FI61486C - NYTT FOERFARANDE FOER FRAMSTAELLNING AV 14-HYDROXIMORFINANDERIVAT - Google Patents

Description

Γηΐ publication, ΛΛΟϊ LBJ (11) uTLAGG NIN GSSKRI FT 6ΐ4θΟ C (45) Patent granted ΙΟ 03 1003 ^ τ ^ (51) Kv.ik.3 / int.ci.3 C 07 D 221/28 FINLAND - FINLAND (21) P »Unttlh» k »mu · - PitwiUiwekfting T70865 (22) Hakemltpilvl - AntBknlngtdtg l8.03 · 77 (23) Alkuptivt — Glttl {h« t * d «g 18.03.77 (41) Tullut julklMk *) - Bllvlt offantHg 21.09.73

National Board of Patents and Registration (44) NthUvUuipro. |. month |

Patant- och ragittarstyralaan 'Anaökai »utiagd och uti.ikriften puMicand 30.Oi. 82 (32) (33) (31) Requested «Begird prto« it «t 23.03.76 i7.02.77 USA (US) 669795, 769808 (71) Bristol-Myers Company, 3l5 Park Avenue, New York, New York 10022, USA (72) Ivo Monkovic, Candiac, Quebec, Carol Bachand, Cote Ste. Catherine,

Quebec, Henry Wong, Candiac, Quebec, Gary Lim, Candiac, Quebec,

The present invention relates to a process for the preparation of 14-hydroxymorphinan derivatives of the formula: The present invention relates to a process for the preparation of 14-hydroxymorphinan derivatives of the following formula: The present invention relates to a process for the preparation of 14-hydroxymorphinan derivatives

/ N-CHLR

. 2 wherein R is cyclobutyl or cyclopropyl and R is hydrogen or 2,61486 lower alkyl.

The misuse of medicines by adventurous people and people fleeing everyday reality has become more and more common in our modern society. A widely misused class of drugs consists of narcotic analgesics such as codeine, morphine, and meperidine. Because these substances are highly addictive, the pharmaceutical industry and authorities have sacrificed a lot of time and money to invent and develop new non-addictive, analgesic and / or drug antibodies.

A new process has now been developed for synthesizing the compounds of formula L described above from readily available 2- (p-alkoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline starting materials, e.g. 2- (methoxybenzyl ) -1,2,3,4,5,6,7,8-isoquinoline.

The method according to the invention is characterized in that

a) reducing compound V

. jgf # iro H0 2

wherein R is cyclobutyl or cyclopropyl and R is lower alkyl, in a borane inert organic solvent of formula VII

to obtain a boron complex of a compound of formula n-ch2r HO "vh, wherein in formula 2 R is cyclobutyl or cyclopropyl] a R is lower alkyl, 61486 3

b) treating the boron complex of compound VII with an acid, LV

/ N-CH2 “R

LV

2 wherein R is cyclobutyl or cyclopropyl and R is lower alkyl, and if desired 2

c) cleaving the LV R O ether function of the compound by treating the compound with NaSC2Hj .: 11a, hydrobromic acid, boron tribromide or pyridine hydrochloride to give the compound LX

/ N-CH - R

wherein R is cyclobutyl or cyclopropyl.

In preferred embodiments of the above process for the preparation of compounds of formula L: 1) step c) is performed at a temperature of 70 to 90 ° C, and 2) step c) is performed with anhydrous phosphoric acid at a temperature of 80 to 85 ° C.

4,61486 The most preferred embodiment of the present invention is a method of formula L '

^ 7 ^ · O

2, wherein R is hydrogen or methyl, characterized by successive steps: a) reducing the compound of formula Va, CH 2 O 6 ho "with borane in a molar ratio of about 1.75 moles of borane and about 1 mole of Va in toluene at n .

50 to 115 ° C to give the boron complex of the compound Vila H ° 't 5 614 8 6 b) treating the boron complex of Vila H with a large excess of a 6.4: 1 mixture of anhydrous phosphoric acid and phosphorus pentoxide at 70-75 ° C until the cyclization is almost complete and a compound of formula LVa is obtained, and if desired c) demethylating the compound LVa with NaSC2H. to its acid addition salt by methods known in the art.

