatment with lithium aluminum hydride in an organic solvent inert to the reactants such as diethyl ether , tetrahydrofuran, dioxane, and the like, preferably with heating to give a compound of formula XI.

In step (e) - - the protecting group - of the hydroxyl group - is cleaved from the compound of the general formula XI by methods known per se. However, when R is a C 1 -C 6 alkyl group, R is preferably cleaved off selectively by treating the compound of formula XI with sodium thioethoxide, boron tribromide, hydrochloride. pyridine or hydrobromic acid in a suitable solvent according to a known method. In particular, the - protecting group R of the hydroxyl group is cleaved by reaction of thioethoxy nitrogen in - dimethylformamide, whereby a compound of the formula L in which R ² is hydrogen is obtained. If the R is acyl or alkanoyl, R is preferably removed by hydrolysis.

In step (f), the - hydroxy group of the compound of formula - L, bound - in the 2-position, is preferably esterified - or etherified by conventional methods. If the - 2‘-hydroxyl - group is to be esterified, - it is converted to a compound of formula L, wherein R 2 is hydrogen, preferably with an equimolar amount of an acid halide, e.g.

4-carboxylic acid, in the presence of a tertiary amine such as poridine, to give the desired 2'-ester of the compound of formula L.

If the hydroxyl group is to be etherified in the 2-position, it acts on. - a compound of the general formula - L, wherein R 2 is hydrogen, preferably - an equitollar amount of - sodium hydride in - anhydrous dimethylformamide; Adds. - an equimolar amount of a suitable halide, for example chloromethyl methyl ether, followed by the addition of an excess of sodium carbonate, to give the desired - 2‘-ester of the compound of formula L.

In step (hj), the acid addition salt of the compound of formula L is preferably prepared in a manner similar to that described in Examples 67 and 76.

The compounds obtained by the process according to the invention and some of their intermediates are present in the form of optical isoimers, for example - levorotatory, - dextrorotatory and racemic mixtures. These compounds are represented by formulas L, XXXX, XXXXI, V, VI, VII. - IX, X, XI and XII. It should be noted that these intermediates and the resulting products can be cleaved as described in optional step (g) at any time during the process of the invention or the compounds of formula (L) can be cleaved. cleavage - at the end of the process according to the invention by conventional methods. When the levorotatory form of the compound (VII) starts at the beginning of the process according to the invention, a levorotatory compound of the formula (L) is formed as described above.

The invention also provides a novel process for preparing a compound of formula

where

R is a hydroxyl protecting group, preferably a C 1 -C 6 alkyl group, in particular a methyl group,

R ³ represents an alkyl group having 1 to 6 carbon atoms or an alkenyl group having 2 to 6 carbon atoms,

R 4 is hydrogen or C 1 -C 6 alkyl;

R ⁵ represents an alkyl group having 1 to 6 carbon atoms or an allyl group, or an acid addition salt thereof, characterized in that (a) a compound of formula VII

R * (VID where

R, R 3 and R ⁴ are as defined above, reacted to attach an electron-withdrawing protecting group and · prevent the amine compound from quaternizing, · a ring nitrogen atom, (b) treating the protected compound obtained with a strong base, preferably an alkali hydride metal, whereupon the compound obtained is alkylated to give the corresponding compound substituted at the 9-position with -OR 5, wherein R, R 3, R ⁴ and R 5 are as defined above, or the protected compound is treated with a lower diazoalkane or a lower diazoalkane trialkyloxonium fluoroborate. for the alkylation of the OH group at the 9-position, and (c) the electron withdrawing protecting group is removed by known methods to give said compound of the formula

Example · 1

3,4-dihydro-7-methoxy-1-methyl-2 (1H) naphthalenone (IIa)

40.5 g (0.5 mol) of pyrrolidine dissolved in 50 ml of benzene are added to a solution of 50 g (0.284 mol) of 3,4-dihydro-7 under stirring under nitrogen atmosphere over 5-10 minutes. of 2-1H-naphthalenone of formula I in 200 µl of anhydrous benzene. The mixture was heated at reflux for 1 hour and 5 ml of water was collected with a Dean-St-apparatus. The mixture was cooled and slowly added to a solution of 0.5 moles of methyl iodide in 300 ml of benzene. The resulting mixture was heated at reflux for 3 hours, 200 ml of water were added and heating was continued.

After 30 minutes the reaction mixture was cooled, the benzene layer was separated, washed with water saturated with sodium sulfite, dried, and evaporated to dryness. The residue obtained is distilled to give the title 3,4-dihydro-7-methoxy-1-methyl-2 (1H) naphthalenone of the formula IIa. ·. Infrared and · nuclear magnetic · resonance spectra (IR), (NMR) correspond to the above structure.

Example 2

1 - <(b-Benzyl- ¹ -methylaminoethyl) -7-imethoxy-1-methyl-3,4-dihydro-3 (1H) naphthalenone hydroxalate · (IIIa)

To a suspension of 0.14 mol of sodium hydride in 100 ml of benzene heated under reflux. solution of 7-methoxy-1-methyl-3,4-dihydro-2 (1H) -naphthalenone (IIa) in 40 ml of benzene was added. The mixture was heated at reflux for 1 hour, then a solution of 0.12 was added. mole of 2-benzylmethylaminoethyl chloride in 100 ml of benzene and refluxing is continued for an additional 18 hours. The reaction mixture was washed with water and extracted with dilute hydrochloric acid. By neutralizing the acidic extract with ammonium hydroxide and extracting with ether, an oil is obtained which is converted to the oxalate of formula IIIa with a melting point of - 137 - -139 ° C. . Yield: 78%.

For C 22 H 22 NO 2. . C2H2O4 calculated:

67.43% C, 6.8.4% H, 3.28 «/ o N found:

% C, 67.25;% H, 7.05;% N, 3.50%

2-Benzyl-2‘-methoxy-5-methyl-9-oxo-6,7-benzomorran-methyl bromide (IVa)

Compound. of formula IIIa is converted to the hydrobromide by reaction with sodium hydroxide solution, isolating. extraction with ether and subsequent reaction with hydrogen bromide. Dissolve -0.21 mol of hydrobromide in 450 ml of acetic acid and. the solution is slowly added to the solution obtained. 11.2 ml of bromine in 50 ml of acid. and the resulting mixture was stirred for míchá30 minutes. Add 2 liters of "Skellysolve B" (essentially n-hexane) diluent and cool the mixture under a nitrogen atmosphere. The &quot; glass-solvate &quot; layer is poured off - from - a gummy precipitate. This residue is partitioned between ether and water. The resulting two-phase system is basified with concentrated ammonium hydroxide. The two layers were immediately separated and the aqueous layer was extracted with ether. Concentration of the ether extracts yielded an oil which was taken up in acetone and stirred for several hours to give the title compound (IVa) as a crystalline solid. Yield: 76%.

of the formula - Va '- o - melting point - 145 to - 149 ° C - in a yield of - 92 -%. This compound is known [E. L. May and co. J. - Org. Chem. 25, p. 1386 (1966)] This synthesis is an improved method for preparing these compounds.

2,5-Dimethyl-9-hydroxyhydroxy-2'-methoxy-6,7-benzomorphane (Via)

0.02 moles of 2,5-diimethyl-2'-methoxy-9-oxo-6,7-benzoimcopane of formula (V) ¹ and 8 g of cobalt chloride hexahydrate are dissolved in 100 ml of 05% ethanol with slight heating; the solution was heated at room temperature for half an hour. 4 g of sodium borohydride are then added portionwise under stirring in a nitrogen atmosphere. The resulting dark mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. Carefully add 75 ml of 6 N hydrochloric acid and remove the ethanol under reduced pressure. The resulting blue solution was basified with concentrated ammonium hydroxide and extracted with methylene chloride. Drying and concentration of the extracts gave 4.9 g of a crystalline solid; according to chromatographic (gas-liquid) analysis - contains - the crystalline substance obtained. 88-% of the .alpha.-hydroxyisomer and 9% of the .alpha.-hydroxyisomer. Recrystallization from ethyl acetate-Skellysolv B (essentially n-hexane) affords the pure α-isomer of formula (VIb), mp 115-116.5 ° C (lit. 2), melting point 115, 5-117 ° C).

¹ J. - G. Muphy, - JH Ager and EL May, J. Org. -Chem., 25, p. 3386 (1960),

H - Kugita and E - - L. 'May' J - 'Org. Ghern.- - ^; 2β

1954- (1961). Example 6 c / ^ o 1 t <'OH - СН _Ь (Vild.)

9α-Liydroxy-2‘-methoxyethoxylate. - (Fairy)

0.014 mole of the compound of formula (VIa) at-steam temperature is acetylated for 2 hours using 50 ml of acetic anhydride to give the 9α-aetoxyl derivative.

This compound is dissolved in -75 ml of benzene and treated with 2 g of carbon monoxide.

2,5-Dimethyl-2‘-methoxy-9-oxo-6,7-benzornorphan (Va)

Reduction of the compound of formula IVa in acetic acid with hydrogen using activated charcoal containing 10% palladium as catalyst affords the above-mentioned potassium lithium compound and 5 ml of ethyl chloroformate with heating at reflux for 18 hours. The resulting mixture was washed with water, dilute hydrochloric acid and saturated sodium chloride solution. The aqueous layers were extracted twice with benzene. The benzene layers were dried with potassium carbonate and concentrated to give 9α-acetoxy-2-carbethoxy-2‘-methoxy-5-methyl-6,7-benzomorphane. This material is hydrolyzed with potassium hydroxide (25 g, 85% pellet) in refluxing 125 ml of 95% ethanol for 66 hours. The ethanol was removed under reduced pressure. Dilute sodium bicarbonate is added to the residue and the mixture is extracted with methylene chloride to give the title compound of Formula VIIa which is converted to the hydrooxalate in 95% ethanol. Mp 212-215 ° C, yield 89%.

For C14H19NO2C2H2O4 calculated:

% C, 59.43;% H, 6.55;% N, 4.33.

% H, 6.31;% N, 4.44

Example 7

2-Cyclopropylmethyl-2 ', 9' - (1 ', 3'-ethyl) -cyclohexan-6,7-benzomorphane hydrochloride of formula (IIa)

0.015 moles of free base of the compound of formula Fairy in 50 mil. . methylene chloride; and. ml of triethylamine was treated with 2.3 ml of cyclopropylcarbonyl chloride under a nitrogen atmosphere. The reaction mixture is stirred for 1 hour, 7 ml of methanol are added, stirring is continued for 5 minutes and the mixture is evaporated to dryness. The residue was dissolved in toluene and washed with dilute hydrochloric acid, water and saturated sodium carbonate solution. After drying and evaporation of the toluene extracts afforded 2-cyclopropylcarbonyl-2'rmetlhoxyr9 _L (5-aíhydrooy methylr -6,7-benzomorphan · IXa výllěžku about 100% with a purity higher than 98% according to gas chromatographic analysis, · · (gaseous A solution of the compound of formula 1Xa in 25 ml of dimethylformamide is added to a suspension of 0.015 mol of sodium hydride in 10 ml of dimethylformamide under a nitrogen atmosphere, after 1 hour 1 ml of methyl iodide and 1 hour of methyl iodide are added. · stirred 16 hours. after removing the solvent under reduced pressure, to the residue water was added and the mixture extracted with methylene chloride · to give in almost 100% yield of 2-cyklopropylkabbonyl-2 * 9 ^«| -dimeCh'O'xy 5 -methyl-6,7-benzomorphane of formula Xa having a purity greater than 98% by gas-liquid chromatographic analysis This compound is reduced for 16 hours with lithium aluminum hydride · LiAlH4 in tetrahydrofuran The title compound is isolated in 85% yield (1.4 g) as crystalline hydrochloride, m.p. 230-233 ° C.

