FI60564B - REFERENCE TO A PHARMACOLOGICAL PROPERTIES OF N-SUBSTITUTES-9-ALCOXY-5-ALKYL-6,7-BENZOMORPHANE - Google Patents

Description

· If.flfaj-! Γοΐ ANNOUNCEMENT / λγ ^ ι [β] (11) UTLÄGGN INGSSKRIFT ° * C / 45J Patent aydnnotty 10 02 1932 Patent aeddelat (51) K ».ik.3 / int.ci.3 C 07 D 221/26 § ^ JQ | V || aBl. |: || ^ laANO (21) Pttunttlhtkumui - PitanCuudknlng 731106 (22) Hakamltpllyi - Ant6kningvdag 15 · 0U.7 5 ^ ^ (23) Alkupllvt — Glltlghetsdag 15.OU.75 (41) Tullut | «Kat - Bltvtt offantilg 19.10.75

Patent and Registration Office .... .. , . . , '(44) Nlhtlviktlpanon | i kuutjutkalsun pvm. -

Patent- oeh registerstyrelsen AnaBkan utlagd och utl.akriftan publkerad 30.10.8l

(32) (33) (31) Requested Fellowship - Bugird prlorltat l8.OU.7U

USA (US) U62007 (71) Bristol-Myers Company, 3U5 Park Avenue, New York, New York, USA (US?) (7?) Thomas Alfred Montzka, Manlius, New York, John Daniel Matiskella, Liverpool, New York, USA (US) (7U) Oy Kolster Ah (5U) Process for the preparation of a pharmacologically useful N-substituted-9-alkoxy-5-alkyl-6,7-benzomorphan - Preparation of a pharmacologically acceptable N-substituted-9-alkoxy-5 ~ al-ky1-6,7-bensomorfan

The present invention relates to a process for the preparation of a pharmacologically useful N-substituted-9-alkoxy-5-alkyl-6,7-benzmorphane of the formula I OR5 R360564 having> ~ C1l2 - <^ j -CH2-7 2 5 4

R is hydrogen or methyl; R is lower alkyl, allyl or propargyl; R

3 is hydrogen or lower alkyl; and R is lower alkyl or allyl; or a pharmaceutically acceptable acid addition salt or racemic mixture or optical isomers thereof.

Drug abuse has become increasingly common in today’s society. One group of widely misused drugs is narcotic analgesics, e.g., codeine, morphine, meperidine, etc. Due to their high preference for these substances, the pharmaceutical industry and governments have sacrificed a lot of time and money trying to invent and develop new analgesics and / or narcotic antibodies. that do not elicit preference. As examples of previous attempts to solve this problem, I refer to the following: (1) Everette May and Hiroshi Kugita, J.Qrg. Chem. 26, 188 (1961), wherein the compounds have the formula

R 0 OB

«3 2 wherein R is H or methyl and R is methyl or phenethyl and which compounds are analgesic agents having a moderate to weak effect; (2) Everette May, James Murphy, and J. Harrison Ager, J. Or g. Chem. 25, 1386 (1960), wherein the compounds have the formula 3 60564 013 2 wherein R is those of style or phenethyl and R is H or methyl, and which compounds are analgesic agents; (3) Everette May, Hiroshi Kugita, and J. Harrison Ager, J. Qrg. Chem. 26, 1621 (1961), wherein the compounds have the formula; ♦ O # I OH CH3 1 3 wherein R is methyl or phenethyl, R is methyl or H, R is H, OH or carpet, which compounds provide varying degrees of analgesia; (4) Everette May, Colin Chignell and J. Harrison Ager, J. Med. Chem. 8, 235 (1965), wherein the compounds have the formula J3 & i R C3H7 6 0 5 6 4 1 2 wherein R is H or methyl and R is methyl, and which compounds have analgesic activity; (5) Everette May and Hiroshi Kugita, J.Qrg. Chem., 26, 1954 (1961), wherein the compounds have the formula

Ro i V

® 3 1 2 wherein R is methyl or phenethyl, R is H or methyl and R is H or acetyl, and which compounds have analgesic activity; (6) Everette May and Seiichi Sato, J. Org. Chem., 26, 4536 (1961), wherein the compounds have the formula R1 2 1 3 wherein R is H or methyl, R is methyl or ethyl, R is methyl or ethyl 4 and R is H or acetyl, and the compounds have analgesic activity ; and (7) N. B. Eddy and E.L. May published a review of 6,7-benzomorphanes in Synthetic Analgetics, Fergancn Press (1966).

It is an object of the invention to provide novel analgesic agents and / or antibodies to narcotic agents which do not confer a preference. According to the invention, there is provided a process for the preparation of the novel compounds mentioned in the introduction, which process is not dependent on starting materials such as opium alkaloids and which process is commercially feasible.

The process of the invention is characterized in that (a) a compound of formula 5 60564 3 4 wherein R is a hydroxy protecting group and R and R are as defined above is reacted to replace the ring nitrogen with an electron withdrawing protecting group which prevents amine quaternization ; (b) treating the resulting protected compound with a strong base, preferably alkaline tallow hydride, then alkylating to form the corresponding 9-OR 4 - 3 4 5 substituted compound wherein R, R and R and R are as defined above, or treating the protected compound with a diazo (lower) compound. ) with an alkane or tri (lower) alkyloxonium fluoroborate to alkylate a 9-OH group and form a 5-9-OR-substituted compound wherein R is lower alkyl and 3 4 R, R and R are as defined above; (c) and when the electron withdrawing protecting group in the ring nitrogen is a functional group other than the group represented by the formula 5_ / 1? The deprotecting group -C or -C- is removed in a manner known per se to form a compound of formula 80 1 R 5 R 3. 3 4 5 wherein R, R, R and R are as defined above, the acyl group is then acylated or alkylated in a manner known per se to form a compound of formula 6 60564 x # 'OR5 R3 O o yv wherein R8 is -C-, - C is -CH 2 -CH = CH 2; g (d) and when R is a carbonyl group-containing group, the carbonyl group is reduced to methylene by treatment with a reducing agent, preferably lithium aluminum hydride, to give a compound of formula already # 1 OR R3 same as above; (e) the hydroxy protecting group R is then cleaved in a manner known per se to form a compound of formula L wherein R is hydrogen; (f) optionally then reacting the 2'-hydroxy group in a manner known per se to form the corresponding compound of formula L, wherein R is methyl; (g) and if the compound L is a racemic mixture then it is optionally decomposed into optical isomers in a manner known per se; (h) and, if desired, an acid addition salt of a compound of formula L is reacted with a pharmaceutically acceptable acid in a manner known per se.

The compounds of the invention have a basic benzmorphane backbone represented by the following plan formula with numbers; 7 60564 3 4 '2 ^ iL I *

R

Although the benzcmorphan molecule has three asymmetric carbon atoms, only two racemic forms are possible because the iminoetano system attached at positions 1 and 5 is contained in a geometric, cis- (1,3-diaxial) linkage. These racemates can therefore differ only in the configuration of carbon 9. The only variable is the cis- and trans-ratio of the 9-alkoxy compound to the iminoetano system. When 9-alkoxy is present in the compounds of the invention with respect to the trans-iminoetano system, we have 9c {alkoxy-benzmorphans. When 9 is alkoxy en cis with respect to the iminoetano system then we have 9f -alkoxybenzomorphans.

As used herein, a graphical representation of benzamorphan refers to a dl-racemic mixture and its decomposed d- and 1-isomers.

Compounds, e.g. 9 / S -alkoxybenzomorphans, can exist as two optical isomers, i. as the levorotatory and right-rotating isomer. The optical isomers can be represented graphically as follows: 9o (-methoxybenzornorphan: »Μλ 3

I H CH- H

ch3

The present invention encompasses all isomers, including optical isomers in their dispersed form.

δ 60564

The optical isomers can be separated and isolated by partitioning the diastereoisomeric salts formed, e.g. with d- or 1-tartaric acid or d - (+) - bramcamphorosulfonic acid. Other conventionally used acids can also be used for decomposition.

Circulating isomers of the compound are the most preferred embodiments.

By the term "lower alkyl" is meant an alkyl radical containing 1 to 6 carbon atoms. By the phrase "pharmaceutically acceptable acid addition salts" is meant all inorganic and organic acid salts of the compounds of the invention which are conventionally used to prepare relatively non-toxic salts of amine-containing drugs. Illustrative examples are those salts formed by mixing compounds of formula L with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, maleic acid, malic acid, ascorbic acid, citric acid, tartaric acid, stearic acid, lauric acid, lauric acid, lauric acid, lauric acid, lauric acid with laurylsulfonic acid, naphthalenesulfonic acid, linolenic acid, fatty acid fumaric acid or the like.

The process according to the invention is illustrated by the following reaction schemes I and II: 6 O 5 6 4

Scheme I

„IQXJl 1» >> JQl3l

CH 2 O O CH 3 O

1 IIa CH3 mT ^ ^ Vf / C "3 j ^ Q - =» 1 ^ jglT ^ vv ·, C1.3 ° IS 0 ch CH3 ° T ° Br® III, VK 2-C6H5 CH3 CH3 iva oxalate yr HBr CH OO CH30 ''

<L -E-? Sign 1 e)> CH ° H

Va 3 λ ^ 3 VIa CH3. % ^ CH3 VIIa / \ ^ ho I ÖCH-CH3 XI Ia '3 10 60564

Figure II

tT Example 17 c) a —- * foi / tt ch3os ^ s> ^ \ / I tu2 j & y 'ch3

XX

<S ~ ^ Y ^ r * N-Cih 17 e>> ÄK (lL ° ch3 ° t \ CH3 C “3 3 ft CH3 CII3

VIr XXI

ffXExample 17ak 3 T “3 X'e,

Vllr yV / 3 N “CH2 ~ <]

JsC ^ JL 0CH-> ho r '> I CH3 Kllr ch3 11 60564

Compounds of formula OR 5 R 3 1 5 4 3 wherein R is as defined above, R en is methyl, R is H and R is methyl, or pharmaceutically acceptable acid addition salts thereof are particularly preferred as narcotic agonists / antagonists.

All of the compounds of the preferred embodiments are novel and valuable as analgesic agents and / or antibodies to narcotic agents or as intermediates in the preparation of compounds having these biological activities.

The compounds of formula XII have the most advantageous properties, i. analgesic and / or narcotic-antagonistic properties. In addition, the compounds of formula XII have antitussive activity, a property generally associated with analgesic activity.

The strongest and most desirable compounds are those compounds of formula XII wherein R 1 is 9β-hydrogen and OR 1 is 9c {alkoxy. This is a surprising finding because in the corresponding series of compounds where OR 1 is OH, the more potent and desired compounds are generally 9/9-OH and 9β-hydrogen or (lower) alkyl.

With respect to known narcotic analgesic agents, it is well known that it is possible for the same compound to have both agonistic and antagonistic properties. An agonist compound is a compound that resembles a narcotic analgesic and has analgesic properties. An antagonist is a compound that acts against the analgesic and euphoric properties of a narcotic analgesic. It is possible that one compound has both properties. A good example of such compounds is cyclazocine.

Finding compounds with the right agonistic / antagonistic effect ratio is important for commercial success. Compounds with too strong an antagonistic effect produce undesirable psychotemic effects (hallucinations), making these compounds undesirable in clinical use.

The compounds of the invention (in the form of their corresponding soluble salts) were tested in vivo to determine their agonistic and / or antagonistic properties. Table I did not show the results of the experiments. The figures in Table I indicate how many mg of compound per kg of body weight when administered subcutaneously produce an agonistic or antagonistic effect in 50% of the mice and rats studied (ED 2 q).

60564 12 i

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co «v p o? Ό Ό Ό 14 6 0 5 6 4 A 50% reduction in the number of phenylquinone-induced distortions (Siegmund, E.A. et al., Proc. Soc. Biol. & Med. 95, 729; 1957).

2

Antimicrobial effect of oxymorphone (2 mg / kg se.) In 50% of mice.

3

Antagonistic effect of loss of straightening reflex induced by oxymorphone (1.5 mg / kg se.) In 50% of rats.

