DE2754062A1 - NEW PHENYL DERIVATIVES - Google Patents

Description

The present invention relates to levorotatory 3-phenoxy-N-substituted Morphinane derivatives of the general formula

wherein R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen; R, hydrogen, lower alkyl, lower alkenyl, the group -CH ₂ (CH ₂ ) R_ or -CO- (CH ₂ ) -R_; R ~ denotes a hetero-aromatic or aromatic radical or cyclo-lower alkyl; ρ is an even number from 0-3; and η means an even number from 1-5,
as well as pharmaceutically acceptable salts thereof.

Klt / November 8, 1977

809823/0906

The term "halogen" used in this specification encompasses the four forms of bromine, chlorine, fluorine and iodine, with fluorine and bromine being preferred. The term "lower alkyl" includes both straight-chain and branched saturated hydrocarbon radicals with 1-7 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl and the like, with methyl being preferred. The term "lower alkenyl" denotes both straight-chain and branched aliphatic hydrocarbon radicals with 2-7 carbon atoms which have an olefinic double bond, such as vinyl, allyl, prop-2-en-1-yl and the like. The preferred lower alkenyl groups are -CH ₂ -CH = CH ₂ ,

CH, CH,

, 3, 3

-CH ₂ -CH = C-CH ₃ and -CH ₂ -C = CH ₂ .

The term "cyclo-lower alkyl" denotes saturated cyclic aliphatic hydrocarbon groups with a ring of 3-6 carbon atoms. Preferred cyclo-lower alkyl groups are: cyclopropyl, cyclobutyl and cyclohexyl. The term "lower alkoxy" denotes lower alkoxy groups with 1-7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy and the like.

The term "hetero-aromatic radical" denotes the radical of a hydrocarbon ring with 5 or 6 ring members and an oxygen, nitrogen or sulfur atom as a hetero atom. Preferred hetero-aromatic radicals are thienyl, Pyrolyl, furyl, pyridyl, pyranyl and the like.

The term "aromatic radical" denotes the radical of an aromatic hydrocarbon, such as phenyl or naphthyl, with phenyl being preferred.

The compounds according to the present invention can be obtained by
35

809823/0908

a) a compound of the formula

wherein R _{1 has} the meaning mentioned above, with a compound of the general formula

IN THE

where R and η have the meaning mentioned above and X is halogen, implements, or

b) for the preparation of a compound of the formula I in which R is hydroxy, an ether of the formula

(R ₃ O) _n

I-A

wherein η and R, have the abovementioned meaning and R _{3 is} lower alkyl, cleaves, or

c) for the preparation of a compound of the formula I in which R 1 is -CO- (CH ₂ ) -R ₂ is a compound of the formula

809823/0906

jr- "6

NCH ₃

10

(R ι

wherein η and R are as defined above, with a compound of the formula

20th

X — CO— (CH ₂ ) p— F »2 IV

wherein R ₂ , ρ and X have the abovementioned meaning, converts, or

d) for the preparation of a compound of the formula I in which R. is -CH ₂ (CH ₂ ) R ₂ , a compound of the formula

IN-CO- (CH ₂ Ip-R ₂

(RI _n

where R, R_ and ρ have the meaning mentioned above, reduced, or

30 35

e) for the preparation of a compound of the formula I, in which R is hydrogen, a compound of the formula

N-CO-OCH ₂ -CCl ₃

Vl

809823/0906

wherein R and η have the meaning mentioned above, treated with zinc in a lower alkanecarboxylic acid, or

f) for the preparation of a compound of the formula I in which R _{1 is} -CH 2 (CH ₂ ) R ₂ is a compound of the formula

R) _n

wherein R and η have the meanings mentioned above, with a compound of the formula

X-CH ₂ - (CH ₂ ) p ~ —R ₂ **

wherein X, R ₂ and ρ have the abovementioned meaning, converts, or

g) for the preparation of a compound of the formula I in which R 1 is hydrogen, i.e. a compound of the formula VII, dealkylates a compound of the formula I-C, or

h) for the preparation of a compound of the formula I in which R _{1 is} -CH ₂ (CH ₂ ) R ₂ , a compound of the formula VII is reacted with a compound of the formula IV, or

i) for the preparation of a compound of the formula I in which R _{1 is} lower alkyl or lower alkenyl, a compound of the formula VII with a compound of the formula

X-R.,

809823/0906

wherein X has the abovementioned meaning and R _{7 is} lower alkyl or lower alkenyl, converts, or

10

k) a compound of the formula

XIII

wherein R, R, and η have the meanings mentioned above, cyclized and if desired

20th

1) a compound of the formula I is converted into a pharmaceutically acceptable acid addition salt.

According to process aspect a), a compound of the formula I prepared by reacting a compound of formula II with a compound of formula III.

A compound of the formula II is reacted with a compound of the formula III in the presence of a copper catalyst. The reaction is carried out in an organic solvent and in the presence of an inorganic alkali metal base carried out. In principle, any conventional organic solvent can be used, but nitrobenzene, collidine, Diglyme and tertiary amines preferred. Among the tertiary amines are the cyclic tertiary amines, such as pyridine and the tri-lower alkylamines such as trimethylamine, triethylamine and the like. Consider. As mentioned earlier, the Reaction carried out in the presence of an inorganic alkali metal base. Preferred bases are alkali metal hydroxides,

809823/0906

such as potassium and sodium hydroxide, as well as alkali metal carbonates and bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate. A preferred inorganic base for this process is a weak base such as potassium carbonate. The temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature and atmospheric pressure be performed. On the other hand, if desired, elevated temperatures can also be used. In general it is preferred to choose temperatures of 100-250 °. As mentioned, the reaction takes place in the presence of a copper catalyst, such as copper (II) chloride, copper (II) bromide, copper (II) sulfate, Copper (I) iodide or a mixture of copper bronze and metallic copper instead, granular copper being preferred.

Compounds of the formula I in which R is hydroxy can, according to the aforementioned reaction, between a compound of the formula II and a compound of the formula III can only be obtained in poor yields. It is therefore preferred to produce these compounds according to process aspect b). Here, a compound of the formula I in which R is lower alkoxy, i.e. a compound of the formula I-A, used as starting material. Following this procedure, a compound of the formula

(HO) _n

obtain.

