DK155999B - ANALOGY PROCEDURE FOR THE PREPARATION OF BENZOMORPHAN DERIVATIVES - Google Patents

Description

in

DK 155999 B

The present invention relates to an analogue and process for the preparation of benzomorphan derivatives of the general formula [alpha] 5 <1 A> ^ T \ 4 R3 10 wherein R * represents -ch 2 or -CE 2 -o 15 2 R represents H or C 1 -C 4 alkyl, 5 1 -0 4 R represents C 1-6 alkyl or allyl, R represents H or C 1-6 alkyl, and R 3 represents C 1-6 alkyl or C 1-6 alkenyl or a pharmaceutically useful acid addition salt or racemic mixture or an optical isomer thereof.

Drug abuse by thrill-seeking youth or people seeking to escape the realities of everyday life has become more and more common in our current society. One group of highly abused narcotics is the narcotic analgesics, e.g. codeine, morphine, meperidine, 25 etc. Due to the highly accustomed ability of these agents, public authorities and the pharmaceutical industry spend a great deal of time and capital in discovering and developing new non-addictive analgesics and / or narcotic antagonists. Examples of the prior art attempts to solve this problem are: 30 (1) Everette May and Hiroshi Kugita, jh Ora. Chem. 26, 188 (1961), wherein compounds of formula 35

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2

Λ-R

in ch3 2 10 where R represents H or methyl and R represents methyl or phenethyl are described as moderately weak analgesics, (2) Everette May, James Murphy & J. Harrison Ager, jL Orq. Chem.

25, 1386 (1960) wherein compounds of formula 15 Λ jo # CH, 20 p where R is methyl or phenethyl, and R is H or methyl, are stated to be potent analogetics, (3) Everette May, Hiroshi Kugita, and J. Harrison Ager, »L Org.

Chem. 26, 1621 (1961), wherein compounds of formula * CH3 wherein R represents methyl or phenethyl, R * represents methyl or H, and

ISLAND

R is H, OH or methoxy, stated to produce varying degrees of analgesia, (4) Everette May, Colin Chignell and J. Harrison Ager, «L Med.

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3

Chem. 8. 235 (1965) wherein compounds of the formula are stirred in SH7 10 1 2 wherein R represents H or methyl and R represents methyl is stated to possess analgesic effect, (5) Everette May & Hiroshi Kugita, "L Ora. Chem., 26, 1954 (1961), wherein the compound of the formula, c 20 CH 3 wherein R represents methyl or phenyl ethyl, R1 represents H or methyl, and 25 R represents H or acetyl are stated to possess analgesic activity, (6) Everette May & Seiichi Sato, "L Ora. Chem. 26, 4536 (1961), wherein the compound of the formula. R1 2 1 3

where R represents H or methyl, R represents methyl or ethyl, R

represents methyl or ethyl, and R 1 represents H or acetyl, 35

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4 possess analgesic activity, and (7) N.B. Eddy & E.L. May, Overview of 6,7-Benzomorphans in Synthetic Analgesics, Pergamon Press (1966).

The object of the present invention is to provide an analogue method for the preparation of novel non-addictive analgesics and / or narcotic antagonists in the form of benzomorphan derivatives of the kind set forth in the preamble of the claim.

The analogue method of the present invention is characterized in that (a) is a compound of the formula

RRA

COW

Where R represents a hydroxy blocking group and R and R have the meaning given above are converted to substitution of the ring nitrogen atom with an electron attracting blocking group which counteracts amine waterization, (b) the resulting blocked compound is treated with a strong base, preferably an alkali metal hydride and then alkylated to prepare 5 4

of the corresponding 9-OR substituted compound wherein R, R, R

and R has the meaning given above, or the blocked compound is treated with a diazo-Cjan alkane or a tri-Cyy alkyloxonium fluoroborate to alkylate the 9-OH function and prepare the 9-OR®

30 is substituted compound wherein R represents C 1-6 alkyl and R, R and R

(c) the electron-attracting blocking group on the ring nitrogen atom, when different from

35 "C0 - <] or -CO -O

is removed in a manner known per se to produce a compound

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5 having the formula Λ. wherein R, R, R and R have the meaning given above, whereupon the 2NH function is then acylated in a manner known per se to prepare a compound of the formula / V Wherein R represents 25 ° co or -CO - (d) the carbonyl function is reduced to a methylene group by treatment with a reducing agent, preferably lithium aluminum hydride, to give a compound of formula 30 N-R1 R3

DK 155999B

Wherein R, R, R, R, and R are as defined above, whereupon (e) the hydroxy-blocking group R is then, if desired or necessary, cleaved in a manner known per se to prepare compound 2 of formula L wherein R represents hydrogen and the 5 (f) 2'-hydroxy function is then reacted, if desired, in a manner known per se to form the corresponding compound of formula L, 2 wherein R represents C 1-6 alkyl and / or (g ) the compound prepared, when it is a racemic mixture, if desired, isolated in the optical isomers in a manner known per se, and / or (h) the compound prepared if desired in a manner known per se. pharmaceutically useful acid addition salt thereof.

The compounds of the invention contain the benzo-morphane basic nucleus which can be represented by the following planar formula in which the 15 different positions are numbered:

2 ° i 11 4 jV0R

R

R

Although there are three asymmetric carbon atoms (stars) in the benzomorphan molecule, only two racemic forms are possible because the iminoethano system attached to the 1- and 5-positions is geometrically limited to a cis- (1,3-diaxy al. ) -configuration. Therefore, these racemates can only differ with respect to the configuration at the 9-carbon atom. The only 30 variables will be that the 9-alkoxy group may be in the cis and trans positions relative to the iminoethano system. When the 9-alkoxy group of the compounds of the invention is in a trans position relative to the iminoethano system, 9a-alkoxybenzomorphans are present. When the 9-alkoxy group is in the cis position relative to the iminoethano system, there are 9β-alkoxybenzomorphans.

The graphical indications of benzomorphans used herein are intended to include the d1 racemic mixture and the isolated d and 1 isomers thereof.

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7

The compounds of the invention, e.g. The 9β-alkoxybenzomorphanes may exist as two optical isomers, viz. such as the left-turning and right-turning isomers. The optical isomers can be graphically represented as follows: 5 9 O -methoxybenzomorane: 10 I 11 / L ^ OCHO Γ nZU'0cH3 09

H ° k H

1 “ΓΗ CH3 υί13 15

The present invention encompasses all of the isomers including the optical isomers in isolated form.

The optical isomers can be separated and isolated by fractional crystallization of the diastereoisomeric salts, e.g. formed with d- or 20-tartaric acid or D - (+) - α-bromocampersulfonic acid. Other acids commonly used for insulation may also be used.

The left-turn isomers of the compounds of the invention are the most preferred.

By the term "pharmaceutically useful acid addition salt" is meant all such inorganic and organic acid salts of the compounds of the invention with acids commonly used to produce relatively non-toxic salts of pharmaceutical agents containing amine functions. Examples of such salts are those formed by mixing the compounds of formula L with an acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, phosphoric acid, hydrochloric acid, maleic acid, malic acid, ascorbic acid, citric acid, tartaric acid, lauric acid, lauric acid, , palmitic acid, oleic acid, myristic acid, lauryl sulphonic acid, naphthalene sulfonic acid, linoleic or linolenic acid, fumaric acid or the like.

The present compounds and starting materials are prepared by a total synthesis, illustrated below in Schemes I and II.

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8

Schedule I

i Λ 1. Ila CH3 m, ch3 j®Q iOc? rN "CH2" C6H5

CH3 ° “3” bP

H, C - N 6 CH 3 CH 3

Illa IVa oxalate Δ '™' ø? F mk

AAlAo 'HBr CH T OH

CH-0 I 3 rH

Example 5 ^ Uil3

Va 6 Via Λ Λ /, NH / ^ N-CH, - <3

EXAMPLE 7 10%, OH, YlYJc0CH3 CH3

Vila ^ eI XIa

SkS®SS2 ± - ^ I5) pr "j HO I 'CH3 0CH3 YTTa

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9

Scheme II

/ n-ch3

Example 48 /] -> JOUXy, CH3 ° vCH2 CH3

XX

Al ^ Al ^ OUj ^ 0H Si-EeL ^ IQKL, „-8-0.3 ^ f ^ TZ3 ce3r ^ J ch3 CH, CH3

XXI

VIr '

/ NH

Example 52 ^ L ^ - ^ JL

Ι ^ λΤΛ ^ ΟΗ -> ch30 I '' CH3 CH3 ° ch ch3 CH3 jxfcr CH3

Xllr

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10

Compounds of formula j4s

R3 XII

Wherein R, R, R and R have the above meanings, or a pharmaceutically useful acid addition salt thereof, are particularly preferred narcotic agonist / antagonistic agents.

All of the preferred compounds of the invention are 15 novel and are valuable because of their properties as analgesics and / or narcotic antagonists or as intermediates in the preparation of compounds with such biological properties.

The compounds of formula XII possess the most desirable properties, viz. properties such as analgesics and / or narcotic antagonists.

Furthermore, some of the compounds of formula XII also possess antitussive activity, a property generally associated with analgesic activity.

The most powerful and desirable compounds prepared 4 according to the invention are the compounds of formula XII wherein R represents 5 9 - hydrogen and OR represents 9a - alkoxy. This is surprising considering that the most potent and most desirable compounds of the corresponding group, wherein OR represents OH, generally contain a 9 / J-OH and a 9a hydrogen or (lower) alkyl.

It is well known in the art that it is possible for some past to possess both agonistic and antagonistic properties. An agonist is a compound that mimics a narcotic analgesic and possesses analgesic properties. An antagonist is a compound that counteracts the analgesic and euphoric properties of a narcotic analgesic. It is possible for a connection to possess both properties. A good example 35 of such a compound is cyclazocin.

The discovery of compounds that possess an appropriate relationship between agonist and antagonistic effect is crucial to commercial success. Compounds with too much antagonistic activity have

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11 tend to induce undesirable psychotomimetic effects (hallucinations), making the compounds undesirable for clinical use.

Various compounds of the invention (in the form of the respective soluble salts) were tested in vivo to determine the agonistic and / or antagonistic properties. Table I gives the results of the studies. In Table I, the number of mg / kg body weight of compounds that produce, by subcutaneous administration, has an agonistic or antagonistic effect in 50% of the mice and rats (ED5Q) * used for the study 10.

12 Φ ω £ ω

to ri • Η φ G tP

0 fH tp> (tf Φ + i Xi cn i — i σ. Two

Cl ID .H rH · · CM · ·. 00 00

ΦΦ OOOPPOPPCMCOO

1 i — I o. S ». ♦ · * »· · * <·« C G o o o 2 2 0- 2 2 cm o o ·· • H Aj Ή

X Φ D.4J tP Η -P

G O O

• H S H

G A <

H

• H _____; _________>

Ai to Ή -P oo to G 1 • Η O Φ r- r ~

GjGio 1 — l 1 — i * · · · · 00 CM

O ao OOOQQPQQHinro co. ha; - '* -' ···· - · '*' G OH 00022222000

-PEG .H

G> 1G <?

<X

ISLAND

CM Φ G t — I O G

XX o uo in ro cm 'Φσι

vo tt 1 cMHiHcMvorominoHCM

h - HrQ

Cr> AND ooo.nooror-cM.HO

H a; £ G H

Φ \> i H p Λ di X -P c

G £ O CO

It ^ _ ________ o in

P

W

Φ 'tf rH

PrOCM ········ -Ρ00ΡΡΡΡΡΡΡΡΡ tP O-- ··· * ···· G H00222222222 · Γ- (

G I

_V ri ----------- i Μ Ό S g „„ «§> G tP co m in 00 o ro σ \ r- S- r§! Jj • HG tOOOCMiHrOrOCOH <P» t-- rO, y XG -HG - - - - - - - - - - to O1 G EooiHcMinoHo ^ ovo ^ j ^ -Η Η <G cm 1-1 m

P> i-H

to G H

-Η Φ> c χ: h O Λ Φ tn to

<C rH

O 'O G

-H G

XI G

H G X

O -H G a

m O -Η H

tonj Χ) ϋΦΌΗ> 0Χ! 0

(JI H (tJHHHHHH N a rH OHHHHHHMM lt5 H rH

wxhxxxxxx-p o g HIXIIIIIlGrH>

• c 13 DK 155999 B

g tø tø H -ri Φ β tn O ft} - ^ v tn> * ° <3 · m Φ 'J „, 6 D.