4

50% reduction in the analgesic effect of morphine (15 mg / kg se.) As measured by the rat cancer procedure (Harris, L.S. and Pierson, A.K., J. Pharmacol. & Expt. Therap., 143, 141; 1964).

^ N.D. - Not done.

^ All reported weights corrected for free base.

From the results of Table I, it is clear that the compounds according to the invention have a strong agenistic and antiganistic effect. The normal parenteral dosage range for the compounds for adults is about 0.25 to 10 mg given three or four times a day. The oral dose is in the range of about 1-50 mg three or four times a day.

Compounds of formula XII can be readily converted to compounds of formula L. Esters and ethers of formula XII may in certain cases have a particular advantage due to their improved solubility, low solubility, simplicity of crystallization, lack of repulsive taste, etc., but these are all less important than the main physiological effect of free phenol, which is independent of the ester or ether. .

The preferred compound has the formula / n-r1 R07 bR5 R3

Preferred compounds of formula XXXX are: A) (+) - 2-cyclopropylmethyl-21-hydroxy-9β-methoxy-5-methyl-6,7-benzemorphan or an acid addition salt thereof.

B) (-) - 2-cyclopropylmethyl-21-hydroxy-9 ° -methoxy-5-methyl-6,7-benzemorphane; or a hydrochloride, fumarate or tartrate salt thereof.

60 5 6 4 C) (+) - 2-Cyclobutylxmethyl-2'-hydroxy-9X-net-5'-methyl-6,7 "benzomorphalea or its acid addition salt.

D) (-) - 2-Cyclobutylmethyl-2'-hydroxy-9H-methoxy-5-methyl-6,7'-benzonioraphane or its hydrochloride, fumarate or tartrate salt.

E) (+) - 2-allyl-2'-hydroxy-9H-methoxy-5-methyl-6,7-benzomorphane or an acid addition salt thereof.

F) (-) - 2-Idlyl-2'-hydroxy-90 H -methoxy-5'-ethyl-6,7-benzomorphan tax its hydrochloride, fumarate tax tartrate salt.

G) (+) - 2-cyclopropylmethyl-9α-ethoxy-2'-hydroxy-5-methyl-6,7-benzomorphane; tax its acid addition salt.

H) (-) - 2-Cyclopropylmethyl-9'-ethoxy-2'-hydroxy-5-methyl-6,7-benzomorphane or its hydrochloride, fumarate tax tartrate salt.

I) (+) - 2-cyclopropylmethyl-2'-hydroxy-9 ', methoxy-5'-allyl-6,7-benzomorphane; tax its acid addition salt.

J) (-) - 2-Cyclopropylmethyl-2R-hydroxy-9α-netoxy-5 "allyl-6,7" benzomorphane; tax hydrochloride, fumarate tax tartrate salt.

K) (+) - 2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-5-allyl-6,7-benzophorane; tax its acid addition salt.

L) (-) - 2-cyclobutylmethyl-2'-hydroxy-9-ethylethoxyl-5-allyl-6,7-benzomorphane; tax its hydrochloride, fumarate tax tartrate salt.

M) (+) - 2-cyclopropylmethyl-2, -hydroxy-9-methomethoxy-5-propyl-6,7-benzomorphane; or an acid addition salt thereof.

N) (-) - 2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-5-propyl-6,7-'oenteomorphane; or its hydrochloride, fumarate tax tartrate salt.

O) (+) - 2-cyclobutylmethyl-2'-hydroxy-9-methoxy-5-propyl-6,7-benzomorphnan, or an acid addition salt thereof.

P) (-) - 2-cyclobutylmethyl-2'-hydroxy-9-methoxy-5-propyl-6,7-benzomorphalea; tax its hydrochloride, fumarate tax tartrate salt.

Q) (-) - 5-allyl-2-cyclobutylmethyl-2'-hydroxy-9-ethoxy-9H-methyl-6,7-benzomorphane; tax its hydrochloride, fumarate tax tartrate salt.

R) (-) - 2-cyclobutylmethyl-2'-hydroxy-9? -Methoxy-N, N-methyl-5-n-propyl-6,7-benzomorphane; tax its hydrochloride, fumarate tax tartrate salt.

S) (-) - 5-allyl-2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-9γG-acetyl-6,7-bentcomorphane; tax its hydrochloride, fumarate tax tartrate salt.

T) (-) - 2-cyclopropylmethyl-2'-hydroxy-9-methomethoxy-9H-methyl-5-n-propyl-6,7-benzomorphane; tax its hydrochloride, fumarate tax tartrate salt.

16 60564

Another preferred compound has the formula

| li 1 l'R XXXXI

ö * ° R

R o

The most preferred compounds of formula XXXXI are: A) (1) -5-allyl-2-cyclobutylmethyl-2'-hydroxy-9/5-methoxy-6,7-benzmorphane; or an acid addition salt thereof.

B) (-) - 5-allyl-2-cyclobutylmethyl-2'-hydroxy-9β-methoxy-6,7-benzanorphane; or a hydrochloride, fumarate or tartrate salt thereof.

C) (i) -5-allyl-2-cyclobutylmethyl-2'-hydroxy-9β-methoxy-9K-methyl-6,7-benzororphane; or an acid addition salt thereof.

D) (-) - 5-allyl-2-cyclobutylmethyl-2'-hydroxy-9β-methoxy-9β-methyl-6,7-benzomorphane; or a hydrochloride, fumarate or tartrate salt thereof.

In treating the ring nitrogen-protected compound in step (b) with a strong base, alkali retallic hydride and most preferably sodium hydride are preferably used in a ratio of about 1 to 1.1 moles of base per mole of the protected nitrogen compound in an inert solvent such as dimethylformamide, dimethylformamide, dimethylacetamide, tetrahydrofuram, or in diethyl ether.

In step (c), when the ring nitrogen protecting group is other than the desired group, it is removed in a manner known per se. For example, when the protecting group is a carbalkoxy or trifluoroacetyl group, the compound is preferably hydrolyzed with a strong alkali metal base, preferably potassium hydroxide in a lower alkanol, preferably 95% ethanol, to give an unprotected secondary ring amine. When the protecting group is a cyano group, the compound is preferably treated with lithium aluminum hydride in tetrahydrofuran under reflux, followed by treatment with water and sodium hydroxide to give an unprotected secondary amine.

The acylation in step c) is preferably carried out with an acid halide, anhydride or mixed anhydride of a compound which does not form:

O O

HO-C - <^ j, -c - <^ or -ch2-ch = ch2 in an inert organic solvent such as methylene chloride, chloroform, diethyl ether and the like without heating or heating, in the presence of a tertiary amine; and the alkylation is preferably performed with a compound of the form: 60564 X-CH -C = CH, X-CH - CH = CH, X-CH -CHC <^ or -CH - CH = CH,

ä £. Δ 2. prj ^ I

Cl wherein X is chlorine, bromine or iodine, in an inert organic solvent, preferably a lower alkanol.

The reduction in step (d) is carried out in an inert organic solvent such as diethyl ether, tetrahydrofuran, dioxane or the like and most preferably with heating.

When R is lower alkyl, the R group is preferably cleaved in step (c) by selective treatment with sodium thioethoxide, boron tribromide, pyridine hydrochloride or hydrobromic acid in a suitable solvent in a manner known per se. Most preferably, the hydroxy protecting group R is cleaved off by reaction with sodium thioethoxide in dimethylformamide. When R is acyl or alkanoyl, R is most preferably removed by hydrolysis.

The compounds of the invention and certain of their intermediates exist as optical isomers, i. as right-handed, left-handed and racemic mixtures. It will be appreciated that these intermediates and final products may be decomposed at any stage of the process, or the compounds L may be decomposed at the end of the process, according to methods known in the art. Starting from the levorotatory form of compound VII at the beginning of the process, the process described above gives compound L as the levorotatory isomer.

Example 1 ^ 3 ° i -7-methoxy-1-methyl-2 (1H) -naphthalenone (IIa) 40.5 g (0.5 mol) of pyrrolidine dissolved in 50 ml of benzene are added under a nitrogen atmosphere and to a stirred solution of 50 g ( 0.284 moles) of 3,4-dihydro-7-methoxy-2 (1H) naphthalenone (I) in 200 ml of dry benzene. The mixture is heated to reflux for 1 hour and 5 ml of water are collected in a Dean-Stark apparatus. The mixture is cooled and slowly added to 0.5 mol of methyl iodide dissolved in 300 ml of benzene. The resulting mixture is heated to reflux for 3 hours. 200 ml of water are then added to the reaction mixture and refluxing is continued. After 30 minutes the mixture is cooled and the benzene is separated off, washed with water saturated with sodium bisulphite, dried and evaporated to dryness. The obtained residue is distilled to give the title compound (Ha). Infrared and nuclear magnetic resonance (NMR) spectra were consistent with the structure.

b) m (c ° 2h) 2 / V ^ S <rS> / ch3 IIIa CH3 ° c <s „2-ch2- <clh_r \ 1- (2-benzylctylaminoethyl) -7-methoxy-1-methyl-3, V-dihydro-2 (1H) -naphthalenone hydrogen oxalate (purple)

A solution of 0.12 moles of 7 "methoxy-1-methyl-3,14-dihydro-2 (1H) naphthalenone (Ha) in 0 ml of benzene is added to a refluxing suspension of 0.1 M moles of sodium hydride. After heating under reflux for 1 hour, the mixture is treated with a solution of 0.12 mol of 2-benzylmethylaminoethyl chloride in 100 ml of benzene and heated under reflux for 18 hours. extraction with ether gives an oil which is converted to the oxalate salt (purple) (yield 78%) mp 137-139 ° C.

Anal Calcd for C 22 H 27 NO 2 * C 2 H 2 O 1: C> H »6.8U; 3.23.

Found: C, 67.25; H, 7.05; N, 3.50.

c) rt & VO.

CH.O J no.

J r.tr w13 g-Benzyl-2, -methoxy-5-methyl-9-oxo-6,7-benzofuromethyl bromide (IVa) The title compound is converted into the hydrobromide salt by treatment with sodium hydroxide solution, separation by extraction with ether and extraction with ether. H3R-Fi. 0.21 mol of the hydrobromide salt is dissolved in 1 + 50 ml of acetic acid and treated slowly with a solution of 11.2 ml of bromine in 50 ml of acetic acid and stirred for 1/2 hour. It is diluted with two liters of "Skellysolve B" (trademark, manufactured by Skelly Oil Company and comprising essentially n-hexane) and cooled under a nitrogen atmosphere. The "Skellysolve B" layer is decanted separately from the gummy precipitate. The residue is partitioned between ether and water. This 2-phase system is basified with concentrated ammonium hydroxide. The layers are separated immediately and the aqueous layer is extracted with ether. Concentration of the ether extracts gives an oil. This oil is taken up in acetone and stirred for several hours to give the title compound (IVa) as a crystalline solid (76% yield).

d). Va £ öf-

CH, 0 i O

<3 1 ch3 2-N-dimethyl-N-methoxy-N-oxo-ethyl-N-benzoniorphane (Va).

Reduction of IVa-acetic acid 3a using hydrogen and 10% palladium on carbon gives the title compound (Va) in a yield of 92 $ S, m.p. II + 5-yl * 9 ° C. This compound is the known compound of L. May et al., J. Org. Chem. »25, 1386 (1960). This synthesis is an improved method for preparing these compounds.

e)> s.

jCÖP-

CH3O'0H

σΐ3 20 60564 2,5-Dimethyl-9H-hydroxy-2 * -methoxy-6H-benzomorphan (Via) 0.02 moles of 2,5-dimethyl-2'-methocai-9'-oxo-6,7'-benzomorphan ( V) Dissolve 1 and 8 g of cobalt chloride hexahydrate in 100 ml of 95% -Bte ethanol with gentle warming and stir for 1/2 hour at room temperature Add U g of sodium borohydride portionwise with stirring under a nitrogen atmosphere The resulting dark mixture is stirred at room temperature under a nitrogen atmosphere for 18 hours. Carefully add 75 ml of 6N hydrochloric acid and remove the ethanol under reduced pressure, basify the resulting blue solution with concentrated ammonium hydroxide and extract with methylene chloride. containing 88% oC-hydroxy isomer and 9% Λ-hydroxy isomer By crystallization from ethyl acetate / "Skellysolve B" to give the pure o-isomer (Vie); mp 115.0-116.5 ° C (m.p. 2 mp 115.5-117 ° C).