809823/0906

J * -

■ j The compound of formula I-A is cleaved by ether converted into the compound of formula I-B. Any conventional method for splitting the ether can be used. Preferred methods include treating or treating a compound of Formula I-A with potassium hydroxide in diglyme a compound of formula I-A with pyridine hydrochloride or aqueous hydrogen bromide in acetic acid. In this split of the ether the conventional conditions for ether splits can be used. It should be noted that this

-JO ether cleavage does not cleave the phenoxy group and that accordingly no products are created that would have an addictive narcotic effect.

Process variant c) is carried out at an elevated temperature, preferably carried out at reflux temperature, and in the presence of an inert organic solvent. Each conventional aromatic solvents can be used in this reaction. Preferred solvents are: aromatic Hydrocarbons such as benzene or toluene.

The reduction according to process aspect d) is carried out with a strong metal hydride reducing agents such as an alkali metal aluminum hydride e.g. lithium aluminum hydride or a Di (lower alkyl) aluminum hydride, such as diisobutyl aluminum hydride, carried out. In this reduction, those conventional in using such aluminum hydride reducing agents can be used Conditions are applied.

According to process aspect e), compounds of the formula VI are obtained by treatment with zinc in a lower alkanecarboxylic acid converted into compounds of the formula VII. The lower alkanecarboxylic acid serves as a solvent in this reaction. Any conventional lower alkanoic acid such as acetic acid, propionic acid and the like can be used. temperature and pressure are not critical to this reaction. The reaction can on the one hand at room temperature and atmospheric pressure or

809823/0906

-JT-

on the other hand carried out at temperatures above 100 ° will.

The compounds of the formula VI are new and can be obtained by treating a compound of the formula I-C with trichloroethyl chloroformate getting produced. Any inert organic solvent can be used in this reaction will. Preferred solvents are aromatic hydrocarbons such as benzene, toluene and the like. Usually this is Reaction carried out in the presence of a weak, inorganic base. To this comes every conventional weak, inorganic one Base into consideration. Preferred weak bases are alkali metal carbonates and bicarbonates such as potassium or sodium carbonate Temperature and pressure are not critical in this reaction. The reaction can be carried out on the one hand at room temperature and atmospheric pressure or alternatively carried out at elevated temperatures and pressures. The reaction is preferred carried out at the reflux temperature of the reaction mixture.

According to process aspect f), a compound of the formula VII in the presence of an organic solvent is preferred a polar solvent, reacted with a compound of the formula X. The conversion takes place between room temperature

and 300 ° C, with a temperature range of 120 C -

300 ° C is preferred. In this reaction, each can be polar Solvents with a boiling point of 120 ° C - 300 ° C can be used. Preferred solvents are high-boiling polar solvents such as dimethyl sulfoxide or dimethyl formamide.

The reaction is carried out in the presence of a base. Every conventional inorganic alkali metal base, such as sodium bicarbonate, Potassium carbonate, sodium carbonate can be used in this reaction. In general, it is preferred to have a use weak inorganic base such as sodium or potassium carbonate or bicarbonate. On the other hand, they can also be strong

809823/0906

tertiary amines, such as triethylamine or diisopropylethylamine, can be used as the base. The temperature and pressure are at this one Reaction not critical. The reaction can be carried out at room temperature and atmospheric pressure, with preferably is operated under reflux conditions.

According to process aspect g), a compound of the formula I-C is converted into a compound of the formula VII by dealkylation convicted. Any conventional dealkylating agent or dealkylation process can be used here. Preferred this dealkylation is carried out by treatment with cyanogen bromide and subsequent treatment with an inorganic mineral acid or by treatment with a chloroformic acid ethyl or phenyl ester and subsequent treatment with a Alkali metal hydroxide carried out in a lower alkanol. In this dealkylation are those in dealkylations conventional conditions applied.

The reaction of a compound of the formula VII with a compound of the formula IV according to process aspect h) is described in carried out an inert organic solvent, a polar solvent is preferred. Any polar solvent can be used for this. Preferred polar solvents are benzene, toluene or methylene chloride. The reaction takes place in the presence of a base. Here are organic

Bases such as triethylamine, pyridine and the like are preferred. Temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature or at an elevated temperature.
30th

Process aspect i) is carried out in the same way as process aspect f).

The cyclization of a compound of the formula XIII according to process aspect k) takes place by treating a compound

809823/0906

of formula XIII with a strong mineral acid. Any conventional Strong mineral acids such as phosphoric acid, sulfuric acid or hydrochloric acid can be used for this purpose, however Phosphoric acid is preferred. The inorganic acid used can serve as a reaction medium. Temperature and pressure are not critical in this reaction. The reaction can be carried out at room temperature and atmospheric pressure or at temperatures up to 250 ° C. In general, it is preferred to carry out this reaction at a temperature of 100-200 ° C perform.

The starting compounds of the formula XIII are new and can be selected from compounds of the formula

—R

Xl

where R. has the meaning mentioned above and Rg lower Alkyl means via an intermediate of the formula

—R

XII

809823/0906

wherein R, R, and η have the meaning mentioned above, are prepared. The transfer of a connection of the Formula XI to a compound of the formula XII takes place by ether cleavage. A conventional ether splitting method is used for this purpose applied. It is preferred to use the compound of formula XI with an alkali metal hydroxide such as sodium or Potassium hydroxide in an ether such as diglyme, to be carried out as a solvent. Usually this reaction occurs at the reflux temperature of the reaction mixture carried out. The compound of formula XII is made by reacting with a compound of the formula III converted into the compound of the formula XIII. This reaction is carried out in the same way such as the reaction of a compound of the formula II with a compound of the formula III.

The intermediates of the formulas II, IV and X are known or can be prepared in a manner analogous to the preparation of the known compounds.

The compounds of the formula I form with inorganic acids such as hydrochloric acid, hydrobromic acid and sulfuric acid and phosphoric acid pharmaceutically acceptable acid addition salts. Also with organic acids such as tartaric acid, oxalic acid, Citric acid, camphorsulphonic acid, ethanesulphonic acid, toluenesulphonic acid, Salicylic acid, ascorbic acid, maleic acid, succinic acid, formic acid, acetic acid and the like can be used pharmaceutically Applicable acid addition salts are formed.