For C19H: 2NOb. HCl calculated:

67.54% C, 8.35 ·% H, 4.15% N y% Д 1 'УО'П Λ ·

⁶⁷ 58% 8.46% H ^4, 36% N

Example 8

: och, fXDaJ

2-cykloρropy lmethylr2'rhyd · _1-Hydroxy-9 ares rmethoxyr5 methylr6,7-benzomorphan (XIIIa)

A mixture of 0.0028 mole of the compound of formula XIa and 0.05 mole of sodium thiothoxide (prepared from sodium hydride and methylmercaplan) in 80 ml of dimethylformamide is heated at reflux for 3 hours. The solvent was removed under reduced pressure. Toluene was added to the residue and the mixture was extracted with dilute hydrochloric acid. The acidic etaract is basified with sodium carbonate and extracted with methylene chloride to give a compound of formula XHa which, upon recrystallization from acttonitrile, melts at 188-189 ° C.

For C 18 H 25 NO 2 calculated:

75.22% C, 8.77% H, 4.87% · N found:

H, 8.85; N, 5.18

199588

S-dimethyl-aa-hydroxy-6-methoxy-6,7-benzomorphane fumarate of formula (VII b)

To a mixture of 9α-eyedroxy-2'-methoxy-2,5,9,11-tr-methyl-6,7-benzo-morphane (0.032 ') [compound prepared and described by Mat' et al. in J. magazine. Org. Chem. 28 p. 188 (1961)] and 26 g of potassium carbonate in 150 ml of benzene heated under reflux. with a condenser, a solution of 0.095 mol of trichloromethyl celloformate in 100 is added. ml benzene. After heating at reflux temperature for 60 hours, 200 ml of water was added to the reaction mixture, and the mixture was stirred for half an hour. The benzene layer is separated, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. evaporated to give crude 2-tri-chlorkarbeehoxy · 5Дó' myr-di ^ ^ι HTL-9α-hydroxy-methoxy-J-beinzoimorfan. This compound was dissolved in 100 ml of acetic acid and, over a half hour, the solution was added under a nitrogen atmosphere to a suspension of 40 grams of zinc in 100 ml of acetic acid. Upon completion of the addition, additional zinc (20 grams) was added and stirring was continued for 1 hour. The zinc was then filtered off and the filtrate was evaporated. Ke. Dilute ammonium hydroxide was added to the residue and the mixture was extracted several times with chloroform to give the compound of formula VHb, which was converted to the fumarate by reaction with 3.9 g of fumaric acid in napropanol. The melting point of the resulting salt is greater than 250 ° C.

For C15H21NO2.1 / 2 C4H4O4 calculated:

% C, 66.86;% H, 7.59;% N, 4.59

Π9.1ΦΖ6 Ho *

H, 7.83; N, 4.66

Example 10

2-Cyclypylcarbonyl-5,9-di-methyl-9α'-hydroxy-2'-meteoxy-6,7-byn67-moranate (IXb)

To a solution of 0.012 mole of free base of the compound of formula VHb in 30 ml of methylene chloride and 4 ml of triethylamine was added a solution of 0.02 mole of cycl7 ^: propylpentylcarbonyl chloride in 20 ml of mythyl chloride. The mixture was stirred at room temperature for several hours and then washed with dilute hydrochloric acid, water and dilute sodium carbonate solution. After drying over magnesium sulfate and evaporating the organic extracts, the title compound of formula IXb is obtained, which is recrystallized from 95% ethanol.

Example 11

2-Cyclopropylmethyl-2 ', 9a-dimethyloxy-5,9 _] -N-dimethyl-6,7-benzyl fumarate. morphane (Xlb)

760 mg of a 60% dispersion of sodium hydroxide in mineral oil are added to a solution of 0.00635 mole of the compound of formula IXb in 30 ml of dimethyl amine amide under stirring under a nitrogen atmosphere. 1 ml of MeOH was added over half an hour. and stirring is continued. An additional 1 ml of meteyl iodide is added after 1 hour and the stirring is continued for 18 hours. A few drops of acetic acid and dimethylene chloride were then added dropwise, and the mamide was removed under reduced pressure. Water was added to the residue and the mixture was extracted with methylene chloride for 9 min to give 2-cyclopropylcarbonyl-2 ', 9a-dimethoxy-5,9f-diyl-6,7-by-morphane of formula Xb contaminated with mineral oil. The mineral oil is removed by treatment with n-pentane and extraction with acetonitrile to give a compound of formula Xb of 96% purity as determined by gas-liquid chromatography. The compound of formula Xb is reduced for 18 hours. 720 mg of LiAlH4 lithium aluminum hydride in 40 ml of thi-aldrofuran afforded the compound of formula XIb which formed a crystalline hydrofumarate, m.p. 154-155 ° C (2.1 g, 78% yield).

For C 20 H 23 NO 2. H, 7.71; N, 3.25.

66.54% 66.44% C, 7.86, 8.00% H, 3.73, 3.43% N

Example 12

2-Cyclopropylmethyl-5,93-dimethyl-2H-hydroxy-9α-4-methoxy-6,7-benzomorphane fumarate (XHb)

By replacing the compound of formula (XIa) used in Example 8 with an equimolar amount of the compounds of formula (XIb), the title compound is obtained. XHb as the hydrofumarate, m.p. 191-194 ° C.

For C19H: 2N02. C4H4O4 calculated: 66.16% C, 7.48% H, 3.36% N π31'6Ζ6ήό *

H, 7.76; N, 3.01; H, 0.35%

Example 13.

2-Cyclobutyl-methyl-2 H, 4 H -dimethoxy-N, N -dimethyl-BJ-benzomorphane fumarate (Xlc)

A) Replacing 'cyclopropenylcarbonyl chloride used in Example 10 with an equimolar amount of α-cyclobutylcarbonyl chloride' gave 2-cyclobutylcarbonyl-5,9 H -dimethyl-9α-hydroxy-2-methyl-7 ', 7-benzomorphane of formula' IXc.

Β) Replacing the compound of formula (IXb) used in Example 11 with an equimolar amount of the compound of formula (IXc) affords the title compound of formula (XIc) as a 3/2 fumarate, m.p. Celsius.

For C21H35NO2.3 / 2 (JC4H4O4) calculated:

% H, 7.41;% N, 2.78

Β β1 Q7Q Y rt ·

· 64.24% C, ⁷ to 70% H 2 · ^61% · N

Example 1.4

2-Cyclobutylmethyl-5,93-dimethyl-2‘-hydroxy-9α'-methoxy-6,7-benzomorphane fumarate (XIIc)

Replacing the compound of formula XIa used in the procedure of the example. 8, an equimolar amount of the compound of formula XIII yields the title compound of formula XIIc, which is isolated as the hydrobromide, m.p. 223-226 ° C.

For Ca0H5NO2. HBr calculated:

60.60% C, 7.63 O / o H, 3.53% N found:

% H, 7.54;% N, 3.54

The hydrobromide or hydrochloride is prepared by dissolving the amine in a minimum amount of anhydrous ethanol and slowly adding to the solution an anhydrous ethanolic solution of hydrogen bromide or hydrogen chloride, previously prepared by introducing gaseous hydrogen bromide or hydrogen chloride into ethanol. The salt is precipitated by slowly adding diethyl ether by scraping the vessel walls. After filtration, the salt is purified by recrystallization.

Example 15

Cleavage of (+,) -2,5-dimethyl-2‘-methoxy-9-oxo-6,7-benzomorphane (Va) in optical antipodes

A) (+) - tartaric acid (-)) - 2,5-dimethyl-2'-methoxoy-9-oxo-6,7-benzomorphane

A mixture of 0.072 mol of the racemate of the compound of formula (V) and 0.072 mol of · (-) - tartaric acid is dissolved in 150 ml of water and 30 ml of 95% ethanol, filtered, concentrated to 150 ml and allowed to crystallize at 0 to Low: 14 ° C. The crystals formed are collected by filtration, washed with 95% ethanol and recrystallized from 50% aqueous ethanol to give 10.1 g (66% yield) of (+) - tartaric acid tartrate (+) - 2.5 Dimethyl-2'-methoxy-9-oxo-6,7-benzomorphane.

For C15H11NO2. C4H6D6. 2 H 2 O calculated;

% H, 6.78;% N, 3.25;% H2O

ΠΟίθΖΘΙΙΟ *

% C, 52.89;% H, 7.07; % N, 8.94% H2O

The free base is isolated by dissolving the tartrate in water and basifying with sodium carbonate. The mixture is extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered, and dried to dryness under reduced pressure. The free base rotation is |>] D12 - ββ, 5Ρ (c = 1,038, 95% ethanol).

B) (- J-tartaric acid - (-) -2,5-dimethyl-2 methoxy-methoxy-9-oxo-6,7-benzcmiorphan)

The first mother liquor of the (+) isomers in (A) above is basified with sodium carbonate and extracted with methylene chloride to give 10.3 g of an oil. To this oil is added 6.5 g of (-) tartaric acid and the mixture is dissolved in 100 ml of water and 30 ml of hot 95% ethanol, then filtered, concentrated to a volume of approx. 100 ml and cooled to 0-5 ° C for crystallization. The crystals are filtered off and recrystallized from 10 ml of 50% aqueous ethanol to give 10.6 g (yield · 68%) of (-) - tartrate (-) -2,5-dimethyl-2'-methoxy-9. -oxo-6,7-benzomorphane, m.p. 157.5-158.5 ° C, [α] D ²² = -48.50 ° (c = 1.047, water).

For C15H11NO2. C4H6O6.2 H2O 'calculated:

C 52.89% C, 6.78% H, 3.25% N, 8.35% H2O found:

% C, 52.17%; H, 6.99%; 3.00% N; 9.10% H2O

The free principle is isolated as described in paragraph (A) above. The rotation [α] _d 22 is -85.5 ° (c = 1.054, 95% · ethanol).

EXAMPLE 16 (-) -2,5-Dimethyl-9a-hydroxy-2H-methoxy-6,7-benzo-morphane.

The 0.0765 imol of (-) -2,5-dimethyl-2'- _1- methoxy-9-oxo-6,7-benzofuran (free base) was hydrogenated in a Parr shaker. In 250 ml of 95% ethanol using 150 · mg of platinum oxide as catalyst. · The theoretical amount of hydrogen is absorbed for 1.5 hours. The catalyst is filtered off and the filtrate is evaporated to dryness to give a crystalline residue which is recrystallized from toluene. This gives 18.2 g of pure title product of m.p. 146.5-148 ° C. Yield = -96%. [ _.alpha. ] _D @ ²¹ = -56.5 DEG (c = 1.022, 95% ethanol).

For C15H21NO2 calculated:

% C, 72.84;% H, 8.56;% N, 5.66.