^ J. G. Murphy, J. H. Ager and E. L. May, J.

Org. Chem., 25, 3386 (1960).

n H Kugita and E. L. Mey, J. Org. Chem., 26, 195U (1961).

f) f / Vila

cnrfKA | ^ r H

3, \

i OH

Ch39,9-hydroxy-2 * -mathoxy-5-methyl-6,7-benzomorphane (VIIa) hydrogen oxalate 0.01 mol of compound Via are acetylated in 50 ml of acetic anhydride at steam bath temperature for 2 hours to give the P-ethoxy compound. This material is taken up in 75 ml of benzene, treated with 2 g of potassium carbonate and 5 ml of ethyl formate and heated under reflux for 18 hours. The resulting mixture is washed with water, dilute hydrochloric acid and saturated sodium chloride. The aqueous layers are extracted twice with benzene. The benzene layers are dried (K 2 CO 2) and concentrated to 90 ° C-acetyl-2'-methoxy-5-methyl-6,7-benzomorphane.

21 60564 This material is hydrolyzed with potassium hydroxide (25 g of 85% beads) under reflux in 95% ethanol (125 ml) for 66 hours. The ethanol is removed under reduced pressure. The residue is treated with dilute sodium carbonate and extracted with methyl chloride to give the title compound (VIIa) which is converted to the hydrogen oxalate salt in 95% ethanol (89% yield); mp. 212-215 ° C.

Anal Calcd for C 14 H 19 NO 2 * C 2 H 2 O 4: C 'H' 6.55; N '4.33.

Found: C, 59.58; H, 6.31; N, 4.44.

g) 0.015 mol of compound VIIa as the free base in 50 ml of methylene chloride and 8 ml of triethylamine are treated with 2.3 ml of cyclopropylcarbonyl chloride under a nitrogen atmosphere. The reaction mixture is stirred for 1 hour and then treated with 7 ml of methanol, stirred for 5 minutes and concentrated to dryness. The residue is taken up in toluene and washed with dilute hydrochloric acid, water and saturated sodium carbonate. Upon drying and concentration of the toluene extracts, 2-cyclopropylcarbonyl-2'-methoxy-9 C-hydroxy-5-methyl-6,7-benzomorphane-IXa, about 100% yield, greater than 98% purity is obtained by GLC analysis. according ^. A solution of IX in dimethylformamide (25 mL) is added to a suspension of NaH (0.015 mol) in 10 mL of dimethylformamide under nitrogen. After 1/2 hour, methyl iodide is added twice at hourly intervals (1 ml at a time) and the mixture is stirred for a further 16 hours. After removal of the solvent under reduced pressure, the residue is treated with water and extracted with methylene chloride using 2-cyclopropylcarbonyl-2 ', 9c-dimethoxy-5-methyl-6,7-benzcmorphane-Xa, about 100% yield, 98% purity GLC according to the analysis. This material is reduced with LiAlH 2 in tetrahydrofuran for 16 hours to give the title compound which is separated as the crystalline hydrochloride salt (1.4 g, 85% yield); mp. 230-233 ° C

'Aneil. Calcd for δ ^ ^^ ΪΚ ^ .ΗΟΙ: C, 67.54; H, 8.35; N, 4.15.

Found: C, 67.58; H, 8.46; N, 4.36.

Example 2 I ji f ^ gH xiia

HO

1 OCH I 3 ch3 6 0 5 6 4 22 2-Cyclopropylmethyl-2'-hydroxy-9g <-methoxy-5-methyl-6,7-benzomorphane (Xlla)

A mixture of compound XIa (0.0028 mol) and 0.05 sodium thioethoxide (prepared from sodium hydride and ethyl mercaptan) in 80 ml of dimethylformamide is heated under reflux for 3 hours. The solvent is removed under reduced pressure. The residue is treated with toluene and extracted with dilute hydrochloric acid. The acid extracts are basified (Na 2 Cl 2) and extracted with methylene chloride to give compound Xlla, which is crystallized from acetonitrile, m.p. 188-189 ° C.

Anal Calcd for C 18 H 18 N 2 O 2: C, 75.22; H, 8.77; N, 4.87.

Found: C, 75.31; H, 8.85; N, 5.18.

Example 3 2-Cyclopropylmethyl-2 *, 9σ {-dimethoxy-5,9 / 3-dimethyl-6,7-benzomorphane (Xlb) -fumarate a) -CH- .0 7 v

J I OH

GHS

5,9 / 5-dimethyl-9g (-hydroxy-21-methoxy-6,7-benzomorphane (VIIb) -futarate

A refluxed mixture of 0.032 mL of 9β-hydroxy-2'-methoxy-2,5,9β-trimethyl-6,7-benzomorphane was prepared according to the method described in May et al. In J. Org. Chem. 26, 188 (1961)) and 26 g of potassium carbonate in 150 ml of benzene are treated with a solution of 0.095 m of trichloroethyl chloroformate in 100 ml of benzene. After refluxing for 60 hours, the reaction mixture is treated with 200 ml of water and stirred for 1/2 hour. The benzene layer is separated, washed with saturated sodium chloride, dried (MgSO 4) and concentrated to give crude 2-trichlorocarbethoxy-5,9-diroethyl-93, C-hydroxy-2-methoxy-6,7-benzomorphane. This substance is taken up in 100 ml of acetic acid and added over 1/2 hour to a suspension of 40 g of zinc in 100 ml of acetic acid under a nitrogen atmosphere. At the end of the addition, more zinc is added

60S 6 A

23 (20 g) and stirring is continued for 1 hour. The zinc is removed by filtration and the filtrate is concentrated. The residue is treated with dilute ammonium hydroxide and extracted several times with chloroform to give substance VIIb, which is converted into the fungarate salt by reaction with 3.9 g of fumaric acid in n-propanol; mp. 250 ° C.

Anal. Calcd for C 18 H 18 NO 2 · 1 / 2C 2 H 2 O 2: C, 66.86? H, 7.59; N, 4.59.

Found: C, 66.92; H, 7.83; N, 4.66.

b) 2-Cyclopropylcarbonyl-5,9β-dimethyl-9β-hydroxy-21-methoxy-6,7-benzomorphane (IXb)

A solution (0.012 m) of compound VIIb (as free base) in 30 ml of methylene chloride and 4 ml of triethylamine is treated with a solution of 0.02 m of cyclopropylcarbanyl chloride in 20 ml of methylene chloride. After stirring for a few hours at room temperature, the reaction mixture is washed with dilute hydrochloric acid, water and dilute sodium carbonate. Drying (MgSO 4) and concentration of the organic extracts gives the title compound IXb, which is crystallized from 95% ethanol.

A solution (IX635 m) of IXb in 30 ml of dimethylformamide is treated with sodium hydride (760 mg of a 60% dispersion in mineral oil) with stirring under a nitrogen atmosphere. After 1/2 hour, add 1 ml of methyl iodide and continue stirring. An additional 1 mL of methyl iodide is then added one hour later and stirring is continued for 18 hours. A few drops of acetic acid are added and the dimethylformamide is removed under reduced pressure. The residue is treated with water and extracted with methylene chloride to give 2-cyclopropylcarbonyl-2 ', 9d, dimethoxy-5,9 / 2'-dimethyl-6,7-benzomorphane (Xb) with mineral oil as an impurity. The mineral oil is removed by treatment with n-pentane and extraction with acetonitrile to give compound Xb (96% pure by GLC). Compound Xb is reduced with 720 mg of LiAlH 4 in 40 mL of tetrahydrofuran for 18 hours to give Xlb to form crystalline hydrogen fumarate (2.1 g, 78% yield), m.p. 154-155 ° C.

Anal. Calcd for. N, 3.25.

Found: C, 66.54, 66.44; H, 7.86, 8.00; N, 3.73, 3.43.

Example 4 2-Cyclopropylmethyl-5,9-dimethyl-21-hydroxy-9 g of 4-methoxy-6,7-benzomorphan (XIIb) fumarate 60564 fumarate; mp. 191-194 ° C.

Anal Calcd for C 18 H 27 NO 2 .C 2 H 4 O 2: C, 66.16; H, 7.48; N, 3.36.

Found: C, 65.63; H, 7.76; N, 3.01; H 2 O, 0.35. Example 5 2-Cyclobutylflethyl-21,9A-dimethoxy-5,9 / 3-dimethyl-6,7-benzorphorphane (XIc) -fumarate A) Using an equimolar amount of cyclobutylcarbonyl chloride instead of cyclopropylcarbonyl chloride in Example 3 b) carbonyl-5,6β-dimethyl-9β-hydroxy-2'-methoxy-6,7-benzomorphane (IXc).

B) Using an equimolar amount of IXc instead of IXb in Example 3, the title compound XIc is obtained as the 3/2 fumarate salt; mp. 150-151 ° C.

Anal Calcd for C 21 H 31 NO 2 .3 / 2 (C 4 H 4 O 4): C, 64.39; H, 7.41; N, 2.78 Found: C, 64.24; H, 7.70; N, 2.61.

Example 6 2-Cyclobutylmethyl 5,9-dimethyl-2'-hydroxy-9β-methoxy-6,7-benzomorphane (XIIc) -fumarate Using an equimolar amount of XIc in Example 2 instead of Xlac gives the title compound XIIc, which is separated hydrobromide salt; mp. 223-226 ° C.

Anal Calcd for C 19 H 18 NO 3 HBr: C, 60.60; H, 7.63; N, 3.53.

Found: C, 60.49; H, 7.54; N, 3.54.

The hydrobromide and hydrochloride salts are prepared by dissolving the amine in a small amount of abosol ethanol, to which is slowly added an aqueous solution of HBr or HCl prepared in advance by introducing HBr or HCl gas into ethanol. The salt is accompanied by the slow addition of diethyl ether with stirring. The salt is recovered by filtration and purified by recrystallization.

Example 7 (-) - 2-Cyclopropylmethyl-21-9 5-dimethoxy-5-methyl-6,7-benzomorphan-f (~) -Xla? a) Decomposition of (+) - 2,5-dimethyl-2'-methoxy-9-oxo-6,7-benzmorphane (Va) 60 60564 A) (+) - 2,5-dimethyl-2'-methoxy- 9-oxo-6,7-benzcmorphane (+) - hydrogen tartrate

A mixture of 0.072 m of compound V (racemic) and 0.0072 m of (+) - tartaric acid is taken up in 150 ml of water and 30 ml of 95% ethanol, filtered and concentrated to a volume of 150 ml and kept at 0 ml. At -5 ° C for crystallization. The crystals are collected, washed with 95% ethanol and recrystallized from 50% aqueous ethanol to give 10.1 g (66% yield) of (+) - 2,5-dimethyl-2'-methoxy-9-oxo- 6,7-benzomorphane dihydrate.

Anal Calcd for C 18 H 18 NO 2. H, 6.78; N, 3.25; H 2 O, 8.3 Found: C, 52.89; H, 7.07; N, 3.17; H 2 O, 8.94.

The free base is separated by dissolving the tartrate in water by basifying the solution with sodium carbonate. The mixture is extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo. The free base rotation is (cK + 86.5 ° (c 1.038, 95% ethanol)).

B) The first mother liquor obtained from the (+) isomer of (-) - 2,5-dimethyl-21-methoxy-9-oxo-6,7-benzcmorphane - (-) - hydrogen tartrate in A) is basified with sodium carbonate and extracted with methylene chloride. to give 10.3 g of an oil. This oil is treated with 6.5 g of (-) - tartaric acid and taken up in 100 ml of water and 30 ml of hot 95% ethanol, filtered, concentrated to a volume of about 100 ml and cooled to 0-5 ° C. for. The crystals are collected and recrystallized from 100 ml of 50% aqueous ethanol to give 10.6 g (68% yield) of (-) - 2,5-dimethyl-2'-methoxy-9-oxo-6,7 -benzcmorphane - (-) - hydrogen tartrate + 86.5 ° (c 1.038, 95% ethanol).