The compounds of the formula I and their pharmaceutically acceptable acid addition salts are valuable as analgesics and / or narcotic antagonists. The connections cause when administered orally or orally, provides pain relief in the same manner as codeine. The compounds according to the present Invention cannot be chemically broken down into compounds that are addictive, such as dromoran.

809823/0906

The compounds of the formula I and their salts can be brought into standard pharmaceutical dosage forms. They are (usable for oral or parenteral administration) with the usual pharmaceutical auxiliaries, such as e.g.

organic or inorganic carrier materials, such as water, Gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum, polyalkylene glycols and the like: The pharmaceutical Preparations can be in solid form, e.g. as tablets, suppositories or capsules, or in liquid form, e.g. as solutions, suspensions or emulsions. Pharmaceutical auxiliaries such as preservatives, Stabilizing agents, wetting or emulsifying agents, or salts for changing the osmotic pressure or Buffer, can be added. The pharmaceutical preparations can also contain other therapeutically active substances.

The daily dose for the compounds of the present invention will vary depending on the potency of each the new compound used, the route of administration chosen and the size of the patient. The one to be followed There are no definite limits on dosage; rather, one becomes one on the pharmacological function of the compound Use the effective dose adjusted to the formula I. A representative, typical method of administering a compound Formula I is the oral route. In this mode of administration, the compound of formula I in one Range of 0.01 micrograms - 0.15 micrograms containing tablet per day and kg body weight.

The compounds of formula I and their salts are valuable as pain relievers. The analgesic effectiveness can be shown on the basis of the “Phenylquinone Writhing test” standard (Sigmund et al., Proc.Soc.Exp. Biol. Med. i) 5: 729 [1957]) will. The compounds of the present invention alleviate

809823/0906

the pain significantly and show in mice which

chemical intraabdominal pain was produced, analgesic effect. The ED, - _O was the dose, which was the total number of
Curvatures reduced by 50%. The following compounds of the formula I are analgesic in comparison with codeine
Effect (expressed as ED ₅₀ ).

(-) - 3-Phenoxy-N-methylmorphinan tartrate, EDc _n 2.0 mg / kg (sc);

(-) - 3- (p-Methyl) phenoxy-N-methylmorphinan hydrochloride, ED ₅₀ 23 mg / kg (sc);

(-) -3- (p-Methoxy / phenoxy-N-methylmorphinane hydrochloride, ED ₅ 2.0 mg / kg (sc);

(-) - S-phenoxy-N-cyclobutylmethylmorphinan hydrochloride, ED ₅₀ 13.0 mg / kg (sc);

(-) - 3-Phenoxy-N-phenethylmorphinane oxalate, ED ₅₀ 0.9 mg / kg (sc);

(-) - 3-Phenoxy-N- [2- (2-fury1) ethy1] morphinan oxalate,
ED ₅₀ 1.0 mg / kg (sc);

(-) - 3-Phenoxy-N- [2- (2-thieny1) ethy1] morphinane sulfate,
ED ₅₀ 13.0 mg / kg (sc);

(-) - 3- (m-Fluoro) phenoxy-N-methylmorphinan-d-tartrate, ED ₅ 6.0 mg / kg (sc);

(-) - 3- (o-Methoxy) phenoxy-N-cyclopropylmethylmorphinan hydrochloride, ED ₅₀ 2.5 mg / kg (sc);

(-) - 3- (p-Methoxy) phenoxy-N-cyclopropylmethylmorphinan hydrochloride, ED ₅₀ 1.3 mg / kg (sc);

(-) - 3- (m-Methoxy) phenoxy-N-methylmorphinane oxalate, ED ₅₀ 2.5 mg / kg (sc);

(-) -3- (o-Methoxy) phenoxy-N-methylmorphinane oxalate, ED, - _O 0.4 9 mg / kg (sc);

(-) - 3- (p-Hydroxy-phenoxy-N-methylmorphinan hydrochloride, ED ₅₀ 1.3 mg / kg (sc);

(-) - 3- (m-Hydroxy) phenoxy-N-methylmorphinan-d-tartrate,
^ED 50 ⁹ '° ^m 9 / ^k 9 (sc);

809823/0906

275-062

(-) - 3- (o-Hydroxy) phenoxy-N-methylmorphinan-d-tartrate, ED ₅₀ 1.8 mg / (sc) ;

(-) - 3- (o-Nitro) phenoxy-N-methylmorphinane hydrochloride, ED ₅₀ 2.8 mg / kg (sc) j

(-) - 3- (p-Fluoro) phenoxy-N-methylmorphinan hydrochloride, ED ₅₀ 1.0 mg / kg (sc) ;

(-) - 3- (o-Fluoro) phenoxy-N-methylmorphinane oxalate, ED ₅₀ 3.0 mg / kg (sc) ;

(-) - 3-Pentafluorophenoxy-N-methylmorphinane oxalate, ED ₅₀ 9.2 mg / kg (sc) ,

(-) - 3-Phenoxy-N-cyclopropylmethylmorphinan hydrochloride (17), ED ₅₀ 1.7 mg / kg (sc) and

Codeine, ED ₅₀ 3.9 mg / kg (sc).

The compounds of the formula I act in morphine analgesia effectively counteract. This activity can be demonstrated on the "mice tail flick test" for morphine antagonism. This test will used to measure narcotic antagonism. The compounds are made 10 minutes before the administration of morphine sulfate administered subcutaneously. The percentage evaluation of the reaction time was during each test for 10 mg / kg se morphine sulfate and the actual percentage increase was used to calculate the percentage antagonism of morphine analgesia. The percent antagonism was calculated according to the formula von Harris and Pierson, J. Pharmakol.Exp.Ther., 143: 141, 1964. Using (-JS-phenoxy-N-cyclopropylmethylmorphinan hydrochloride as representative of a compound according to the invention, it was possible to obtain a morphine-antagonistic effect, as can be seen from the EDc ₀ of 40.28 mg / kg s.c. emerges.

The following examples illustrate the invention, but do not limit it. All temperatures are in ⁰ C. The term ether refers to diethyl ether. If millimeters (mm) are given, they mean mm Hg.

