CA1091675A - 2-cycloalkylmethyl-9,10-dihydroxy-1-(p- methoxybenzyl)perhydroisoquinoline compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
N-substituted-14-hydroxy-3-substituted-morphinan derivatives have been found to possess potent narcotic agonist or antagonist activity. In particular, the compound N-cyclo-butylmethyl-3,14-dihydroxymorphian has been found to possess potent agonist/antagonist activity as a non-narcotic analgesic.
An improved total synthesis of these compounds is described herein from the starting material 2-(p-methoxybenzyl)-1,2,3,4, 5,6,7,8-octahydroisoquinoline. A preferred feature of the process involves borane reduction of 2-cyclobutylcarbonyl-9,10-dihydroxy-1-(p-methoxybenzyl)perhydroisoquinoline (Va) to provide the corresponding cyclobutylmethyl derivative complexed with borane, which forms the subject matter of this divisional specification. This intermediate is converted directly to N-cyclobutylmethyl-14.beta.-hydroxy-3-methoxymorphinan (LVa) by treating with acid.

Description

IMPROVED PROCESS FOR THE PREPARA~ION

This invention relates to a new and novel synthesis of N-substituted-14-hydrox~-3-substituted-morphinans having the formula A

R2O ~ \ ~ ~ L

in which R2 is H or (lower)alkyl and R is cyclobutylmethyl or cyclo propylmethyl.
Drug abuse by thrill-seeking youth or by people looking for an escape from the realities of everyday life has become more and more commonplace in our present society. One class of widely abused drugs are the narcotic analgetics such as codeine, morphine, meperidine, etc. It is because of the high addictive potential of these agents that much time and mone~ are ~eing expended ~y the pharmaceutical industry and by governments to try to discover and develop new~-non-addicting analgetics and~or narcotic antagonists.
It was an object of the present invention to develop a method of synthesis for the above-described compounds characterized by Formula L that would not be dependent upon opium alkaloids as starting materials and yet would be commercially feasihle.
The objectives of~the present invention have heen achieved by the process of preparing the compounds of Formula L by their total synthesis from readily available 2-tp-alkoxybenzyl)-1,2,3,4, 5,6,7,8-octahydroisoquinoline starting material such as 2-~methox-benzy~ 1,2,3,4,5,6,7,8-octahydroisoquinoline.

- 1 - `'~

The compounds prepared by the instant invention have the basic morphinan nucleus which i5 num~ered and represented by the ~ollowing plane ~ormula:

--N~l 7 3 e~

Although there are three asymetric carbons (asterisks~ in the morphinan molecule, only two diastereoisomé~ic(racemic) forms are possible, because the iminoethano system, attached to position 9 and 13, is geometrically constrained to a cis-tl,3-diaxial)-fusion. These racemates can, therefore, differ only at the junc-tion of rings B and C--in other words, in the configuration of carbon 14. The only variable will be the cis and trans relation-ship between the 5 (13~ and 8 (14~ bonds (Analgetics. Ed. George de Stevens, Academic Press, New York, p. 137 (1965~. When the 5 (13) and 8 (14) bonds are cis to each other, the compounds are commonly designated as "morphinans". The use of a graphic repre-sentation of a "morphinan" is meant to include the dl racemic mixture and the resolved d and 1 isomers thereo~.
The "morphinan" compounds of the present invention charac-terized by Formula L can each exist as two optical isomers, the levorotatory and dextrorotatory isomers. The optical isomers can be graphically illustrated as:
M0 8HIN~NS ~ R