+), q <ϋ Ή (d

Cl 0.0 O CO. 'M & mm ^ Η ro oo -¾ ®. 5¾ ih ooooH Φ £ <** «j * F *

C m w w k k *. Φ O EH

• Η x | ooooo · empty β ·.

t n xl Q) 2 44 -P

C a + J * S ω X! Λ

• Η β -P W O 3 X

C o O m XI tho W

44 2 P 'm k_ „

Li * 0 t7 * ° 3 • Η β <#> β 44 s -------- β om 's. ·

g in + J tn H

M tn β g o

rn Φ tø 44 O

-, - j * ri o rQ m m jj m ω x: β h g m β ^ 01 ^ b η o m, r; _ ^ 2 rjrlCQ (\ J C \ J · · · M CtP C Λ * O Οι O HOQQQ 0> 'ί04? N

L} ^ · »<· ♦ · fcj * * M N, rC W

m O P OOSJSS G 31? P * J 5 -p g m '2 n g n ^ Λ

cJ> 1 β c Λ Q

£ * raping *. *

^ O -ri tø - · P

V) H IW «IH

> tn - m · 44 f <m m \ β -P m -P u> o m · * 'ti g x! tn β β η cu mom _i m ni ρ ω ω η 44 —'OP p tn mg ^ g ° mm β th N N φ ^^ g1 PH ftj 4J βΗ PO> 4 O P9 g P om V n ° * “h u_ .

O O xlx: L P1 ^

ti I Qil (-! pv · * £ tnO

~ M o * § ^ "~ 1 °. °. ^ § Si -5 · <D

^ ε x ”m - O ω Τ '^ d Γ 5 η> ι Ό m ί> ~ · Η m O β Q) ^ 4 tö tn £ GS Φ · g g Φ -Η β H Q xl ~ m 44 p m

S --—----- CUr ^ + J Sh tø P

-------- in nd Ή -H m h IM <Tl H tø a -ri m h m X) φ w -p 44 m tn

• P · - g -Ρ Η β -P

m φ cn φ ω mm φ 4J ..... H m p 44 ilfl β tn 4JOQQQQ ° ίϋ c n · · · · · m Ή -P tn

Η ρ 3 £ S S! 3 -P - Φ Μη βΦ * H

c β in Η Φ mg β _j m <n | m ρ τ) ι β ti β xi ω ω o .η o ------ m · i tn mm λ: £ c tn m τ) xi β m ω · HC r- vo o Φ β -rl Η - P p β -Η -ντ mo Φ2Φβ ΦΦΦΦ w θ 'β tø ο om w jj -P RrnH'm> Γι -j rt «.«. h oa -p φ h mm

-P> ι · η g ooooo Φ ωβ Φ> -P-P

m c j. (m rM * 44 Φ · Φ tn • η m> ^ ωπτίΌ ω λ - β ft} cri C * TdO Φ Φ Ό I 'S' o> OQi βτΐ>> ti mw m

Ji ^ -H m Η Η cn m ^ u gmmgmHmfi * φ β · gg β xl 44> ω Οϋ «ω · ΟΦ ·· -44-β, —im O -Η -Η Φ <4-1 -P h - H tn m 0) βββ-Ρ ^ β rr) df> O Οβ C * 0 O Η I mco · tn tn Φ o β in to mx> m v. <D

_o O -P -P-P OmQH

T, c ββββΟβ Φ- ^ r · H

O -ri MOi << <JPW> -hs1 <m O Π g β -P ^ men ^ mo

tn N O H H H

T & m X H H H

tho H O X X X

β O Η I I I

>!> «(Rt O? O? O?

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14

It is clear from the results in Table I above that the compounds of the invention possess potent agonistic and antagonistic activity. The normal parenteral dosing range of the compounds of the invention 5 is in adult humans from ca. 0.25 to approx. 10 mg three to four times a day. Orally, the doses range from approx. 1 to approx. 50 mg three to four times a day.

It is stated in the literature that the compound haloperidol, i.e. 4 [4- (p-chlorophenyl) -4-hydroxypiperidino] -4 / fluorobutyrophenone (Merck 10 Index 8th edition, page 515) has found no experimental use to relieve withdrawal symptoms in drug use. Therefore, it is a preferred embodiment to combine haloperidol with the narcotic antagonists prepared according to the invention to provide a composition which not only counteracts drug abuse but at the same time enables supportive therapy in the absence of opiates.

Haloperidol is usually administered orally at a dose of 0.5 to 5.0 mg two or three times daily depending on the severity of the disease. A dose of haloperidol in this range may be administered simultaneously with an effective dose to produce the desired result of a narcotic antagonist prepared according to the invention.

Examples of other preparations which may be prepared may be mentioned a narcotic antagonist prepared according to the invention in combination with an anti-anxiety agent such as chlorordiazepoxide or diazepam, or a phenothiazone such as chlorpromazine, promazine or methotrimeptrazine.

The compounds referred to herein by XII can be readily converted into compounds of formula L. Esters and ethers of the compounds of formula XII may in some cases possess special advantages due to increased solubility, diminished solubility, crystallization willingness, deficiency on repulsive taste, etc., but these 30 special advantages are all subordinate to the physiological main effect of the free phenol, which effect is independent of the nature of the ester or ether group used.

Another preferred compound of the invention is the compound of formula 35

DK 155999B

15 • Χφ '-

R 0; V

R 3 is 10 1 3 4 5 2 wherein R, R, R and R are as defined above and R is H or C 1-6 alkyl, or a pharmaceutically useful acid addition salt thereof.

A more preferred compound prepared according to the invention is the compound of the formula n ~ r1 20 r2 (/

; OR5 XXXX

R 3 1 2 3 4 5 25 wherein R, R, R, R and R have the meaning set forth above, or a pharmaceutically useful acid addition salt thereof.

Among preferred compounds of formula XXXX may be mentioned: A) (±) -2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-5-methyl-6,7-benzomorphan, or an acid addition salt thereof.

B) (-) - 2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-5-methyl-6,7-benzomorane, or a hydrochloride, fumarate or tartrate salt thereof.

C) (1J-Z-cyclopropylmethyl-Z'-hydroxy-ga-methoxy-S-methyl-G, - - benzomorphane, or an acid addition salt thereof.

D) (-) - 2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphan, or the hydrochloride, fumarate or tartrate salt thereof.

E) (±) -2-allyl-2, -hydroxy-9a'-methoxy-5-methyl-6,7-benzomorphan, or an acid addition salt thereof.

F) (-) - 2-allyl-2'-hydroxy-9a-methoxy-5-methyl-6,7-benzomorphan,

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16 or the hydrochloric, fumarate or tartrate salt thereof.

G) (±) -2-cyclopropylmethyl-9a-ethoxy-2'-hydroxy-5-methyl-6,7-benzomorphan, or a pharmaceutically useful acid addition salt thereof.

H) (-) - 2-cyclopropylmethyl-9a-ethoxy-2'-hydroxy-5-methyl-6,7-5-benzomorphan, or the hydrochloride, fumarate or tartrate salt thereof.

I) (±) -2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-5-allyl-6,7-benzo-morphane, or an acid addition salt thereof.

J) (-) - 2-Cyclopropylmethyl-2'-hydroxy-9a: -methoxy- 5-anyl-6,7-benzomorphan, or the hydrochloro, fumarate or tartrate salt thereof.

10 K) (±) -2-Cyclobutylmethyl-2, -hydroxy-90'-methoxy-5-allyl-6,7-benzoromphane, or an acid addition salt thereof.

L) (-) - 2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-5-allyl-6,7-benzo-morphane, or the hydrochloride, fumarate or tartrate salt thereof.

M) (±) -2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-5-propyl-6,7-benzomorphan, or an acid addition salt thereof.

N) (-) - 2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-5-propyl-6,7-benzomorphan, or the hydrochloride, fumarate or tartrate salt thereof.

O) (±) -2-cyclobutylmethyl-2β-hydroxy-9α-methoxy-5-propyl-6,7-benzomorphan, or an acid addition salt thereof.

20 P) (-) - 2-cyclobutylmethyl-2'-hydroxy-9a-methoxy-5-propyl-6,7-benzomorphan, or the hydrochloride, fumarate or tartrate salt thereof.

Q) (-) - 5-Allyl-2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-9β-methyl-6,7-benzomorphan, or the hydrochloride, tartrate or fumarate salt thereof.

R) (-) - 2-cyclobutylmethyl-2'-hydroxy-9α-methoxy-9β-methyl-5-n-propyl-6,7-benzomorphan, or the hydrochloride, tartrate or fumarate salt thereof.

S) (-) - 5-Allyl-2-cyclopropylmethyl-2'-hydroxy-9α-methoxy-9β-methyl-6,7-benzomorane, or the hydrochloride, tartrate or fumarate salt thereof.

T) (-) - 2-cyclopropylmethyl-2'-hydroxy-9a-methoxy-90-methyl-5-n-propyl-6,7-benzomorphan, or the hydrochloride, tartrate or fumarate salt thereof.

Another preferred compound prepared according to the invention 35 has the formula

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17 n-r1 R O T V0R5 in P3

R XXXXI

Wherein R *, R 2, R 2, R 2 and R 5 are as defined above, or are a pharmaceutically acceptable acid addition salt thereof.

As the most preferred compounds of formula XXXXI are mentioned: A) (±) -5-allyl-2-cyclobutylmethyl-2'-hydroxy-9β-methoxy-6,7-benzo-morphane or a pharmaceutically useful acid addition salt thereof .

B) (-) - 5-allyl-2-cyclobutylmethyl-2'-hydroxy-9β-methoxy-6,7-benzo-morphane, or the hydrochloride, fumarate or tartrate salt thereof.

C) (±) -5-allyl-2-cyclobutylmethyl-2 '-hydroxy-9β-methoxy-9α-methyl-6,7-benzomorphan, or a pharmaceutically useful acid addition salt thereof.

D) (-} - 5-allyl-2-cyclobutylmethyl-2'-hydroxy-90-methoxy-9a-methyl-6,7-benzomorphan, or the hydrochloride, fumarate or tartrate salt thereof.

When treating the ring nitrogen blocked compound under step 25 (b) with a strong base, sodium hydride is preferably used at a ratio of from about 1: 1.1 mole of base per mole of blocked nitrogen compound in a reaction-inert solvent such as dimethyl formamide, dimethylacetamide, tetrahydrofuran, hexamethylphosphoramide, benzene, toluene, diethyl ether and the like.

When the ring nitrogen blocked group is not desired, it is removed as indicated in step (c) in a manner known per se. For example, when the blocking group. is a carbalkoxy or trifluoroacetyl group, the compound is preferably hydrolyzed with a strong all potassium base, preferably sodium hydroxide in a (lower) all channel, preferably 95% ethanol, to prepare the unblocked secondary amine ring. When the blocking group is a cyano group, the compound is preferably treated with lithium aluminum hydride in tetrahydrofuran under reflux, after which the mixture is treated with water and sodium hydroxide to form the

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18 unblocked secondary amines.

After the ring nitrogen blocking group is removed, the secondary amine compound is then preferably acylated with an acid halide, anhydride or mixed anhydride of a compound in the form of 5 O p HO-C 2 J or H 2 O - in a reaction-inert organic solvent, such as methylene chloride, chloroform, diethyl ether and the like, with or without heat, in the presence of a tertiary amine.