The compounds N-cyclopropylmethyl-14β-hydroxy-3-methoxymorphinan, N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan, N-cyclopropylmethyl-3,14H-dihydroxymorphinan and N-cyclobutylmethyl-3, 14/2-Dihydroxymorphinan are known and described in U.S. Patent 3,819,635.

6,61486 In this specification, the term "unreacted organic solvent" means an organic solvent which, when not involved in the reaction, is removed unchanged. Such solvents include, for example, methylene chloride, chloroform, dichloroethane, tetrachloromethane, benzene, toluene, ether, ethyl acetate, xylene, tetrahydrofuran, dioxane and dimethylacetamide.

The compounds of the invention have a morphine core which is numbered as follows: 16

SSVSsN

1 10/17 2 l lv5 5 ^^ 7 6

Although the morphinan molecule has three asymmetric carbon atoms, only two diastereoisomeric (racemic) forms are possible because the iminoethanol structure at the 9- and 13-positions is always cis- (1,3) -diaxial for geometric reasons. Thus, these racemates can differ only at the junction of rings B and C, i.e. as a 14-carbon atom structure. The only variable is the cis- and trans-relationship between 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 in the cis position relative to each other, the compounds are commonly referred to as "morphinanes". The graphical representation of "morphinans" includes the dl-racemic mixture and its separated d- and 1-isomers.

'v' · 7 61486

The "morphinan" compounds prepared according to the invention can exist as two optical isomers, i.e. as levorotatory and levorotatory isomers. The optical isomers can be represented graphically as follows:

Morphinanes / N-CH2R / \

//. / ___ / N-CH? R

i RO N

The optical isomers can be separated by fractional crystallization of the diastereoisomeric salts formed, for example, with d- or 1-tartaric acid or D- (+) - Gf-bromocamphorosulfonic acid. The levorotatory isomers of the compounds of the present invention are the most preferred embodiments.

In this specification, the term "lower alkyl" means an alkyl group having 1 to 6 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and sec-butyl. By the phrase "pharmaceutically acceptable acid addition salt" is meant the inorganic and organic acid salts commonly used in the preparation of non-toxic salts of drugs having amine functions. Illustrative examples are salts formed by mixing compounds of formula L and e.g. hydrogen chloride, sulfur, nitrogen, phosphorus, hydrogen bromide, maleic, apple, ascorbic, lemon, wine, pamoin, lauric. , stearic, palmitic, oleic, myristic, lauryl sulfur, naphthalenesulfonic, linoleic, or linolenic acid or phosphoric acid.

According to the invention, the morphinan compounds LV (wherein R is 2 cyclopropyl or cyclobutyl and R is lower alkyl) and LX (where R is cyclopropyl or cyclobutyl) are prepared by a total synthesis of 4-6 steps in good overall yield. Schemes I show a process for the preparation of N-cyclobutylmethyl-3,14-dihydroxymorphinan (LXa) using N-cyclobutylmethyl-14-hydroxy-3-methoxymorphinan (LVa).

Scheme I

A / 1

Ia

Example 2 ® / l ° vei2f ° ch3 ° t IVa IIIa ^ Example 3 - mf °

CH30X ^^, Χ j CH30 | "-" OH

Ho 'I J l

Via

Va

Example 4 Ψ 9 61 4 86

Chart I (continued)

Example 4

V A

ν 'N ^ Vn N-CH - • Q ^ VTon Example 5 JV ^ Y ^ / j ^ H L <

CH_o '' Λ ^ Vj ch3o ^ - ^ V

ό h ° I J i j / \ / LVa

Villa /

Example 12 / LXa

For example, opening the 9,1O-epoxy group of the compounds lila and IVa according to the method of Example 3 gives 9,1O-diol compounds of the formulas:

CH 0 H

s

k ^ Jny / N'C'R

“N5> -" S \ s / »· λ- 'VI' '-' (cis-diol) (trans-diol) 10 614 8 6 (continued)

OH 0H

° Γ "0" 1 1. n-c-r HO (-.

"\ §H

V

(cis-diol) (trans-diol) wherein R is cyclobutyl or cyclopropyl and R is lower alkyl.