H, 8.62; N, 5.66

Example 17 (-) - Ba-Hydroxy12-dimethoxy-5'-methyl-6,7-benzomorphan [(-) - Villa]

To the 'mixture' of the 0 · 033 moles of the (-) isomers of the compound of formula VIa. and 16.5 g of potassium carbonate in 160 ml of toluene are added, with stirring, 16.5 ml of trichloroethyl chloroformate. The reaction mixture was refluxed under nitrogen for 18 hours. After cooling, 100 ml of water are added to the mixture and the resulting layers are separated. The aqueous layer was extracted again with toluene. The combined toluene extracts were washed with saturated sodium chloride solution, dried over potassium carbonate and evaporated. The residue is dissolved in a mixture of 120 ml of methanol and 12 ml of water, the solution is cooled, and 12 g of potassium hydroxide are added thereto, followed by stirring for 45 minutes at 0-5 ° C. 12 ml of acetic acid are then added and the solution is evaporated. The residue was dissolved in dilute hydrochloric acid and extracted with toluene to give (-) - trichlorocarbothioxy-9α-hydroxymethyl-methoxy-5-methyl-6,7-benzomorphane. This was dissolved in 100 ml of acetic acid and the solution was slowly added to a warm suspension of 15 g of zinc powder in 50 ml of acetic acid under a nitrogen atmosphere. Once the reaction has ceased, the mixture is heated at reflux for half an hour. The zinc was filtered off under a nitrogen atmosphere and the filtrate was evaporated. The residue was dissolved in dilute ammonium hydroxide and the solution was extracted with chloroform to give 8 g (100% yield) of the - (-) - isomers of the compound of formula (VIIa). - the purity of the material obtained is 97%, which forms crystalline hydrochloride at a melting point above 250 DEG C. [ _.alpha .] _D @ 21 = -29.6 DEG (c = 1.015, 95% · ethanol). '

For C 14 H 11 NO 2. HCl calculated:

% C, 62.33;% H, 7.47;% N, 5.19

% H, 7.22;% N, 5.56

EXAMPLE 18 (-) 12-Cyclohexylmethyl-2,9,9-trifluoromethoxy-15-methyl-6,7-benzomorphane [(()) Xla]

Substitution of the compound of formula VIIa, used in Example 7, with an equimolar amount of (-) isomers of the compound of formula VIIa, gives the title compound of formula (-) XIa in 92% yield after purification by chromatography on alumina ( elution with a mixture of benzene and ether). Instead of methylene chloride, toluene is used in the first reaction step. Upon recrystallization, the product is obtained as the oxalate, m.p. 185.5-186.5 ° C. Celsius. [ _.alpha. ] _D @ 20 = -48.9 DEG (c = 0.966, 95% ethanol).

For C19H »N0ž. C2H2O4 calculated:

% C, 64.43;% H, 7.47;% N, 3.58.

H, 7.31; N, 3.70

EXAMPLE 1 a d 19 (-) - 2- ^{(cyclopropylmethyl-2'-hydroxy-9-hydroxy-o!} I-Methoxy-5-methyli6,7 be6zomorfan [:( -) XIIa]

Replacing compound XIa used in Example 8 with an equimolar amount of the (-) isomer-compound of formula XIa affords the title compound, m.p. 180-180.5 ° C.

For - C15H25NO2 calculated:

75.22 -% - C, 8.77% - H, - 4.87% N found:

75.62% C, 8.50-% H, 4.69% -N (-) isomer - compounds of formula XIIa - form crystalline fumarate - o - melting point - 179-180 ° C. [.Alpha.] D @ ²⁰ = -57.4 DEG (c = -1.011, 95% ethanol). .......

For C18H2NO2.1 / 2 - (C4H4O4) calculated:

69.54% C, 7.88 -% H, 4.06%

69.70% C - 7.07% H- 3.78% N

EXAMPLE 20 (-) -2-Cyclopropylmethyl-2'-hydroxy-19'-4-methoxy-5-methyl-11,7-benzomorpholin [&lt; + &gt;

199386

By successively replacing the levorotatory isomer used in the procedures of Examples 16-19 with an equimolar amount of the dextrorotatory isomer of the compound of Formula VIa, the title product of formula (+) XIIa is obtained. The melting point of his tartrate is 147-148 ° C. [ _.alpha. ] _D @ 20 = + 37.3 DEG (c = 1.002, 95% ethanol).

ΡΓΟ (C 18 H 25 NO 2) 2. C4H6O6.1 / 2 H2O calculated:

% C, 64.67;% H, 7.87;% N, 3.77.

2.42% 1203 found:

% C, 65.14;% H, 7.68;

3.14% H2O

Example 21

2-Cyclopropylmethyl-9α-ethoxy-2‘-methoxy-5-methyl-6,7-benzomorphane (Xld)

Substitution of the methyl iodide used in Example 7 with an equimolar amount of ethyl iodide affords the title compound of Formula Xld, which is isolated as the hydrochloride, m.p. 236-240 ° C. The yield was 83%.

For C20IH2NO2. HCl calculated:

68.216% C, 8.59% H, 3.98 '% N found:

% C, 68.65;% H, 8.56;% N, 4.13

Example 22

2-Cyclopropylimethyl-9i (: α-ethoxy-2‘-hydroxy-5-methyl-6,7-benzomorphane (XIII))

Replacing the compound of formula XIa used in Example 8 with an equimolar amount of compound Xld provides the title compound which is isolated in the form of the hydrochloride containing one mole of the acetone solvate. Melting point: 136-145 ° C.

For C19H12INNO2. HCl. C3H6O 'calculated:

66.78% C, 8.60% H, 3.54% N with allyl bromide gave the title compound as the hydrochloride, m.p. 222-227 ° C.

For C 21 H 22 NO 2. HCl calculated:

% C, 69.30;% H, 3.81;

ПЯ1Р7РПЛ ·

H, 8.38; N, 3.95

Example · 24

9iai-allyloxy-2-cyclopropylmethyl-2H-hydroxy-5-methyl-6,7-benzomorphane (XIII)

Replacement of the compound of formula XIa used in Example 8 with an equimolar amount of compound Xle yields the title compound of formula XIle, which is isolated as the hydrochloride, m.p. 255-260 ° C.

For C 20 H 22 NO 2. HCl calculated:

68.65% -C, 8.07 ·% · H, 4.00 Nο N n and 1 ртдл n *

% C, 68.39;% H, 7.94;% N, 4.22

Example 25

2-Cyclopropylmethyl-2'-methoxy-5-methyl-9a-propargyloxy-6,7-benzoimorphan hydrochloride (XL1)

Replacement of the methyl iodide used in the procedure of Example 7 with an equimolar amount of propargyl bromide affords the title compound of formula Xf as the hydrochloride.

Example 26

2-Cyclopropylmethyl-2H-hydroxy-5-methyl-9M-propargyloxy-6,7-bonzo-morphane- (XIII)

By replacing the compound of formula XIa used in the procedure of Example 8 with an equimolar amount of the compound of formula XIf, the title compound of formula X-If is obtained.

found:

67.15% C, 8.60% H, 3.8% N

Example 23

9.alpha.-Allyloxy-2-byclo [(.alpha.) - .epsilon.-methyl-2H-methoxy-5-methyl-6,7-benzofuran (XI-ej) hydrochloride

Replacing the methyl iodide used in Example 7 with an equimolar amount

3,4-dihydro-7-methoxy-1-ethyl-2 (1H) naphthalenone (IIk)

To a solution of 50 g (0.284, mole) of 3,4-dilydryo-7-methoxy-021H) onaftalynone of formula Ia and 200 ml of anhydrous benzene is added a solution of 40.5 g ( 0.5 mol) of pyrrolidine in 50 ml of benzene. The mixture was heated to reflux with pyridine and 5 ml was collected in a Dean-Stark apparatus. 'of the Vedas. The mixture was cooled and added slowly to 0.5 ml of ethyl 4-di-4 dissolved in 300 ml of benzene. The resulting mixture was heated to reflux for 3 hours. Thereafter, 200 ml of each was added and the pyd reflux was continued. Py · 30 minutes the mixture 'ychladí, · benzenyvá layer was separated, washed with _a saturated vydyu acid · sodium sulfite and dy ydpaří dryness. The residue was distilled to give the title compound (Ilk).

The compound of formula IIIk is converted to the hydrobromide by treatment with a solution of sodium hydroxide, isolation by extraction with ether and subsequent reaction with a brymyloxy. The hydrobromide obtained is dissolved in glacial acid and a solution of bromine in 50 ml of acetic acid is added slowly to the solution obtained. The resulting mixture is stirred with half of the poultry, then diluted with 2 liters of "Skellysvu B" (essentially n-hexane) and cooled in a nitrogen atmosphere. The layer "Skellysylvu B" is poured off yd 'of the gummy precipitate. This residue was partitioned between ether and dichloromethane. The resulting biphasic system was basified with concentrated ammonium hydroxide. The layers were immediately separated and the aqueous layer was extracted with ether. Concentration of the ether extracts yields an oil which is taken up in acetone and stirred for pyrocyanide. to obtain the title compound IVk in the crystal form.

Example 30

1- (2-Benzylmethylaminoethyl) -7-methoxy-1-methyl-3,4-dihydro-2 (1H) -naphthalenone i (Illk)

A solution of 0.12 · mylu _7o: methoxy loythyl ^ .a-dihydro-ZtlHy formula Ilk--naphthalenone in 40 ml benzene was added to a suspension of 0.14 ml · hydride sydíku in 100 ml of benzene, heated PYD · reflux condenser. After 1 hour of heating, a solution of 0.12 mole of 2-benzylmethylaminoe ^, thyl chloride in 100 ml of benzene was added to the mixture, and the resulting mixture was heated at reflux for 18 hours. The reaction mixture was washed with water and extracted with dilute hydrochloric acid. Neutralization of the acidic extract with ammonium hydroxide and extraction with ether yields an oil which is converted to the oxalate of formula Illk.

Ethyl-2‘-methoxy-2-methyl-9-oy-N-lienz-rimorphan (Vk)

Reduction of the compound of formula IVk in acetic acid with hydrogen using a palladium catalyst (10%) on charcoal gives the compound of formula Vk.

Example 1 a d 31 CP.O ' : OP 5 CP ₃ (Wolves)

5oythylo9a'ohydroxyo2‘omethoxy-2-methylo-6,7-benzomorphine (Vlk)

A mixture of 0.02 mole of 5-ethylo-2-methoxy-2-methyl-9-oxo-6 ', 7-benzofuran of formula V and 8 g of cobalt (II) chloride lyahydrate was dissolved in 100 ml of 95%. The mixture was stirred gently at room temperature for half an hour. While stirring, 4 g of sodium hydride are added in portions under a nitrogen atmosphere and the resulting dark mixture is stirred at room temperature for 18 hours under a nitrogen atmosphere. Then, carefully add 75 ml of 6 N hydrochloric acid and 2-benzylo-5-ethyl-2-methoxy-9-oxo-G, 7-benzomorphane (IVk). 199586 nol was removed under reduced pressure. The blue solution obtained was. basified with concentrated ammonium hydroxide and extracted with methylene chloride. Drying and evaporation of the extracts yields a product which, according to gas-liquid chromatography, is the predominantly desired 9α-isomer of the compound of formula -Vlk.

Example 32

5-Ethyl-9a-hydroxy-2‘-methoxy-6,7-benzomorphane hydrooxalate (Vilik)

0.014 mol of the compound of formula Vlk is acetylated using 50 ml of acetic anhydride at a steam bath temperature for 2 hours to give the compound of formula Vl, acstoxylated at the 9 'position. This compound is dissolved in 75 ml of benzene, 2 g of potassium carbonate and 5 ml of ethyl chloroformate are added to the solution, and the mixture is refluxed for 18 hours. The resulting mixture was washed with water, dilute hydrochloric acid and saturated aqueous sodium chloride solution. The aqueous layers were extracted twice more with benzene. The benzene layers were dried over potassium carbonate and evaporated to give 9c-ethoxy-2-carbethoxy-2H-methoxy-5-ethyl-6,7-benzomorphane. This compound. was hydrolyzed with potassium hydroxide (25 g, 85% pellet) in 125 ml 95% ethanol for 66 hours under reflux. A dilute sodium bicarbonate solution was added to the residue, followed by extraction with methylene chloride to give the compound of formula VIk, which was converted into the hydrooxalate salt in 95% ethanol.

Example 33 í ^ i сир ' v. CHi (Xlk)

ml of triethylamine is added under atmosphere. nitrogen 2.3 ml of cyclonronylcarbonyl chloride. . The reaction mixture is stirred for 1 hour, then 7 ml of methanol are added, stirred again for 5 minutes and then evaporated to dryness. Zby-.

The reaction mixture was dissolved in toluene and washed with dilute hydrochloric acid, water and saturated aqueous sodium carbonate. Drying and evaporation of the toluene extracts afforded 2-cyclopropylcarbonyl-2‘-methoxy-9α-hydroxy-5-ethyl-, 7-benzomorphane of formula (IXk). Solution of this compound in. 25 ml of methylformamide. is added. to a suspension of 0.015 mol of hydride. of sodium in 10 ml of dimethylformamide under a nitrogen atmosphere. After 1 hour 1 ml of methyl iodide was added and after 1 hour another. 1 ml of methyl iodide is added and the mixture is stirred for a further 16 hours.