The reduction of step (d) is carried out in a reaction-inert organic solvent such as diethyl ether, tetrahydrofuran or dioxane, and preferably by heat.

During step (e), the R group is preferably selectively decomposed by treatment with sodium thioethoxide, boron tribromide, pyridine hydrochloride or hydrobromic acid in a suitable solvent. Preferably, the hydroxy protecting group R is quenched by reaction with sodium thioethoxide in dimethyl formamide. When R represents acyl or alkanoyl, R is preferably removed by hydrolysis.

20

Example 1 25 CH3 °} OCH3 Xla ch3 Z-cyclopropylmethyl-Z7.9o: -dimethoxy-5-methyl-6,7-benzomorphane a) 4 35 JL / ½ X7 a

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19 3,4-Dihydro-7-methoxy-1-methyl-2 (1H) sodium acetone (Hal 40.5 g (0.5 mole) of pyrrolidine dissolved in 50 ml of benzene was added under nitrogen and over a period of 5 to 10 minutes to a stirred solution of 50 g (0.284 mol) of 3,4-dihydro-7-methoxy-2 (1H) naphthalenone (I) in 200 ml of dry benzene. The mixture is refluxed for 1 hour and 5 ml of water The mixture was cooled and slowly added to 0.5 mole of methyl iodide dissolved in 300 ml of benzene, the resulting mixture was refluxed for 3 hours, then 200 ml of water was added to the reaction mixture and the reflux was resumed. For 30 minutes, the mixture was cooled and the benzene layer separated, washed with water saturated with sodium hydrogen sulfite, dried and then evaporated to dryness.

The resulting residue was distilled to give the desired compound (Ha). The IR and NMR spectra were consistent with the structure.

B) <CO 2 H, 2? N ch, IIIa 20 CH, 0/3 3 CH 2 -CH 2 -N 2 xCH 2 - 1- (2-Benzylmethylaminoethyl-1-7-methoxy-1-methoxy-3,4-dihydro-1H) 2 (llnaphthalenone hydrogen oxalate (IIIa)

A solution of 0.12m 7-methoxy-1-methyl-3,4-dihydro-2 (1H) naphthalenone (IIa) in 40 ml of benzene was added to a refluxed suspension of 0.14m sodium hydride in 100 ml of benzene. . After 1 hour 10 -30 reflux, this mixture was treated with a solution of 0.12m 2-benzylmethylaminoethyl chloride in 100ml of benzene and heated at reflux for 18 hours. The reaction mixture was washed with water and then extracted with dilute hydrochloric acid. Neutralization of the acid extract with ammonium hydroxide and extraction with ether gave an oil which was converted to an oxalate salt (IIIa) (yield 78%), mp 137-139 ° C.

Analysis calculated for ^ 2 ^ 27 ^ 2 * WV 67.43; H, 6.84; N, 3.28.

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

c)

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20 µgH, for Xch2-0 q 5 Br CH-, 0 f 0 3 CH3 IVa 10 2-Benzyl-2 '-methoxy-5-methyl-9-oxo-6,7-benzomorphanomethyl bromide (IVa) - Compound IIa was converted to the hydrobromide salt thereof by treatment of sodium hydroxide solution, isolation by extraction with ether and then treatment with HBr. 0.21m of the hydrobromide salt was dissolved in 450 ml of acetic acid and slowly treated with a solution of 11.2 ml of bromine in 50 ml of acetic acid and stirred for 1/2 hour. The solution was diluted with 2 liters of Skellysolve B (essentially consisting of n-hexane) and cooled under nitrogen. The "Dissolve Solve B" layer was decanted from the rubbery precipitate. This residue is partitioned between ether and water.

This two-phase system was made basic with concentrated ammonium hydroxide.

The layers were immediately separated and the aqueous layer extracted with ether. Concentration of the ether extracts gave an oil. This oil was taken up in acetone and stirred for several hours to give the desired compound (IVa) as a crystalline solid (76% yield).

D), HBr 30 CH2 O T o CH3 Va 355-Dimethyl-2'-methoxy-9-oxo-6,7-benzomorphan (Va)

Reduction of IVa in acetic acid using hydrogen and 10% palladium-on-carbon gave the desired compound (Va) in a yield of 92%, m.p. 145-149 ° C. This compound is known (E.L. May et al., JL

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21

Org. Chem., 25, 1386 (1960)). This synthesis represents an improved process for preparing these compounds.

e) 5 3 CH 3 in CH 3 1 3a 3 3 3 2,5-Dimethyl-9Q1-hydroxy-2 H -methoxy-6,7-benzomorphane (Via) 0.02 mole of 2,5-dimethyl-2 H -methoxy 9-oxo-6,7-benzomorphane (VI) 1 and 8 15 g of cobalt chloride hexahydrate were dissolved in 100 ml of 95% ethanol under gentle heating and then stirred for 1/2 hour at room temperature. 4 g of sodium borohydride were added portionwise with stirring and under nitrogen. The resulting dark mixture was stirred at room temperature under nitrogen for 18 hours. 75 ml of 6N hydrochloric acid were added carefully and ethanol was removed at 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 crystalline material which, by gas-liquid chromatography analysis, was found to consist of 88% α-hydroxy and 9% β-hydroxy isomers. Crystallization from ethyl acetate "Skellysol ve B" (essentially n-hexane) gave the pure α-isomer 2 (Via), mp 115-116.5 ° C (in the literature stated to be 115.5-177 ° C ).

^ .G. Murphy, J.H. Ager & E.L. May, J. Org. Chem., 25, 3386 (1960).

30 ^ H. Kugita & E.L. May, J. Org. Chem., 26, 1954 (1961).

35

DK 155999 B

22 A, CH.O // iVSs ^ N | '

3 '0H VIIA

chloro9oro-hydroxy-2H-methoxy-5-methyl-6,7-benzomorphan (Vila). Hydrogen oxalate 0.014 mole of compound Via was acetylated with 50 ml of acetic anhydride at steam bath temperature for 2 hours to form the 9α-acetoxy compound. This material was taken up in 75 ml of benzene, treated with 2 g of potassium carbonate and 5 ml of ethyl chloroformate and heated at reflux temperature for 18 hours. The resulting mixture was washed with water, dilute hydrochloric acid and saturated sodium chloride. The aqueous layers are further extracted twice with benzene. The benzene layers were dried (KgCO3) and concentrated to give 9a-acetoxy-2-carbethoxy-2'-methoxy-5-methyl-6,7-benzomorphan. This material was hydrolyzed with potassium hydroxide (25 g - 85% beads) to reflux 95% ethanol (125 ml) for 66 hours. The ethanol was removed at reduced pressure. The residue was treated with dilute sodium bicarbonate and extracted with methylene chloride to give the desired product (Vila) which was converted to the hydrogen oxalate salt in 95% ethanol (89% yield), mp 212-25 215 ° C.

Analysis calculated for C1414HigNNO₂ * CgHgOO: C, 59.43; H, 6.55; N: 4.33.

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

g) 30 Λ CHio ^^

35 3. J

CH3

DK 155999 B

23 2-Cyclopropylmethyl-2- [9a-dimethoxy-5-methyl-6,7-benzomorphane (XIah hydrochloricl 0.015 mol of compound Vila as the free base in 50 ml of 5 methylene chloride and 8 ml of triethylamine was treated with 2.3 The reaction mixture was stirred for 1 hour and then treated with 7 ml of methanol, stirred for 5 minutes and concentrated to dryness. The residue was taken up in toluene and washed with dilute hydrochloric acid, water and saturated sodium carbonate solution. of the toluene extracts gave 2-cyclopropylcarbonyl-2'-methoxy-9a-hydroxy-5-methyl-6,7-benzomorphan (IXa, about 100% yield and one with purity greater than 98% according to gas-liquid chromatographic analysis). A solution of compound IXa in dimethyl formamide (25 ml) was added to a suspension of NaH (0.015 mol) in 10 ml of dimethyl formamide under nitrogen. After 15 1/2 hours a portion of methyl iodide was added and after another 1 hour a portion of methyl iodide (1 ml each time) and the mixture is stirred iy another 16 hours. After removal of the solvent at reduced pressure, the residue was treated with water and extracted with methylene chloride to give 2-cyclopropyl carbonyl-2 ', 9ar-dimethoxy-5-methyl-6,7-benzo-morphane (Xa, about 100% yield with a purity of about 98% according to gas-liquid chromatographic analysis). This material was reduced with LiAlH 2 in tetrahydrofuran for 16 hours to give the desired product, which was isolated as the crystalline hydrochloride salt (1.4 g, 85% yield), mp 230-233 ° C.

Calcd for C CjHgyONO₂HCl: C, 67.54; H, 8.35; N, 4.15.

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

Example 2 άί3 3 XIIa 2-Cyclopropylmethyl-2 '-hydroxy-9.0-methoxy-5-methyl-6,7-benzomorohan (XIla)

DK 155999 B

24

A mixture of compound Xla (0.0028 mol) and 0.05 m sodium thioethoxide (prepared from sodium hydride and ethyl mercaptan) in 80 ml of dimethyl formamide was heated at reflux temperature for 3 hours. The solvent was removed at reduced pressure. The residue was treated with toluene and extracted with dilute hydrochloric acid. The acid extracts were made basic (3 COg) and extracted with methylene chloride to give XIIa, which crystallized from acetonitrile, m.p. 188-189 ° C.

Analysis calculated for C C ^H ^ NOOg: C, 75.22: H, 8.77; N, 4.87.

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

Example 3 2-Cyclopropylmethyl1-2,99-dimethoxy-5,98-dimethyl-6,7-brenzomorphane (Xlb) fumarate a) 20 CH, O in OH OH -methoxy-6,7-benzomorphan (VIIb) fumarate

A reflux mixture of 0.032 m 9a-hydroxy-2'-methoxy-2,5,9j3-trimethyl-6,7-benzomorphan (the compound prepared and disclosed by May et al. In J. Org. Chem. 26, 188 (1961)) and 26 g of potassium carbonate in 150 ml of benzene were treated with a solution of 0.095 m of trichloroethyl chloroformate in 100 ml of benzene. After heating at reflux temperature for 60 hours, the reaction mixture was treated with 200 ml of water and stirred for 1/2 hour. The benzene layer was separated, washed with saturated sodium chloride, dried (MgSO4) and concentrated to give crude 2-trichlorocarbethoxy-5,90-dimethyl-9a-hydroxy-2-methoxy-6,7-benzomorphan. This material was taken up in 100 ml of acetic acid and added over a period of 1/2 hour to a suspension of 40 g of zinc in 100 ml of acetic acid.

DK 155999 B

25 hydrochloric acid under nitrogen. After completion of the addition, more zinc (20 g) was added and stirring was continued for 1 hour. The zinc was removed by filtration and the filtrate was concentrated. The residue was treated with dilute ammonium hydroxide and extracted several times with chloroform to form material IIb, which was converted to a fumarate salt by reaction with 3.9 g of fumaric acid in n-propanol, melting point higher than 250 ° C.

Analysis calculated for, 1 / 2C 4 H 4 O: C, 66.86; H, 7.59; N, 4.59.