and l~t3 1.~ 7rj The present invention embodies the preparation of all of the morphinan isomers including the optical ;somers in their resolved form.
The optical isomers can be separated and isolated by frac-tional crystalliza~ion oE the diaskereoisomeric salts ~ormed, for instance, with d- or l-tartaric acid or D~ bromocamphor sul-fonic acid. The levorotatory isomers of the compounds of the pre-sent invention are the most preferred embodiments.
For the purpose of this disclosure, the term "(lower~alkyl"
is defined as an alkyl radical containing 1 to 6 carhon atoms, e.g., methyl, ethyl, propyl, isopropyl, _-butyl, iso-butyl, sec-butyl, etc. The term "pharmaceutically acceptable acid addition salt" is defined to include all those inorganic and organic acid salts of the compounds of the instant invention, which salts are commonly used to produce nontoxic salts of medicinal agents con-taining amine functions. Illustrative examples would be those salts-fo ~ ~rby'mixing-,~ e~cc ~ un-dsl~iF.o ~ ulatL~with hydrochl`ortic'~ s~ uric, nitric,:phosphoric,,phosphorous,-hydrobromic,L;ma~leic,!mali~-, asc~rbic, citric, or tartaric, pam~ic;-liauric, stearic, pa~mitic, oleic,~myristic, lauryl sul-furic,~naphthalenésulfoDic,!linoleicror linolenic-acid,-and the llke.~
The morphinan compounds LV ~wherein R is cyclopropyl or cyclobutyl and R is (lower)alkyl) and LX (wherein R is cyclo-propyl or cyclobutyl) of the instant invention are prepared by a total synthesis comprising 4-6 steps. The synthesis is efficient and appears commercially feasible. Chart I illustrates the pro-ce~s for the preparation of N-cyclobutylmethyl-3,14-dihydroxy-morphinan (LXa) utilizing N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (LVa).

R2O ~ 0H HO ~ C~2-R

J i~J
_ 3 _ LX

3~ 7~fj C~IART I
A~

. Ia ExamPle 2 / I~a ,, ,~ O

CY,~ Cd,O

~ IVa IIIa 1Exam~le 3 O . . O

- ~d.~"~ C~i~
- ya - VIa Exam~le 4 ~ ~ ~d VIla LYa ~r Example 1~ ! /\
~C~

, , l~a In opening the 9,10-epoxide ~roup o~ compounds such as IIIa and IVa according to the procedure of Example 3, there are obtained 9,10-diol compounds capa~le of existing in conformations illustrated by the following planer formulas (.and the four optical isomers thereof~ wherein R is cyclo~utyl or cyclopropyl and R2 is (lower)alkyl.

OH
OH

N-C-R ~ "
" _~' ~ ~ N-C-R

\~0~ DR2 ~oR2 VI' (cis-dioll ~,trans-diol~

OH

~-C-R C~-C--R

HO j~ oR2 V

(cis-diol) ~trans-diol) According to the process of the instant invention, it is thought that substantially all of the product obtained by the opening of the 9,10 epoxide group of compounds IIIa and IVa posses~es the trans-9~,10a-diol relationship of compound Va ~and its corresponding mirror image) with only a trace of the less desirable diol VIa.
Thus, the instant invention includes the novel intermediates of the formula ,IX
R20 ~ / -C-R

HO'''U

in which X is carbonyl (-O) or H2~ R is cyclopropyl or cyclobutyl and R2 is (lower) alkyl, pre~erably methyl.
In this divisional specification the invention is the pro-cess for pr~paration of intermediates VII for making compounds having the formula L:

R20 [~U
J

wherein R is cyclobutyl or cyclopropyl and R2 is H or Clower~alkyl comprising the step of (a) reducing the compound having the formula V
o /1 "
~ ~ -C-R V

U
in which R is cyclobutyl or cyclopropyl and R2 is tlower)alkyl with borane or a source of borane in an inert organic solvent to produce a boron complex of the compound having the formula VII

/~-`CH2'-R

Ho ~ V~I

in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl.
hisr~in-termediat~e compound(V~ m~ay b~ ~urther processed by ~ b~-~.treati~3~h~-boron complex ofi~.ompound vII w.ith acid to produce the compound having the formula LV

R20 ~ CH2-R LV
J
in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl;
and, when desired, (c) cleaving the R20-ether function of compound LV by treating with Nasc2H5~ hydrobromic acid, boron tribromide or pyridine hydrochloride to produce the compound having the formula LX

/ \ l:,X

in which R is cyclopropyl or cyclobutyl.
Preferred embodiments of the foregoing process for pre-paration of compounds characterized by Formula L are those wherein:
(1) step (a) is carried out in tetrahydrofuran, toluene or benzene;
~2) in step (a~, the formula V compound is reduced with borane dimethylsulfide;