After removal of the solvent under reduced pressure, the residue was dissolved in water and extracted with methylene chloride to give 2- &lt; 1 &gt;

cyclopropylcarbonyl-2?, 9a-dimethoxy-5-ethyl-6,7-benzomorphane? This compound was reduced for 16 hours with lithium aluminum hydride. LiAlHd. in tetrahydrofuran to give the title compound which is isolated as crystalline hydrochloride.

Example 1. and d '34

CWj (Xllk) z cykloipropylmethyl ^ -hydroxy-S-tthyl ^9α- ι-methoxy-6,7-benzomorphan (Xllk)

A mixture of 0.0028 mol of the compound of formula. Xlk and 0.05 mol. sodium thioethoxide (prepared from sodium hydride and ethyl mercaptan in 80 ml. of dimethylformamide is heated under reflux for 3 hours. The solvent is then removed under reduced pressure. Toluene is added to the residue and the resulting solution is extracted. The acidic extracts are basified with sodium carbonate and extracted with methylene chloride to give the title compound of Formula XIII, which is recrystallized from acetonitrile.

Example 35

2-Cyclopronylmethyl-2H-9a-dimethoxy-5-ethyl-6,7-benzomorphane hydrochloride (Xlk)

To 0.015 mol of the free base of the compound of formula VIk in 50 ml of methylene chloride and 8

S.e-dlhydro-γ-methoxy-1-allyl-Zf (1H) naphthalenone (lim)

In the atmosphere. of nitrogen during 5 to 10. Add 40.5 g (0.5 mol) of pyrimidine dissolved in 50 ml of benzene with stirring to a solution of 50 g (0.0284 mol) of N, N-dimethoxy-2 ((H) -naphthalenone) with stirring. of formula (Ia) in 200 · ml of anhydrous benzene. The mixture was heated to reflux for 1 hour - and 5 ml of water was collected in a Dean-Stark apparatus. Then the mixture is cooled. a. slowly add to

60.5 g (<1.5 mol) of allyl bromide dissolved. in -3C-0 ml of benzene. The mixture obtained. -heated _: for 3 hours. 200 ml of water are then added to the reaction mixture and refluxing is continued. Mon 90. minutes, the mixture is cooled. The benzene layer is separated, washed with water and then with saturated sodium chloride solution, dried with sodium sulphate and evaporated to dryness. The residue was distilled to give 52.20 g (85% yield) of the title compound of formula Hm, bp 106-112 ° C / 1.33-6.66 Pa. The infrared and nuclear magnetic resonance spectra are consistent with the above structure.

For C14H16O2 calculated: 77.74% C, - 7.45% H found: 77.47 -% C, 7.50% H

Example 36

3,4-Dihydryo-7-methyl-1-allyl-1- (2-dimethylamino-ethyl) -2 (1H) -naphthalenone hydrobromide (IHm) ¹ Mixture of 400 ml of anhydrous benzene, 22- g (0.25 mol) ); - teř. of amyl alcohol and 10.62 g (0.25 mole) of sodium hydride are heated under reflux in a nitrogen atmosphere for 30 minutes - or until all hydride has reacted. Subsequently, 47.2 g (0.22 * mol) of the compound of formula (Um) in 100 ml of benzene are slowly added to distill off the excess amyl alcohol. An additional 100 ml of -benzene is added and distilled off. Then SE- was added dropwise 28 g (0.3 - mole) of 2-chloh-N, N-di-amine .methy ^ι <yethanu 100 ml). benzene. The reaction mixture was then heated with a reflux condenser for 20 hours, then washed twice with water, diluted with ether and extracted with 1 N hydrochloric acid. The acidic extract was heated at 60 ° C for 1 hour, then cooled and extracted with ether to give 15 g of the compound of formula -lm. The acid extract was then cooled, basified with ammonium hydroxide - and extracted with ether. It is dried with potassium carbonate, treated with activated carbon and treated with dry hydrogen bromide gas for filtration. This is obtained. -33.87 g - (61.5% yield) of the hydrobromide of formula IHm. After recrystallization from a mixture of methanol and ether, the compound obtained has a melting point of 139-140 ° C. The infrared and nuclear magnetic resonance spectra are consistent with the above structure. ·

For C1eH: ®N.O2. HBr calculated:

% C, 58.69;% H, 3.71%;

% H, 7.16;% N, 3.59

Example - .37

3-Bromo-3,4-dihydro-7o-methoxy-1-allyl-1 (2-dimethylamino-ethyleth-2-OH) -naphthalene (LVm)

To the solution of 15 g (41 mmol) of the compound of formula IHm in 100 ml of methylene chloride and 300 ml of tetrahydrofuran is added a solution of 20.58 g (41.5 mmol) of pyrrolidinylhydhytribhymidide in 300 ml of tetrahydrofuran over 4 hours with stirring. After the addition was complete, the reaction mixture was left overnight at room temperature. The solvents are evaporated to dryness and the solid residue is recrystallized from 700 ml of isyphopanyl to give 12.7 g of (68.5% yield) of the compound of formula LVm - m.p. 149-150 ° C. The infrared and nuclear magnetic resonance spectra are consistent with this structure.

For C 18 H 22 NO 2 Br. . HBr calculated:

% C, 48.34;% H, 5.63;% N, 3.13.

% C, 48.64;% H, 5.70;% N, 3.14%

Example 38

199588

5-Allyl-2‘-methoxy-2-methyl-9-oxo-6,7-benzomorphane methobromide (LXm)

12,6 g. (0.028 mol) of hydrobromide of the compound of formula LV-m is dissolved in ice cold water, the solution is added to a separatory funnel and poured into ether. Concentrated ammonium hydroxide is added to make the mixture alkaline and the liberated base of the compound of formula IVm is extracted and separated as quickly as possible. The ether was evaporated and the residue was dissolved in acetone and allowed to stand overnight. It is obtained. thus 6.55 g (yield 65.5%) of a solid compound of formula LXm. After recrystallization from isopropanol, it melts at 175-177 ° C. Infrared and nuclear magnetic resonance spectra. they are consistent with that structure.

For C17H21N.O2. CHsBr. 1/2 H2O calculated:

% C, 57.60;% H, 6.71;% N, 3.73.

57.44% C, 6.78. % H, 3.58% N

Example 39

5-allyl-2‘-methoxy-2H-methyl-9-oxo-6,7-benzomorphane (vm)

A suspension of 2 g (5.46 mmol) of the compound of formula LXm in 25 mL of 1-octanol was heated under nitrogen. under reflux condenser after. Fifteen minutes. After cooling, the mixture is poured into 40 ml of 0.5 N hydrochloric acid and extracted twice with 100 ml of petroleum ether each time to remove the octanol. The aqueous layer was basified with aqueous ammonia solution and the liberated base was extracted with benzene to dry and evaporate the solvent. 1.23 g of an oil of Compound VI is obtained. The oil was stirred with a solution of 350 mg of oxalic acid from 5 ml of water for 1 hour and then kept at 5 ° C for 16 hours. The precipitated solid was filtered to give 980 mg (47% yield) of oxalate of the compound of formula Vm, mp 156-162 ° C, containing · mol of crystalline water. After recrystallization from water, the product melts at 160-161 ° C with water loss at 110 ° C.

Pro CrzHaNOž. C2H2O4. H2O calculated:

% C, 60.15;% H, 6.64;% N, 3.69.

% C, 60.52;% H, 6.72;% N, 3.70

Example 40

5-allyl-9a-hydroxy-2‘-methoxy-2-methyl-6,7-benzomorphane (I know)

A solution of diisobutylaluminum hydride (62 mL) (25% solution, approximately 60 mmol) was diluted with 150 mL of anhydrous tetrahydrofuran and cooled to -45 ° C under nitrogen. A solution of 8.58 g (31.6 mmol) of the compound of formula Vm in 100 ml of anhydrous tetrahydrofuran is then added dropwise. After stirring at 45 [deg.] C. for 1 hour, the gelatinous mass thus obtained is concentrated under reduced pressure. The remaining oil was dissolved in ether, washed with water, dried over sodium sulfate and evaporated under reduced pressure to give 8.88 g of the alcohol I above. Crystallization of the residual oil from a mixture of ether and petroleum ether (distillation range 30-60 ° C) afforded 6.32 g (yield 72%) of the crystalline compound VI. The mother liquor is purified by chromatography on 100 g of silica gel using a 1: 1 mixture of MeOH and ether to give 2.00 g (yield 23%). of pure alcohol formula I know. A sample of this compound was recrystallized from a mixture of acetone, ether and petroleum ether (distillation range 30-60 ° C); after recrystallization, it has a melting point of 73-79 ° C.

For C17H23NO2 calculated:

74.69% C, 8.48% H, 5.12% N found:

H, 8.73; N, 5.19

Example 41

5-Allyl-9a-Hydnoxy-2‘-methoxy-6,7-benzomorphane hydrooxalate (VHmj)

By replacing the compound of formula VIa used in Example VI with an equimolar amount of the compound of formula VIm, the title compound of the formula Vilm is obtained. The compound is purified by recrystallization of the oxalate from a mixture of methanol and ether to give a sample having a melting point of 173-176 C. The sample for analysis is purified by molecular addition of the free base at 150 ° C / 0.066 Pa.

For C 16 H 21 NO 6 calculated:

% C, 74.10;% H, 8.16;% N, 5.40.

% C, 73.92;% H, 8.27;% N, 5.36

199588

44

Example 42

5-allyl-2-cyano-2-cyano-2-methyl-2,7-dimethoxy-6,7-ben-Zomorphane (X 1, 4);

A) 5-allyl-N-cyclopropylcarbnyl-α; -hydroxy-2‘-methoxy-6,7-benzomorphane (IXm)

Under nitrogen, 1.80 was added dropwise. g (17.25 mmol) of cyclopropylcarbonyl chloride to a solution of 4.07 g (15.7 mmol) of the hydroxylamine of formula Vilm in 200 ml of dichloromethane and 5 ml of itriethylamine. The reaction mixture was washed with dilute acid, hydrochloric acid, then water, dried over magnesium sulfate, and the solvent was removed under reduced pressure to give 4.12 g (yield: 80%) of the crude amide of formula IXm. Crystallization from benzene / ether: mp 146-147 ° C.

For C 20 H 25 NO 3 calculated:

73.37% C, 7.70% H, 4.28% N found:

H, 7.71; N, 4.3-2

B) 5-allyl-N-cyclbpa ^, bpy-carbonyl-2'9a-dimethoxy-6,7-benzomorphane (Xm)

To the suspension. 950 mg - (21.9 mmol) of a 55% dispersion of sodium hydride in benzene-washed mineral oil in 125 ml of anhydrous dimethylformamide are added under an atmosphere of nitrogen 2.39 g (7.30 mmol) of the alcohol IXm. The mixture was stirred. The reaction mixture was cooled to room temperature and methyl iodide (5.18 g, 36.5 mmol) was added. Stirring was continued for 3 hours. The reaction mixture was poured into 500 ml of water and extracted with benzene. The extracts were washed with water, dried over magnesium sulfate and evaporated under reduced pressure to give 2.45 g (quantitative yield) of the amide Xm. The crude product is purified by evaporative distillation at 160 ° ϋ / 0.0 & 6 Pa.