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

b) 2-Cyclopropylcarbonyl-5,9g-dimethyl-9-hydroxy-2H-methoxy-6,7-benzo-morphane (IXb)

A solution of (0.012 m) Vllb (free base) in 30 ml of methylene chloride 15 and 4 ml of triethylamine was treated with a solution of 0.02 m of cyclopropylcarbonyl chloride in 20 ml of methylene chloride. After stirring for a few hours at room temperature, the reaction mixture was washed with dilute hydrochloric acid, water and dilute sodium carbonate. Drying (MgSO4) and concentration of the organic extracts gave the desired compound IXb, which crystallized in -20 from 95% ethanol.

c) 2-Cyclodrodylmethyl-2- [9a-dimethoxy-5.9g-dimethyl-6,7-benzomorphan (Xlbhfumarate

A solution of (0.00635 m) IXb in 30 ml of dimethyl formamide was treated with sodium hydride (760 mg of a 60% dispersion in mineral oil) with stirring and under nitrogen. After 1/2 hour, 1 ml of methyl iodide was added and stirring was continued. An additional 1 ml of methyl iodide was added one hour later and stirring was continued for 18 hours. A few drops of acetic acid were added and the dimethyl formamide removed under reduced pressure. The residue was treated with water and extracted with methylene chloride to give 2-cyclopropylcarbonyl-2 ', 9α-dimethoxy-5,9 / J-dimethyl-6,7-benzomorphan (Xb) contaminated with mineral oil. The mineral oil was removed by treatment with n-pentane and extraction with acetonitrile to give compound Xb (purity 96% by gas-liquid chromatographic analysis).

Material Xb was reduced by 720 mg of LiAli 40 ml of tetrahydrofuran for 18 hours to give Xlb, forming one crystalline hydrogen fumarate (2.1 g, 78% yield), mp 154-155 ° C.

DK 155999B

26

Analysis calculated for C20 + W2 O2 (WV C, 66.80; H, 7.71; N, 3.25.

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

5

Example 4 2-Cyclopropylmethyl-5,9,18-dimethyl-2H-hydroxy-9ci; -methoxy-6,7-benzomorphane (XIIbhfumarate

By replacing Example XIa of Example 1 with a 10 equimolar amount of compound XIb, the desired compound XIIb was prepared in the form of a hydrogen fumarate, mp 191-194 ° C.

Analysis calculated for C, 66.16; H, 7.48; N, 3.36.

Found: C, 65.63; H, 7.76; N, 3.01; Η £ 0: 0.35.

Example 5 2-Cyclobutylmethyl-2'9a-di methoxy-5.98-di methvi-6,7-benzomorphane (Xlc. fumarate A) -5,9'-dimethyl-9a-hydroxy-2'-methoxy-6,7-benzomorphane (IXc).

B) By replacing Compound IXb in Example 11 with an equimolar amount of IXc, the desired compound XIc was prepared in the form of the 3/2 fumar salt, mp 150-151 ° C.

Analysis calculated for C21 + 31 ° C C, 64.39; H, 7.41; N, 2.78.

Found: C, 64.24; H, 7.70; N, 2.61.

EXAMPLE 6 2-Cyclobutylmethyl-5,95-dimethyl-2'-hydroxy-9ft-methoxy-6,7-benzomorphan 30 fXIIl.fumarate T By substituting compound Xla which was isolated as the hydrobromide salt, mp 223-226 ° C.

Analysis calculated for C C CH gMMMHBr: C, 60.60; H, 7.63; N, 3.53.

Found: C, 60.40; H, 7.54; N, 3.54.

The hydrobromide and hydrochloride salts are prepared by dissolving the amine in a minimal amount of absolute ethanol to which a

DK 155999 B

27 anhydrous ethanolic HBr or HCl solution prepared in advance by passing HBr or HCl gas into ethanol. The salt is precipitated by slow addition of di ethyl ether during scraping. The salt is collected by filtration and purified by recrystallization.

Example 7 a) (-) - 2-Cyclopropylmethyl-2'-9'-dimethoxy-5-methyl-6,7-benzomorphane Isolation of (1-2,5-dimethyl-2'-methoxy-9-oxo-6,7-benzomorphane (Va) A) f +) - 2,5-Dimethyl-2 H -methoxy-9-oxo-6,7-benzomorphan (+) - hydrogen tartrate

A mixture of 0.072 m of compound V (racemic mixture) and 0.072 m (+) - tartaric acid was taken up in 150 ml of water and 30 ml of 95% ethanol, filtered and concentrated to 150 ml and stored at 0-5 ° C. crystallization. The crystals were collected, washed with 95% ethanol and recrystallized from 50% water ethanol to give 10.1 g (66% yield) (+) - 2,5-dimethyl-2'-methoxy-9-oxo-6, 7-benzomorphan (+) hydrogen tartrate dihydrate.

Analysis calculated for 015Η19Ν02.04Η606, Η20: C, 52.89; H, 6.78; N, 3.25; H2 O, 8.3.

Found: C, 52.89; H, 7.07; N, 3.17; H 2 O, 8.94.

The free base was solubilized by dissolving the tartrate in water and basifying the solution with sodium carbonate. The mixture was extracted with diethyl ether, washed with water, dried over anhydrous sodium sulfate, filtered and brought to dryness in vacuo. The free base optical rotation is [α] + + 86.5 ° (c = 1.038, 95% ethanol).

D

B) (-) - 2,5-Dimethyl-2'-methoxy-9-oxo-6,7-benzomorphane (-1-hydroenone tartrate

The first mother liquor from the (+) isomer under A) above was basified with sodium carbonate and extracted with methylene chloride to give 10.3 g of an oil. This oil was 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 ca. 100 ml and cooled at 0-5 ° C for crystallization. The crystals were collected and recrystallized from 100 ml of 50% aqueous

DK 155999B

28 ethanol to give 10.6 g (68% yield) (-) - 2,5-dimethyl-2'-methoxy-9-oxo-6,7-benzomorphane (-) - hydrogen tartrate, m.p. 157.5 - 158.5 ° C, [α] 22 -48.50 (c = 1.047, water).

D

Analysis calculated for C C HjH₂NNO * * V * 666.2 2 2₂: C, 52.89; H, 6.78; N, 3.25; H 2 O, 8.35.

Found: C, 52.17; H, 6.99; N: 3.00, H2 O, 9.10.

The free base was soldered as described under A) above, and the optical rotation was [α] 22 -85.5 ° (c = 1.054, 95% ethanol.

D

b) (-) - 2,5-Dimethyl-9β-hydroxy-2 H -methoxy-6,7-benzomorphanyl-1-ylal 0.0765 m (-) - 2,5-dimethyl-2'-methoxy-9-oxo- 6,7-Benzomorphan (free base) was hydrogenated on a Parr shaker in 250 ml of 95% ethanol using 150 mg of platinum oxide as catalyst. The theoretical hydrogen uptake was observed after 1 1/2 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness to give a crystalline residue which was recrystallized from toluene to give 18.2 g of the pure desired product (96% yield), m.p.

148 ° C, [α] 21 -56.5 ° (c = 1.022, 95% ethanol). Gas-liquid D

chromatographic analysis shows that there is one pure compound (the α-isomer).

Analysis calculated for C for forHH ^NO C C> 72.84; H, 8.56; N, 5.66.

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

c) f -) - 9tt-Hydroxy-2H-methoxy-5-methyl-6,7-benzomorphan ΓΜ-VIIa

A mixture of 0.033 m (-) - VIa and 16.5 potassium carbonate in 160 ml of toluene was treated with 16.5 ml of trichloroethyl chloroformate with stirring. The reaction mixture was heated at reflux under nitrogen for 18 hours. After cooling, the mixture was treated with 100 ml of water and the layers were separated. The aqueous layer was extracted again with toluene. The toluene extracts were washed (saturated sodium chloride solution), dried (K 2 CO 2) and concentrated. The residue was taken up in methanol (120 ml) -water (12 ml), cooled, treated with 12 g of potassium hydroxide and stirred at 0-5 ° C for 45 minutes. 12 ml of acetic acid was added and the solution concentrated. The residue was treated with dilute hydrochloric acid and extracted with 29 toluene to give (-) - 2-chloro-carbethoxy-9a-hydroxy-2'-methoxy-5-methyl-6,7-benzomorphan. This material was taken up in 100 ml of acetic acid and slowly added to a hot suspension of 15 g of zinc dust in 50 ml of acetic acid under nitrogen. After the initial reaction subsided, the mixture was heated at reflux temperature for 1/2 hour. The zinc was removed by filtration (under nitrogen) and the filtrate was concentrated. Treatment of the residue with dilute ammonium hydroxide and extraction with chloroform gave 8 g (-) - VIIa (100% yield), which by gas-liquid chromatographic analysis was found to be approx. 97% pure. This material forms a crystalline hydrochloride salt, melting point higher than 250 ° C. [?] -29.6 ° (c = 1.015, 95% ethanol).

D

Analysis calculated for C C CH₂gM ^ jHCl: C, 62.33; H, 7.47, N, 5.19. Found: C, 62.31; H, 7.22; N, 5.56.

D) (-) - 2-cyclopropylmethyl-2'-9ar-dimethoxy-5-methyl-6,7-benzomorphan [(-) XIa]

In Example 1, by replacing Vila with an equimolar amount of (-) -

Afterwards, the desired product (-) - XIa was formed in 92% yield after purification 20 by chromatography on alumina (eluting with benzene ether). Toluene was used in the first reaction step instead of methylene chloride. The product was crystallized as the oxalate salt, m.p. 185.5-186.5 ° C, [ar] -48.9 °

D

(c = 0.966, 95% ethanol).

Analysis calculated for C, 64.43; H, 7.47; N, 3.58.

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

Example 8 (-1-2-Cyclopropylmethyl-2'-hydroxy-9α-methoxy-5-methyl-6,7-benzomorphan 30 M-XIIal

By substituting in Example 2 Xa with an equimolar amount of (-) - XIa, the desired compound was formed, m.p. 180 to 180.5 ° C.

Calcd. For C jHHggNNOg: C, 75.22; H, 8.77; N, 4.87. Found: C, 75.62; H, 8.50; N, 4.69.

(-) - XIIa forms a crystalline fumarate salt, mp 179-180 ° C, [α] 20 -57.4 ° (c = 1.011, 95% ethanol).

D

35 DK 155999 B 1 30

Analysis calculated for C 18 H 25 NO 2 1/2 (C 4 H 4 ° 4): 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-9a-methoxy-5-methyl-6,7-benzomorphan (+ t-Xual)

In Examples 7b) -8, successively replacing the left-rotating isomer with an equimolar amount of the right-rotating isomer (+) - VIa, the desired product (+) - XIla, melting point (as tartrate salt), is 147-148 ° C. [α] 20 + 37.3 ° (c = 1.002, 95% ethanol).

D

Analysis calculated for (C CjH₂ gNOg ^CCHgOg, 1/2 1O: C, 64.67; H, 7.87; N, 3.77; HgO, 2.42.

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

Example 10 2-Cyclopropylmethyl-9Qr-ethoxy-2 H -methoxy-5-methyl-6,7-benzomorphan (XId)

By substituting in Example 1 the methyl iodide used with an equimolar amount of ethyl iodide, the desired compound Xld was prepared, which was solubilized as the hydrochloric salt, 83% yield, mp 236-240 ° C.

Analysis calculated for C20 H29 NO2 +: C, 68.26; H, 8.59; N, 3.98.

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

Example 11 2-Cyclopropylmethyl-900; -ethoxy-2H-hydroxy-5-methyl-6,7-benzomorphan-XIIdl

By replacing in Example 2 the compound Xla used with an equimolar amount of compound Xld, the desired compound was obtained, which was isolated as the hydrochloride salt containing one mole of acetonesol vat, mp 136-145 ° C.

Analysis calculated for CjgH NOgjN₂ClH, C3HgO: C, 66.78; H, 8.60; N, 3.54.

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

EXAMPLE 12 9-α-11oxy-2-cyclopropylmethyl-2'-methoxy-5-methyl-6,7-benzomorphan hydrochloride (XIII 35

DK 155999B

31

By replacing in Example 1 the methyl iodide used with an equimolar amount of allyl bromide, the desired compound was prepared in the form of the hydrochloride salt Xle, mp 222-227 ° C.

Analysis calculated for C21H2NO2, HCl: C, 69.30; H, 8.31; N, 3.85.