The free base is separated as described in A) and has an optical rotation of 85.5 ° (c 1.054, 95% ethanol).

b) (-) - 2,5-dimethyl-9,7 (.-hydroxy-21-methoxy-6,7-benzopropane / (-) - VIa? \ - -jr 0.0765 m (-) - 2,5-Dimethyl-2'-irethoxy-9-axo-6,7-benzanorphane (as free base) is hydrogenated on a Parr shaker in 250 ml of 95% ethanol using 150 mg of platinum oxide as catalyst, the theoretical amount being consumed in 1 1/2 hours. The catalyst is removed by filtration and the filtrate is concentrated to dryness to give a crystalline residue which is recrystallized from toluene to give 18.2 g of pure title product (96% yield), mp 146.5-148 ° C, 56.5 ° (c 1.022, 95 % ethanol) GLC shows one pure compound (^ isomer alone).

26 6 0 5 6 4

Anal Calcd for C 18 H 10 NO 2: C, 72.84; H, 8.56; N, 5.66.

Id Z \ Z

Found: C, 73.29; H, 8.62; N, 5.66.

c) (-) - 90 (-hydroxy-21-methoxy-5-methyl-6,7-benzonorphane / (-) - VIIIa)

A mixture of 0.033 m of (-) - VIa and 16.5 g of potassium carbonate in 160 ml of toluene is treated with 16.5 ml of trichloroethyl chloroformate with stirring. The reaction mixture is heated to reflux under nitrogen for 18 hours. After cooling, the mixture is treated with 100 ml of water and the layers are separated. The aqueous layer is extracted with toluene. The toluene extracts are washed (saturated sodium chloride), dried and concentrated. The residue is taken up in methanol (120 ml) and water (12 ml), cooled, treated with 12 g of potassium hydroxide and stirred at 0-5 ° C for 45 minutes. Add 12 ml of acetic acid and concentrate the solution. The residue is treated with dilute hydrochloric acid and extracted with toluene to give (-) - 2-trichlorocarbethoxy-9 ° -hydroxy-2'-methoxy-5-methyl-6,7-benzcmorphane. This substance is taken up in 100 ml of acetic acid and added slowly to a slurry of 15 g of zinc dust in 50 ml of acetic acid under a nitrogen atmosphere. After the reaction has started, the mixture is heated to reflux for 1/2 hour. The zinc is removed by filtration (under a nitrogen atmosphere) and the filtrate is concentrated. Treatment of the residue with dilute ammonium hydroxide and extraction with chloroform gives 8 g of compound (-) - VIIa (100% yield), which is shown by GLC to be 97% pure. This material forms a crystalline hydrochloride salt; mp. 250 ° C, 29.6 ° (c 1.015, 95% ethanol).

Anal Calcd for C 18 H 18 NO 2 N 2 O 2: C, 62.33; H, 7.47; N, 5.19.

Found: C, 62.31; H, 7.22; N, 5.56.

Using an equimolar amount of (-) - VIIa instead of VIIa in Example 1, the title compound (-) - IXa is obtained in 92% yield after purification by chromatography using alumina (elution with benzene ether). Toluene is used in the first reaction step instead of methylene chloride. The product is crystallized as the oxalate salt; mp. 185.5 to 196.5 ° C

-48.9 ° (c 0.966, 95% ethanol).

Anal Calcd for C 2 H 20 O 4: C 1 H 7 7.47; N, 3.58.

Found: C, 64.32; H, 7.31; N, 3.70.

Example 8 (-) - 2-Cyclopropylmethyl-2 * -hydroxy-9β-methoxy-5-methyl-6,7-benzonorphane / (-) - XIIa) In Example 2, using an equimolar amount of (-) - instead of Xla XIa gives the title compound; mp. 180.0-180.5 ° C.

6 O 5 6 4 27

Anal Calcd for C 11 H 11 ClN: C, IS, 22 ·, H, 8.77; N, 4.87.

Z o Zd Z

Found: C, 75.62; H, 8.50; N, 4.69.

(-) - XIIa forms a crystalline fumarate salt, m.p. 179-180.0 ° C, λmax - 57.4 ° (c 1.011, 95% ethanol).

Anal Calcd for C 18 H 25 NO 2 .1 / 2 (C 4 H 4 Cl 2): C, 69.54; H, 7.88; N, 4.06.

Found: C, 69.70; H, 7.87; N, 3.78.

Example 9 (+) - 2-Cyclopropylmethyl-2'-hydroxy-1H-ethoxy-5-methyl-6,7-benzomorphane ((+) -XLla)

Subsequent replacement of the levorotatory isomer used in Examples 7 b) to 8 with an equimolar amount of the levorotatory isomer (+) - XIa gives the title product (+) - XIIa; m.p., as the tartrate salt, 147.0-148 ° C; + 37.3 ° (c 1.002, 95% ethanol).

Anal Calcd for (C 18 H 28 N 2 O 2) 2. C 4 H 9 O 1 • 2H 2 O: C, 64.67; H, 7.87; N, 3.77; H 2 O, 2.42.

Found: C, 65.14; H, 7.68; N, 4.10; H 2 O, 3.14.

Example 10 2-Cyclopropylmethyl-9α-ethoxy-2 * -methoxy-5-methyl-6,7-benzomorphane (Xld) Using an equimolar amount of ethyl iodide instead of methyl iodide in Example 1 gives the title compound Xld, which is separated off as the hydrochloride salt; 83% yield, m.p. 236-240 ° C.

Anal Calcd for C 20 H 28 N 2 O 2 .HCl: C, 68.26; H, 8.59; N, 3.98.

Found: C, 68.65; H, 8.56; N, 4.13.

Example 11 2-Cyclopropylmethyl-94-ethoxy-2'-hydroxy-5-methyl-6,7-benzomorphane (Xlld) Using an equimolar amount of Xld in Example 2 instead of XI gives the title compound, which is isolated as the hydrochloride salt containing 1 moles of acetone solvate; mp. 136-145 ° C.

Anal Calcd for C 10 H 27 NO 2 .HCl.C 3 H 6 O: C, 66.78; H, 8.60; N, 3.54.

Found: C, 67.15; H, 8.60; N, 3.85.

6 0 5 6 4 28

Example 12 9 ¢ (-Alyloxy-2-cyclopropylmethyl-2'-methoxy-5-methyl-6,7-benzomorphane hydrochloride (Xle) Using an equimolar amount of allyl bromide instead of methyl iodide in Example 1 gives the title compound as the hydrochloride salt Xle, mp 222 -227 DEG C. Anal. Calcd for C21H29NO2.HCl: C, 69.30; H, 8.31; N, 3.85.

Found: C, 69.21; H, 8.38; H, 3.95.

Example 13 9β-Allyloxy-2-cyclopropylmethyl-21-hydroxy-5-methyl-6,7-benzomorphane (Xlle)

Replacing Compound Xla in Example 2 with an equimolar amount of Compound Xle affords the title compound Xle, which is isolated as the hydrochloride salt; mp. 255-260 °.

Anal Calcd for CH 2 Cl 2: CH 2 Cl 2: H, C, 68.65; H, 8.07; N, 4.00.

Found: C, 68.39; H, 7.94; N, 4.22.

Example 14 5-Allyl-N-cyclopropylmethyl-21,9Λ-dimethoxy-6,7-benzcmorphane (Xlm) 3) 3,4-Dihydro-7-methoxy-1-allyl-2 (1H) -naphthalenone (Ilm) 40.5 g (0.5 mol) of pyrrolidine dissolved in 50 ml of benzene are added over a period of 5 to 10 minutes to a stirred solution of 50 g (0.0284 mol) of compound Ia (3,4-dihydro-7-methoxy) under a nitrogen atmosphere. 2 (1H) -naphthalenone) in 200 ml of dry benzene. The mixture is heated to reflux for 1 hour and 5 ml of water are collected in a Dean-Stark apparatus. The mixture is cooled and slowly added to 60.5 g (0.5 moles) of allyl bromide dissolved in 300 ml of benzene. The resulting mixture is heated to reflux for 3 hours. 200 ml of water are then added to the reaction mixture 29 60564 and the reflux is stopped. After 90 minutes, the mixture is cooled, the hensene layer is separated, washed with water and then with water saturated with sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue is distilled to give 52.20 g (85% yield) of the title compound Hm; tr. 10o-112 ° C / 0.01-0.05 mm. The infrared and nuclear magnetic resonance spectra correspond to the structure.

Anal Calcd for C 18 H 24 N 2 O 2: C, 77.7 ° C; H, 7 »^ 5.

Found: C, 77 »** 7 · H, 7.50.

b) N, N-dihydro-7-methoxy-1-allyl-1- (2-dimethylamine; solid) -2 (1H) -naphthalenone · hydrobrocide (Hirn).

A mixture of 1 x 00 ml of dry benzene, 22 g (0.25 moles) of tert-amyl alcohol and 10.62 g (0.25 moles) of sodium hydride is heated under reflux under a nitrogen atmosphere for 30 minutes or until all the hydride is used. U7.2 g (0.22 mol) of Hm in 100 ml of benzene are then slowly added while the excess amyl alcohol is distilled off. A further batch of 100 ml of benzene is then added and further distilled. 28 g (0.3 mol) of 2-chloro-N, N-dimethyl'-ninoethane in 100 ml of benzene are then added dropwise. The reaction mixture is heated to reflux for 20 hours, washed twice with water, diluted with ether and extracted with HCl. The acidic extract is dissolved in 60 ° C over 1 hour, cooled and extracted with ether to give 15 g of Hm. The acidic extract is cooled, basified with NH 4 OH and extracted with ether. It is dried over potassium carbonate, treated with charcoal and, after filtration, with dry HBr. 33.87 g (61.5% yield) of the Hirn HBr salt are obtained. After crystallization from methanol / ether, the compound melts at 139 "· 3 ° C. The IR and HMR spectra correspond to the structure.

Anal Calcd for C 11 H 30 Br 2 O: C, 58.69; H, 7.11; N, 3.80.

J.O c.j d Found: C, 53.63; H, 7.16; N, 3.59.

30 60 5 64 c) T LVtn \ 3 * HBr CH3 S-bromo-N, N-dihydro-4-methoxy-1-allyl-1-theethylethylaminoethyl-g-dH) -naphthalenone hydrobromide (LVm).

To a stirred solution of 15 g (* 1 mmol) of 100 μM methylene chloride and 300 mL of tetrahydrofuran α (THF) is added a solution of 20.56 g (μL, 5 mmol) of pyrrolidone hydrotribromide 300 over 1 hour. mlrssa THF. After the addition, the reaction mixture is allowed to stand overnight at room temperature. The solvents are evaporated off and the solid residue is recrystallized from 700 ml of isopropanol to give 12.7 g (68.5% yield) of LVm; mp. 149-150 ° C IR and NMR spectra are consistent with structure.

Anal Calcd for c Br.HBr: C, U.3.3H; H, 5.63; K, 3.13.

Found: C, U 8.6 U; H, 5.70; N, 3.1U.

d) 5S 5 * 5-Al-5-allyl-2-netocyano-2-methyl-9-oxo-6,7-benzomorphane etobromide (LXm) 12.6 g (0.028 mol) of the HBr salt of LVm are dissolved in ice-cold water. , place in a separatory funnel and cover with ether. Sufficient concentrated ammonium hydroxide is added to make the mixture basic and the free base of IVm is extracted and separated as quickly as possible. The ether is evaporated off and the residue is dissolved in acetone and allowed to stand overnight. 6.55 g of 60564 (65 * 5% yield) of solid LXm are obtained. After crystallization from isopropanol, it melts at 175-177 ° C. The IR and NMR spectra correspond to the structure.