809823/0906

example 1

A mixture of 6.0 g (0.0023 mol) of (-) - 3-hydroxy-N-methylmorphinane, 60 ml of freshly distilled pyridine, 4.8 g of potassium carbonate, 9.0 g of hexafluorobenzene and 6.0 g of granular copper heated in a stainless steel container to 120 ° for 7 days. After cooling down, the container is opened. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether (700 ml) and 5N aqueous sodium hydroxide. The residue obtained after removal of the ether is extracted from hexane (200 ml). The residue obtained after removing the hexane (5.0 g) is chromatographed over neutral alumina (75 g) and eluted with methylene chloride, diethyl ether and ethyl acetate. The fractions are combined and the solvents are removed under reduced pressure to give crude (-) - 3-pentafluorophenoxy-N-methylmorphinane. A sample of this compound is distilled for analytical purposes. Boiling point 150-160 ° / O.1 mm. [α] ²⁵ -39.69 ° (c = 1.21 in methanol).

A solution of 0.8 g of oxalic acid in 20 ml of ether is added to 3.6 g (0.01 mol) of the above base in 20 ml of diethyl ether. The crude oxalate was crystallized from Essigester and are (-) - 3-pentafluorophenoxy-N-methylmorphinanoxalathemihydrat, mp 157-160 °, [α] ²⁵ -24.50 ° (c = 1.00 in methanol).

809823/0906

Example 2

A solution of 10.2 g (0.04 mol) (-) - 3-hydroxy-N-methylmorphinan in 240 ml of freshly distilled pyridine is mixed with 18.5 g of bromobenzene and 13.8 g of potassium carbonate with stirring and nitrogen and refluxed 13.0 g of granular copper for 8 days. The reaction mixture is filtered, and that The filtrate is concentrated under reduced pressure. The residue is between ether (500 ml) and 5 N aqueous sodium hydroxide (200 ml) distributed. The ethereal solution is washed with water and dried. The one after removing the aether residue obtained is distilled. (-) - 3-Phenoxy N-methylmorphinane with a boiling point of 180-185 ° / 0.1 mm Hg is obtained Sample of this compound is recrystallized from ether,

Melting point 87-88 °, [a] ^ ⁵ -60.10 ° (c = 0.01 in methanol).

10.0 g (0.03 mol) of the above-mentioned base in 150 ml of ether are mixed with a solution of 3.2 g of oxalic acid in 100 ml of ether. The crude oxalate is recrystallized from ethanol and gives (-) - 3-phenoxy-N-methylmorphine anoxalate with a melting point of 184-185 ° (decomp.), [Α] * ⁵ -35.47 ° (c = 1.00 in methanol) .

A solution of 3.5 g of D-tartaric acid is added with stirring to 7.0 g (0.02 mol) of the base mentioned earlier in 25 ml of acetone given in 75 ml of acetone. The reaction mixture is for 0.5 hours at room temperature and then for 4 hours at Stirred 0-5 °. The tartrate salt is removed by filtration and recrystallized from ethanol (40 ml). (-) - 3-Phenoxy-N-methylmorphinane is obtained d-tartrate with a melting point of 131-133 °,

[a] £ ⁵ -20.08 ° (c = 0.99 in methanol).

Example 3

A solution of 5.0 g (0.01 9 moles) (-) - 3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is taken under

809823/0906

-W-

Stir and nitrogen with 6.4 g p-bromotoluene, 4.0 g potassium carbonate and refluxed 0.2 g of granular copper for 9 days. The reaction mixture is filtered, and that The filtrate is concentrated under reduced pressure. The residue is extracted with ether (200 ml). The ethereal solution is washed first with 2N sodium hydroxide (100 ml) and then with water and then dried. The one after removal the residue obtained from the ether is distilled and gives (-) - 3- (p-methyl) -phenoxy-N-methylmorphinane with boiling point

125-140 / 0.15 mm Hg. A sample of this compound is crystallized from ether, melting point 94-96 °, [a] ^ ⁵ -55.98 ° (c = 1.00 in methanol).

Treatment of 3.3 g (0.01 mol) of the above base with anhydrous hydrogen chloride in ethyl acetate (5 ml) gives 3.3 g of crude hydrochloride. Recrystallization from ethyl acetate gives (-) - 3- (p-methyl) -phenoxy-N-methylmorphinan hydrochloride, Schmi
0.69 in methanol).

hydrochloride, melting point 223-224 °, [a] ^ ⁵ -37.85 ° (c =

Example 4

A solution of 5.1 g (0.02 mol) (-) - 3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is mixed with 7.5 g of p-bromanisole and 4.01 g of potassium carbonate with stirring and nitrogen and 0.2 g of granular copper refluxed for 7 days. The reaction mixture is filtered, and that The filtrate is concentrated under reduced pressure. The residue is between ether (400 ml) and 10N sodium hydroxide (100 ml) distributed. The ethereal solution is washed with water and dried. The one obtained after removing the ether The residue is distilled and gives (-) - 3- (p-methoxy) phenoxy-N-methylmorphinane boiling point 139-155 ° / O, 15 mm Hg. This

Product of melting point 130-132 °, [a] ^ -51.59 ° (c = 0.99

Compound is crystallized from ether and gives pure product of the Si
in methanol).

809823/0906

275A062

2.0 g (0.006 mol) of the above product deliver Treating with anhydrous hydrogen chloride in ethyl acetate crude hydrochloride, which after crystallization from ethyl acetate (-) - 3- (p-methoxy) phenoxy-N-methylmorphinane hydrochloride

with a melting point of 170-172 ° gives [a] * ⁵ -34.22 ° (c = 0.99 in methanol).

Example 5

A solution of 5.1 g (0.02 mol) (-) - 3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is under Stir and reflux nitrogen with 7.5 g of N-bromanisole, 4.1 g of potassium carbonate and 0.2 g of granular copper for 10 days. The reaction mixture becomes double the volume Aether is added, whereupon it is filtered. The filtrate is evaporated under reduced pressure. The residue is between Ether and 5N sodium hydroxide distributed. The ethereal solution is washed with water and dried. The residue obtained after removing the ether is distilled and delivers (-) - 3- (N-Methoxy) phenoxy-N-methylmorphinane of boiling point 145-16O ° / E, 1 mm Hg. A sample of this is used for analysis Compound crystallized from ether, melting point 88-90 °, [α] "-61.81 ° (c = 1.00 in methanol).