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

EXAMPLE 13 9a-Allyoxy-2-cyclopropylmethyl-2'-hydroxy-5-methyl-6,7-benzomoranone XIII 10 By substituting in Example 8 the compound Xla used with an equimolar amount of compound Xle, the desired compound XI as a hydrochloride salt, mp 255-260 ° C.

Analysis calculated for C₂qH₂ ^NO₂, HCl: C, 68.65; H, 8.07; N, 4.00.

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

EXAMPLE 14 5-α1β-2-cyclopropylmethyl-2'-9β-dimethoxy-6,7-benzomorphan (xml 20

CH 0 8 T

glue 25 (3,4-dihydro-7-methoxy-1-yl-2-n-naphthalenone film) 40.5 g (0.5 mole) of pyrrolidine dissolved in 50 ml of benzene was added over a period of 5-10 minutes and under nitrogen to a stirred solution of 50 g (0.0284 mol) of compound 1a (3,4-dihydro-7-methoxy-2 (1H) naphthalenone) in 200 ml of dry benzene. The mixture was refluxed for 1 hour and 5 ml of water was collected in a Dean-Stark apparatus. The mixture was cooled and slowly added to 60.5 g (0.5 mole) of allyl bromide dissolved in 300 ml of benzene. The resulting mixture for baking is steamed for 3 hours. Then 200 ml of water was added to the reaction mixture and the reflux was resumed. After 90 minutes, the mixture was cooled, the benzene layer separated, washed with water followed by water saturated with sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was distilled to give 52.20 g (85% yield) of the desired compound glue, DK 155999B at 32 boiling point 106-112 ° C / 0.01-0.05 mm. The IR and NMR spectra were consistent with the structure.

Analysis calculated for C, 77.74; M5.

Found: C, 77.47; H, 7.50.

B) = v v I \ Ul, Ulm N \, HBr CH3 15 3,4-Dihydro-7-methoxy-1-aryl-1- (2-dimethylaminoethyl) -2 (1H) -naphtha-lenon hydrobromide (Iurn)

A mixture of 400 ml of dry benzene, 22 g (0.25 mole) of tert-amyl alcohol and 10.62 g (0.25 mole) of sodium hydride for baking is evaporated under nitrogen for 30 minutes or until all the hydride was consumed. Then 47.2 g (0.22 mol) of compound glue in 100 ml of benzene was added slowly while the excess amyl alcohol was distilled off. An additional 100 ml of benzene was added and distilled off. Then, 28 g (0.3 mole) of 2-chloro-Ν, Ν-dimethylaminoethane in 100 ml of benzene was added dropwise. The reaction mixture was refluxed for 20 hours, washed twice with water, diluted with ether and extracted with 1N HCl. The acidic extract was heated to 60 ° C for one hour, cooled and extracted with ether to obtain 15 g of compound glue. The acidic extract was then cooled, basified with NH 2 OH and extracted with ether. The extract was dried over potassium carbonate, treated with charcoal and post-filtration with dry HBr. 33.87 g (61.5¾ yield) of HBr salt of compound Ulm were obtained. After recrystallization from methanol-ether, the compound melted at 139-140 ° C. The IR and NMR spectra were consistent with the structure.

Calcd for C 28 H 2 W 2 Br: C, 58.69; H, 7.11; N, 3.80.

Found: C, 58.63; H, 7.16; N, 3.59.

DK 155999 B

33

• "JXX

3-Bromo-3,4-dihydro-7-methoxy-1-anvil-1 (2-dimethylaminoethyl) 1-2 (1H) naphthalene hydrobromide (LVm)

To a stirred solution of 15 g (41 mmol) of compound Ulm in 100 ml of methylene chloride and 300 ml of tetrahydrofuran in the dark was added a solution of 20.58 g (41.5 mmol) of pyrrole idone hydrotribromide in 300 ml of tetrahydrofuran over a period of time. in 4 hours. After the addition, the reaction mixture was allowed to stand at room temperature overnight. The reaction mixture was evaporated to dryness and the solid residue was recrystallized from 700 ml of isopropanol to give 12.7 g (68.5% yield) of compound LVm, mp 149-150 ° C. The IR and NMR spectra were consistent with the structure.

Analysis calculated for C CjH ^ MM ^B ^HBr: C, 48.34; H, 5.63; N, 3.13.

Found: C, 48.64; H, 5.70; N, 3.14.

25 CH3 °! 0 LXm 5-yl-2'-methoxy-2-methyl-9-oxo-6,7-benzomorphanemethobromide (LXm) 12.6 g (0.028 mol) of the HBr salt LVm was dissolved in ice-cold water, placed in a separatory funnel and covered with ether. An additional 35 was added

DK 155999B

34 sufficient amount of concentrated ammonium hydroxide to make the mixture alkaline, and the free base of LVm was extracted and separated as quickly as possible. The ether was evaporated and the residue dissolved in acetone and allowed to stand overnight. 6.55 g (65.5% yield) of 5 solid LXm were obtained. After recrystallization from isopropanol, the compound melted at 175-177 ° C. The IR and NMR spectra were consistent with the structure.

Analysis calculated for C, 57.60; H, 6.71; N, 3.73.

Found: C, 57.44; H, 6.78; N, 3.58.

E) at CH, O; 3 Vm 5-Use-2H-Methoxy-2-methyl-9-oxo-6,7-benzomorane (Vml)

A suspension of 2 g (5.46 mmol) of LXm in 25 ml of 1-octanol was heated under reflux and nitrogen atmosphere for 15 minutes. After cooling, the mixture was poured into 40 ml of 0.5 N HCl and extracted twice with 100 ml of petroleum ether to remove octanol. The aqueous layer was basified with aqueous ammonia and the free base was extracted with benzene to form, after drying and evaporation of solvent, 1.23 g of an oil (VIm). The oil was stirred with a solution of 350 mg oxalic acid in 5 ml of water for 1 hour and then allowed to stand at 5 ° C for 16 hours. The precipitated solid was filtered off to obtain 980 mg (47% yield) of Vm-oxalate 30 containing one mole of crystallization water, mp 156-162 ° C. The product recrystallized from water melted at 160-161 ° C under water loss at 110 ° C.

Analysis calculated for CO 2 4 04 1120: C, 60.15; H, 6.64; N, 3.69.

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

f) 5-α1β-9β-hydroxy-2β-methoxy-2-methyl-6,7-benzomorphan (VIm)

A solution of diisobutylaluminum hydride (62 ml of a 25% solution

DK 155999 B

35, approx. 60 mmol) was diluted with 150 ml of dry tetrahydrofuran and cooled to -45 ° C under nitrogen. Then, a solution of 8.58 g (31.6 mmol) (Vm) in 100 ml of dry tetrahydrofuran was added dropwise. After stirring for 1 hour at -45 ° C, the gelatinous material thus obtained was concentrated in vacuo. The oily residue was dissolved in ether, washed with water, dried (50 SO) and evaporated in vacuo to give 8.88 g of the alcohol (VIm). Crystallization of the oily residue from ether-petroleum ether (bp 30-60 ° C) gave 6.32 g (72% yield) of crystalline material (VIm). The obtained mother liquor was purified by chromatography 10 on 100 g of silica gel using a 1: 1 mixture of methanol-ether to give 2.00 g (23% yield) of the pure alcohol (VIm). The analytical sample was recrystallized from acetone-ether-petroleum ether (bp 30-60 ° C) and melted at 73-79 ° C.

Analysis calculated for C, 74.69; H, 8.48; N, 5.12.

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

g) 5-allyl-900; hydroxy-2 H -methoxy-6,7-benzomoridane (VIIm).

By replacing in Example 6 the compound used Via with an equimolar amount of compound VIm, the desired compound was prepared, see VIIm. The compound was purified by crystallization of the oxalate salt from methanol-ether to give a sample melting at 173-176 ° C.

The analyte sample was purified by molecular distillation of the free base at 150 ° C / 5x104 mm Hg.

Analysis calculated for Cjg ^ jNOg: C, 74.10; H, 8.16; N, 5.40.

Found: C, 73.92; H, 8.27; N, 5.36. 1 5-allyl-N-cyclopropylcarbonyl-900; -hydroxy-2'-methoxy-6,7-benzomorphan (xm)

A solution of 4.07 g (15.7 mmol) of the hydroxyamine V11m in 200 ml of dichloromethane and 5 ml of triethylamine under nitrogen was treated dropwise with 1.80 g (17.25 mmol) of cyclopropylcarbonyl chloride. The reaction mixture was washed with dilute hydrochloric acid and water, dried (MgSO 4) and the solvent removed in vacuo to give 4.12 g (80%) of the crude amide (IXm). Crystallization from benzene ether gave a sample melting at 146-35 147 ° C.

Analysis calculated for C20H253: C, 73.37; H, 7.70; N, 4.28.

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

I) S-Allyl-N-cycloDroDylcarbonyl-g'.gtt-dimethoxy-e.y-benzomoradane (Xm)

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 nitrogen was added 2.39 g (7.30 mmol) of the alcohol (IXm) . The mixture was stirred at 50 ° C for 1/2 hour, then cooled to room temperature and treated with 5.18 g (36.5 mmol) of methyl in odide. Stirring was continued for 3.0 hours. Then the reaction mixture was poured into 500 ml of water and extracted with benzene. The extracts were washed with water, dried (MgSO 4) and evaporated in vacuo to give 2.45 g (quantitative) of the 4 -4 amide (Xm). The crude product was purified by distillation at 160 ° C / 5x10 mm Hg.

Analysis calculated for ¢ 21.27 ° C: C, 73.87; H, 7.97; N, 4.10.

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

J) 5 "of N-CycloDroDylmethyl-2- [9ft-dimethoxy-6,7-benzomoridane (XIm) 2.30 g (7.74 mmol) of the amide (IXm) was added to a suspension of 770 mg (20.2 mmol) lithium aluminum hydride in 125 ml of dry tetrahydrofuran. The resulting mixture was refluxed for 3 hours and then cooled, and the excess hydride was destroyed by successive addition of 0.77 ml of water, 0.58 ml of 20% NaOH and finally 2.70 ml of water. The inorganic salts were filtered off and washed with tetrahydrofuran. The filtrate was evaporated to dryness and the oily residue was taken up in N hydrochloric acid and extracted with ether. The aqueous phase was made basic with ammonium hydroxide and extracted with dichloromethane. The extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo. 1.97 g (90%) yield of the tertiary amine (Xm) was obtained. The hydrochloride salt thereof melted at 156-157 ° C after recrystallization from methanol-ether.

Analysis calculated for C i iHggNOg: C »77.04; H, 8.93; N, 4.28.

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

Example 15 5-Use-2-Cyclopropylmethyl-2 H -hydroxy-9β-methoxy-6,7-benzomorphane fXIIml 35 A solution of sodium thioethoxide was prepared by adding 1.70 ml (22.2 mmol) of ethanethiol to 970 mg (22, 2 mmol) of a 55% sodium hydride dispersion in mineral oil washed with benzene in 175 ml of dry dimethylformamide under nitrogen. Then 1.32 g (4.04 mmol) of dimethyl acid was added.

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37 ether Xlm, and the solution for baking is evaporated for 4 hours. The reaction mixture was 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 were washed with water, dried (MgSO 4) and evaporated in vacuo to give 1.23 g (97% yield) of the phenol (XIIm). The hydrochloride salt melted after crystallization from methanol-ether at 223-225 ° C.

Analysis calculated for C20 H27 NO2: C, 76.64; H, 8.68; N, 4.47.

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

10

Example 16

HAY

0 Xlln 20 2-CycloDroDylmethyl-2β-hydroxy-9β-methoxy-5-DroDyl-6,7-benzomoradane fXIl Inl

By replacing in Example 8 the compound Xla used with an equimolar amount of compound Xln, the desired compound 25, which is identical to the compound prepared in Example 24, was obtained.