For C21H27NO3 calculated:

% C, 73.87;% H, 7.97;% N, 4.10;% ^{C ,} 74.08 ^; % H, 4.0 ^;

C) O-Al-N-cyclopropylmethyl-2,9,9-dimethoxy-6,7-bromo-morphane (Xln)

2.30 g of i (6.74 mmol) of the amide of formula IXm are added to a suspension of 770 mg (20.2 mmol) of lithium aluminum hydride in 125 ml of anhydrous tetrahydrofuran. The resulting mixture was heated below. After cooling for 3 hours, the excess hydride is destroyed by adding, in a shameful manner, 0.77 ml of water, then 0.58 ml of 20% sodium hydroxide and finally. 2.70 ml water. The inorganic salts are filtered off and washed with tetrahydrofuran. The filtrate is evaporated to dryness and. the residual oil was dissolved in HCl and extracted with ether. The faulty phase is made alkaline with hydroxide. ammonium chloride and extracted with dichloromethane. The extracts were washed with water, dried over magnesium sulfate and the solvent was removed under reduced pressure. 1.97 g (yield 90%) of a tertiary amine of formula Xm1 is obtained. Its hydrochloride melts after recrystallization from a mixture of methanol and ether at. 156 DEG -157 DEG.

For C 21 H 29 NO 2.

calculated: '

77.04% -C, - 8.93% H, 4.28% N found:

% C, 77.02;% H, 9.03;% N, 4.30

Example 1 and d 43

5-allyl-2-cyclopropylmethyl-2H-hydroxybenzyl-9α'-methoxy-6,7-benzofuran (XIII)

A solution of sodium thioethoxide in 175 ml of anhydrous dimethylamine (1.00 ml) was added under a nitrogen atmosphere by adding 1.70 ml (22.2 mmol) of ethanethiol to 970 mg (22.2 mmol). A 55% dispersion of sodium hydride in a benzene-washed mineral oil was then added. 1.32 g (4.04 mmol) of dimethyl ether of formula Xlm were added and the solution was heated under reflux for 4 hours. The reaction mixture is poured into 500 ml of ice-cold water, acidified to pH 4 with hydrochloric acid, basified with ammonium hydroxide and extracted with benzene, and the extracts are washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give a solid. 23g - (yield - 97%) of the phenol of formula XIII The melting point of the hydrochloride recrystallized from a mixture of methanol and ether is in the range of 223-225 ° C.

For C20H2ZNO3 calculated:

% C, 76.64;% H, 8.68;

H, 8.80; N, 4.39

Example 1 a d 44

199588

2-cyclopropylmethyl-2, 9a-dimethoxy-5-propyl-6,7-benzomorph and Xln

A solution of 0.600 g (1.87 mmol) of the compound of formula Xm in 200 g of anhydrous ethanol is placed in a hydrogenation vessel containing 0.100 g of activated carbon containing 10% palladium. The resulting mixture was shaken for 2 hours at room temperature under a partial hydrogen pressure of 50 psi. Then, the catalyst is filtered off and the filtrate is evaporated to dryness to give the title compound of formula Xln.

Example 45

2-Cyclopropylmethyl-2H-hydroxy-9α-methoxy-5-propyl-6,7-benzomorphane (XIII)

Replacing the compound of Formula XIa used in Example 8 with an equimolar amount of the compound of Formula Xln gives the title compound, which is the same as that prepared in Example 6OA.

Example 46

2,5-Dimethyl-9/3-hydroxy-2‘-methoxy-6,7-benzomorphine hydrobromide (VIp)

To a suspension of 0.04 mole of the compound of formula IVa in 200 mL of ether was added 50 mL of a 2.5-m-solution of isopropylmagnesium chloride in tetrahydrofuran. This mixture was stirred under nitrogen for ¹ 17 hours. 200 ml of water and 25 ml of concentrated hydrobromic acid are then slowly added to the cooled stoic. The ether was removed by evaporation under reduced pressure. Extraction of the aqueous mixture with methylene chloride gave 17 g of a tan foam. This foam was taken up in 200 mL of 95% ethanol and hydrogenated in a Parr shaker using palladium hydroxide on activated carbon as the catalyst to give 10.3 g (78 percent yield) of pure compound of formula VIp after crystallization from 2-propanol.

See H. Kugita and E. L. May, J. Org. Chem., 26, 1954 (1961).

Example 47 ч £ Д — он • č сн, «Μ

9J / J-hydroxy-2--methoxy-5-methyl-6,7-benzomorphane (VIIp)

A mixture of 0.031 mol of the free base of formula VIp and 90 ml of acetic anhydride is heated at 100 ° C for 1 hour. The acetic anhydride was removed under reduced pressure. Treatment of the residue with sodium carbonate and extraction with methylene chloride afforded 2,5-dimethyl-2‘-methoxy-9H-acetoxy-6,7-benzomorphane in quantitative yield. This compound is dissolved in 100 ml of benzene and 5 g of potassium carbonate and 10 ml of ethyl chloroformate are added. The resulting mixture was heated to reflux under nitrogen for 26 hours. Water is then added to the mixture. The benzene layer was separated and washed with dilute hydrochloric acid and saturated aqueous sodium chloride solution to give 5-methyl-2‘-methoxy-2-carbethoxy-9 H -acetoxy-6,7-benzomorphane in quantitative yield. This compound is dissolved in 250 ml of 95% ethanol and 30 g of potassium hydroxide are added to the solution. The mixture was refluxed under nitrogen for 90 hours. The ethanol was removed under reduced pressure. Addition of a 10% aqueous solution of sodium bicarbonate to the residue and extraction with methylene chloride afforded 7.2 g (yield 100%) of the compound of formula VIIp. Recrystallization from toluene yielded 6.8 g (94% yield) of an analytically pure compound, mp 132.0-133.5 ° C.

For C14H19NO2 calculated: 72.01% C, 8.21% H, 6.00% N found *

% H, 8.08;% N, 6.08

Example 48

2,5-dimethyl-9- (spiro-N-epoxy) -2‘-methoxy-6,7-benzomorphane (XX)

A solution of 0.05 mole of 2m-dimethyl-2'-methoxy-h-oxo-6,7-benzomorphone of formula Va in 125 ml of anhydrous dimethyl sulfoxide was added to a 55% dispersion of sodium hydride (0.1 mol) with stirring under nitrogen. . To this mixture was added 0.1 mol of trimethyteulfomumiodide with stirring. After stirring under nitrogen for 4 hours, the mixture was diluted with water and extracted with methylene chloride. Drying and concentration of these extracts yields an oil which, according to chromatographic analysis (iplyn-liquid), contains 86% of the β-isomer of the compound of formula XX, 6-7% of another α-isomer, and some starting ketone. Chromatography on alumina followed by crystallization from cyclohexane yields pure compounds of formula XX with a melting point of h3 to h5 ° C (yield 64% over 95% isomeric purity).

For C 16 H 21 NO 2 calculated:

74.10% C, 8.16% H, 5.4% N found:

H, 8.30; N, 5.36

Example 1 a d 4h

11H-hdroxy-2‘-methoxy-2,5, ha-methyl-6,7-benzomorphane hydrochloride (Vir)

A solution of 0.028 mol of 2,5- (4-methyl-9- (spiro-1-epoxy) -2-methoxy-6,7-benzomorphane of formula XX in 75 ml) was added to a suspension of 0.045 mol of lithium aluminum hydride in 25 ml of stirring. · Ml tdirahddrofuran. The mixture was stirred at 25 ° C for 16 hours and then heated at reflux for 2 hours. 5 ml of a saturated aqueous solution of sodium sulfate is carefully added to the obtained mixture. The solids were filtered. and the filtrates are evaporated to dryness. The remaining oil is converted to the hydrochloride salt and crystallized from a mixture of ethanol, ethyl acetate and water to give pure hydrochloride hydrate of the compound of formula Vir, mp 13h-143 ° C (83% yield). According to chromatographic analysis: (gas-liquid) free base isomeric purity h6%. The infrared spectrum in carbon tetrachloride solution at various concentrations appears to be only the OH band, indicating a 3'-OH configuration.

[See E.L. May and H. Kugita, J. Org. Chem., 26, 186 (1074)].

Example 50

Preparation of γ / 3-Acetoxy-2-carbethoxdy5, hαy

-dimethyl-γ-methoxy-S-benzomorphane (XXI)

To 0.022 mole of N -hydroxy-2'-methoxy-5,5,9a-trimethyl-6,7-benzoylfuran of formula VI, 50 ml of acetic anhydride is added and the mixture is heated on a water bath for 3 hours. After removal of the acetic anhydride under reduced pressure, dilute aqueous sodium carbonate solution was added to the residue, and the mixture was extracted with benzene. Drying and evaporation of the benzene extracts gave the acetoxyl compound, i.e. ^, 6,6-acetoxy-2,5,9-tri-trimethylsilyl-methoxy-N-benzomorphane. To a solution of this material in benzene was added 2.5 g of potassium carbonate and 6.5 ml (0.07 mol) of ethyl chloroformate, and the mixture was heated under reflux for 16 hours. 120 ml of 1N hydrochloric acid are then carefully added to the mixture. The resulting layers were separated and the aqueous layer was extracted with benzene. Drying and concentration of the combined benzene extracts gives the title compound (XXI), which, after recrystallization from %5% ethanol, melts at 87.5-88.5 ° C.

For C20H27NO5 calculated:

% C, 66.46;% H, 7.53;% N, 3.88.

% C, 66.18;% H, 7.62;% N, 3.75

Example 51

Preparation of 5,9a · -dimethylУ-93-hddroxy-2'-methyl-6,7-benzo · phane (Vir)

A mixture of 0.002 mol of H / 3-acedooy-У-Уarbethoxy _5,9ι ί-TR-dimethyly2'ymethoxd 6,7ybdnzomory Fano-XXI, the potassium hydroxide 2.5 g 20 ml h5% ethanol was heated to reflux. cooler for 18 hours. After concentration, water was added to the residue, and the mixture was extracted with methylene chloride to give the title compound of formula IIIr, which melts at 147-148 ° C after recrystallization from ethyl acetate.

For C15H21NO2 calculated:

% C, 72.84;% H, 8.56;% N, 5.66

1Ί 1’Ρ7ΡΤΊ n *

H, 8.63; N, 5.82

Example 52

50

2-cyclopropylmethyl-2 &apos;, 9 &apos; -dimethoxy-5 &apos; -fluoromethyl-2 &apos; i ^ ^ an (Xlr)

To a solution of 5,9a-dimethyl-9: 3'-hydroxy-2‘-methoxy-6,7-benzomorphane of formula VIIr in 25 ml of methylene chloride and

7.5 ml of triethylanine are added under stirring with 3 ml of cyclohexylcarbonyl chloride. The resulting mixture was stirred for 18 hours before dilute aqueous sodium carbonate solution was added. The resulting layers were separated and the aqueous layer was extracted with methylene chloride. Drying and concentration of the unhylene chloride extracts gave 2-cyclopropylcarbonyl-5,9a- ¹ -dimethyl-9H-hydroxy-2'-methyl-6,7-benzomorphane of formula IXr as an oil.

A solution of the compound of formula IXr in 25 ml of diethylformamide was added to a suspension of 0.15 mol of sodium hydride in 10 ml of diethylformanide under a nitrogen atmosphere. After half an hour, 1 ml of methyl ether was added and after one hour again one ml of methyl ether, followed by stirring for a further 16 hours. After removal of the solvent under reduced pressure, water was added to the residue, and the mixture was extracted with methylene dichloride to give 2-cyclopropyloxycarbonyl-1,2,7,7-dimethoxy-5,9-d-methyl-6,7-benzomorphane of formula Xr. This compound was dissolved in 3 ° mL of tetrahydrofuran and the solution was added with stirring to a suspension of 1.0 g of ithiuninium hydride in 20 mL of tetrahydrofuran. The mixture was heated to reflux for 18 hours, then 3 mL of saturated aqueous sodium sulfate solution was carefully added and the mixture was heated until the solids turned white. Filtration of the solids and concentration of the filtrate gave an oily compound of formula Xr, which was converted to the hydrochloride, m.p. 226-229 ° C.