The major part of the product obtained by opening the 9,10-epoxide group of the compounds IIIa and IVa is in the trans-9 / 5,10Q-diol form of Va (and the corresponding mirror image); only traces of the less desired diol are formed.

The starting compounds used in the process of the invention have the formula

HO

wherein X is carbonyl (= O) or H », R is cyclopropyl or cyclo-2z butyl and R is lower alkyl, preferably methyl, are novel compounds.

In the following examples illustrating the invention, all temperatures are in degrees Celsius.

Example 1 2-Cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (Ha)

22.2 g (0.22 moles) of triethylamine were slowly added to a solution of 29.4 g (0.1 moles) of 1- (p-methoxybenzyl) 1,2,3,4,5 in an ice bath under cooling and stirring. 6,7,8-octahydroisoquinoline hydrochloride Ia in 200 ml of methylene chloride. 13 g (0.107 mol) of cyclobutylcarbonyl chloride in 30 ml of methylene chloride were then added dropwise to the mixture with stirring, maintaining the temperature at 0-5 ° C. After the reaction mixture was stirred for one hour at room temperature, 100 ml of water was added, the mixture was acidified by adding 50 ml of 10% sulfuric acid, and the methylene chloride layer was isolated. If desired, the methylene chloride solution containing Compound Ha can be used immediately in the next step or evaporated to an oil which crystallizes on standing. Recrystallization of a solid sample from acetone gave the crystalline product Ha, m.p. 89-91 ° C.

Example 2 2-Cyclobutylcarbonyl-9,10-epoxy-1- (p-methoxybenzyl) perhydroisoquinolines (IIIa and IVa)

Method A - Peracetic acid oxidation

To a solution of 0.1 mol of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (IIa) in 230 ml of methylene chloride was added 23.8 g of g (0.12 moles) of 40% peracetic acid at such a rate that the temperature remained between 30 and 35 ° C. After stirring the resulting solution for one hour at room temperature, 200 ml of water was added and the excess peracetic acid was discarded by adding 100 ml of 10% sodium bisulfate solution. The methylene chloride phase was separated and evaporated in vacuo to give a residue containing the isomeric epoxides trans-IIIa and cis-IVa in a ratio of 23:78 (gas chromatographic analysis).

If desired, both epoxides can be separated by column chromatography using an alumina or silica column (eluted with diethyl ether).

With the epoxide component trans-IIIa, m.p. 118 ° C, has a "trans structure" and the epoxide component cis-IVa, m.p. 82-84 ° C, is a "cis structure" in a steric relationship to the p-methoxybenzyl group and the oxirane group.

Method B - Pertrifluoroacetic acid oxidation

To a solution of 0.05 mol of 2-cyclobutylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (IIa) in 125 ml of methylene chloride was added 20 g (0 , 19 moles) of 12 61,486 sodium carbonate and the mixture was cooled to 0 ° C. A pertrifluoroacetic acid solution was prepared by stirring at 0 ° C 16.6 g (0.077 moles) of trifluoroacetic anhydride and 2.94 g (0.077 moles) of 90% hydrogen peroxide in 35 ml of methylene chloride. The peracid solution was added dropwise to the reaction mixture containing Compound Ha at such a rate that the reaction temperature remained at 0 to 5 ° C. At the end of the addition, the reaction mixture was stirred for half an hour at 0-5 ° C and then the excess peracid was discarded by adding 10% sodium sulfite solution with stirring until the evolution of carbon dioxide ceased. The methylene chloride phase was washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to an oily residue consisting of isomeric epoxides IIIa and IVa in a trans ratio of 35:65 (gas chromatographic analysis).

Example 3 2-Cyclobutylcarbonyl-9,10-dihydroxy-1- (p-methoxy-benzyl) -perhydroisoquinoline (Va and Via).