.ti~

(3) in step (al, the formula V compound is reduced with borane generatin~ in situ ~y reacting sodium boro-hydride with a compound selected fro~ the group of boron-trifluoride, boron-trifluoride tetrahydrofuran complex, or boron-trifluoride alkyletherate;
(4) in step (a) borane is employed in the ratio of about 1 mole of compound V to 1.33 to 2.0 moles o~ boranei (5] in step (a) borane is employed in the ratio of about 1 mole of compound V to 1.6 to l.9 moles of borane;
(6) in step (a) borane is employed in the ratio of about 1 mole of compound V to 1.75 moles of borane;
(7) step (a~ is carried out with the aid of heat in the range of about 50-115C.
(8) step (a1 is carried out in refluxing toluene;
(9~ in step (b~ the boron complex of compound V~I is treated with an acid selected from the ~roup consisting of phosphoric, orthophosphoric, pyrophosphoric, and polyphosphoric;
(10~ in step (b~ the boron complex of compound VII is treated with anhydrous phosphoric acid and phosphorous pentoxide;
(11) in step (b~ the boron complex of compound VII is treated with a large excess of anhydrous phosphoric acid and phosphorous pentoxide;
(12~ step (b~ i9 carried out at a temperature in the range of 50-100C.;
(131 step (b) is carried out at a temperature in the range of 70-75C.;

.fi~;

step (b) is carried out at a temperature in the range of 70-75C. with anhydrous phosphoric acid and phos-phorous pentoxid~.
Another em~odiment oE the overall process is the process for the preparation of compounds having the formula /\
/ ~-CH2R L
R20 ~U

wherein R is cyclobutyl or cyclopropyl and R2 is H or ~lowerlalkyl comprising the consecutive steps of (b) hydrolyzing the ~oron complex of compound VII with aqueous acid to provide compound VII;
(c) treating compound VII with an acid selected from the group consisting of phosphoric, orthophosphoric, pyrophosphoric, and polyphosphoric until cyclization is essentially complete to produce the compound having the formula LV

R20 ~ LV

in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl; and, when desired, ~ d~ cleaving the R~O-ether ~unction o~ compound LV ~y treating with NaSC2H5, hydro~romic acid, ~oron-tri~romide or pyridine hydrochloride to produce the compound having the formula LX

_ g _ / ~-CH2~R

H LX
HO , J

in which R is cyclobutyl or cyclopropyl.
Alternatively step (c) can be carried out in a separate step by treating compound VII with borane followed by an acid catalyst as described above.
Preferred embodiments of the above process for the prepara-tion of compounds characterized by Formula L are those wherein:
(1) step (c~ is carried out at a temperature in the range of 70-90C.; and (2~ step (c) is carried out with anhydrous phosphoric acid at a temperature in the range of 80-85 C.
The most preferred embodiment of the present invention is a process for the preparation of an intermediate VIIa for making the compound having the formula L' R2O ~ N~2 ~ L' wherein R is hydrogen or methyl comprising the step of i~i'J.~ L~'75 (a~ reducin~ the compound having the formula Va CH3~ Va with borane in a molar ratio of about 1.75 mole o~ borane to a-bout 1 mole of compound Va in toluene ~ith the aid of heat in the range of about 50-115C. to produce a boron complex of the compound having the formula VIIa ~ N ~

CH30 ,~ ~ VIIa This intermediate compound V~Ia may be further processed by:
(b) treating the boron complex of compound V~Ia with a large excess of a 6.4:1 mixture of anhydrous phosphoric acid:
phosphorous pentoxide with the aid of heat in the range of about 70-75C. until cyclization is essentially complete to pro-duce the compound having the formula LVa ~ LVa ~ 3~ 7.~j and, when desired ~ d~ demethylatin~ compound LVa ~ith NaSC2H5, hydrobromic acid, boron-tri~romide or pyridine hydrochloride to produce the compound having the ~ormula LXa ~ 2 ~ ~Xa and, when desired (d~ converting compound LXa into a nontoxic pharmaceutically acceptable acid addition salt thereof by methods known in the art.
The compounds N-cyclopropylmethyl-14~-hydroxy-3-methoxy-morphinan, N-cyclobutylmethyl-14~-hydroxy-3-methoxymorphinan, N-cyclopropylmethyl-3,14~-dihydroxymorphinan and N-cyclo~utylmethyl-3, 14~-dihydroxymorphinan are known and described in U.S. Patent 3,819,`635.
For the purpose of this disclosure the term "inert organic solvent" means an organic solvent that does not participate in the reaction to the extent that it emerges unchanged from the reaction. Such solvents are methylene chloride, chloroform, dichlorethane, tetrachloromethane, henzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran dioxane, dimethylacetamide, and the like.