For C20H12NO0. HCl calculated:

68.26% C, · 8.59% H, 3.98 «/ o N found:

H, 8.85; N, 4.02

Example 53

2-cykloprppylnethyll5,9α-dimethyl-2 ^{<-hydroxy-9ι} / ЗΊmnthopχ -), 7-benzomorphan (Xllrj

Replacing the compound of formula XIa used in Example 8 with an equilibrium amount of the compound of formula XIr affords the title compound of formula XIII as the hydrochloride, m.p. 27 DEG-278 DEG C. with decomposition.

found:

67.32% C, 8.52% H, 4.37 ° / ° N

Example 54

2-cyclobutylmethyl-2,9,9-dimethyl-5-methyl-6,7-benzoforphinan (XIs),

Substitution of the compound of formula VIIr and the cyclohexyrylcarbonyl chloride used in Example 52 with equimolar amounts of the compound of formula VIHp and cyclobutylcarbonyl chloride affords the title compound of formula XIs as the hydrochloride, m.p. 205 DEG-209 DEG.

For C 20 H 22 NO 2. HCl calculated:

68.26% C, 8.59% H, 3.98% N found ·:

68.58% C, 8.50% H, 4.07% N

Example 55

2-cyclobutylmethyl-2'-hydroxy-93'-methyl-5'-methyl-6,7-benzoforphinan (XIIis). .

Substituting the compound of Formula XIa used in Example 8 with an equimolar amount of the compound of Formula XIs, the title compound of Formula XIIs is obtained in the form of the hydride with a melting point of 214-219 ° C.

For C 18 H 25 NO 2. HCl calculated:. % H, 8.35;% N, 4.15

Τ JÍ1 07Й ťί *

^67, 88% ^(8, 41% ^{H 4,} 02% N

Example 1 and d · 56

2-cyclopropylmethyll2 ‘, 9β-dimethoxy-4-methyl-4'-benzomorphane (Xlt)

Substitution of compound VIIr used in Example 52 with an equivalent amount of compound VIIp yields the title compound Xlt as the hydrochloride, m.p. 217-220 ° C. Celsius.

For C19H27NO2. HCl calculated:

H, 8.35; N, 4.15

For C19HJ2NO2. HCl calculated:

% H, 8.35;% N, 4.15. Found:

% C, 67.53;% H, 8.65;% N, 3.86

Example. 57

2-Cyclopropyl-methyl-2'-hydroxy-93-methoxy-5-methyl-6 ', 7-benzomorphane (XHt)

Replacing the compound of formula XIa used in Example 8 with an equimolar amount of the compound of formula 'Xlt' affords the title compound of formula XHt as the Oydrrcrride, m.p. 245-255 ° C (dec.).

Pro. HCl calculated:

% C, 66.75;% H, 8.09;% N, 4.33.

% H, 8.28;% N, 4.17

Example 58

2-cyclobutylmethyl-2 ' ₎ 93-dimethyryl-5 ₁ 9α-dimethyl-6,7-eenzymurphan (XII)

Replacing the cyclopropylpropylcarbonyl chloride used in Example 52 with an equimolar amount of cyclrbutylcarernyl chloride. The title compound (XIv) is obtained as an oil which can be used as in Example 59.

Example 59

2-cyklobutylιmethy - ^{5,93-dimethoxy-metOyl} 2'y. -hydrryy-9.3-methyl-6,7-benzomorphane (XIII)

Replacing the compound of Formula XIa used in Example 8 with a quadrimal amount of the compound of Formula XIv yields the title compound of Formula XIII as hydrochloride with a melting point above 245 ° C (dec.).

For C 20 H 29 NO 2. . HCl calculated:

68.26%, C, 8.59% H, 3.98% N found

H, 8.88; N, 4.02

Attached ........

N-cyclopentylmethyl-2‘-hydrryy-9α-methyl-5-propyl-6,7-benzomorphane · (XILn)

A solution of 495 mg (1.51 mmol) of an olefin of formula XIII in 150 ml of anhydrous ethanol was hydrogenated for 1 hour using 250 mg of an activated carbon catalyst containing 10% palladium at an initial pressure of 0.288 MPa. The catalyst was filtered off using celite and the solvent was evaporated, yielding 486 mg (98% yield) of the saturated compound of formula XILn. Its Oydrrchlr rid after recrystallization from the mixture. methanol and ether, melting at 236-239 ° C. The sample to be analyzed is purified by sublimation at 160 mm / s.

For C 20 H 29 NO 2 calculated:

% C, 76.15;% H, 9.27;% N, 4.44.

H, 9.08; N, 4.41

Example 60B

2-Cyano-9'-hydroxy-2'-methoxy-5-methyl-6,7-benzomorphane (XXIl)

0.015 mol of the compound of formula VIa is dissolved in 75 ml of benzene, 2 g of potassium carbonate and 5 ml of ethyl chloroformate are added to the solution, and the mixture is refluxed for 18 hours. The resulting mixture was washed with water, dilute hydrochloric acid and saturated aqueous sodium chloride solution. The aqueous layers were extracted twice more with benzene. The benzene layers were dried over potassium carbonate and evaporated to give 9α-hydroyy-2‘-methyl-2-carbetoyl-5-methyl-6,7-benzomorphane (XXI1), which was used as the starting material in Example 61.

Example · 61

2-carbethryy-2 ', 9 (α-dimethyry-5-methyl-6,7-benzomorphane (XXIII))

A solution of 0.014 mole of a compound of formula XXII in 25 ml 0Imethylfrrmami0u was added to a suspension of 0.015 mole of sodium hydride in 10 ¹ ml 0imethylformamidu under nitrogen. After half an hour, 1 ml of methyl iodide was added and after 1 hour again 1 ml of methyl iodide, followed by stirring for another. · 16 hours The solvent was removed under reduced pressure, water was added to the residue, and the solution was extracted with methylene chloride to give the compound of formula XXII. This was isolated by evaporation under reduced pressure and used as the starting compound in Example 62.

Example · 62

2 ', 9 _J α-dimethryy-5-methyl-6,7-benzmorphane (XXV)

0.014 mol of the compound of formula XXIII is hydrolyzed using 25 g of potassium hydroxide (85% pellet) in 125 ml of refluxing 95% ethanol for 66 hours. The ethanol was then removed under reduced pressure. A dilute aqueous solution of sodium bicarbonate was added to the residue, and the mixture was extracted with methylene chloride to give the title compound. . the title compound of formula XXIV, which is isolated by evaporation to give the title compound of formula XXV; reduced pressure. The remaining 99586 was used as the starting compound in Example 63.

Example 63A

2-allyl-2H, 9a-dimethoxy-5-methyl-6,7-benzomorphane [XIw]

A mixture of 0.500 g (1.8 mmol) of the compound of formula XXIV, 0.300 g sodium bicarbonate and 1.8 mmol of allyl bromide in 5 ml of anhydrous dimethylformamide was stirred overnight at room temperature. The reaction mixture was diluted with ether and filtered. The filtrate was extracted with 0.05 N hydrochloric acid, the resulting layers were separated, and the acidic layer was basified with concentrated ammonium hydroxide before being extracted with ether. After drying with potassium carbonate, the compound of formula XIw is obtained in the form of a colorless oil.

Example - 63B

2-Allyl-2H-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphane (XIIw)

A solution of 0.420 g (1.35 mmol) of the compound of formula XIw in 10 ml of methylene chloride is slowly added to a solution of 0.350 g (1.4 mmol) of boron tribromide v3 in 10 ml of methylene chloride, maintained at -10 ° C. The resulting mixture was stirred at room temperature overnight. In the usual manner, an oil is obtained which crystallizes from a mixture of water and methanol and is the title compound of formula XIIw. .

Example 64 (-) -2-cyclopropylmethyl-2H-acetoxy-9α-methoxy-5-methyl-6,7-benzomorphane

0.001 mol (-) of the compound of formula XIIa in the free base form - is - dissolved in 1 ml of acetic anhydride and 0.08 ml of pyridine and the solution is refluxed for 1 hour. The mixture was evaporated under reduced pressure, the residue was dissolved in ether and the ether solution was washed with dilute ammonium hydroxide solution. The ether layer was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure to give the title compound.

Example 65 (-) -2-cyclopropylmethyl-2H-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphane-2H-<(4-nicotnoate)

To a solution of 0.002 mol of the free base of formula IIIa in 3 ml of pyridine was added 0.002 mol of 4-nicotinoyl chloride hydrochloride.

The mixture was refluxed for an hour, after which the solvent was evaporated. The residue was partitioned between ether and dilute ammonium hydroxide. The ether layer was separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give the desired nicotinoyl ester.

Example 66 (-) -2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-5-methyl-6,7-benzomorphine-2'- (3-nicotnoate)

Replacing the 4-nicotinoyl chloride hydrochloride used in Example 65 with an equimolar amount of 3-nicotinoyl chloride affords the title compound.

Example 67

2'-m-2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-5-methyl-6,7- (2-methyl-2-cyclopropylmethyl) -2- benzomorphane

To 10 ml of anhydrous dimethylformamide was added 0.01 mol of chloromethyl methyl ether. The resulting solution was added to a solution of 0.0075 mol (-) of the compound of formula XIIa in the free base form in 20 ml of anhydrous dimethylformamide. At room temperature, 0.011 mol of anhydrous sodium carbonate in the form of a fine powder is added to this solution with stirring. Stirring was continued for 5 hours. The solution is then filtered - to remove sodium carbonate -, evaporated to dryness under reduced pressure to give a substantially pure title compound.

General procedure - for the preparation of fumarates:

An equimolar amount of fumaric acid powder and the corresponding amine (e.g., amine of formula XIIb) in a ratio of 1: 1 is dissolved in sufficient hot isopropanol or n-propanol to achieve dissolution. By cooling-with possible scratching on the walls or inoculation, the fumarate crystallizes. The product is isolated by filtration.

General procedure for oxalate preparation:

0.01 mol of the compound of formula IIIa is dissolved in a minimum amount of hot acetone. A hot solution of 0.01 mol of oxalic acid is added to the solution with stirring, and the oxalate is eliminated by scraping on the walls and / or by inoculation and isolated by filtration.

Example 68

Cleavage of 5-alkyl-2-cyclopropylmethyl-2‘-hydroxy-9α-methoxy-6,7-benzomorphane in its left-handed and right-handed isomer i

To a solution of 5.3 g (16.9 mmol) of the title compound of formula XIII in 150 mL of acetone was added 2.6 g - (17.0 mmol) of mandelic acid. The precipitated 2.0 g of partially cleaved solid was recrystallized three times from acetone, yielding 0.69 g of a salt which finally showed a rotation [.alpha.] D @ ²⁵ = + 8.4; (concentration 286 mg / 100 ml methanol). ₍ Rotation of free base is (α) η ²⁵ = + 61.0 ° (concentration 189 mg / 100 ml methanol), while rotation of its hydrochloride (mp 222 to 224 ° C) (a] _D ² 4 = +58.9 ° (concentration - 229 mg / 100 ml methanol).

'The levorotatory isomer is obtained by dissolution

5.3 g (16.9 mmol) of the title compound in 125 ml of acetone and 2.6 g (17.0 mmol) of d-mandelic acid were added. The precipitated 2.86 g of salt is recrystallized from acetone to give a rotation of [α] _D ²⁵ = -9.4 ° (concentration 287 mg / ml methanol). The free base is released from the salt ([.alpha.] D @ ²⁵ = -62.0 DEG, concentration 266 mg / 100 ml methanol), which is recrystallized from a mixture of acetone and ether, such as hydrochloride. (1.3 g, mp 222-224 ° C, ( _.alpha. ) _D @ ²⁵ = -99.4 DEG, concentration 281 mg / ml methanol).

When the dextrorotatory or levorotatory isomer of the compound of formula (IIIm) is hydrogenated to the dextrorotatory or levorotatory isomer of the compound of formula (XIII), the rotation of the dextrorotatory isomer is (α) _D ²⁵ - + 52.8 ° (concentration 303 mg / 100 ml methanol, melting point hydrochloride) 228-230 ° C) and otáčlvost levorotatory isomers (a] ² 4 - - -512.7 ° - (concentration 294 mg / ml methanol, mp of the hydrochloride 228 DEG C.).