A mixture of the purple and IVa isomeric epoxides obtained from the peracetic acid oxidation of Example 2 was dissolved in 300 ml of acetone and cooled to 0 ° C. To this solution was added first 30 ml of water and then 30 ml of concentrated sulfuric acid at such a rate that the temperature remained below 25 ° C. The reaction mixture was stirred for 1.5 hours at 25 ° C and 150 ml of water and 300 ml of toluene were added. The resulting biphasic mixture was basified with sodium hydroxide solution, the toluene layer separated and evaporated? the resulting oily residue was stirred in 300 ml of cyclohexane to form a suspension of a white solid; and the solid was separated by filtration. According to gas chromatographic analysis, the white solid consisted mainly of the desired trans-diol Va and the impurity was the isomeric trans-diol Via. Based on the starting amine Ia, the yield of compound Va was 75%. The cyclohexane filtrate was re-treated with sulfuric acid to give an additional 10% trans-diol. The white solid was further purified by crystallization from acetonitrile and the resulting material had a melting point of 145-147 ° C.

Hydrolysis of the pure trans-epoxide lila gives only the desired trans-diol Va and hydrolysis of the main component, cis-epoxide IVa, gives the desired trans-diol Va and slightly. . * 13 61 486 isomeric trans-diols Via, Va / VIa in a ratio of 86:14.

Example 4 2-Cyclobutylmethyl-9,10-dihydro-1- (p-methoxybenzyl) -perhydroisoquinoline (VIIa)

To a solution of 30 g (0.08 mol) of 2-cyclobutylcarbonyl-9,10-dihydroxy-1- (p-methoxybenzyl) perhydroisoquinoline Va in 300 ml of tetrahydrofuran was added 14 ml (0.14 mol) of a clear solution of borane dimethyl sulfide through a syringe needle under a nitrogen blanket. The resulting mixture was heated at reflux for two hours and evaporated in vacuo to remove the solvent. The borane complex formed by cyclobutylmethylamine Vila can be used immediately in the next reaction or can be hydrolyzed with an aqueous solution of an acid such as hydrochloric acid to give Via, m.p. 120-122 ° C.

Example 5 N-Cyclobutylmethyl-1,4-hydroxy-3-methoxymorphinan (LVa)

To 0.08 mol of the borane complex residue of the borane reduction reaction of Example 4, 320 g of anhydrous phosphoric acid (prepared from 85% phosphoric acid and phosphorus pentoxide) and 50 g of phosphorus pentoxide were added. The mixture was stirred at room temperature for half an hour and then for four hours at 70-75 ° C. The reaction mixture was diluted with 200 ml of water and poured into a mixture of 600 ml of concentrated ammonium hydroxide solution and 1 L of crushed ice.

The mixture was extracted with 400 ml of heptane and the heptane extract was dried over sodium sulfate. Evaporation of the dried heptane extract gave 23.1 g of LVa as an oil (85% yield). This oil was dissolved in acetone and treated with anhydrous hydrogen chloride gas to give crystalline hydrochloride of the product LVa, m.p. 248-250 ° C.

Example 6

Left-turning N-cyclobutylmethyl-14γS-hydroxy-3-methoxymorphinan (LVa *)

Replacing the dextrorotatory 1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline hydrochloride by the method of Example 1 with the racemic compound Ia and using the methods of Examples 2-5 gave the levorotatory product LVa '.

The procedures of Examples 4 and 5 were performed as follows. To a solution of 10 g (0.0267 mol) of 2-cyclobutylcarbonyl-9,10-dihydroxy-2- (p-methoxybenzyl) perhydroisoquinoline in 100 ml of toluene was added 6 ml (0.057 mol) of a clear solution of borane methyl sulfide through a syringe needle under a nitrogen blanket. The resulting solution was heated under reflux for three hours, evaporated in vacuo to remove about 40 ml of solvent, and the left-flowing cyclobutylmethylamine Vila 'borane complex was used immediately in the cyclization reaction.

The cyclization of the levorotatory cyclobutylmethylamine Vila 'was carried out by portionwise addition of the above toluene-borane complex mixture to 200 g of anhydrous phosphoric acid and 35 g of phosphorus pentoxide with stirring and maintaining the temperature at 0-25 ° C. At the end of the addition, the mixture was heated with stirring for 5 hours at 70 ° C and poured into a mixture of 400 ml of concentrated ammonium hydroxide solution and enough ice to maintain the temperature at about 25 ° C. The mixture was extracted with toluene, the toluene extract washed with water and evaporated in vacuo to give the levorotatory N-cyclobutylmethyl-14γ-hydroxy-3-methoxymorphinan base (LVa ') · The oily base was converted to sulphate by treatment with sulfuric acid to give 7.2 g (yield 61 g). %) to the levorotatory N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan, m.p. 232-237 ° C (decomposes), = 55.4 ° (c = 0.56, CH 3 OH).