Experimental All temperatures are expressed in degrees centrigrade,VPC
means vapor phase chromatography. IR means in~rared spectrum.
NMR means nuclear magnetic resonance spectrum.

ti7~5 Exam~'le 1

2~C clo~utylcarbonyl~ methox benz 1~-1!2,~,4,5,6,7~,8-oct~ah~dro~'s'o'q'uin'o~'in'e'~I'I'a) Triethylamine ~22.2 g., 0.22 mole~ is 510wly added io 1 (~-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroiso~uinoline hydro-chloride Ia (29.~ g., 0.1 mole) dissolved in 200 ml. of methylene chloride with stirring and ice-bath cooling. Cyclobutylcarbonyl chloride (13 g., 0.107 mole~ in 30 ml. of methylene chloride is then added dropwise with stirrin~ to the mixture while maintain-ing a temperature of 0 to 5C. After stirring the reaction mix-ture for 1 hr. at room temperature, lQQ ml. of water is added,the mixture acidified by adding sn ml. of 10% sulfuric acid, and the methylene chloride layer separated. If desired, the methylene chloride solution containing Ira can be used for the next step directly or concentrated to give an oil which solidi-fies upon standing. Recrystallization of a sample of the soli~-fie-ae-l material from acetone provides crystalline product IIa, m.p. 89-91~.
Various organic tertiary amines commonly employed as proton acceptors in acylation reactions may ~e substituted for triethylamine in the above procedure. Such amines are tritlower) alkylamines, e.g., trimethylamine, triethylamine and the like, pyridine, dimethylaniline, N-methylpiperidine, and the like.
Example 2 2-Cyclobutylcarbonyl-9,10-epoxy-1-tp-methoxy-benzyl)perhydroisoquinoline-s tIIIa and IVa~
Method A - Peracetic acid oxidation To a solution of 2-cyclobutylcarbonyl~ -methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline (IIa) ~0.1 mole1 in 230 ml.
of methylene chloride is added peracetic acid ~40%, 23.8 g., 0.12 mole) at such a rate so as to keep the temperature at 30-35 C.
After stirring the resulting solution at room temperature for 1 hr., 200 ml. of water is added and the excess peracetic acid :~i3~ aki~7~

destroyed by adding lQ0 ml. of 10~ sodium bisulfite solution.
The methylene chloride phase is separated and concentrated under reduced pressure to give an oily re~idue comprised o~ the isomeric epoxides trans IlIa and c IVa in ratio of 23:78 according to vapor phase chromatography analysis (VPC~. The two epoxides can be separated, if desired, ~y column chroma-tography using alumina or s;lica column (eluting with diethyl-ether).
The minor epoxide (IIIa1, m.p. 118, has the-"tran~-configuration" and the major epoxide (IVa~ m.p. 82-84, has the"cls configuration" with respect to steric relationship of the ~-methoxybenzyl group and the oxirane group.
Method B - Pertrifluoroacetic acid oxidation To a solution of 2-cyclobutylcar onyl-l-C~methoxy~enzyl~-1,2,3,4,5,6,7,8-octahydroisoquinoline tI~a) C~.Q5 mole~ in 125 ml. of methylene chloride is added sodium car~onate t2Q g.,~
0.19 mole) and the mixture cooled to a. A solution of pertri-fluoroacetic acid is prepared by mixing trifluoroacetic anhy-dride (16.6 g., Q.~77 mole~ and 9Q% hydrogen peroxide ~2.94 g., 0-077 mole1 in 35 ml. of mRthylene chloride at 0. The peracid solution is added to the reaction mixture of IIa dropwise at such a rate so as to maintain the reaction temperature at Q
to 5. After completing the addition, the reaction mixture is stirred for a period of Q.5 hr. at ~ to 5C. and excess peracid then destroyed by addition of 10% sodium bisulfite solution with agitation until the evaluation of C02 ceased. The methy-lene chloride phaoe iæ washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to an oily residue co~prised of the isomeric epoxides rIIa and IVa in a trans:cis ratio of 35:65 according to VPC.