Example- 69

5-allyl-N-cyclobutylcarbonyl-9a-hydroxy-2'-methoxy-6,7-benzomorphane (IXz)

A solution of 4.62 g (39.0 mmol) of cyclohutylcarbonyl chloride in a nitrogen atmosphere at 0 DEG C. was added dropwise to a solution of 9.20 g (35.5 mmol) of the free base of formula (Vilm) in 400 ml of dichloromethane and 15 ml of triethylamine under nitrogen. - 100 ml of dichloromethane. After the addition, the cooling bath was removed and the solution was stirred for 1 hour at room temperature. The reaction mixture was washed with 1 N hydrochloric acid, water and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gave - 11.40 g (yield 94-%) of the hydroxyamide of formula IXz.

Recrystallization from a mixture of -ether and petroleum ether (b.p. 30-60 ° C) gave a sample for analysis, m.p. 116-118 ° C.

For - C21H27NO3 calculated:

73.87% C, - 7.97% H, 4.10% N found:

H, 8.11; N, 4.01

Example 70

5-allyl-N-cyclobutylcarboxy-2,9-a-dimethoxy-6,7-benzomorphane (Xz)

5.0 g (14.6 mmol) of hydroxyamide IXz is added to a suspension of 1.02 g (43.9 mmol) of sodium hydride (55% in oil, washed with benzene) in 500 ml of dimethylformamide. The mixture is heated for 30 minutes at 50 ° C, then cooled to room temperature and methyl iodide (10.4 g, 73.0 mmol) is added. The mixture was stirred for 3 hours, then poured into water and extracted with benzene. The extracts were washed with water, dried (MgSO4) and concentrated under reduced pressure to give 5.0 g (96% yield) of the dimethoxyamide of formula Xz as viscous. -oil. A sample for analysis is prepared by evaporative distillation at 170 ° C at 0.066 Pa.

For C22H29NO5 calculated:

74.33% C, 8.22-% H, 3.94% N found:

H, 8.39; N, 3.89

Example 71

5-allyl-N-cyclobutylmethyl-2,9,9-dimethoxy-6,7-benzomorphane (X1z)

A solution of 4.28 g (12.0 mmol) of dimethoxyamide of formula Xz in 50 mL of tetrahydrofuran was added to a solution of 1.38 g (36.0 mmol) of lithium aluminum hydride in 300 mL of tetrahydrofuran. The reaction mixture was heated at reflux for 1 hour, cooled, and the excess hydride was destroyed by successive addition of 1.38 ml of water, 1.02 ml of 20% sodium hydroxide solution and then 4.80 ml of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The yellow oil was dissolved in dilute hydrochloric acid and extracted with ether. The aqueous phase was basified with concentrated ammonium hydroxide and extracted with dichloromethane.

The extracts were washed with water, dried over magnesium sulphate and evaporated under reduced pressure to give 3.80 g (92.7% yield) of the amine of formula XIII. The oxalate melts after recrystallization from methanol / ether at 184-186 ° C.

By distilling the free base at 135 ° C at 0.066 Pa, a sample was obtained for analysis.

For C22H31NO2 calculated:

% C, 77.38;% H, 9.15;% N, 4.10.

% C, 77.50;% H, 9.32;% N, 4.08

Example 72

5-allyl-N-cyclobutylmethyl-2‘-hydroxy-9a-methoxy-6,7-benzomorphane (XIIIz)

A solution of sodium ethanethiolate is prepared by adding 1.87 ml (25.5 mmol) of ethanediol to a suspension of 1.07 g (25.5 mmol) of 55% sodium hydride · (suspension in mineral oil washed with benzene) in 200 ml of dimethylformamide. To this solution was added 1.52 g (4.6 mmol) of dimethoxyamine of formula Xlz and the solution was heated at reflux for 5 hours, then poured into water, acidified with concentrated hydrochloric acid, basified with ammonium hydroxide. The extracts were washed with water, dried over magnesium sulphate and evaporated to dryness.

The crude material obtained is dissolved in acetone, one equivalent of oxalic acid is added to the solution, and the ether is added until crystallization occurs. 1.62 g (83% yield) of oxalate is obtained, which, after recrystallization from methanol / ether, melts at 193-194 ° C.

A sample is prepared for analysis at 160 ° to 165 ° C by distilling the free base. Celsius at 0.066 Pa.

For C21H29NO2 calculated:

% C, 77.02;% H, 8.93;% N, 4.28.

% C, 77.31;% H, 9.04;% N, 4.18

Example 73

N-cyclobutylmethyl-2'-hydroxy-9'-methoxy-5-propyl-6,7-benzomorphane (XIII)

1.04 g (3.18 mmol) of an olefin of the formula III is dissolved in 200 ml of anhydrous ethanol and hydrogenated for 2 hours on an activated carbon catalyst containing 10% palladium at an initial pressure of 0.323 MPa. The catalyst is then filtered off through Celite and the filtrate is evaporated to dryness. The obtained crude material (922 mg, 88% yield) was dissolved in acetone, one equivalent of oxalic acid was added to the solution, and the ether was added until crystallization began. 214 DEG-216 DEG C. are obtained after recrystallization from a mixture of methanol and ether.

Sublimation of the free base at 160 ° C at 0.066 Pa gives a sample for analysis, m.p.

For C21H51NO2 calculated:

% H, 9.48;% N, 4.25. Found:

% C, 76.65;% H, 9.76;% N, 4.25

Example 74

2-Cyclobutylmethyl-2H, 9.alpha.-dimethoxy-5-methyl-6,7-benzomorphane hydrochloride (X1x)

By replacing the cyclopropylcarbonyl chloride used in the procedure of Example VII with an equal amount of cyclobutylcarbonyl chloride, the title compound of Formula Xx is obtained, m.p. 181-184 ° C. Celsius.

For -C20H29-NO2. HCl calculated:

68.26% C, 8.59% H, 3.98% N found:

% C, 67.99;% H, 8.52;% N, 3.76

Example 75

2-Cyclobutyl-ethyl-2'-hydroxy-9'a-methoxy-5-methyl-6,7-benzomorphine fumarate (XIIx)

By replacing the compound of formula XIa used in Example 8 with an equimolar amount of the compound of formula XIII, the title compound of formula XIIx is obtained as the free base. Instead of isolating this compound as the hydrochloride salt, it is isolated in the form of a fumarate, m.p.

For C19H27NO2 · (C4H4O4) calculated:

70.17 O / o C, 8.13% H, 3.90% N found:

% H, 8.04;% N, 3.62

Example 76

General procedure for preparing tartrates:

An equimolar amount (1: 1) of right or levosial or racemic tartaric acid and a suitable amine (e.g. an amine of formula IIIa) is dissolved in a minimum amount of hot Isopropanol or n-propanol to effect dissolution. By cooling and possibly scraping against the walls or by inoculation, the tartrate crystallizes and is isolated by filtration.

Example 77 (-) -2-Cyclopropylmethyl-2H-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphane d-tartrate

Replacing the corresponding amine of formula XII ¹¹ used in Example 76 with (-) -2-cyclopropylmethyl-2'-hydroxy-9? -Methoxy-5-methyl-6,7-benzomorphane of formula (-) XIIa is obtained in the title d-tartrate ((- β-XIIa-d-tartrate) having a temperature of 146.5 to 148.5 ° C. (α) _D ²⁰ = -37.5 ° (c = 0.986, 95% ethanol).

For (Ο18Η25ΝΟζ) 2 С4НбОб. 1/2 H2O calculated:

% C, 64.67;% H, 7.87;% N, 3.77.

% C, 64.34;% H, 7.51;% N, 3.86

Example 1 a d 78

5-allyl-2,9-dimethyl-9a-hydroxy-2'-methoxy-6,7-benzomorphane (VIu)

A solution of 113.5 g [0.80 mmol] of methyl iodide in 100 mL of anhydrous ether was added dropwise to 19.4 g (0.80 mmol) of magnesium coated with 400 mL of anhydrous ether in a 3-neck 3-neck flask. After completion of the reaction with magnesium, the mixture was heated to 60 ° C in an oil bath, the solvent was evaporated under a stream of nitrogen and the residue was subjected to a vacuum of 1 mm Hg. The flask, equipped with a mechanical stirrer and a dropping funnel, contains a nitrogen atmosphere. Then a solution of 57.4 g (0.20 mmol) of the ketone of formula Vm in 1 liter of petroleum ether with a distillation range of 30 to 60 ° C is added over 15 minutes with vigorous stirring. The mixture is stirred at 20-25 ° C for 18 hours, then 400 ml of water are carefully added and concentrated hydrochloric acid is added to the obtained suspension to adjust the pH to 8. The organic layer is separated and the aqueous phase is extracted twice 600 ml of ether each. The organic extracts were dried over sodium sulfate and concentrated in vacuo to give 57.5 g (100% yield) of the compound of formula VIu as an oil containing traces of the β-OH isomers. Recrystallization of the oxalate from methanol-ether gave the analytical sample, mp 208-209 ° C ^Q

For C 18 H 25 NO 2. C2H2O4 calculated:

% C, 63.65;% H, 7.21;% N, 3.71

% C, 63.78;% H, 7.41;% N, 3.92

Example 1 a d 79

5-Allyl-2-cyano-9α-hydroxy-2‘-methoxy-9/3-methyl-6,7-benzomorphane (XXVu)

A solution of 0.60 g (5.75 mmol) of cyanogen bromide in 25 ml of chloroform was added dropwise to a solution of 1.52 g (5.26 mmol) of the compound of formula VIu in 25 ml of chloroform. The mixture was heated to reflux for 22 hours, then the solvent was evaporated under reduced pressure to give 1.69 g of a brown oil which was chromatographed over silica gel. Elution with ether gave 1.32 g (83.5% yield) of the compound of formula XXVu. Recrystallization from ether / petroleum ether gave an analytical sample having a melting point of 103-105 ° C.

For C 18 H 22 N 2 O 2 calculated:

72.45% C, 7.43% H, 9.39% N from q 1 р '7РП ΓΊ ’

% C, 72.56;% H, 7.48;% N, 9.23

Example 1 a d 80

5-allyl-9a-hydroxy-2H-methoxy-9H-methyl-6,7-benzomorphane (Vilu)

To a suspension of 0.20 g (5.3 mmol) of lithium aluminum hydride in 25 ml of anhydrous tetrahydrofuran cooled in an ice bath was added dropwise a solution of 0.75 g (2.5 mmol) of the compound of formula XXVu in 30 ml of tetrahydrofuran. The mixture was heated under reflux for 17 hours, then cooled in an ice bath and the excess hydride was destroyed by successive addition of 0.2 ml of water, 0.15 ml of 20% sodium hydroxide solution and 0.70 ml of water. The solid thus obtained was filtered off and the filtrate was evaporated to dryness to give 0.58 g (85% yield) of an oil of formula VIIu, which was N-acylated without purification as described in Example 81.

Example 81

5-Allyl-2-cyclopropylcarbonyl-9α-hydroxy-2‘-methoxy-9,1-methyl-6,7-benzomorphane (IXu)

To a solution of 0.75 g (2.7 mmol) of the compound of formula VIIu in 20 ml of methylene chloride and

0.4 ml of itriethylamine, cooled in an ice bath, is added a solution of 0.31 g (3.0 mmol) of cyclopropylcarboxylic acid chloride in ml of methylene chloride. Remove the cooling bath, leave the reaction mixture at 20 ° C for 30 minutes, and filter the solid and wash with ether. The remaining filtrate was washed with dilute ammonium hydroxide and water, dried over sodium sulfate and evaporated under reduced pressure to give 1.00 g of an oil which was crystallized from ligroin. Yield: 0.79 g (84%).