Example 17 2-Cyclopropylmethyl-2 / -95-dimethoxy-5,9o-dimethyl-6,7-benzomorphene (R) a), N_CH

\ JU - ^ 0H

35 CH_0 'H VIp ch3

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38 2,5-Dimethyl-9fl-hydroxy-2'-methoxy-6,7-benzomorphanhydromodromide CVip)

A suspension of 0.04 m IVa in 200 ml ether was treated with 50 ml 2.5 m solution of ispropylmagnesium chloride in tetrahydrofuran. This mixture was stirred under nitrogen for 17 hours. The cooled mixture was treated slowly with 200 ml of water and 25 ml of concentrated hydrochloric acid. The ether was removed by evaporation under reduced pressure. Extraction of the aqueous mixture with methylene chloride gave 17 g of a brown foam.

This foam was taken up in 200 ml of 95% ethanol and hydrogenated on a Parr 10 shaker using palladium hydroxide-on-carbon as catalyst to give 10.3 g (78% yield) of pure Vip after crystallization from 2-propanol.

Reference: H. Kugita & E.L. May, J. Org. Chem., 26, 1954 (1961).

B)

20 VHP

CH-, 0 · H P

• 5 I

ch3 96-Hydroxy-2H-methoxy-5-methyl-6,7-benzomorphan (VIId)

A mixture of 0.031 m Vip free base and 90 ml acetic anhydride was heated at 100 ° C for one hour. The acetic anhydride was removed under reduced pressure. Treatment of the residue with sodium carbonate and extraction with methylene chloride gave in quantitative yield 2,5-dimethyl-2'-methoxy-9 / J-acetoxy-6,7-benzomorphan. This material was taken up in 100 ml of benzene and treated with 5 g of potassium carbonate and 10 ml of ethyl chloroformate.

The resulting mixture was heated at reflux under nitrogen for 26 hours. This mixture was treated with water. The benzene layer was separated and washed with dilute hydrochloric acid and a saturated aqueous solution of sodium chloride to give, after concentration, a quantitative yield of 5-methyl-2'-methoxy-2-carbethoxy-9β-acetoxy-6,7-benzomorphane. This material was taken up in 250 ml of 95% ethanol and treated with 30 g of potassium hydroxide. The material was treated at reflux temperature below

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39 nitrogen for 90 hours. The ethanol was removed under reduced pressure. Treatment of the residue with a 10% aqueous solution of sodium hydrogen carbonate and extraction with methylene chloride gave 7.2 g of VIIp (100% yield). Recrystallization from toluene gave 6.8 g (94% yield) of analytically pure material, mp 132-133.5 ° C.

Analysis calculated for C C HjH₂gNO₂: C, 72.07; H, 8.21; N, 6.00.

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

c) 2,5-Dimethyl-9-phospho-1-epoxy-2'-methoxy-6,7-benzomorphane (XX)

A solution of 0.05 m 2,5-dimethyl-2'-methoxy-9-oxo-6,7-benzo-morphane (Va) in 125 ml of dry dimethyl sulphoxide was added to a 55% sodium hydride dispersion (0 , 1 m) with stirring and under nitrogen. To this mixture was added 0.1 m trimethyl sulphonimide under stirring. After stirring for 4 hours under nitrogen, the mixture was diluted with water and extracted with methylene chloride. Drying and concentration of these extracts gave an oil which, by gas-liquid chromatographic analysis, was found to contain 86% of the isomer (XX), 6-7% of another product which was presumably the α-isomer and some of the starting ketone. Chromatography on alumina followed by crystallization from cyclohexane gave pure XX (64% yield with a purity of the isomer greater than 95%), m.p. 30 93-95 ° C.

Analysis calculated for C C CH₂NNO₂. C, 74.10; H, 8.16; N, 5.40.

Found: C, 73.89; H, 8.30; N, 5.36.

d) 9β-Hydroxy-2β-methoxy-2,5,9a-trimethyl-6,7-benzomorphan hydrochloride (Vir)

A solution of 0.028 m 2.5 dimethyl-9- (spiro- / S-epoxy) -2-methoxy-6,7-benzomorphane (XX) in 75 ml tetrahydrofuran was added to a stirred suspension of 0.045 m lithium aluminum hydride in 25 ml tetrahydrofuran . This

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The mixture was stirred at 25 ° C for 16 hours and heated at reflux temperature for 2 hours. The resulting mixture was treated gently with 5 ml of a saturated aqueous solution of sodium sulfate. The solids were removed by filtration and the filtrates concentrated to dryness. The oily residue was converted to a hydrochloride and crystallized from ethanol-ethyl acetate water to give pure VIr, hydrochloride hydrate (86% yield), mp 139-143 ° C. Gas-liquid chromatographic analysis on the free base shows an isomer purity of 96%. The IR spectrum (CCl +) at different solution concentrations shows only the bottom OH, suggesting the / J-OH configuration.

Reference: E.L. May & H. Kugita, J. Org. Chem., 26, 188 (1974).

e) Preparation of 96-acetoxy-2-carbethoxy-5.9tt-dimethyl-2β-methoxy-6,7-benzomorphane (XXII

0.022 m 9 ^ -hydroxy-2β-methoxy-2,5,9tt-trimethyl-6,7-benzomorphan (Vir) was treated with 50 ml of acetic anhydride and heated on a steam bath for 3 hours. After removal of the acetic anhydride under reduced pressure, the residue was treated with a dilute aqueous solution of sodium carbonate and extracted with benzene. Drying and evaporation of the 20 benzene extracts gave acetoxy compound late 9β-acetoxy-2,5,9a-trimethyl-2, -methoxy-6,7-benzomorphane. A solution of this material in benzene was treated with 2.5 g of potassium carbonate and 6.5 ml of ethyl chloroformate (0.07 m) and heated at reflux temperature for 16 hours. This mixture was treated gently with 120 ml of 1 N hydrochloric acid. The layers were separated, and the aqueous layer was extracted with benzene. Drying and concentration of the combined benzene extracts gave the desired compound (XXI), which crystallized from 95% ethanol, mp 87.5-88.5 ° C.

For C for forH₂ NONO: C, 66.46; H, 7.53; N, 3.88.

Found: C, 66.18; H, 7.62; N, 3.75.

F) Preparation of 5.9a-Dimethyl-9g-hydroxy-2β-methoxy-6,7-benzomoridane IVIIrl

A mixture of 0.002 m @ 9 - acetoxy-2-carbethoxy-5,9a-dimethyl-2'-methoxy-6,7-benzomorphane (XXI), 2.5 g of potassium hydroxide and 20 ml of 95% ethanol was heated at reflux temperature for 18 hours. After concentration, the residue was treated with water and extracted with methylene chloride to give the desired compound Vllr, which was recrystallized from ethyl acetate, mp 147-148 ° C.

Analysis calculated for C C ^H NC NCN₂O: C, 72.84; H, 8.56; N, 5.66.

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

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41 5 g) YlYYl * CH2 <l10 0c3 d "3" 3 15 2-Cycloprodylmethyl-2 / -9g-dimethoxy-5.9tt-dimethyl-6,7-benzonioridane (XIr)

A solution of 0.005 m of 5,9a-dimethyl-9β-hydroxy-2'-methoxy-6,7-benzomorphan (VIIr) in 25 ml of methylene chloride and 7.5 ml of triethylamine was treated with 3 ml of cyclopropyl carbonyl chloride with stirring. The resulting mixture was stirred for 18 hours and then treated with a dilute 20 aqueous solution of sodium carbonate. The layers were separated and the aqueous layer was extracted with methylene chloride. Drying and concentration of the methylene chloride extracts gave 2-cyclopropylcarbonyl-5,9a-dimethyl-9β-hydroxy-2'-methoxy-6,7-benzomorphane (IXr) as an oil.

A solution of IXr in 25 ml of dimethyl formamide was added to a suspension of 0.015 m NaH in 10 ml of dimethyl formamide under nitrogen. After 1/2 hour, 1 ml of methyl iodide was added and 1 hour later another 1 ml of methyl iodide was added and the mixture was stirred for a further 16 hours. After removing the solvent at reduced pressure, the residue was treated with water and extracted with methylene chloride to give 2-30 cyclopropyl carbonyl-2 ', 9β-dimethoxy-5,9a-dimethyl-6,7-benzomorphane (Xr).

This material was 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 an 18 hour reflux period, this mixture was treated gently with 3 ml of a saturated aqueous solution of sodium sulfate and heated until the solids were white. Removal of the solids by filtration and concentration of the filtrate gave an oil (Xlr) which was converted to its hydrochloride salt, mp 226-229 ° C.

Analysis calculated for C C C ^ gNO₂HCl: C, 68.26; H, 8.59; N, 3.98.

Found: C, 68.16; Η, ί>, 85; N, 4.02.

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42

Example 18 2-Cyclopropylmethyl-5.9tt-dimethyl-2'-hydroxy-9g-methoxy-6,7-benzomorphan (5XIIr)

In Example 2, by replacing the compound XIa used with an equimolar amount of compound XIr, the desired compound XIIr was prepared in the form of the hydrochloride salt, mp 270-278 ° C during decomposition.

Calcd for C CjHgjONO₂HCl: C, 67.54; H, 8.35; N, 4.15.

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

Example 19 2-Cyclobutylimethvi-2'.95 ~ dimethoxy-5-methyl-6,7-benzomorphane (XIs) the desired compound XIs was prepared in the form of the hydrochloride salt, mp 205-209 ° C.

Calcd for ^ g ^ gNO₂HCl: C, 68.26; H, 8.59; N, 3.98.

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

Example 20 2-Cyclobutylmethyl-2H-hydroxy-96-methoxy-5-methyl-6,7-benzomorphane (XIIs)

In Example 8, by replacing the compound Xla used with an equimolar amount of compound XIs, the desired compound XIIs was formed in the form of the hydrochloride salt, mp 214-219 ° C.

For CjglHj NON₂gjHCl: C, 67.54; H, 8.35; N, 4.15.

Found: C, 67.88; H, 8.41; N, 4.02.

Example 21 2-Cyclopropylmethyl-2'9,1-dimethoxy-5-methyl-6,7-benzomorphan (Xlt)

By substituting in Example 17 g) the used compound Vllr with an equimolar amount of compound VIlp, the desired compound Xlt was formed in the form of the hydrochloride salt, mp 217-220 ° C.

Analysis calculated for C C CHg ^NO₂HCl: C, 67.54; H, 8.35; N, 4.15.

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

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43

Example 22 2-Cyclopropylmethyl-2β-hydroxy-9β-methoxy-5-methyl-6,7-benzomorphan (XII)

In Example 8, by replacing the compound Xla used with a 5 equimolar amount of compound Xlt, the desired compound XIIt was formed in the form of the hydrochloride salt, mp 245-255 ° C under decomposers! ng.

Analysis calculated for C 18 H 25 NO 2 · C: C, 66.75; H, 8.09; N, 4.33.

found; C, 67.11; H, 8.28; N, 4.17.

10

Example 23 2-Cyclobutylmethyl-2β-9g-dimethoxy-5,9-dimethyl-6,7-benzomorphane (XIV)

By replacing in Example 17g) the cyclopropylcarbonyl chloride used with an equimolar amount of cyclobutyl carbonyl chloride, the desired compound XIv is formed in the form of an oil which could be used as such in Example 24.

Example 24 2-Cyclobutylmethyl-5,9g-dimethyl-2H-hydroxy-9g-methoxy-6,7-benzomorphan (XIIvi

In Example 8, by replacing the compound Xla used with an equimolar amount of compound XIv, the desired compound XIIv was formed in the form of the hydrochloride salt, melting point higher than 245 ° C during decomposition.

Analysis calculated for C20 H29 NO2 +: C, 68.26; H, 8.59; N, 3.98.