Anal Calcd for C17H2JNC> 2.CH3Br.1 / 2H2O: C, 57.60; H, 6.71; H, 3.73.

Found: C, 57 »1 * 1 *; H, 6.78; N, 3.58.

e) -5-allyl-2'-methoxy-2-ylethyl-9-oc30-6,7-benzomorphane (Vm).

A suspension of 2 g (5 x 5 mmol) of LXm in 25 nl of 1-octol is heated under reflux under nitrogen for 15 minutes. After cooling, the mixture is poured into 0.5 ml of 0.5H HCl and extracted twice with 100 ml of petroleum ether to remove octanol. The aqueous layer is basified with ammonia and the free base is extracted with benzene to give, after drying and evaporation of the solvent, 1.23 g of an oil (VIm). The oil is stirred with a solution of 350 mg of oxalic acid in 5 ml of water for 1 hour and then allowed to stand at 5 ° C for 16 hours. The separated material is filtered to give 980 mg (1-7% yield) of Vm-oxalate containing 1 mole of water of crystallization, m.p. 156-L62 ° C. The product is crystallized from water, m.p. 160-116 ° C, leaving water at 110 ° C.

Anal Calcd for C 10 H 19 N 2 O 5 H, 6.6 U; N, 3.69.

Found: C, 60.52; H, 6.72; N, 3.70.

f) 5-allyl-9H-hydroxy-2'-methoxy-2-methyl-6,7-benzylquorphane (VIm).

A solution of diisoutouthylluninium hydride (62 ml of a 25 # solution, about 60 mmol) is diluted with 150 ml of dry tetrahydrofuran and cooled to -1 + 5 ° C under a nitrogen atmosphere. A solution of 8.58 g (31.6 mmol) of Vm in 100 ml of dry tetrahydrofuran is then added dropwise.

After stirring for 1 hour at -I * 5 ° C, the gelatinous substance obtained is concentrated in vacuo. The residual oil is dissolved in ether, washed with water, dried (Ka 2 O 4) and evaporated in vacuo to give 8.80 g of alcohol (VIm).

6 O 5 6 4 32

Crystallization of the residual oil from ether / petroleum ether (b.p. 30-60 ° C) gives 6.32 g (72% yield) of crystalline material (Vlm). The mother liquors are purified by chromatography on 100 g of silica gel and eluted with a 1: 1 mixture of methanol and ether to give 2.00 g (23% yield) of pure alcohol (Vlm). The analytical sample is recrystallized from acetone / ether / petroleum ether (b.p. 30-60 ° C) and melted at 73-79 ° C.

Anal Calcd for C, 74.69; H, 8.48; N, 5.12.

Found: C, 74.26; H, 8.73; N, 5.19.

g) 5-3ΐ1γ7ΐϊ-9 (Λ-hydroxy-21-methoxy-6,7-benzomorphane (VIIm) -hydrogen oxalate

Substituting compound Via in Example 1 f) with an equimolar amount of compound VIII gives the title compound VIIm. The compound is purified by crystallization of the oxalate salt from methanol / ether to give a sample melting at 173-176 ° C.

The analytical sample is purified by molecular distillation of the free base at -4 ° C / 5x10 nm Hg.

Anal Calcd for C 18 H 18 NO 3: C, 74.10; H, 8.16; N, 5.40.

Found: C, 73.92; H, 8.27; N, 5.36.

h) 5-Allyl-N-cyclopropylcarbanyl-9fA-hydroxy-2 * -methoxy-6,7-benzcmorphane (IXm)

A solution of 4.07 g (15.7 nmoles) of hydroxyamine and VI im in 200 ml of dichloromethane and 5 ml of triethylarinoine under a nitrogen atmosphere is treated dropwise with 1.80 g (17.25 nmoles) of cyclopropylcarbonyl chloride. The reaction mixture is washed with dilute hydrochloric acid, water, dried (MgSO 4) and the solvent removed in vacuo to give 4.12 g (80%) of crude amide (IXm). Crystallization from benzene / ether gives a sample melting at 146-147 ° C.

Anal Calcd for C, 73.37; H, 7.70; N, 4.28.

Found: C, 73.53; H, 7.71; N, 4.32.

(i) 5-allyl-N-cyclopropylcarbonyl-21.90 (.-dimethoxy-6,7-benzomorphane (Xtn)

To a suspension of 950 mg (21.9 mmol) of a 55% sodium hydride dispersion in mineral oil washed with benzene in 125 ml of dry dimethylformamide under a nitrogen atmosphere is added 2.39 g (7.30 mmol) of alcohol (IXm). The mixture is stirred at 50 ° C for 0.5 hours, then cooled to room temperature and treated with 5.18 g (36.5 mmol) of methyl iodide. Stirring is continued for 3.0 hours. The reaction mixture is then poured into 500 ml of water 33 60564 and extracted with benzene. The extracts are washed with water, dried (MgSO 4) and evaporated in vacuo to give 2.45 g (quantitative) of the amide (Xm).

o —4

The crude product is purified by evaporative distillation at 160 C / 5x10 mm Hg. Anal Calcd for C 18 H 18 N 2 O 2: C, 73.87; H, 7.97; N, 4.10.

Found: C, 74.08; H, 8.11; N, 4.05.

j) 5-Allyl-N-cyclopropyl-3-ethyl-2 ', 9? -dimethoxy-6,7-benzcmorphane (Xlm) 2.30 g (6.74 mmol) of amide (IXm) are added to a suspension of 770 mg (20m). .2 mmol) of lithium aluminum hydride in 125 ml of dry tetrahydrofuran. The resulting mixture is heated under reflux for 3 hours, then cooled and the excess hydride is decomposed by successive addition of 0.77 ml of water, 0.58 ml of 20% NaQH and finally 2.70 ml of water. The inorganic salts are filtered off and washed with THF. The filtrate is evaporated to dryness and the residual oil is taken up in N hydrochloric acid and extracted with ether. The aqueous phase is basified with ammonium hydroxide and extracted with dichloromethane. The extracts are washed with water, dried (MgSO 4) and the solvent removed in vacuo. 1.97 g (90% yield) of a tertiary amine (Xlm) are obtained. Its hydrochloric acid salt melts at 156-157 ° C after crystallization from methanol / ether.

Anal Calcd for C, 77.04; H, 8.93; N, 4.28.

Found: C, 77.02; H, 9.03; N, 4.30.

Example 15 5-Allyl-2-cyclopropylmethyl-21-hydroxy-9g-methoxy-6,7-benzomorphane (XIII)

A solution of sodium ethoxide is prepared by adding 1.70 ml (22.2 mmol) of ethanethiol to 970 mg (22.2 mmol) of a 55% dispersion of sodium hydride in mineral oil washed with benzene in 175 ml of dry dimethylformamide under a nitrogen atmosphere. 1.32 g (4.04 mmol) of dimethyl ether Xmm are then added and the solution is heated under reflux for 4 hours. The reaction mixture is then poured into 500 ml of ice-cold water, acidified to pH 4 with hydrochloric acid, basified with ammonium hydroxide and extracted with benzene. The extracts are washed with water, dried (MgSO 4) and evaporated in vacuo to give 1.23 g (97% yield) of phenol (XIII). The hydrochloric acid salt crystallized from methanol / ether melts at 223-225 ° C.

Anal. Calcd for .b.p.

Found: C, 76.59; H, 8.80; N, 4.39.

34 605 64

Example 16 2-Cyclopropylmethyl-2'-hydroxy-9β-methoxy-5-propyl-6,7-benzomorphane (XIII)

Replacing the compound Xla used in Example 2 with an equimolar amount of the compound Xln gives the title product, which is identical to the product prepared in Example 24.

Example 17 n_ch2— <i I | i ^ och ^ XIr

JO-CH

J 1 '

I CH

αί 3 2-Cyclopropylmethyl-2'-9/4-dimethoxy-5,9a {-dimethyl-6,7-benzomorphane (XIr) 35 60564 a) fxA ™ '

I H

ch3 2,5-Dimethyl-9/3-hydroxy-21-methoxy-6,7-benzomorphane hydrobromide (VIp)

A suspension of 0/04 m of compound IVa in 200 ml of ether is treated with 50 ml of a 2.5 m solution of isopropylmagnesium chloride in tetrahydrofuran. The mixture is stirred under a nitrogen atmosphere for 17 hours. The cooled mixture is slowly treated with 200 ml of water and 25 ml of concentrated hydrochloric acid.

The ether is removed by evaporation under reduced pressure. Extraction of the aqueous mixture with methylene chloride gives 17 g of a brown foam. This foam is taken up in 200 ml of 95% ethanol and hydrogenated on a Parr shaker using palladium hydroxide on carbon as a catalyst to give 10.3 g (78% yield) of pure compound Vip after crystallization from 2-propanol.

Papers: H. Kugita and E. L. May, J. Qrg. Chem., 26, 1954 (1961).

b)

I 'H

ch3 9/4 -hydroxy-21-methoxy-5-methyl-6,7-benzcmorphane (VIIp)

A mixture of 0.031 m of Vip as the free base and 90 ml of acetic anhydride is heated at 100 ° C for 1 hour. The acetic anhydride is removed under reduced pressure. Treatment of the residue with sodium carbonate and extraction with methylene chloride gives 2,5-dimethyl-2'-methoxy-β-acetoxy-6,7-benzanorphane in quantitative yield. This substance is taken up in 100 ml of benzene and 5 g of potassium carbonate in 10 ml of ethyl chloroformate are added. The resulting mixture is heated to reflux under a nitrogen atmosphere for 26 hours. The mixture is then treated with water. The benzene layer is separated and washed with dilute hydrochloric acid and aqueous saturated with sodium chloride to give, after concentration, a quantitative yield of 5 "-methyl-2'-methoxy-2-carbethoxy-9/2-acetoxy-6,7-benzomorphane. This substance is taken up in 230 ml of 95 J ethanol and treated with 30 g of potassium hydroxide. It is heated to reflux under a nitrogen atmosphere for 90 hours. The ethanol is removed under reduced pressure. When treating a residue of sodium bicarbonate 10? With aqueous solution and extraction with methylene chloride, 7-2 g of compound VIIp are obtained (100% yield). Recrystallization from toluene gives 6.8 g (9 ** 1 yield) of analytically pure material; mp. 132.0 to 133.5 ° C.

Anal Calcd for C, 72.07; H, 8.21; N, 6.00.

Found: C, 72.08; H, 8.03; N, 6.08.

c) 2,5-Dimethyl-9- (spiro-γ-epoxy) -2 * -methoxy-6,7-benzomorphane (XX) CH 2

A solution of 0.05 m of 2,5 “dimethyl-2'-methoxy-9-oxo-6,7” benzomarphan (Va) in 125 ml of dry dimethyl sulphoxide is added to a 55 l dispersion of sodium hydride (0.1 m) while stirring under a nitrogen atmosphere. To this mixture is added 0.1 m of trimethylsulfonium iodide with stirring. After stirring for 1 hour under a nitrogen atmosphere, the mixture is diluted with water and extracted with methylene chloride. On drying and consolidation, these extracts give an oil which, by GLC analysis, shows 66% of the ^ isomer (XX), 6-7% of the second product believed to be the J1 isomer, and some starting ketone. Chromatography using aluminum ocoid followed by crystallization from sclohexane gives pure XX (6U% yield of isomer with a purity greater than 95 2);

Anal. Calcd. For C.-dL-NO: C, 17l *, 10; H, 8.16; N, 5,! * 0.

Ib <L \. 2 Found: C, 73.89; H, 8.30; N, 5.36.

3 7 605 6 4 d) 9β-Hydroxy-2,1-ethoxy-2,5,9,9β-triethyl-6,7-benzomorphaldehyde hydrochloride (VIr)

A solution of 0.028 m of 2,5-dimethyl-9- (spiro-γ-epoxy-2-methoxy-6,7 "benzomorphane (XX) in 75 ml of tetrahydrofuran is added to a stirred suspension of 0, 0h5 m of lithium aluminum hydride in 25 ml of tetrahydrofuran (THF) The mixture is stirred at 25 ° C for 16 hours and refluxed for 2 hours. the oil is converted to the hydrochloride and crystallized from ethanol / ethyl acetate / anhydrous to give pure VIr hydrochloride hydrate (86% yield), mp 139 * 0-1l + 3 * 0 ° C. GLC analysis of the free base shows 96% isomer purity Infrared spectra of the solution. (CCl 2) at different concentrations show only the bound OH group, which means the β-3-OH configuration.