For C21H27NO3 calculated:

H, 7.97; N, 4.10. Found:

H, 8.00; N, 4.01

Example 82

5-allyl-2-cyclopropylcarbonyl-2H, 9.alpha.-dimethoxy-9.alpha.-methyl-6,7-benzomorphane (Xu)

To a suspension of 130 mg (3 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 10 ml of dimethylformamide was added a solution of 341 mg (1 mmol) of the alcohol of formula IXu in 10 ml of dimethylformamide. The mixture was stirred at 70 ° C for half an hour, then cooled to room temperature and 710 mg (5 mmol) of methyl iodide in 10 ml of dimethylformamide were added. The reaction mixture was stirred for 3 hours, then poured into water and extracted with benzene. The organic extracts were dried over magnesium sulfate and evaporated to dryness to give 350 mg (99% yield) of the compound of formula Xu as a colorless oil.

By distillation at a temperature of 150-155 ° C at a pressure of 3.99 Pa, a sample is obtained for analysis.

For C22H29NO3 calculated:

% H, 8.23;% N, 3.94

H, 8.40; N, 3.87

Example 83

5-allyl-2-cyclopropylmethyl-2,9a-dimethoxy-9,3-methyl-6,7-benzomorphane (Xlu)

A solution of 711 mg (2 mmol) of the amide of formula Xu in 15 ml of tetrahydrofuran was added to a suspension of 228 mg (6 mmol) of lithium aluminum hydride in 35 ml of tetrahydrofuran. The resulting mixture was heated to reflux for 45 minutes, then cooled to room temperature and the excess hydride was destroyed by successive addition of 0.23 ml of water, 0.17 ml of 20% sodium hydroxide solution and then 0.81 ml of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The residue was dissolved in 1 N hydrochloric acid, extracted with ether, basified with ammonium hydroxide, and extracted with di 82 chloromethane. The extracts were washed with water, dried over magnesium sulphate and evaporated to give 570 mg (83.5% yield) of the amine Xlu as an oil. Distillation at 145 ° C at 0.66 Pa gives a sample for analysis.

For C22H31NO2 calculated:

% C, 77.38;% H, 9.15;% N, 4.10

% C, 77.19;% H, 9.23;% N, 4.06

Example 1 a d 84

5-Allyl-2-cyclopropylmethyl-2H-hydroxy-9'-methoxy-9/3-methyl-6,7-benzomorphane (XIIu)

A solution of sodium ethanethiolate is prepared by adding 2.2 ml (29 mmol) of ethanethiol to a suspension of 1.27 g (29 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 150 ml of dimethylformamide. To this was added a solution of 1.8 g (5.27 mmol) of the amine of formula Xlu in 25 mL of dimethylformamide, and the mixture was refluxed under nitrogen for 6 hours. The reaction mixture was poured into water, acidified to pH approximately 3 with concentrated hydrochloric acid, basified with concentrated ammonium hydroxide and extracted with benzene. The extracts were washed with brine, dried (MgSO4) and evaporated to dryness. The oil thus obtained is dissolved in ether, ethereal hydrogen chloride is added to the solution, and the precipitated salt is recrystallized from a mixture of methanol and ether to give the hydrochloride of the compound of formula XIIu.

Yield 1.32 g (70%), mp 248-250 ° C.

Distilling the free base at 145-150 ° C at 0.66 Pa yielded a sample for analysis.

For C21H29NO2 calculated: 77.02% C, 8.93% H, 4.28% N πλΙρτρϊίπ *

H, 9.10; N, 4.38

Example 85

2-Cyclopropylmethyl-2'-hydroxy-9of-methoxy-9H-methyl-5-propyl-6,7-benzomorphane (XIIuu)

A solution of 800 mg (2.38 mmol) of olefins of formula XIIu in 150 ml of anhydrous ethanol was hydrogenated for 1.5 hours using 250 mg of an activated carbon catalyst containing 10% palladium at an initial pressure of 50 psi. The catalyst is then filtered off and the solvent is filtered off. is removed under reduced pressure to give 670 mg (yield 84 prop.) of the compound of formula XUuu. The saturated compound was purified by crystallization of the hydrochloride from a mixture of methanol and ether. Mp 238-240 ° C.

By pre-distillation of the free base at 145 ° C at 0.266 Pa, a sample is obtained for analysis.

For C21H31NO2 calculated-:

76.55% - C, 9.48% H, - 4.25% N found:

% C, 76.36;% H, 9.55;% N, 4.20

Example 86

.. 5 allol-2-cykl.obutylkarbonyl-9a-hodroxy-2 ^{<-me'thoxy-9β-menthol-6,7-benzomorphan} - (IX-q)

A solution of 720 mg (2.63 mmol) of hydroxylamine of formula VII in 25 ml of dichloromethane and 2 ml of 1-ethylamine was cooled to 0 ° C and 343 mg (2.90 mmol) of the acid chloride were added dropwise. The cooling bath was removed and the solution was stirred at room temperature for 1 hour, then the reaction mixture was washed with 1 N hydrochloric acid, water, dried over magnesium sulfate and evaporated to dryness to give 810 mg. (86.6% yield) of an amide of formula (IXq), which is recrystallized from a mixture of ether - petroleum ether with a distillation range of 30 to 60 ° C, mp 112 - 113 ° C.

For C22H29NO3 calculated:

74.33 ° / o c, 8.22 θ / ο H, 3.94% N found:

H, 8.47; N, 3.83

Example 87

5-allyl-2-cyklpbu'tylkarbonol-2 ', 9 _l ^and, -dimet.hoxy-9- ^ meιehyl - 7 - Enzo <Alfan (Xq)

To a suspension of 262 mg (6 mmol) of sodiumhodride (55% in mineral oil, washed with benzene) in 50 ml of dimetholformamide was added 711 mg (2 mmol) of hydroxiamide of formula IXq and stirred at 85 ° C for minutes. The reaction mixture was cooled to room temperature and 1.42 g (10 mmol) of methyl iodide was added. After stirring for 1 hour, the solution was diluted with water and extracted with benzene. The extracts were washed with water, dried (MgSO4) and the solvent removed under reduced pressure. The dimethoxyamide of formula (Xq) is obtained in the form of a viscous oil in quantitative yield.

For C23H31NO3 calculated:

74.76 -% C, - 8.46% H, - 3.79-% N found:

74.50% -C, 8.87% H, 3.72% N

Example 88

5-allol-2-cyclobutylmethyl-2 ', 9a! _{Dimethoxy-9-one} 3-methyl-6,7-benzomorphan (Xlq)

A solution of 740 mg (2 mmol) of the amide of formula Xq in 50 ml of tetlahodrofuran is added to a suspension of 380 mg (10 mmol) of lithium aluminum bromide in 50 ml of tetrahodrofuran. The reaction mixture is heated at reflux for 1.5 hours, then cooled and the excess hydride is destroyed by the successive addition of 0.38 ml of 20% sodium hydroxide solution and finally 1.33 ml of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The residual oil was dissolved in 1 N hydrochloric acid, extracted with ether, basified with concentrated ammonium hydroxide and extracted with dichloromethane. The organic extracts were washed with water, dried (MgSO4) and evaporated to give 470; mg (yield 66%) of the compound of formula XIq as a going. Its hydrochloride melts after recrystallization from methanol-ether at 206 DEG-209 DEG.

For - C233H35NO2. HCl calculated:

70.48% C, 8.74 0/0 H, 3.57% N found:

% C, 70.42;% H, 9.00;% N, 3.44

Example 1 and -d 89

5-Allol-2-cyclobutol-methanol-2'-hydroxy-9-methoxy-methoxo-9 H / 3-methyl-6,7-benzomorphane (XIII)

A solution of sodium ethanethiolate was prepared by adding 0.84 ml (11 mmol) of ethanethiol to a suspension of 480 mg (11 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 50 ml of dimethylformamide. To this reagent was added 711 mg (2 mmol) of dimethoxoamine of formula XIIl dissolved in 25 mL of dimetholformamide. The reaction mixture was then refluxed under nitrogen for 4 hours. The solution was poured into 350 ml of water, acidified to pH 4 with concentrated hydrochloric acid, basified with concentrated ammonium hydroxide and finally extracted with benzene. The extracts were washed with water, dried over magnesium sulfate and evaporated to a residue. drought. The residual oil was dissolved in ether and ethereal hydrogen chloride solution was added. The precipitated salt was recrystallized from a mixture of methanol and ether. Yield 400 mg (53%), mp 22.2-224 ° C (compound of formula XII-qj).

By distilling the free base at 150 ° C at 0.066 Pa, a sample is obtained for analysis.

For C22H31NO2 calculated:

% C, 77.38;% H, 9.15;% N, 4.10%.

77.45% C, 9.41% H, 4.05% N

Example 90

2-Cyclobutylmethyl-2‘-hydroxy-9α-methoxy-9β-methyl-5-propyl-6,7-benzomorphane (XIqq)

A solution of 900 mg (2.6 mmol) of olefins of formula XHq in 300 ml of anhydrous ethanol is hydrogenated for 1.5 hours at an initial pressure of 300 psi using 300 mg of an active carbon catalyst containing 10% palladium. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to give 870 mg (96.5% yield) of a compound of Formula IIIqq as a thick oil. This compound. is purified by recrystallization of its hydrochloride. Melting point: 226-228 ° C.

The free base was distilled at 150 ° C at 0.066 Pa to give a sample for analysis.

For C22H33NO2 calculated:

% C, 76.92;% H, 9.68;% N, 4.08.

% C, 76.74;% H, 9.84;% N, 4.05

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of 6,7-benzomorphanes derivatives of the general formula L wherein R ¹ represents a group of the formula R ² represents hydrogen or alkyl .s 1 to 6 carbon atoms, R ⁵ represents an alkyl group having 1 to 6 carbon atoms; (C 2 -C 6) alkenyl, R ⁴ is hydrogen or C 1 -C 6 alkyl; R ⁵ represents an alkyl group having 1 to 6 carbon atoms or an allyl group, or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutically acceptable salt thereof. a racemic mixture thereof or an optical isomer thereof, characterized in that the compound of formula (VII): wherein: R is a hydroxyl protecting group, preferably an alkyl group having from 1 to 6 carbon atoms and R 3 and R 4 'are as defined above, to react with a compound of the general formula to attach a protecting group to a ring nitrogen atom X-CO-Ζ »Х-СО— <ф>, X-CO-CF ₃ I 4kde X is chlorine, bromine or iodine; R 10 represents an alkyl group having 1 to 6 carbon atoms, optionally with a compound of the general formula X is as defined above, the compound thus protected is treated with an alkali metal hydride, preferably sodium hydride, and the resulting compound is then alkylated to prepare a compound of formula VII. X — CN where R, R ^3, R ⁴ and R ⁵ are as defined above, and optionally, if the protecting group attached to a ring nitrogen atom, a group ^-CO-O-R10, -CO-CF3, or -CN, wherein R ¹⁰ has the abovementioned meaning, this protective group is removed, the resulting compound of formula VII 'wherein R, R ^3, R ⁴ and R ⁵ are as defined above, \ is acylated or alkylated NH group to give a to give compound of formula X wherein R ^{@ 3} , R ^{@ 3} , R ^{@ 4} and R ^{@ 5} are as defined above and R ^{@ 8} is a radical of formula -co— · -CO-- <2> члЬо-Ср СН ^ ^ _k * CH and. when R ⁸ radical containing a carbonyl group, the carbonyl group is reduced to methylene with a reducing agent, preferably lithium aluminum hydride to give a compound of formula XI known, then the protective group R hydroxyl group removed to give compound wherein R ² is hydrogen and R ¹ , R ³ , R ⁴ and R ⁵ are as defined above, optionally converting the hydroxyl group in the position to -OR ² wherein R ² is an alkyl group of 1 to 6 carbon atoms, and when the compound of formula L is a racemic mixture, it is optionally resolved into its optical isomers, a. if an acid addition salt of a compound of Formula L is to be prepared, the compound is reacted with a pharmaceutically acceptable acid. R, R ¹ , R ³ , R ⁴ and R ⁵ have the aforementioned