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

Example 25 N-Cyclopropylmethyl-2β-hydroxy-9α-methoxy-5-propyl-6,7-benzomorphan

A solution of 495 mg (1.51 mmol) of the olefin (XIIm) in 150 ml of absolute ethanol was hydrogenated for 1 hour over 250 mg of 10% Pd / C at an initial pressure of 42 psi. The catalyst was filtered off with Celite and the solvent was evaporated to give 486 mg (98% yield) of the saturated compound XIIn. The hydrochloride salt crystallized from methanol-ether melted at 236-239 ° C. The analytical sample was purified by sublimation at 160 ° C / 5x100 mmHg.

Analysis calculated for C 20 H 29 NO 2: C, 76.15; H, 9.27; N, 4.44.

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

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44

General Procedure for Preparation of Fumarate Salts 5 A 1: 1 equimolar amount of fumaric acid powder and the appropriate amine (e.g., XIIb) are dissolved in a sufficient amount of hot isopropanol or n-propanol. After cooling and during scraping or grafting, the fumarate salt crystallizes. The product is collected by filtration.

10 General Procedure for Preparation of the Oxalate Salt

Compound IIa (0.01 mol) is dissolved in a minimal amount of hot acetone. A hot solution of oxalic acid (0.01 mol) is added with stirring, scraping and / or grafting. The oxalate salt crystallizes on cooling and is collected by filtration.

15

Example 26

Isolation of 5-aryl-2-cyclopropylmethyl1-2 / -hydroxy-9Q: -methoxy-6,7-benzomorohan in the left- and right-handed isomers thereof 20/ IVv 25

A solution of 5.3 g (16.9 mmol) of compound XIIm in 150 ml of acetone was treated with 2.6 g (17.0 mmol) of 1-mandelic acid. 2.0 g of partially separated solid were obtained, which was recrystallized three times from acetone 25 to finally obtain 0.69 g of an optical rotation salt [<*]

D

= + 8.4 ° (concentration = 286 mg / 100 ml CH 3 OH). The optical rotation of the free base was [a] + = + 61.0 ° (concentration = 189 mg / 100 ml

D

CH30H);

DK 155999 B

Whereas the rotation of the hydrochloride salt thereof (m.p. 222 - 224 ° C) was [ar] 2 = + 58.9 ° (concentration = 229 mg / 100 ml CFLOH).

D J

The 5 1 isomer was isolated by dissolving 5.3 g (16.9 mmol) of the above compound in 125 ml of acetone and treating the solution with 2.6 g (17.0 mmol) of d-mandelic acid. The resulting 2.86 g of salt was recrystallized once from acetone to obtain an optical rotation [or]

D

-9.4 ° (concentration = 287 mg / 100 ml CHgOH). The free base was generated ([a] 2® = -62.0 °, concentration = 266 mg / 100 ml CH-OH)

D J

and then recrystallized from acetone-ether as the hydrochloride salt thereof (15 g, m.p. 222-224 °). The optical rotation was [a] =

D

-59.4 ° (concentration = 281 mg / 100 ml CH 2 OH).

When d- or -XIIm was hydrogenated to d- or -XIIn, the measured rotation of the d-isomer (mp 228-230 ° C, HCl salt) was: [a] 25

20 D

= + 52.8 ° (concentration = 303 mg / 100 ml of CH 2 OH) and the rotation of the isomer (mp 228 ° C, HCl salt): [α] 25 = -52.7 °

D

concentration = 294 mg / 100 ml CHgOH).

25

Example 27 5-Allyl-N-cyclobutylmethyl-2β-9tt-dimethoxy-6,7-benzomorphan-xyzl a) 5-allyl-N-cyclobutylcarbonyl-9β-hydroxy-2β-methoxy-6,7-benzomorphan

A solution of 9.20 g (35.5 mmol) of the hydroxyamine VIIm free base in 400 ml of dichloromethane and 15 ml of triethylamine was treated dropwise at 0 ° C and under a nitrogen atmosphere with a solution of 4.62 g (39.0 mmol) of cyclobutylcarbonyl chloride. in 100 ml of dichloromethane. The cooling bath was removed after completion of the addition and the solution was stirred at room temperature for 1 hour. Then, the reaction mixture was washed with 1N hydrochloric acid, water and dried over magnesium sulfate. Evaporation of the solvent in vacuo afforded 11.40 g (94% yield) of the hydroxyamide (IXz).

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46

Crystallization from ether-petroleum ether (bp 30-60 ° C) gave an analytical sample melting at 116-118 ° C.

Analysis calculated for C 21 H 27 NO 3: C, 73.87; H, 7.97; N, 4.10.

Found: C, 74.08; H, 8.11; N, 4.01.

5 b) 5-Allyl-N-cyclobutylcarboxyl-2.9Q; -dimethoxy-6,7-benzomorane (Xzl 5.0 g (14.6 mmol) of the hydroxyamide IXz was added to a suspension of 1.02 g (43.9 mmol) NaH (55% in oil, washed with benzene) in 500 ml of dimethyl formamide The mixture was heated at 50 ° C for 1/2 hour, then cooled to room temperature and treated with 10.4 g (73.0 mmol) of methyl iodide.

After stirring for 3 hours, the reaction mixture was poured into water and extracted with benzene. The extracts were washed with water, dried (MgSO 4) and concentrated in vacuo to give 5.0 g (96% yield) of the dimethoxyamide (X 2) as a viscous oil. An analytical sample is prepared by distillation at 170 ° C / 5x10 mm Hg.

Calcd for C22 299 ° C: C, 74.33; H, 8.22; N, 3.94.

Found: C, 74.08; H, 8.39; N, 3.89.

c) 5-Al 1 vi -N-cyclobutylmethyl -2'9or-dimethoxy-6,7-benzomorphane (XIzl) A solution of 4.28 g (12.0 mmol) of the dimethoxyamide 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 refluxed for 1 hour, cooled, and the excess hydride was destroyed by successively adding 1.38 ml of water, 1.02 ml of 20% sodium hydroxide and 25 ml. finally 4.80 ml of water The inorganic salts were filtered off, washed with tetrahydrofuran and the filtrate was evaporated to dryness. The oily residue was taken up in dilute hydrochloric acid and extracted with ether. The aqueous phase was made basic with concentrated ammonium hydroxide and extracted with dichloromethane. with water, dried (MgSO4) and evaporated in vacuo to give 3.80 g (92.7% yield) of the amine XIz. The oxalic acid salt melted at 184-186 ° C after crystallization from methanol-ether.

-4

Distillation of the free base at 135 ° C / 5x10 mmHg gave an analytical sample.

Analysis calculated for C C CH₂NNOg: C, 77.38; H, 9.15; N, 4.10.

Found: C, 77.50; H, 9.32; N, 4.08.

47

UK 1 bb999 E

Example 28 5-Allyl-N-cyclobutylmethyl-2H-hydroxy-9Q; -methoxy-6,7-benzomorphane (XIIzl) A solution of sodium ethanethiolate was prepared by adding 1.87 ml (25.5 mmol) of ethanethiol 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 dimethyl formamide To this solution was added 1.52 g (4.6 mmol) of the dimethoxyamine XIz and the solution was added The reaction mixture was poured into water, acidified with concentrated hydrochloric acid, basified with ammonium hydroxide and extracted with benzene.

The extracts were washed with water, dried (MgSO 4) and evaporated to dryness. The crude material was dissolved in acetone, treated with one equivalent of oxalic acid, and ether added until crystallization emerged. The oxalic acid salt weighed 1.62 g (83% yield) and melted at 193-194 ° C after crystallization from methanol-ether.

An analytical sample was prepared by distilling the free base at 160-165 ° C / 5x10 4 mmHg.

Analysis calculated for H, 8.93; N, 4.28.

Found: C, 77.31; H, 9.04; N, 4.18.

Example 29 N-Cyclobutylmethyl-2β-hydroxy-9β-methoxy-5-propyl-6,7-benzomorphan CXI-V) 1.04 g (3.18 mmol) of the olefin XIIz was dissolved in 200 ml of absolute ethanol and hydrogenated in 2 hours above 10% Pd / C at an initial pressure of 47 psi. The catalyst was then filtered using Cel in tea and the filtrate was evaporated to dryness. The crude material (922 mg, 88% yield) was dissolved in acetone, treated with one equivalent of oxalic acid, and ether added until crystallization emerged. The salt thus obtained (1.04 g) melted at 214-216 ° C after crystallization from methanol-ether.

An analytical sample was prepared by sublimating the free base at 160 ° C / 5x10 4 mmHg. Mp 181-183 ° C.

Analysis calculated for C 21 H 31 NO 2: C, 76.55; H, 9.48; N, 4.25.

Found: C, 76.65; H, 9.76; N, 4.25.

35

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48

Example 30 2-Cyclobutylmethyl-V, 9ft-dimethoxy-5-methyl-6,7-benzomorphan hydrochloride (XIxl)

By replacing Example 1 with the cyclopropylcarbonyl-5 chloride used with an equimolar amount of cyclobutylcarbonyl chloride, the desired compound XIx, mp 181-184 ° C, was prepared.

Calcd. For C Q gHfK ^HCl: C, 68.26; H, 8.59; N, 3.98.

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

Example 31 2-Cycloobutylmethyl1-2- hydroxy-9ft-methoxy-5-methyl-6,7-benzomorphan fumarate (XIIx)

In Example 2, by replacing the compound Xla used with an equimolar amount of compound XIx, the desired free base 15 XIIx was prepared. Instead of isolating the compound as the hydrochloride salt, it was solubilized as the fumarate salt, mp 163.5-165.5 ° C.

Analysis calculated for C CiqH «7NO C. (C.H.O.), δ: C, 70.17; H, 8.13; N, 3.90.

Found: C, 70.01; H, 8.04; N, 3.62.

20

General process for the preparation of tartaric salts

A 1: 1 equimolar amount of a d- or - or d-tartaric acid and the appropriate amine (e.g., XIIa) are dissolved in a sufficient amount of hot iso-propanol or n-propanol. After cooling and during scraping or grafting, the tartaric acid crystallizes. The product is collected by filtration.

Example 32

Preparation of fl-2-cyclopropylmethyl-2β-hydroxy-9β-methoxy-5-methyl-6,7-benzomorphan d-tartaric acid salt Using (-) - XIIa, (-) - 2- cyclopropylmethyl -2'-hydroxy-9-methoxy-5-methyl-6,7-benzomorphane, the desired d-tartaric acid salt was prepared. [(-) - XIIa-d-tartrate], mp 146.5-148.5 ° C. The optical rotation was [a] =

D

-37.5 ° (c = 0.986, 95% ethanol).

Analysis calculated for C C HH₂Og, 1/21 ^O: C, 64.67; H, 7.87; N, 3.77; H 2 O, 2.42.

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

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49

Example 33 5-Allyl-2-cyclodropylmethyl-2β-9Q; -dimethoxy-9g-methyl-6,7-benzomorphane IXIul 5a) 5-Any-2,9-dimethyl-9ft-hydroxy-2'-methoxy-6,7-benzomorphan 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 covered with 400 ml of anhydrous ether in a 3-1 ether three-neck flask. After completion of the reaction with magnesium, the mixture was heated to 60 ° C in an oil bath and the solvent was evaporated under a stream of nitrogen, whereupon the residue was subjected to vacuum (0.5 mmHg / 60 ° C) for 1 hour. The flask, which was held under nine trogen atmosphere, was provided with a mechanical stirrer and a drip funnel. Then, a solution of 57.4 g (0.20 mmol) of ketone Vm in 1.0 liter of petroleum ether (boiling point 30-60 ° C) was added over a period of 15 minutes and with vigorous stirring. After stirring at 20-25 ° C for 18 hours, carefully added 400 ml of water and the thus obtained slurry was treated with concentrated hydrochloric acid and the pH was adjusted to 8. The organic layer was separated and the aqueous phase was extracted twice. with 600 ml of ether. The organic extracts were dried (Na 2 SO 4) and evaporated in vacuo to give 57.5 g (100% yield) of Compound VIu in the form of an oil containing a trace of the Fi-OH isomer. Crystallization of the oxalic acid salt from methanol-ether gave an analytical sample melting at 208-209 ° C.