~ '7 Example 3 2-Cyclobutylcar~onyl-9,10-dihydroXy-l-t ~
methoxybenæyl~perhydroisoquinollne tVa anX VIa) The mixture of isomeric epoxides IIIa and IVa ~rom peracetic acid oxidation of Example ~ is dissolved in 3~0 ml. of acetone and cooled to 0. To this solution is first added 30 ml. of water and then 30 ml. of concentrated sulfuric acid at such a rate as to keep the temperature below 25. After stirring the reaction mixture for a period of 1.5 hr. at 25, a 150 ml. por-tion of water and a 300 ml. portion of toluene are added. The10 resulting two phase mixture is made basic with sodium hydroxide solution and the toluene layer separated and concentrated to a residue oil. This oil~ stirred ~ith 300 ml. of cyclohexane, provides a suspension of white solid which is collected on a filter. The ~hite solid consists principally of the desired trans diol Va contaminated with the isomeric trans diol VIa as indicated by VPC. The yield of Va calculated from the starting amine Ia is 75~. The cyclohexane filtrate is retreated with sulfuric acid to give another 10~ yield of-trans diol. Further ~0 purification of the white solid is carried out by crystalliæation from acetonitrile to provide material ~ith m.p. 145-147. In place of the concentrated sulfuric acid used a~ove, other acids such as nitric, hydrochloric hydro~romic or stron~ organic acids such as alkylsulfonic, trifluoroacetic and the like ma~ ~e employed.
Hydrolysis of the pure minor trans epoxide IIIa accordin~
to the above procedure gives only the desired-trans diol Va while hydrolysis of the major cis epoxide IVa gives the desired trans diol Va with some of the isomeric trans diol VIa in a Va:VIa ratio of 86:14.

Example 4 2-Cyclobutylmethyl-g,10-dihydroxy-1-~p-methoxy~enzyl~perhYdroisoquinoline (VIIa) To a solution o 2-cyclobutylcarbonyl-9,10-dihydroxy-1-(~-methoxybenzyl)perhydroisoquinoline Va t30 g., 0.08 mole~ in 300 ml. of tetrahydrofuran is added ~orane dimethylsulfide neat solution ~14 ml., 0.14 mole) through a syrinye needle under nitrogen atmosphere. The resulting mixture is heated to reflux for 2 hr. and then concentrated under reduced pressure to remove the solvent. The resulting borane com~lex of the cyclo~utylmethyl amine VIIa can be used directly for the next reaction or it can by hydrolyzed with a~ueous acid such as hydrochloric acid to pro-vide VIaa, m.p. 120-122C. Reduction of the trans diol Va amido function with the following ~orane sources also provides VIIa.
1~ Borane-tetrahydrofuran complex.
2) In 'situ' generated borane in tetrahydrofuran using sodium borohydride and ~oron trifluoride gas or ~oron trifluoride tetrahydrofuran complex or ~oron-trifluoride alkyletherate.

Example 5 N-Cyclobutylmethyl-14~-hyaroxy-3:-methoxymorphinan ~Va~
Method A. Cyclization with borane complex To the borane complex residue from ~orane reduction reac-tion (0.08 mole) of Example 4 is added 32a g. of anhydrous phosphoric acid (prepared from 85~ phosphoric acid and phosphor-ous pentoxide) and 50 g. of phosphorous pentoxide. The mixture is stirred at room temperature for 0.5 hr. and then at 70-75 for a period of 4 hr. The reaction mixture is diluted with 200 ml. of water and then poured into a mixture of 600 ml. of con-centrated ammonium hydroxide and 1 liter of crushed ice. The mixture is extracted with 4Qa ml. of heptane and the heptane jr7 ~