Report: E. L. May and H. Kugita, J. Org. Chem., 26, 188 (1971 *) · e) Preparation of 9β-ethoxy-2-carbethoxy-5,9-fedmethyl-2, -methoca-6,7-beazomorphonic (XXI)? -0.022 m-9β-hydroxy-2, -methoxy-25.9 ° -trimethyl-6,7 "benzomorphane (VIr) is treated with 50 ml of acetic anhydride and heated on a steam bath for 3 hours. Evaporation of the benzene extracts gives the acetoxy compound 9H-acetoxy-2,5 * 9c-methylmethyl-2, -methoxy-6,7-benzomorphan A solution of this substance in benzene is treated with 2.5 g of potassium carbonate and 6.5 ml of ethyl chloroformate a (0.07 m) and heated under reflux for 16 hours.This mixture is carefully treated with 120 ml of 1 N hydrochloric acid.The layers are separated and the aqueous layer is extracted with benzene. again 9 5% ethanol; mp. 87.5 "88.5 ° C.

Anal Calcd for C 12 H 9 N 2 O 2: C, 66, H 6, 7.53; N, 3.88.

Found: C, 66.18; H, 7.62; Preparation of N, 3,75- f) 5,9 ° -dimethyl-9β-hydroxy-2, -methoxy-6,7-benzomorphane (VIIr)

A mixture of 0.002 ml of 9β-acetoxy-2-carbethoxy-5,9-dimethyl-2'-methoxy-6,7-benzomorphane (XXI), 2.5 g of potassium hydroxide and 20 ml of 95 # ethanol, 38 6 O 5 6 4

heated to reflux for 18 hours. After concentration, the residue is treated with water and extracted with methylene chloride to give the title compound VIIIr, which is recrystallized from ethyl acetate; mp. 147.0-148.0 ° C

Anal Calcd for C 15 H 21 NO 2: c '72' ^ 4; H '8.56; N, 5.66.

Found: C, 73.12; H, 8.63; N, 5.82.

g) A solution of 0.005 m of 5.9 .mu.-dimethyl-9H-hydroxy-21-methoxy-6,7-benzomorphane (VIIr) in 25 ml of methylene chloride and 7.5 ml of triethylamine is treated with 3 ml. The resulting mixture is stirred for 18 hours and then treated with dilute aqueous sodium carbonate solution, the layers are separated and the aqueous layer is extracted with methylene chloride. Drying and concentration of the methylene chloride-9-dimethyl-9-carbonyl-9-carbonyl-9-carbonyl N-hydroxy-2'-methoxy-6,7-benzomorphane (IXr) as an oil.

A solution of IXr in 25 mL of dimethylformamide is added to a suspension of 0.015 m NaH in 10 mL of dimethylformamide under a nitrogen atmosphere. After 1/2 hour, methyl iodide is added twice every hour (1 ml each time) and the mixture is stirred for a further 16 hours. After the solvent is removed under reduced pressure, the residue is treated with water and extracted with methylene chloride to give 2-cyclopropylcarbonyl-2,1-dimethoxy-5,9-dimethyl-6,7-benzomorphane (Xr). This material is taken up in 30 ml of tetrahydrofuran and added to a stirred suspension of 1.0 g of lithium aluminum hydride in 20 ml of tetrahydrofuran. After refluxing for 18 hours, this mixture is carefully treated with 3 ml of saturated aqueous sodium sulphate solution and heated until the solids are white. Removal of the solids by filtration and concentration of the filtrate gives an oil (Xlr) which is converted to the hydrochloride salt; mp. 226-229 ° C.

Anal Calcd for C20H29NO2'HCl2: C, 68.26; H, 8.59; N, 3.98.

Found: C, 68.16; H, 8.85; N, 4.02.

Example 18 2-Cyclopropylmethyl-5,9o-dimethyl-21-hydroxy-methoxy-6,7-benzomorphane (XIII) 39,60564

Replacing Compound Xla in Example 2 with an equimolar amount of Compound Xlr gives the title compound Xllr as the hydrochloride salt; mp. 270-278 ° C with decomposition.

Anal Calcd for gH27NO2 · HCl: C, 67.54; H, 8.35; N, 4.15.

Found: C, 67.32; H, 8.52; N, 4.37.

Example 19 2-Cyclobutylmethyl-2 ', 9β-dimethoxy-5-methyl-6,7-benzomorphane (XIs)

Substituting Compound VIIr and cyclopropylcarbonyl chloride in Example 17 with equimolar amounts of Compound VIIp and cyclobutylcarbonyl chloride, respectively, affords the title compound XIs as the hydrochloride salt; mp. 205-209 ° C.

Anal Calcd for C 20 H 29 NO 2 .HCl: C, 68.26; H, 8.59; N, 3.98.

Found: C, 68.58; H, 8.50; N, 4.07.

Example 20 2-Cyclobutylmethyl-2'-hydroxy-N-methoxy-5-methyl-6,7-benzomorphane (XIIs)

Substituting Compound XIa in Example 2 with an equimolar amount of Compound XIs gives the title compound XIIs as the hydrochloride salt; mp. 214-219 ° C.

Anal Calcd for HCl: C, 67.54; H, 8.35; N, 4.15.

Found: C, 67.88; H, 8.41; N, 4.02. Example 21 2-Cyclopropylmethyl-2 ', 9β-dimethoxy-5-methyl-6,7-benzomorphane (Xlt)

Replacing Compound VIIr in Example 17 with an equimolar amount of Compound VIIp gives the title compound Xlt as the hydrochloride salt; mp. 217-220 ° C.

Anal, calculated for c- | gH27NO2 * HCl: C, 67.54; H, 8.35; N, 4.15.

Found: C, 67.53; H, 8.65; N, 3.86.

Example 22 2-Cyclopropylmethyl-21-hydroxy-9β-methoxy-5-methyl-6,7-benzomorphane (XIII)

Substituting Compound Xla in Example 2 with an equimolar amount of Compound X11t to give the title compound Xllt as the hydrochloride salt; mp. 245-255 ° C with decomposition.

Anal, calculated for C. O. HCl: C, 66.75; H, 8.09; N, 4.33.

Found: C, 67.11; H, 8.28; N, 4.17. Example 23 2-Cyclobutylmethyl-21,9β-dimethoxy-5,9M-dimethyl-6,7-benzomorphane (XIv)

Replacing cyclopropylcarbonyl chloride in Example 17 with an equimolar amount of cyclobutylcarbonyl chloride gives the title compound XIv as an oil which can be used as such in Example 24.

Example 24 2-Cyclobutylmethyl-5,9,3-dimethyl-21-hydroxy-9β-methoxy-6,7-benzomorphane (XIIv)

Replacing Compound Xla in Example 2 with an equimolar amount of Compound XIv gives the title compound XIIv as the hydrochloride salt; mp. above 245 ° C with decomposition.

Anal Calcd for C 18 H 18 N 2 O 2 .HCl: C, 68.26; H, 9.59; N, 3.98.

Found: C, 68.07; H, 8.88; N, 4.02.

Example 25 N-Cyclopropylmethyl-21-hydroxy-N, N-methoxy-5-propyl-6,7-benzomorphane (XIII)

A solution of 495 mg (1.51 mmol) of olefin (XIII) in 150 ml of abosol ethanol is hydrogenated for 1 hour using 250 mg of 10% Pd / C at an initial pressure of 2.9 kg / cm 3. The catalyst is filtered off with celite and the solvent is evaporated to give 486 mg (98% yield) of the saturated compound XIII. The hydrochloride salt crystallized from methanol / ether melts at 236-239 ° C. The analytical sample is purified by sublimation at 160 ° C / 5x10 mm Hg. Anal Calcd for C 20 H 19 N 2 O 2 C, 76.15; H, 9.27; N, 4.44.

Found; C, 76.17; H, 9.08; N, 4.41.

General Procedure for the Preparation of Fumarate Salts Equimolar amounts of fumaric acid powder and the appropriate amine (e.g., XIIIb) are dissolved in a sufficient amount of hot isopropanol or n-propanol to obtain a solution. Upon cooling and stirring or seeding, the fumarate salt is crystallized. The product is recovered by filtration.

General method for the preparation of oxateates

Compound lila (0.01 mol) is dissolved in as little hot acetone as possible. A hot solution of oxalic acid (0.01 mol) is added while stirring and / or seeding. The oxalate salt crystallizes on cooling and is recovered by filtration.

Example 26 Decomposition of 5-alkyl-2-cyclopropylmethyl-21-hydroxy-9β-methoxy-6,7-benzomorphine into levorotatory isomers

.tk

X "X) CH3

A solution of 5 x 3 g (16.9 mmol) of the title compound (XIII) in 150 ml of acetone is treated with 2.6 g (17.0 mmol) of 1-mandelic acid.

2.0 g of the partially decomposed solid which separates are recrystallized three times from acetone to finally give 0.69 g of a salt with a circulating capacity of <<*? D5 = + 8.1 *. väkev. 286 mg / 100 ml CH 2 OH. The free base rotation is' · + 61.0i concentrated. 189 mg / 100 ml CH OH, while its hydrochloride salt (m.p. 222-221 ° C)

ΛΡ J

rotation capacity is +58.9; väkev. 229 mg / 100 ml CH 3 OH.

The L-isomer is obtained by dissolving 5.3 g (16.9 mmol) of the title compound in 125 ml of acetone and treating the solution with 2.6 g (17.0 mmol) of d-mandelic acid. 2.86 g of the salt which separates are recrystallized once from acetone to give a circulating water (99 * 9.1 *; conc. 287 mg / 100 ml CH OH.

pc 3

A free base is formed (conc. 26.0 mg / conc. 266 mg / 100 ml CH 2 Cl 2) and crystallized from acetone / ether as the hydrochloride salt: -59.1 ° C, conc. 281 mg / 100 ml ch.

When d- or 1-XIIu is hydrogenated to the d- or 1-XII isomers, the measured rotation of the d-isomer is +52.8; väkev. 303 mg / 100 ml ClI OH; mp. 228-30 ° C

(HCl salt) and β-isomer rotation -52.7; väkev. 294 mg / 100 ml OLjOH; mp. 228 ° C (HCl salt).

60564 42

Example 27 5-Allyl-N-cyclomethylmethyl-2 ', 9β-dimethoxy-6,7-benzomorphane (XIz) a) 5-Allyl-H-3-cyclobutylcarbonyl-90-hydroxy-2, -methoxy-8,7-7,7 -benzomorphic sound (IXz)

A solution of 9 to 20 g (35.5 mmol) of hydroxyamine VIII as the free base in 100 ml of dichloromethane and 15 ml of triethylanine is treated dropwise at 0 ° C and under a nitrogen atmosphere with a solution of U, 62 g ( 39.0 oil limol) cyclobutylcarbonyl chloride 100 nl: S3a dichloromethane. The cooling bath is removed after the addition is complete and the solution is stirred at room temperature for 1 hour. The reaction mixture is then washed with 1K hydrochloric acid, water and dried over magnesium sulfate. Evaporation of the solvent in vacuo gives 11.0 g (91 *% yield) of hydroxyamide (IXz).

Crystallization from ether / petroleum ether (b.p. 30-60 ° C) gives an analytical sample melting at 11-18 ° C.

Anal Calcd for C, 73.87 ', H, 7.97; H, U, 10.