Analysis calculated for C, 63.65; H, 7.21; N: 3.71.

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

b) 5-yl-2-cyano-9β-hydroxy-2'-methoxy-9β-methyl-6,7-benzomorphan tXXVul

A solution of 0.60 g (5.75 mmol) of cyanobromide in 25 ml of chloroform 30 was added dropwise to a solution of 1.52 g (5.26 mmol) of compound VIu in 25 ml of chloroform. After refluxing for 22 hours, the solvent was evaporated in vacuo to give 1.69 g of a brown oil which was chromatographed dry on silica gel. Elution with ether afforded 1.32 g (83.5% yield) of compound XXVu. An analytical sample (mp 35 103-105 ° C) was obtained from ether-petroleum ether.

Analysis calculated for C »72.45; H, 7.43; N, 9.39.

Found: C, 72.56; H, 7.48; N, 9.23.

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C) 5-Allyl-9β-hydroxy-2 H -methoxy-90-methyl-6,7-benzomorphan (VIIu)

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 was added dropwise a solution of 0.75 g (2.5 mmol) of compound XXVu in 30 ml of tetrahydrofuran. After refluxing for 17 hours, the reaction mixture was cooled in an ice bath and the excess hydride was destroyed with 0.2 ml of water, 0.15 ml of a 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 (VIlu) which was N-acylated without purification as in Example 33 (d).

d) 5-ally-2-cyclopropylcarbonyl-9β-hydroxy-2'-methoxy-98-methyl-6,7-benzomorphane

A solution of 0.31 g (3.0 mmol) of cyclopropyl carboxylic acid chloride in 5 ml of methylene chloride was added to a solution of 0.75 g (2.7 mmol) of compound VIIu in 20 ml of methylene chloride and 0.4 ml of triethylamine cooled in an ice bath. The cold bath was removed and the reaction mixture was allowed to stand at 20 ° C for 30 minutes, after which the solid was filtered off and washed with ether. The remaining filtrate was washed with dilute 20 ammonium hydroxide and water, dried (NagSO 4) and evaporated in vacuo to give 1.00 g of an oil crystallized from ligroin, 0.79 g (84% yield).

Analysis calculated for C, 73.87; H, 7.97; N, 4.10.

Found: C: 73.80; H, 8.00; N, 4.01.

E) 5-Allvi-2-cyclopropylcarbonyl-2'9a-dimethoxy-9β-methyl-6,7-benzo-morphane fXul

To a suspension of 130 mg (3 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 10 ml of dimethyl formamide was added a solution of 30 341 mg (1 mmol) of the alcohol IXu in 10 ml of dimethyl formamide. The mixture was stirred at 70 ° C for 1/2 hour, then cooled to room temperature and treated with 710 mg (5 mmol) of methyl iodide in 10 ml of dimethyl formamide.

After stirring for 3 hours, the reaction mixture was poured into water and extracted with benzene. The organic extracts were dried (MgSO4) and evaporated to dryness to give 350 mg (99% yield) of Compound Xu as a colorless oil.

_island

By distillation at 150-155 ° C / 3x10 mmHg, an analytical sample was obtained.

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51

Analysis calculated for C22H2NO3: C, 74.33; H, 8.22; N, 3.94.

Found: C, 74.14; H, 8.40; N, 3.87.

f) 5-Use-2-Cyclopropylmethyl-2'9ate-dimethoxy-9β-methyl-6,7-benzo-morphane (XIu)

A solution of 711 mg (2 mmol) of the amide 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 mixture was refluxed under nitrogen for 45 minutes, then cooled to room temperature, and the excess of hydride was destroyed by the addition of 0.23 ml of water, 0.17 ml of 20% sodium hydroxide and finally 0.81 ml of water. The inorganic salts were filtered off, washed with tetrahydrofuran and the filtrate was evaporated to dryness. The residue was taken up in 1N hydrochloric acid, extracted with ether, basified with ammonium hydroxide and extracted with dichloromethane. The extracts were washed with water, dried (MgSO 4) and evaporation of the solvent gave 570 mg (83.5% yield) of the amine XIu as an oil. Distillation at 145 ° C / 3 5x10 mmHg gave an analytical sample.

Analysis calculated for C C HH ^NO ,,: C, 77.38; H, 9.15; N, 4.10.

Found: C: 77.19; H, 9.23; N, 4.06.

Example 34 5-Alibino-2-cyclopropylmethyl-2'-hydroxy-9β-methoxy-9β-methyl-6,7-benzozo-morohan (XIlu) A solution of sodium ethanethiolate was 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 dimethyl formamide.

To the reagent was added a solution of 1.8 g (5.27 mmol) of the amine XIu in 25 ml of dimethyl formamide and the mixture was refluxed under nitrogen atmosphere for 6 hours. Then the reaction mixture was poured into water, acidified to a pH of ca. 3 with concentrated hydrochloric acid, basified with concentrated ammonium hydroxide and extracted with benzene. The extracts were washed with brine, dried over MgSO 4 and evaporated to dryness.

The oil thus obtained was dissolved in ether, treated with ethereal hydrogen chloride, and the precipitated salt was recrystallized from methanol-ether to give XIlu hydrochloride.

The yield was 1.32 g (70%), mp 248-250 ° C.

_3

Distillation of the free base (145-150 ° C / 5x10 mmHg) afforded one

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52 analytical sample.

Analysis calculated for C, 77.02; H, 8.93; N, 4.28.

Found: C, 76.76; H, 9.10; N, 4.38.

Example 35 2-CycloDroDylmethyl-2H-hydroxy-9α-methoxy-98-methyl-5-DroDVI-6,7-benzo-morphane (XIIuu)

A solution of 800 mg (2.38 mmol) of the olefin XIIu in 150 ml of absolute ethanol was hydrogenated for 1.5 hours over 250 mg of 10% Pd / C at an initial pressure of 52 psi. The catalyst was then filtered off and the solvent removed in vacuo to give 670 mg (84% yield) of Compound XIIuu. The compound was purified by crystallization of the hydrochloride salt from methanol ether, mp 238-240 ° C.

-3

Distillation (145 ° C / 2x10 mmHg) of the free base provided an analytical sample.

Analysis calculated for C CgjH₂jN₂O: 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-2'-9-dimethoxy-9β-methyl-6,7-benzomorphan IXIphli a) 5-Allyl-2-cyclobutylcarbonyl-9α-hydroxy-2β-methoxy-9β-methyl -6,7-benzomorphan ΠΧαΙ 25 A solution of 720 mg (2.63 mmol) of the hydroxyamine VIIu in 25 ml of dichloromethane and 2 ml of triethylamine was cooled to 0 ° C and treated dropwise with 343 mg (2.90 mmol) of cyclobutyl carboxylic acid chloride in 10 ml. dichloromethane. The cooling bath was removed and the solution was stirred at room temperature for 1 hour. The reaction mixture was then washed with 1 N HCl water, dried (MgSO 4) and evaporated to dryness. 810 mg (86.6% yield) of the amide IXq was obtained, which was crystallized from ether-petroleum ether (bp 30-60 ° C), mp 112-113 ° C.

Analysis calculated for &lt; 22 &gt;29; 3: C, 74.33; H, 8.22; N, 3.94.

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

35

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B) S-Allyl-Z-cyclobutylcarbonyl-Z'-Qα-dimethoxy-Qg-methyl-ε-benzo-morphane (Χα)

To a suspension of 262 mg (6 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 50 ml of dimethyl formamide was added 711 mg (2 mmol) of the hydroxyamide IXq and the mixture was stirred at 85 ° C for 1/2 hour. .

The reaction mixture was then cooled to room temperature and treated with 1.42 g (10 mmol) of methyl iodide. 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 in vacuo.

The dimethoxyamide Xq was obtained as a viscous oil in quantitative yield.

Calcd for C HjjHNOg: C, 74.76; H, 8.46; N, 3.79.

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

c) 5-Ally-2-cyclobutylmethyl-2H-9ft-dimethoxy-98-methyl-6,7-benzomorphan

A solution of 740 mg (2 mmol) of the amide Xq in 50 ml of tetrahydrofuran was added to a suspension of 380 mg (10 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran. The reaction mixture was refluxed for 1.5 hours, then cooled, and the excess hydride was destroyed by the addition of 0.38 ml of water, 0.29 ml of 20% sodium hydroxide and finally 1.33 ml of water. The inorganic salts were filtered off, washed with tetrahydrofuran and the filtrate was evaporated to dryness. The oily residue was taken up in 1N hydrochloric acid, extracted with ether, basified with concentrated ammonium hydroxide and extracted with dichloromethane. The organic extracts were washed with water, dried (MgSO 4) and evaporated to give 470 mg (66% yield) of XIq as an oil. The hydrochloride salt melted at 206-209 ° C after recrystallization from methanol-ether.

For CΙ forH ,ΗΟΙ: C, 70.48; H, 8.74; N, 3.57.

Found: C, 70.42; H, 9.00; N, 3.44.

EXAMPLE 37 5-α1β-2-Cyclobutylmethyl-2'-hydroxy-9β-methoxy-9β-methyl-6,7-benzo-morphane (XIlo) 35 to a suspension of 480 mg (11 mmol) of sodium hydride (55% in mineral oil, washed with benzene) in 50 ml of dimethylformamide. To the reagent was added 711 mg (2 mmol) of the dimethoxyamine XIq

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54 dissolved in 25 ml of dimethyl formamide and the reaction mixture was refluxed under nitrogen atmosphere for 4 hours. Then 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 (MgSO 4) and evaporated to dryness. The oily residue was taken up in ether and treated with ethereal hydrogen chloride. The precipitated salt was crystallized from methanol-ether. The yield was 400 mg (53%) and the salt had a melting point of 222-224 ° C

(XHq).

The free base was distilled (150 ° C / 5x10 - mmHg) to give an analytical sample.

Analysis calculated for C 22 H 30 NO 2: C 77 77 3 Q5 9.15; N, 4> 10 ·

Found: C, 77.45; H, 9.41; N, 4.05.

Example 38 2-Cyclobutylmethyl-2'-hydroxy-9Q1-methoxy-9g-methyl-5-propyl-6,7-benzo-morohan (XIIool)

A solution of 900 mg (2.6 mmol) of the olefin XIIq in 300 ml of absolute ethanol was hydrogenated using 300 mg of 10% Pd / C for 1.5 hours at an initial pressure of 51.5 psi. The catalyst was then removed and evaporation of the filtrate afforded 870 mg (96.5% yield) of XIIq in the form of a thick oil. The compound was purified by crystallization of the hydrochloride salt thereof. The melting point was 226-228 ° C. The free base -4 was distilled at 150 ° C / 5x10 mm Hg to give an analytical sample.

Analysis calculated for C 22 H 33 NO 2: C, 76.92; H, 9.68; N, 4.08.

Found: C, 76.74; H, 9.84; N, 4.05.

Claims (2)

Wherein R, R3, R4 and R5 have the aforementioned meaning, whereupon the -NH function is then acylated in a manner known per se to prepare a compound of the formula (D) the carbonyl function is reduced to a methylene group by treatment with a reducing agent, preferably lithium aluminum hydride, to forming a compound of formula 5 R 13 4 5 15 wherein R, R, R, R and R have the aforementioned meaning, whereupon (e) the hydroxyblating group R is then, if desired or necessary, cleaved in a manner known per se to preparing the 2 compounds of formula L wherein R represents hydrogen and the 20 (f) 2'-hydroxy function thereof is, if desired, reacted in a manner known per se to form the corresponding compound of formula L, 2 wherein R represents C g-alkyl, and / or (g) the compound prepared, when it is a racemic mixture, if desired, isolated in the optical isomers in a manner known per se, and / or (h) the compound prepared if desired. and known per se, is converted into a pharmaceutically useful acid addition salt thereof. 35