A solution of 0.4 g of oxalic acid in ether is added to 1.5 g (0.04 mol) of the above product in ether. The raw one Oxalate is crystallized from ethanol / ether and delivers (-) - 3- (N-Methoxy) phenoxy-N-methylmorphine oxalate from the enamel

2! D.

point 148-150 °, [a] j? ⁵ -39.60 ° (c «1.00 in methanol).

Example 6

A solution of 5.1 g (0.02 mol) (-) - 3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is under 35

809823/0906

Stir and nitrogen with 7.5 g of o-bromoanisole, 4.1 g of potassium carbonate and refluxed 5.0 g of granular copper for 3 days. The reaction mixture is filtered, and that The filtrate is concentrated under reduced pressure. The residue is partitioned between ether and 5N sodium hydroxide. The ethereal solution is washed with water and dried. The residue obtained after removing the ether is distilled and provides (-) - 3- (o-methoxy) phenoxy-N-methylmorphinane with a boiling point of 165 ° / 0.2 mm Hg. For analysis purposes, a

Sample of this compound crystallized from ethyl acetate, melting point 87-89 °, [a] ^ ⁵ -59.32 ° (c = 1.16 in methanol).

A solution of 0.7 g of oxalic acid in ether is added to 2.7 g (0.01 mol) of the above product in ether. The crude oxalate is recrystallized from ethanol / ether and gives (-) - 3- (o-methoxy) phenoxy-N-methylmorphine anoxalate, melting point 185-187 ° (decomp.), [A] ^ ⁵ -37.19 ° (c = 0.99 in methanol).

Example 7

A mixture of 2.0 g (0.005 mol) of (-) - 3- (p-methoxy) -phenoxy-N-methylmorphinan and 20 g of pyridine hydrochloride is heated to 220 ° for 25 minutes with stirring and nitrogen, then cooled in an ice bath and finally diluted with water (50 ml). The reaction mixture is made basic with concentrated airanonium hydroxide and extracted with chloroform (100 ml). The chloroform solution is washed with water (50 ml) and dried. Removal of the solvent in vacuo gives a residue which is treated with ether and filtered and gives (-) - 3- (p-hydroxy) -phenoxy-N-methylmorphinane. For analytical purposes, a sample of this compound from ethanol / ether is crystallized, mp 188-190 °, [a] £ ⁵ -51.6 ° (c = 0.86 in methanol).

Treatment of 1.4 g (0.004 mol) of the above product with anhydrous hydrogen chloride in ethyl acetate (10 ml)

809823/0906

όό

one the crude hydrochloride. Crystallization of this compound from ethanol / ethyl acetate gives (-) - 3- (p-hydroxy) phenoxy-N-methylmorphinan hydrochloride with a melting point of 160-163 ° (decomp.), [Α] * ⁵ -34.55 ° (c = 0.99 in methanol).

Example 8

A mixture of 3.8 g (0.01 mol) of (-) - 3- (m-methoxy) phenoxy-N-methylmorphinan and 30 g of pyridine hydrochloride is heated to 220 ° for 25 minutes with stirring and nitrogen and cooled in an ice bath and then diluted with water. The reaction mixture is made basic with concentrated ammonium hydroxide and extracted with ether. The ether extracts are washed with water and dried. The residue obtained after removal of the solvent gives (-) - (m-hydroxy) -phenoxy-N-methylmorphinane. For analytical purposes, a sample of this compound is recrystallized from ethanol, melting point 212-214 °, [a] p ⁵ -53.13 ° (c = 1.00 in methanol).

A solution of 1.0 g of d-tartaric acid in ethanol (20 ml) is added to 2.2 g (0.01 mol) of the above product in ethanol given. The solution is diluted with ether and the precipitated crystals are collected. The raw salt is crystallized from ethanol / ethyl acetate and delivers

(-) - 3- (m-Hydroxy) phenoxy-N-methylmorphinan-d-tartrate-ethanolate, melting point 135-138 °, [α] * ⁵ -19.21 ° (c = 1.26 in methanol).

Example 9

A mixture of 2.5 g (0.007 mol) of (-) - 3- (o-methoxy) -phenoxy-N-methylmorphinane and 25.0 g of pyridine hydrochloride are heated to 220 ° for 25 minutes with stirring and nitrogen, chilled in an ice bath and diluted with water (50 ml). The reaction mixture is made with concentrated aqueous ammonium hydroxide basified and extracted with chloroform (80 ml).

809823/0906

The chloroform solution is washed with water and dried. After removing the solvent in vacuo, one obtains a crude base, which after crystallization from ethyl acetate / hexane gives pure (-) - 3- (o-hydroxy) phenoxy-N-methylmorphinane,

Melting point 167-168 °, [a] ^ ⁵ -52.91 ° (c = 1.07 in methanol).

0.152 g (0.001 mol) of the above product and 0.07 g of d-tartaric acid are dissolved in 1 ml of hot ethanol, whereupon it is allowed to crystallize at room temperature. The crude salt is recrystallized from ethanol and gives (-) - 3- (o-hydroxy) -phenoxy-N-methylmorphinane-d-tartrate ethanolate, melting point 111-112 °, [a] p ⁵ -15.96 ° ( c = 1.07 in methanol).

Example 10

A solution of 6.4 g (0.02 mol) of (-) - 3-hydroxy-N-methylmorphinane in 30 ml of freshly distilled pyridine is mixed with 10.0 g of l-bromo-2-nitrobenzene, 6, with stirring and nitrogen. 0 g of potassium carbonate and 0.3 g of granular copper heated to reflux for 3 days. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is partitioned between ether and 5N sodium hydroxide. The ethereal solution is washed with water and dried. The residue obtained after removing the ether is again partitioned between chloroform and 5N sodium hydroxide. The residue obtained after removal of the chloroform in vacuo is crystallized from ether and gives (-) - 3- (o-nitro) -phenoxy-N-methylmorphinane, melting point 158-160 °, [a] _D -53.16 ° (c = 0.99 in methanol).

Treatment of 2.0 g (0.005 mol) of the above product with anhydrous hydrogen chloride in ethyl acetate gives crude hydrochloride, which after crystallization from ethyl acetate (-) - 3- (o-nitro) phenoxy-N-methylmorphinane-hydrochloride-hemi-

809823/0906

hydrate yields, melting point 155-157 ° (dec.), [α] £ ⁵ -32.62 ° (c = 0.99 in methanol).