extract dried over sodium sul~ate, Concentration o~ the dried heptane extract provides 23.1 y. of oil (85~ yield~ of product LVa. This oil is dissolved in acetone and treated with anhydrous hydrogen chloride gas to af~ord crystalline hydrochloride salt of product LVa, m.p. 2~8-250.
Method B. Cyclization without bo'ro'n 'com'plex''o~ an~ kind 1.5 g. o~ 2-Cyclo~utylmethyl-~,lO-dihydroxy~ -methoxy-benzyl)perhydroisoquinoline VIIa and 16.0 g. o~ anhydrous phosphoric acid are stirred at 80-85 for 23 hr. The reaction mixture is diluted with 20 ml. of water and poured into a mix-ture of ice and 35 ml. of concentrated ammonium hydroxide. The mixture is extracted with 40 ml. of methylene chloride and the methylene chloride extract concentrated to give 1.15 g. of oil. According to vapor phase chromatography-mass spectrometry analysis, the oil contained 57% of the desired N-c~clo~utylmethyl-14~-hydroxy-3-methoxymorphinan LVa, 27% o~ a dehydrated by-product and 15% of uncyclized VIIa starting material.
EXample 6 Levorotatory-N-Cyclobutylmethyl-14~-h~droxY-3'-metho'xYmorphinan (LVa'~
Substitution in the procedure of Example l o~ deXtrorotatory-l-(_-methoxybenzyl~-1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride for racemic Ia and sequentially applying the pro-cedures of Examples 2 5 provides the levorotatory product LVa'.
The pro~ed~res of Examples ~ and 5 are carried out as follows. To a solution of levorotatory-2-cyclobutylcar~onyl-9, lO-dihydroxy-2-(p-methoxybenzyl~perhydroisoquinoline ClO g., 0.0267 mole~ in lO0 ml. of toluene is added borane dimethyl-sulfide neat solution (6 ml., 0.057 mole~ through a syring~
needle under nitrogen atmosphere. The resulting solution is refluxed for 3 hr., concentrated under reduced pressure to remove approximately 4Q ml. of solvent and the borane complex of ,it7.5 levorotatory cyclobutylmethyl amine VII,a' is used directly in the cyclization reaction.
Cyclization of the le~o~otatory-cyclobutylmethyl amine VIIa' is carried out by adding the a~ove toluene-borane complex mixture portionwise to 200 g. o~ anhydrous phosphoric acid and 35 g. of phosphorus pentoxide with stirring while maintaininy a temperature range of 0-25C. A~ter the addition is complete, the mixture is heated and stirred for a period of 5 hr. at 70C. and then poured into a mixture of 40Q ml. of concentrated ammonium hydroxide with sufficient ice to maintain a temperature o~ approximately 25C. ~he mixture is extracted ~ith toluene, the toluene extract washed with water and then concentrated under reduced pressure to provide levorotatory-N-cyclobut~lmethyl-14~-hydroxy-

3-methoxy-morphinan (LVa') base. The oily base is con~erted to the sulfate salt by treating with sulfuric acid to accord 7.2 g.
(61% yield) of levorotatory-N-cyclobutylme,thyl-14~-hydroxy-3-methoxy-morphinan, m.p. 232-237~C. tdec.l, L~J d-55.4?C~
(C = 0.56, CH30H~.
Example 7 2-Cyclopropylcarbonyl-l-~p-methoxybenæyl~-1,2,3,4,5,6,7,8-octahydroisoquinol-ine tIIb) Substitution in the procedure of Example 1 for the cyclobutylcarbonyl chloride used therein of an equimolar quanti-ty of cyclopropylcarbonyl chloride produces the title material IIb.
Example 8 2-cyclopropylcarbonyl-g~lo-epoxy-~tp-meth benz~l)perh~roisoquinol'ine's' tIrIb and'rV~1 Substitution in the procedure of Example 2 for the racemic IIa used therein of an equimolar quantity of IIb produces the title compounds IIIb and IVb.