Example 7 2-Cyclopropylcarbonyl-1- (p-methoxybenzyl) -1,2,3,4,5,6,7,8-octahydroisoquinoline (Hb)

Replacing cyclobutylcarbonyl chloride with an equimolar amount of cyclopropylcarbonyl chloride in the procedure of Example 1 gave the title compound Hb.

Example 8 2-Cyclopropylcarbonyl-9,10-epoxy-1- (p-methoxybenzyl) -perhydroisoquinolines (IIIb and IVb)

By replacing the racemic Ha with an equimolar amount of Hb in the method of Example 2, the title compounds IIIb and IVb were obtained.

Example 9 2-Cyclopropylcarbonyl-9,10-dihydro-1- (p-methoxybenzyl) -perhydroisoquinoline (Vb, VIb)

In the method of Example 3, substituting an equimolar amount of racemic lila and III 61,486 IVa for IIIb and IVb gave the title compounds Vb and VIb.

Example 10 2-Cyclopropylmethyl-9,10-dihydroxy-1- (p-methoxybenzyl) -perhydroisoquinoline (VIIIb)

In the method of Example 4, substituting an equimolar amount of racemic Va for Vb gave the title compound VIIb.

Example 11 N-Cyclopropylmethyl-14,3-hydroxy-methoxymorphinan (LVb)

In the method of Example 5, substituting an equimolar amount of racemic VIIa for VIIb gave the title compound LVb.

Example 12 N-Cyclobutylmethyl-3,14-dihydroxymorphinan (LXa)

A mixture of 1.0 g (2.58 mmol) of N-cyclobutylmethyl-14β-hydroxy-3-methoxymorphinan (LVa) and 10 ml of 48% hydrobromic acid was heated under reflux for 5 minutes under a nitrogen blanket. After cooling, the reaction mixture was diluted with water and basified with aqueous ammonium hydroxide solution. The basic aqueous mixture was extracted with several portions of chloroform, and the combined chloroform extracts were dried over anhydrous sodium sulfate. After evaporation of the solvent, 730 mg of an oil was obtained, which was dissolved in dry ether, and the resulting solution was filtered through diatomaceous earth and activated carbon. The filtrate was treated with a saturated aqueous solution of hydrogen chloride in dry ether, the hydrochloride thus obtained was isolated and crystallized from methanol-acetone to give 565 mg (56.5%) of N-cyclobutylmethyl-3,4,4-dihydroxymorphinan hydrochloride (LXa), m.p.

272-274 ° C (decomposes). IR and NMR spectra were consistent with the structure.

Analysis for C21H29NO2 * HCl * * CH3OH

Calculated: C 67.97 H 8.49 N 3.49%

Found: C 68.10 H 8.14 N 3.80

Claims (8)

A process for the preparation of 14-hydroxymorphorin derivatives of the formula / N-CH 2 -R 3 wherein R is cyclobutyl or cyclopropyl and R is hydrogen or lower alkyl, characterized in that a) a compound of formula V y. Wherein R is cyclobutyl or cyclopropyl and R is lower alkyl, is reduced with borane in an inert organic solvent to prepare a boron complex of the compound of formula VII / n-ch9-R 6 is a cyclobutyl or cyclopropyl and R is lower alkyl, b) the boron complex of compound VII is treated with acid to produce a compound of formula LV \ J or cyclopropyl and R is lower alkyl and, if desired, 2) c) the R „-R HO I | Where R is cyclobutyl or cyclopropyl. Process according to claim 1, characterized in that in step a) the compound of formula V is reduced by borane dimethyl sulfide. Process according to claim 1, characterized in that in step a) the compound of formula V is reduced with boron which has been generated in situ by reaction of sodium borohydride and boron trifluoride or sodium borohydride and boron trifluoride-tetrahydrofuran complex or sodium borohydride and tear-off luoride alkyl etherate. 4. A process according to any one of claims 1 to 3, characterized in that in step a) the borane is used in a