Example 11

A solution of 5.1 g (0.02 mol) (-) - 3-hydroxy-N-methylmorphinan in 20 ml of freshly distilled pyridine is mixed with 17.0 g of p-fluorobromobenzene, 4.1 g of potassium carbonate and with stirring and nitrogen 0.2 g of granular copper heated to reflux for 5 days. The reaction mixture is mixed with twice the amount of ether and filtered. The filtrate is concentrated in vacuo. The residue is suspended in 150 ml of hot hexane and filtered. The filtrate is washed with 5N sodium hydroxide and then with water and dried. The residue obtained after removal of the solvent is crystallized from hexane and yields (-) - 3- (p-fluoro) phenoxy-N-methylmorphinan, mp 102-104 ° C, [α] £ ⁵ -53.36 ° (c = 1.00 in methanol).

4.0 g (0.01 mol) of the above product gives crude hydrochloride after treatment with anhydrous hydrogen chloride. Recrystallization from ethyl acetate gives (-) - 3- (p-fluoro) phenoxy-N-methylmorphinan hydrochloride hemihydrate from the melting point

162-164 °, [a] p ⁵ -34.83 ° (c = 0.98 in methanol).

Example 12

A solution of 2.0 g (0.007 mol) of (-) - 3-hydroxy-N-methylmorphinane in 10 ml of freshly distilled pyridine is mixed with 3.5 g of o-fluorobromobenzene, 2.0 g of potassium carbonate and 2, 0 g of granular copper heated to reflux for 2 days. The reaction mixture is mixed with twice the amount of ether and filtered. The filtrate is concentrated in vacuo. The residue is taken up in ether (200 ml) and washed with 5N sodium hydroxide. The ethereal solution is washed with water and dried. By

809823/0906

275-062

Removal of the ether gives crude (-) - 3- (o-fluoro) -phenoxy-N-methylmorphinane. For analytical purposes, a sample of this compound is crystallized from ether, melting point 113-115, [a] p ⁵ -48.67 ° (c = 0.95 in methanol).

A solution of 0.7 g of oxalic acid in ether (25 ml) is added to 2.5 g (0.007 mol) of the above product in ether. The crude oxalate is recrystallized from ethanol and gives (-) - 3- (o-fluoro) -phenoxy-N-methylmorphine anoxalate with a melting point of 180-182 °, [a] ^ ⁵ -30.98 ° (c = 1.00 in methanol).

Example 13

3.3 g of 2,2,2-trichloroethyl chloroformate are added dropwise to a mixture of 2.3 g (0.007 mol) of (-) - 3-phenoxy-N-methylmorphinane, 150 ml of benzene and 0.35 g of potassium carbonate. The reaction mixture is refluxed with stirring for 6 days. The reaction mixture is diluted with ether and extracted with 4N hydrochloric acid. The organic phase is washed with dilute ammonium hydroxide and with water and then dried. Removal of the solvent gives (-) - S-phenoxy-N-trichlorocarbethoxymorphinan. For analytical purposes, a sample of this compound is distilled, boiling point 23O-24O ° / O, 0.5 mm Hg, [α] ^ ⁵ -119.65 ° (c = 0.95 in methanol).

Example 14

To a solution of 3.4 g (0.007 mol) (-) - 3-phenoxy-N-trichlorocarbethoxymorphinan 2.0 g of zinc dust are added in portions to 40 ml of 90% acetic acid. The reaction mixture is stirred at room temperature for 16 hours and filtered. The filtrate is concentrated in vacuo. The residue is distributed between ether and dilute ammonium hydroxide. The ethereal solution is extracted with 4N hydrochloric acid.

809823/0906

The acidic solution is extracted with chloroform. After removal of the chloroform, the crude hydrochloride is crystallized from ethanol and gives (-) - 3-phenoxymorphinan hydrochloride with a melting point of 322-324 °, [a] ^ ⁵ -33.88 ° (c =

1.00 in methanol).

Example 15

A solution of 5.8 g of cyclopropanecarboxylic acid chloride in 25 ml of toluene is added dropwise at 5 ° to a solution of 3.7 g (0.011 mol) of (-) - 3-phenoxy-N-methylmorphinane in 50 ml of toluene. The reaction mixture is first allowed to warm to room temperature and then heated to reflux for 15 hours. The residue obtained after removal of the solvent is partitioned between ether and dilute hydrochloric acid. The ethereal solution is washed with water and dried. Removal of the solvent in vacuo gives (-) - 3-phenoxy-N-cyclopropylcarbonylmorphinane. For analytical purposes, a sample of this compound was distilled, boiling point 230-24O ° / O, O5 mm Hg, [a] ^ ⁵ -173.45 ° (c = 0.99 in methanol).

Example 16

To a suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran, a solution of 4.6 g (0.011 mol) of (-) - S-phenoxy-N-cyclopropylcarbonylmorphinane is added for 15 minutes placed in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is left under nitrogen for 16 hours heated to reflux and then cooled to room temperature. Water is then added dropwise. The received The suspension is filtered and the filtrate is concentrated. The residue is partitioned between ether and 4N hydrochloric acid. The acidic phase is made basic with concentrated ammonium hydroxide. The aqueous solution is extracted with ether. 35

8098 2 3/0906

- / if -

The ethereal solution is washed with water and dried. Removal of the ether under reduced pressure gives (-) - S-phenoxy-N-cyclopropylmethylmorphinane. For analysis purposes if a sample of this compound is distilled, boiling

point 190-2OO ° / 0.1 mm Hg, [a] ^ ⁵ -89.07 °, (c = 0.99 in methanol).

Treatment of 2.6 g (0.007 mol) of the above product with anhydrous hydrogen chloride in ether gives the crude hydrochloride which, after crystallization from ethyl acetate, gives (-) ^ - phenoxy-N-cyclopropylmethylmorphinane hydrochloride. Melting point 186-188 °, [a] £ ⁵ -67.16 ° (c = 1.00 in methanol).