Example' 9 2-Cyclopropylcarbonyl-9~l~-dihydr ethoxybenzylJperhydroisoquinoline (V~', VIb~
Substitution in the procedure o~ Example 3 for the racemic IIIa and IVb used therein of an equimolar quantity of I-IIb and IVb produces the title compounds Vb and VIb.
Example 10 2-Cycloprop lmethyl-9,l~-dihydroxy-l~cP
methoxy~enzy~lperhydroisoquinoline '(VI'I J
Substitution in the procedure of Example 4 for the racemic Va used therein of an equimolar quantity of Vb produces the title compound VIIb.
EXample 11 7- ~ clopropylmethyl-14~-hydroxy--3--methoxymorp~inan 5ubstitution in the procedure of Example 5 for the racemic VIIa used therein of an equimolar quantity of VIIb produces the title product LVb.
Example 12 N-CYclobutvlmethyl-'3,14'-dihydr'oxymo'r'phin'an '~L'Xa~

A mixture of N-cyclobutylmethyl-14~-hydroxy-3-methoxymor-phinan (LVa) (1.0 g., 2.58 m mole~ and 10 ml. of 48~ HBr is refluxed under a nitrogen atmosphere for a period of five minutes. After cooling, the reaction mixture is diluted with water and mad~ basic with aqueous ammonium hydroxide. The aqueous basic mixture is extracted with several portions of chloroform and the combined chloroform extracts dried over anhydrous sodium sulfate. After evaporating the solvent, the residual ~il t730 mg.~ is taken up in dry ether and the result-ing solution filtered through diatomaceous earth-charcoal. The filtrate is treated ~ith a saturated solution of hydrogen chloride in dry ether and the hydrochloride salt thus ohtained is collected and crystallized from methanol-acetone to afford 565 mg. (56.5%~ of N-cyclobutylmethyl-3,14-dihydroxymorphinan ;7~

hydrochloride (LXa), m.p. 272-274 (dec.). The IR and NMR

spectra were consistent with the structure.
Ana'l'y's'is - Calc'd. ~or C21H'2gN02 HCl ~CH'30H ~percent~:
C, 67.~7; ~, 8.4~; N, 3.49. Found (percent~: C, 68.10; H, 8.14; N, 3.80.
Acidi~ication of the filtered dry ether solution re~erred to ahove with appropriate acids provides various "pharmaceutical-ly acceptable acid addition salts" of LXa.
The 3-methoxy ether function of N-cyclobutylmeth,yl-14~-hydroxy-3-methoxymorphinan may also ~e cleaved hy treatment with ether cieaving agents such as NaSC2~'3, horon tri~romide, or pyridine hydrochloride to produce the desired demethylated product LXa.

- 2a

Claims (9)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of an intermediate VII for making compounds having the formula L

wherein R is cyclobutyl or cyclopropyl and R2 is H or (lower)alkyl comprising the step of reducing the compound having the formula V

V

in which R is cyclobutyl or cyclopropyl and R2 is (lower)alkyl with borane in an inert arganic solvent to produce a boron complex of the compound having the formula VII
VII

- 21 _

2. The process of Claim 1 wherein the formula V
compound is reduced with borane dimethylsulfide.

3. The process of Claim 1 wherein the formula V compound is reduced with boron generated in situ by reacting sodium borohydride and boron trifluoride or sodium borohydride and boron-trifluoride tetrahydrofuran complex or sodium borohydride and boron-trifluoride alkyletherate.

4. The process of Claim 1, 2 or 3 wherein borane is employed in a ratio of about 1 mole of compound V to 1.33 to 2.0 moles of borane.

5. The process of Claim 1, 2 or 3 wherein the reaction is carried out with the aid of heat in the range of about 50 to 115°C.

6. A process as in Claim 1 wherein R2 is methyl.

7. A process as in Claim 2 or 3 wherein R2 is methyl.

8. A boron complex of a compound of the formula VII

VII

in which R is cyclopropyl or cyclobutyl and R2 is (lower)alkyl, whenever prepared or produced by the process of Claim 1, 2 or 3, or by an obvious chemical equivalent thereof.

9. A boron complex of a compound of the formula in which R is cyclopropyl or cyclobutyl and R2 is methyl, whenever prepared or produced by the process of Claim 6, or by an obvious chemical equivalent thereof.