Found: C, 7M8; H, 8.11; N, U, 01.

b) 5-Allyl-N-cyclobutylcarboxyl-2,9-iodomethoxy-6,7-benzonorphane (Xz) 5.0 g (11 *, 6 mmol) of hydroxyamide IXz are added to a suspension of 1.02 g (^ 3, 9 mmol) of NaH (55-55 in oil, washed with benzene) in 500 ml of dimethylformamide. The mixture is heated at 50 ° C for 0.5 h, then cooled to room temperature and treated with 10 k, U g (73.0 mmol) of methyl iodide. After stirring for 3 hours, the reaction mixture is poured into water and extracted with benzene. The extracts are washed with water, dried (MgSO 4) and concentrated in vacuo to give 5.0 g (96% yield) of dimethoxyamide (X 2) as a viscous oil. An analytical sample is prepared by evaporative distillation at 170 ° C / 5x10 μm Hg.

Anal, tap on C22H29NO3! C, 71 *, 33; H, 8.22; N, 3.9 * +.

Found: C, 07-08; H, 8.39; N, 3.89.

c) A solution of 1 +, 28 g (12.0 mmol) of dimethoxyamide Xz in 50 ml of tetrahydrofuran is added to a solution of 1.38 g (30.0 mmol) of lithium aluminum hydride in 300 ml. tetrahydrofuran. The reaction mixture is heated under reflux for 1 hour, cooled and the excess hydride is decomposed by successive addition of 1.38 ml of water, 1.02 ml of 20% sodium hydroxide and finally U, 80 ml of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The residual oil is taken up in dilute hydrochloric acid and extracted with ether. The aqueous phase is basified with concentrated ammonium hydroxide and extracted with dichloromethane. The extracts are washed with water, dried (MgSO 4) and evaporated in vacuo to give 3.80 g (92.7% yield) of amine XIz. The oxalic acid salt melts at 18U-186 ° C after crystallization from methanol / ether.

o ** 1 ^

Evaporation on distillation of the free base at 135 C / 5x10 mm Hg gives an analytical sample.

Anal Calcd for C 22 H 31 NO 2: C, 77.38; H, 9.15; N, U, 10.

Found: C, 77.50; H, 9.32; N, U, 08.

Example 28 5-Allyl-N-cyclobutylmethyl-2H-hydroxy-90β-methoxy-6,7-benzomorphane (XIIz).

A solution of sodium urethane thiolate is prepared by adding 1.87 ml (25.5 mmol) of ethanethiol to a suspension of 1.07 g (25.5 mmol) of 55 g of sodium hydride (suspension in mineral oil; washed with benzene) in 200 ml of dimethyl lyforanid. 1.52 g (U, 6 mmol) of dimethoxyamine XIz are added and the solution is heated under reflux for 5 hours. The reaction mixture is then poured into water, acidified with concentrated hydrochloric acid, basified with ammonium hydroxide and extracted with benzene. The extracts are washed with water, dried (MgSO 4) and evaporated to dryness. The crude material is dissolved in acetone, treated with one equivalent of oxalic acid and ether is added until crystallization begins. The oxalic acid salt weighs 1.62 g (83% yield) and melts at 193 ~ 19 ° C after crystallization from ethanol / ether.

An analytical sample is prepared by evaporation distillation of the free base at 160-5 ° C / 5x10 μm Hg.

Anal Calcd for C 18 H 18 NO 3 C, 77.0a; H, 8.93; N, U, 28.

Found: C, 77.31; H, 9.0U; N, k, 18.

Example 29 N-Cyclobutylmethyl-2'-hydroxy-9H-methoxy-5-propyl-6,7-benz30morphane imxL ·.

1.0 * 4 β (3.18 mmol) of olefin XIIz are dissolved in 200 ml of absolute ethanol and hydrogenated for 2 hours using an initial pressure of 10% Pd / c of 3.3 kg / 2 cm. The catalyst is then filtered off with cclite and the filtrate is evaporated to dryness. The crude material (922 mg, 88% yield) is dissolved in acetone, treated with 1 equivalent of oxalic acid and ether is added until crystallization begins. Thus 1.0U of salt is obtained, melting at 21 DEG-166 DEG C. after crystallization from methanol / ether.

An analytical sample is prepared by sublimation of the free base at 160 ° C / 5x10 11 mm Hg., M.p. L8L "L83 ° C.

Anal Calcd for C 21 H 31 NO 2: C, 76.55; H, 9.8; N, 1 +, 25.

Found: C, 76.65 »H, 9.76; N, U, 25.

Example 30 2-Cyclobutylmethyl-2,9,9-dimethoxy-5-acetyl-6,7-benzomorphane hydrochloride (XIx)

Replacing the cyclopropylcarbonyl chloride used in Example 1 with an equimolar amount of cyclobutylcarbonyl chloride gives the title compound XIx; mp. 181-18U ° C.

Anal Calcd for C 18 H 18 N 2 O 2 .HCl: C, 68.26; H, 8.59; H, 3.93.

Found: C, 67.99 *, H, 8.52; H, 3.76.

Example 31 2-Cyclobutylmethyl 2H-hydroxy-9H-methoxy-5-methyl-6,7-benzomorphane fumarate (XIIx)

Replacing Compound X1a used in Example 2 with an equinolar amount of Compound XIx gives the title compound XIIx as the free base. The compound is not isolated as the hydrochloride salt but as the fumarate salt, m.p. 163.5 * 165.5 ° C.

Anal Calcd for C 18 H 18 NO 3 (C 2 O 2) 2: C, 70.17; H, 8.13; N, 3.90.

Found: C, 70.01; H, 8, Ok; N, 3.62.

General method for the preparation of tartaric acid salts

Equimolar amounts of d- or 1- or dl-tartaric acid and the appropriate amine α (e.g. XIIa) are dissolved in a sufficient amount of hot isopropanol or n-propanol to give a solution. On cooling and stirring or inoculation, the t & ltrate salt crystallizes. The product is recovered by filtration.

Example 32 Preparation of (-) - 2-Cyclopropylmethyl-2'-hydroxy-9-methoxy-5-methyl-6,7-benzomorphane-d-tartrate salt

Using (-) - XIIa as the amine, (-) - 2-cyclopropylmethyl-2'-hydroxy-9β-methoxy-5-methyl-6,7-benzomorphane forms the title d-tartrate salt (E) -XHa-d tartrate); mp. 146.5 to 148.5 ° C

60564 ° C - 37.5 ° (C, 0.986), 95% ethanol).

Anal. Calcd for (C 18 H 18 N 2 O 2) 2 C 4 H 6 O 6 · 1 · H 2 O: C, 64.67; H, 7.87; N, 3.77;

Found: C, 64.34; H, 7.51; N, 3.86; Y1, 3.25.

Example 33 5-Allyl-2-cyclopropylmethyl-2 ', 9o (-dimethoxy-9β-methyl-6,7-benzanorphan (XIu)) a) 5-Allyl-2,9H-dimethyl-9β-hydroxy-21 -methoxy-6,7-benzomorphane (Vlu)

A solution of 113.5 g (0.80 mmol) of methyl iodide in 100 ml of anhydrous ether is added dropwise to 19.4 g (0.80 mmol) of magnesium covered with 400 ml of anhydrous ether in a 3-liter, In a 3-necked bottle. After completion of the reaction with magnesium, the mixture is heated to 60 ° C in an oil bath, the solvent is evaporated under a stream of nitrogen and the residue is placed under vacuum (0.5 nm Hg / 60 ° C) for 1 hour. The flask, kept under a nitrogen atmosphere, is equipped with a mechanical stirrer and a dropping funnel. A solution of 57.4 g (0.20 mmol) of ketone Vhi in 1.0 liter of petroleum ether (30-60 ° C) is then added over 15 minutes with vigorous stirring. After stirring at 20-25 ° C for 18 hours, 400 ml of water are carefully added and the slurry thus obtained is treated with concentrated hydrochloric acid and the pH is adjusted to 8. The organic layer is separated and the aqueous phase is extracted twice with 600 ml of ether. The organic extracts are dried (Na 2 SO 4) and evaporated in vacuo to leave 57.5 g (100% yield) of Vlu as an oil containing traces of the (1-OH isomer) Crystallization of the oxalic acid salt from methanol / ether gives an analytical sample, m.p. 208-209 ° C.

Anal Calcd for C, 63.65; H, 7.21; N, 3.71.

Found: C, 63.78; H, 7.41; N, 3.92.

b) 5-Allyl-2-cyano-9β-hydroxy-21-methoxy-9-methyl-6,7-benzcmorphane (XXVu)

A solution of 0.60 g (5.75 mmol) of cyanobromide in 25 ml of chloroform is added dropwise to a solution of 1.52 g (5.26 mmol) of Vlu in 25 ml of chloroform. After refluxing for 22 hours, the solvent is evaporated off under vacuum to leave 1.69 g of a brown oil which is dried by chromatography on silica gel. Elution with ether gives 1.32 g (83.5% yield) of XXVu. An analytical sample (m.p. 103-105 ° C) is obtained from ether / petroleum ether.

Anal Calcd for C 18 H 22 N 2 O 2: C '72'45; H '7'43' * N '9'39 · Found: C, 72.56; H, 7.48; N, 9.23.

46 60 5 6 4 c) 3-Ethyl-9H-hydroxy-3,2-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 dry tetrahydrofuran cooled in an ice bath is added dropwise a solution of 0.75 g (2.5 mmol) of XXVu in 30 ml of tetrahydrofuran. . After refluxing for 17 hours, the reaction mixture is cooled in an ice bath and the excess hydride is decomposed by adding 0.2 ml of water, 0.15 ml of 20% sodium hydroxide solution and 0.70 ml of water. The resulting solid is filtered and the filtrate is evaporated to dryness to give 0.58 g (85% yield) of an oil (Vilu) which is N-acylated without purification according to Example 81.

d) 5-allyl-2-3-cyclopropylcarbonyl-9-hydroxy-21-methyl-9H-methyl-6,7-benzororphane (iXu),

A solution of 0.31 g (3.0 mmol) of cyclopropylcarboxylic acid chloride in 5 g of methylene chloride is added to a solution of 0.75 g (2.7 mmol) of Vilu in 20 ml of methylene chloride and 0.1+ ml of triethylamine under cooling. The ice bath is removed, the reaction mixture is allowed to stand at 20 [deg.] C. for 30 minutes and the solid is filtered off and washed with ether. crystallized from naphtha: 0.79 g (8U% yield).

Anal Calcd for C 18 H 18 N 2 O 3 C 3 T 3.87; H, 7 »97 i N, U, 10.

Found: C, 73.80; H, 8.00; N, U, 01.

e) 5-allyl-2-cyclopropylcarbonyl-21,9c dimethoxy-9H-methyl-6,7-benzomorphane (Xu).

To a suspension of 130 mg (3 mmol) of sodium hydride (55% mineral oil; washed with benzene) in 10 ml of dimethylformamide is added a solution of 31 mg (1 mmol) of alcohol IXu in 10 ml of dimethylloamide. The mixture is stirred at 70 ° C for 0.5 hours, then cooled to room temperature and treated with 710 mg (5 mmol) of methyl iodide in 10 ml of dimethylformamide.

After stirring for 3 hours, the reaction mixture is poured into water and extracted with benzene. The organic extracts are dried (MgSO 4) and evaporated to dryness to leave 350 mg (99% yield) of Xu as a colorless oil.

Evaporation support distillation at 150-55 ° C / 3x10 mm Hg gives an analytical sample.

47 605 64

Anal Calcd for C 9 H 11 NO: C, 7 * +, 33; H, 8.22¾ N, 3.91 *.

Found: C, 74.14; H, 8.40; N, 3.87, f) A solution of 711 mg (2 mmol) of amide Xu in 15 ml of tetrahydrofuran is added to a suspension of 223 mg (6 mmol) of lithium aluminum hydride in 35 ml of tetrahydrofuran. The mixture is heated to reflux under a nitrogen atmosphere for 1 + 5 minutes, then cooled to room temperature and the excess hydride is decomposed by adding 0.23 ml of water, 0.17 ml of 20 l of sodium hydroxide and finally 0.8 l of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The residue is taken up in 1N hydrochloric acid, extracted with ether, basified with ammonium hydroxide and extracted with dichloromethane. The extracts are washed with water, dried (MgSO 4) and evaporation of the solvent gives 570 mg (83.5% yield) of amine XIu as an oil. Evaporation distillation at 11 * 5 ° C / 5x10 2 mm Hg gives an analytical sample.