Example 17

A mixture of 253.9 g (0.935 moles) of (-) - 1- (p-methoxybenzyl) -2-methyl-1,3,4,5,6,7,8-octahydroisoquinoline and 1.2 l of diethylene glycol is heated to 80-100 °, whereupon potassium hydroxide is added. The reaction mixture is heated to 210 ° heated and with stirring and a constant stream of nitrogen

held at this temperature for 36 hours. The stopcock is opened from time to time to allow water vapor to escape. If this is not done, the desired internal temperature of 210 ° cannot be maintained. The black-brown solution is cooled to room temperature, diluted with water (600 ml) and extracted with ether (400 ml). The aqueous solution is acidified with concentrated hydrochloric acid and then made alkaline with concentrated ammonium hydroxide. The aqueous suspension is extracted with ethyl acetate (4 times 250 ml). The ethyl acetate solution is washed with water and dried. Removal of the solvent gives (-) - 1- (p-hydroxybenzyl) -2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For analytical purposes, a sample of this compound is crystallized from tetrahydrofuran / heptane, melting point 119-120 °, [a] ^ ⁵ -36.01 ° (c = 0.98 in methanol).

809823/0906

Example 18

A solution of 2.4 g (0.009 mol) of (-) - 1- (p-hydroxybenzyl) -2-methyl-l, 2,3,4,5,6,7,8-octahydroisoquinoline and 10 ml fresh distilled pyridine is stirred under nitrogen with 3.1 g of bromobenzene, 2.0 g of potassium carbonate and 0.1 g of granular Copper heated to reflux for 9 days. The reaction mixture is filtered and the filtrate under reduced pressure Pressure is concentrated. The residue is washed with ether (150 ml) added, whereupon insoluble material is filtered off from the ether will. The filtrate is extracted with 2N sodium hydroxide, washed with water and dried. By removing the (-) - (p-Phenoxybenzyl) -2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline is obtained in a solvent. For analysis purposes, distilled a sample of this compound. boiling point

12O ° / O, 15 mm Hg, [α] ²⁵ -18.53 ° (c = 1.14 in methanol).

A solution of 0.3 g of oxalic acid in ether is added to a solution of 1.0 g (0.003 mol) of the above product in 5 ml of ether. The crude oxalate is recrystallized from ethanol and gives (-) - l - (- p-phenoxybenzyl) -2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline oxalate with a melting point of 160-162 °. [Ot] ² J ⁵ -37.17 ° (c »1.00 in methanol).

Example 19

A mixture of 0.5 g (0.002 mol) of (-) - 1- (p-phenoxybenzyl) -2-methyl-l, 2,3,4,5,6,7,8-octahydroisoquinoline and 5 ml of 99% strength Phosphoric acid are stirring and nitrogen during

Heated to 135 ° for 3 days. The reaction mixture is poured onto ice water and made basic with concentrated ammonium hydroxide posed. The aqueous suspension is extracted with chloroform. The combined chloroform extracts are washed with water washed and dried. Removal of the solvent

809823/0906

■ j yields crude (-) - 3-phenoxy-N-methylmorphinan.

Example 20

To a solution of 3.9 g (0.01 mol) (-) - 3-phenoxy-N-methylmorphinan a solution of 6.9 g of cyclobutanecarboxylic acid chloride is added dropwise in 50 ml of toluene at room temperature added in 30 ml of toluene. The reaction mixture is stirred for 1 hour at room temperature and then for 12 days

• JO heated to reflux. The reaction mixture is cooled to room temperature and washed successively with 4N hydrochloric acid, water and 5N sodium hydroxide. The organic phase is dried and filtered. Removal of the solvent in vacuo gives (-) - 3-phenoxy-N-cyclobutylcarbonyl-morphinan. A sample of this compound is distilled for analytical purposes. Boiling point 220 ° (0.1 mm Hg), [a] £ ⁵ -163.25 ° (c = 0.98 in methanol).

Example 21

To a suspension of 0.4 g of lithium aluminum hydride

a solution of 2.1 g (0.005 mol) of (-) - S-phenoxy-N-cyclobutylcarbonylmorphinane is added dropwise to 40 ml of anhydrous tetrahydrofuran placed in 20 ml of anhydrous tetrahydrofuran.

The reaction mixture is heated to reflux under nitrogen for 3 hours, then cooled to room temperature and finally water is added dropwise. The suspension obtained is filtered. The filtrate is concentrated and the residue is dissolved in ether (50 ml). The solution is extracted with 4N hydrochloric acid (75 ml). The aqueous solution is made alkaline with 10N sodium hydroxide and extracted with ether (75 ml). The ethereal solution is washed with water and dried. Removal of the solvent in vacuo gives crude (-JS-phenoxy-N-cyclobutylmethylmorphinane. A sample of this compound is distilled for analysis purposes. Boiling point 215-225 ° (0.5 mm Hg), [a] p ⁵ -73.25 ° (c = 0.99 in methanol).

809823/0906 original inspected

-OA-

By treating 1.1 g (0.003 mol) of the above base with anhydrous hydrogen chloride in ethyl acetate, the crude hydrochloride is obtained, which after crystallization from ethyl acetate is pure (-JS-phenoxy-N-cyclobutylmethylmorphinane hydrochloride with a melting point of 175-177 ° provides, [a] ^ ⁵ -66.59 ° (c = 1.03 in methanol).

Example 22

To a mixture of 4.0 g (0.012 mol) of (-) - 3-phenoxymorphinan, 2.5 g of triethylamine and 15 ml of methylene chloride is added A solution of 2.9 g of phenylacetyl chloride in 15 ml of methylene chloride was added dropwise. The reaction mixture is heated to reflux for 14 hours, then cooled and then successively with water, 4N hydrochloric acid, 2N sodium hydroxide and washed water. The organic solution is dried and the solvent is evaporated. Man receives crude (-J-S-phenoxy-N-phenylacetylmorphinan. For A sample of this compound is distilled for analytical purposes.

Boiling point 240-250 ° (0.05 mm Hg), [α] £ ⁵ -133.27 ° (c = 1.11 in methanol).

Example 23

To a suspension of 0.8 g of lithium aluminum hydride in 40 ml of anhydrous tetrahydrofuran is added over 45 minutes a solution of 4.2 g (0.01 mol) of (-) - 3-phenoxy-N-phenylacetylmorphinane placed in 40 ml of anhydrous tetrahydrofuran. The reaction mixture is left under nitrogen for 3 hours heated to reflux, then cooled to room temperature and added dropwise with water. The suspension obtained is filtered and the filtrate is concentrated. The residue is partitioned between ether and water. The essential Solution is dried. Evaporation of the solvent gives crude (-) - 3-phenoxy-N-phenethyl-morphinane. For

809823/0906

- yr-

A sample of this compound is distilled for analytical purposes. Boiling point 16 (
in methanol).