Anal Calcd for C22H31IIO2: C * 17 · 28 'H »9.15; N »1 *» 10 · Found: C, 77.19 *. H, 9.23; H, U.06.

Example 34 5-Allyl-2-cyclopropylmethyl-2'-hydroxy-9β-net-3β-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% mineral oil; washed with benzene) in 150 ml of dimethyl / lyformamide. To this reagent is added a solution of 1.8 g (5.27 mmol) of amine XIu in 25 ml of dimethylformamide, and the mixture is heated under reflux under a nitrogen atmosphere for 6 hours. The reaction mixture is then poured into water, acidified to pH 3 with concentrated hydrochloric acid, basified with concentrated ammonium hydroxide and extracted with benzene. The extracts are washed with brine, dried over MgSO 4 and evaporated to dryness. The resulting oil is dissolved in ether, treated with ethereal hydrogen chloride and the precipitated salt is recrystallized from methanol / ether to give AlIu hydrochloride. Yield: 1.32 g (70%), ep. 2U8-250 ° C. Evaporation distillation of the free base (l ** 5-150 ° C / 5x10 ^ mm Hg) gives an analytical sample.

Anal Calcd for C 21 H 29 NO 2: C, 77.02; H, 8.93; N, U, 28.

Found: C, 76.76; H, 9.10; N, U, 33.

48 605 64

Example 35 2-Cyclopropylmethyl-21-hydroxy-9g (-methoxy-9-methyl-5-propyl-6,7-benzornorphan (XIIuu)

A solution of 800 mg (2.38 mmol) of olefin XIIu in 150 ml of absolute ethanol is hydrogenated for 1.5 hours using 250 mg of 10% Pd / C at an initial pressure of 3.7 kg / cm 2. The catalyst is then filtered off and the solvent is removed in vacuo to leave 670 mg (84% yield) of compound XIIuu. The saturated compound is purified by crystallization of its hydrochloride salt from methanol / ether, m.p. 238-240 ° C. Distillation of the free base (145 ° C / 2x10 μm Hg) gives an analytical sample. Anal Calcd for C 18 H 18 N 2 O 2: C, 76.55; H, 9.48; N, 4.25.

Found: C, 76.36; H, 9.55; N, 4.20.

Example 36 5-Allyl-2-cyclobutylmethyl-21,9o-4-dimethoxy-9γ-methyl-6,7-benzomorphane (Xlq) a) 5-Allyl-2-cyclooctylcarbonyl-9o (-hydroxy-2'- methoxy-9β-methyl-6,7-Bent Sonar fan (IXq)

A solution of 720 mg (2.63 mmol) of hydroxyamine Vilu in 25 ml of dichloromethane and 2 ml of triethylamine is cooled to 0 [deg.] C. and treated dropwise with 343 mg (2.90 mmol) of cyclobutylcarboxylic acid chloride in 10 ml. dichloromethane. The cooling bath is removed and the solution is stirred at room temperature for 1 hour. The reaction mixture is then washed with 1N HCl, water, dried (MgSO 4) and evaporated to dryness. 810 mg (86.6% yield) of amide IXq are obtained, which is crystallized from ether / petroleum ether (30-60 ° C), m.p. 112-113 ° C. Anal Calcd for C 21 H 22 N 2 O 3: C, 74.33; H, 8.22; N, 3.94.

Found: C, 74.25; H, 8.47; N, 3.83.

b) 5-Allyl-2-cyclbutylcarbonyl-21,9c-dimethoxy-9β-methyl-6,7-benzanorphane (Xq)

To a suspension of 262 mg (6 mmol) of sodium hydride (55% mineral oil; washed with benzene) in 50 ml of dimethylformamide is added 711 mg (2 mmol) of hydroxydiamide IXq and the mixture is stirred at 85 ° C for 0.5 hour.

The reaction mixture is then cooled to room temperature and treated with 1.42 g (10 mmol) of methyl iodide. After stirring for 1 hour, the solution is diluted with water and extracted with benzene. The extracts are washed with water, dried (MgSO 4) and the solvent removed in vacuo. Dimethoxyamide Xq is obtained as a viscous oil in quantitative yield.

Anal Calcd for € 23 ^ 1 ^ 3: C, 74.76; H, 8.46; N, 3.79.

Found: C, 74.50; H, 8.87; N, 3.72.

! 49 60 5 6 4 c) A solution of 7 mg (2 mmol) of amide Xq in 50 ml of tetrahydrofuran is added to a suspension of 330 mg (10 mmol) of lithium aluminum urahydride in 50 ml of tetrahydrofuran. The reaction mixture is heated to reflux for 1.5 hours, then cooled and the excess hydride is decomposed by adding 0.38 ml of water, 0.29 ml of 20 l of sodium hydroxide and finally 1.33 ml of water. The inorganic salts are filtered off, washed with tetrahydrofuran and the filtrate is evaporated to dryness. The residue is taken up in 1N hydrochloric acid, extracted with ether, basified with ammonium hydroxide and extracted with dichloromethane. The extracts are washed with water, dried (MgSO 4) and after evaporation of the solvent, k70 mg (66% yield) of compound Xlq are obtained in the form of an oil. The hydrochloride salt melts at 206-209 ° C after crystallization from methanol / ether.

Anal. Calcd for ^ 23 ^ 33 ^ 2 * ® ^ ·: 70, U8; H, 8.7; N, 3 * 57 · Found: C, 70, U2; H, 9.00; N, 3 »UU.

Example 37 5-Allyl-2-cyclobutylmethyl-21-hydroxy-9c (methyl-9H-methyl-6,7-benzonorphane (X11q))

A solution of sodium ethanethiolate is prepared by adding 0.8 U ml (11 mmol) of ethanethiol to a suspension of L80 mg (11 mmol) of sodium hydride (55% in mineral oil; washed with benzene) in 50 ml of dimethylformamide. To this reagent is added 711 mg (2 mmol) of dimethoxyamine Xlq dissolved in 25 ml of dimethylformamide and the reaction mixture is heated under reflux under nitrogen for U hours. The solution is then poured into 350 ml of water, acidified to pH 1+ with concentrated hydrochloric acid, basified with concentrated ammonium hydroxide and finally extracted with benzene. The extracts are washed with water, dried (MgSO 4) and evaporated to dryness. The residual oil is taken up in ether and treated with ethereal hydrogen chloride. The precipitated salt is crystallized from methanol / ether. Yield: 1x00 mg (53%), m.p. 222-22 ° C (XIII) .

The free base is evaporated (150 ° C / 5x10 mm Hg) to obtain an analytical sample.

Anal Calcd for C 22 H 23 N 2 O 2 C * 77.38; H, 9.15 »N. ä, 10.

Found: C, 77.5%. H, 9, M; N, 1 », 05.

50 60564

Example 38 2-8-Cyclobutylmethyl-2 * -hydroxy-.beta.-methoxy-.beta.-methyl-S-propyl-6,7-benzomorphane (X11qq).

A solution of 900 mg (2.6 mmol) of olefin X11q in 300 ml of absolute ethanol is hydrogenated using 300 mg of 10% Pd / C for 1.5 hours at an initial pressure of 3.6 kg / cm. The catalyst is then filtered off and the filtrate is evaporated to give 870 mg (96.5% yield) of X11qq as a thick oil. The compound is purified by crystallization of its hydrochloride salt, m.p. 226-228 ° C. The free base is distilled at 150 ° C / 5x10 μm Hg to obtain an analytical sample.

Anal Calcd for CoOH, NO 0: C, 76.92; H, 9.68; N, U, 08.

dd $ 5 d Found: C, 76.71 *; H, 9.8U; N, M5.

Claims (5)

60564 A process for the preparation of a pharmacologically useful N-substituted-9-alkoxy-5-alkyl-6,7-benzomorphane of the formula R 3 wherein R 1 is -CH 2 -CH = CH 2, -CH 2 - <] or -CH 2; R 5 is hydrogen or methyl; R is lower alkyl, allyl or propargyl; R is hydrogen or lower alkyl; and R is lower alkyl or allyl; or a pharmaceutically acceptable acid addition salt or racemic mixture or optical isomers thereof; characterized in that (a) a compound of formula jCX 8: 3 wherein R is a hydroxy protecting group and R and R are as defined above is reacted to replace the ring nitrogen with an electron withdrawing protecting group which prevents amine quaternization; (b) treating the resulting protected compound with a strong base, preferably an alkali metal hydride, followed by alkylation to form the corresponding 9-OR 3 -substituted compound, wherein R, R and R and R are as defined above, or treating the protected compound with a diazo (lower) compound. ) with time or tri (lower) -5 alkyl alkonium fluoroborate to alkylate the 9-OH group and form a 9-OR-substituted compound, wherein R 5 is lower alkyl 3 and R, R and R are as defined above? 52 60564 (c) and when the electron withdrawing protecting group on the ring nitrogen is a functional group other than a group of the formula 0 ° / v or an electron withdrawing protecting group is removed in a manner known per se to form a compound of the formula 1. In R 3 4 5] R, R, R and R are as defined above, the NH group is then acylated or alkylated in a manner known per se to form a compound of formula J0 $ f RO j OR3 R3 0. yv wherein R® is -C - '-C - or -CH 2 -CH = CH 2; g (d) and when R is a carbonyl group-containing group, reducing the carbonyl group to methylene by treating with a reducing agent, preferably lithium aluminum hydride, to give a compound of formula R3 53 60564 13 4 5 wherein R, R, R, R and R are as defined above; (e) the hydroxy protecting group R is then cleaved in a manner known per se to form a compound of formula L, wherein R is hydrogen; (f) optionally then reacting the 2'-hydroxy group in a manner known per se to form the corresponding compound of formula L, wherein R is methyl; (g) and if the compound L is a racemic mixture then it is optionally decomposed into optical isomers in a manner known per se; (h) and, if desired, an acid addition salt of a compound of formula L is reacted with a pharmaceutically acceptable acid in a manner known per se. A process according to claim 1 for the preparation of 2-cyclopropylmethyl-21-hydroxy-9β-methoxy-5-methyl-6,7-benzomorphane or an acid addition salt thereof. 54 60564 A process for the preparation of pharmacologically active N-substituted-9-alkoxy-5-alkyl-6,7-benzomorphan with the formula rr / r:. color R1 Sr -CH2-CH = CH2, -CH2- <3 or _CH2 / '2 5 R betecknar Väte eller methyl; R is alkyl, allyl 4 3 or propargyl; R is other than alkyl; and R is alkyl or alkyl; or a pharmaceutical compound having a racemic bond or an optical isomer which, in the case of R1 3 4 color, has the same value as the hydroxyl-blocking group of the electron-withdrawing group, R Amine quaternization, which is substituted by ring quaternary; (b) yielding a blocker with a starch base, a derivative of an alkali metal hydride, having an alkylate for the further preparation of a 9-OR 2 -substituted compound, color 3 4 5 R, R and R and R having the same characteristic, or blockers with diazo (carbon) alkane or tri (alkyl) - alkylloxonium fluoroborates and alkylation with 9-OH groups and 5 * 5 fractions with 9-OR substituents, color R or 4 alkyls with R, R and R are ovarian angydated; 55 605 6 4 (c) and the electron-withdrawing blocking group of the group is given by the functional group of the group of formulas 0. y \ -C - <^ j or the -C- source of the electron-blocking blocking group is given above framställning av en förening med formeln A '3 4 5 color R, R, R and R har ovan angivna betydelser, därefter acylerar eller alkylerar NH-Gruppen pä i och för sig känt sätt för framställning av en formören med Formeln Ov <' \ RO | OR ^ i? O O Λ color R8 is -C—, -C or -CH2 ~ CH = CH2; g (d) and, in the case of a group of which a carbonyl group, a reducing carbonyl group and a methyl genome are used for the reduction, for the conversion of lithium aluminum hydride, for the conversion to the formulation xd ::,. OR R3