Boiling point 160-165 ° (0.1 mm Hg), [α] * ⁵ -100.27 ° (c = 0.55

A solution of 0.8 g of oxalic acid in ether is added to a solution of 3.2 g (0.007 mol) of the above base in ether. The crude oxalate is recrystallized twice from ethanol and gives pure (-) - 3-phenoxy-N-phenethylmorphine anoxalate with a melting point of 217-219 °. M ^ ⁵ -72.17 ° (c = 1.06 in methanol).

Example 24

To a mixture of 4.0 g (0.012 mol) (-) - 3-phenoxymorphinan, A solution of 2.7 g of 2-furylacetyl chloride is added dropwise to 2.5 g of triethylamine and 15 ml of methylene chloride. The reaction mixture is heated to reflux for 14 hours, then cooled to room temperature and successively washed with water, 4N hydrochloric acid, 5N sodium hydroxide and water. The organic solution is dried and

evaporated to give crude (-) - 3-phenoxy-N - [(2-furylmethyl) carbonyl] morphinan. A sample of this compound is distilled for analytical purposes. Boiling point 215-225 ° (0.1 mm Hg), [α] "-135.36 ° (c = 1.06 in methanol). 25th

Example 25

A suspension of 0.8 g of lithium aluminum hydride in 40 ml of anhydrous tetrahydrofuran is added dropwise Solution of 5.1 g (0.012 mol) of (-) - 3-phenoxy-N - [(2-furylmethyl) carbonyl] morphinan placed in 40 ml of anhydrous tetrahydrofuran. The reaction mixture is left under nitrogen for 3 hours heated to reflux, then cooled to room temperature and added dropwise with water. The suspension obtained is filtered. The filtrate is concentrated. The residue is partitioned between ether and water. the

809823/0906

ethereal solution is washed with 5N sodium hydroxide and dried. By removing the solvent in vacuo an oily residue is obtained. The residue is purified by chromatography over silica gel (50 g) and eluting with ether purified and yields (-) - 3-phenoxy-N - [- 2- (2-furyl) ethyl] ~ morphinan. A sample of this compound is distilled for analytical purposes. boiling point (c = 1.06 in methanol).

distilled. Boiling point 145-150 ° (0.1 mm Hg), [α] * ⁵ -94.15 °

To a solution of 1.2 g (0.003 mol) of this base in

A solution of 0.3 g of oxalic acid in ether is added to ether. The crude oxalate is recrystallized twice from ethanol and gives (-) - 3-phenoxy-N- [2- (2-furyl) ethyl] morphine oxalate with a melting point of 195-197 ° (decomp.). [α] * ⁵ -64.52 ° (c = 1.03 in methanol).

Example 26

A solution of 3.3 g of 2-methylene acetyl chloride in 15 ml of methylene chloride is added dropwise to a mixture of 4.0 g (0.012 mol) of (-) - 3-phenoxymorphinane, 2.5 g of triethylamine and 15 ml of methylene chloride. The reaction mixture is heated to reflux for 15 hours, cooled to room temperature, diluted with methylene chloride and washed successively with water, 4N hydrochloric acid, 5N sodium hydroxide and water. The organic phase is dried and evaporated. Crude (-) - 3-phenoxy-N - [(2-thienylmethyl) carbonyl] morphinane is obtained. A sample of this compound is distilled for analytical purposes. Boiling point 235-240 ° (0.05 mm Hg). [a] £ ⁵ -134.17 ° (c = 1.03 in methanol).

ORIGINAL INSPECTED

809823/090 $

Example 27

To a suspension of 0.8 g of lithium aluminum hydride a solution of 6.2 g (0.014 mol) of (-) - 3-phenoxy-N - [(2-thienylmethyl) is added dropwise to 40 ml of anhydrous tetrahydrofuran carbonyl] morphinan in 40 ml of anhydrous tetrahydrofuran was added. The reaction mixture is kept under nitrogen during Heated to reflux for 3 hours, then cooled to room temperature and water was added dropwise. The received The suspension is filtered. The filtrate is evaporated.

The residue is dissolved in ether. The ethereal solution is extracted with 4N hydrochloric acid. The aqueous phase is made alkaline with 10N sodium hydroxide and extracted with ether. The organic phase is dried. After removing the solvent, crude (-) - 3-phenoxy-N- [2- (2-thienyl) ethyl] morphinan is obtained. A sample of this compound is distilled for analytical purposes. Boiling point 150 ° (0.05 mm Hg), [α] ^ ⁵ -96.45 ° (c = 1.23 in methanol).

A solution of 3.0 g (0.007 mol) of the above base in ether is treated with sulfuric acid. The crude sulfate is crystallized from methanol / ether and gives pure (-) - 3-phenoxy-N- [2- (2-thienyl) ethyl morphinane sulfate with a melting point of 135-138 °. [a] p ⁵ -67.28 ° (c = 1.00 in methanol).

Example 28

A mixture of 3.0 g (0.011 mol) (-) - 3-hydroxy-N-methylmorphinan, 50 ml of freshly distilled pyridine, 2.2 g of 3-bromofluorobenzene, 2.4 g of potassium carbonate and 3 g of granular copper are heated to 120 ° for 8 days in a stainless steel container. After cooling, the container is opened and the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is between ether and 10N sodium hydroxide distributed. The ethereal solution is with

809823/0906

Water washed and dried. Removal of the solvent in vacuo gives a black residue which is distilled at 131-140 ° (0.15 mm Hg) and gives (-) - 3- (m-fluoro) -phenoxy-N-methylmorphinane. [a] _D -56.79 ° (c = 1.04 in methanol).

A solution of 0.4 g (0.001 mol) of the above base in 2 ml of acetone is mixed with a solution of 0.2 g of d-tartaric acid in 10 ml of acetone. The crude tartrate is recrystallized from acetone and gives (-) - 3- (m-fluoro) phenoxy-N-methylmorphinan-d-tartrate hemihydrate with a melting point of 121-123 °. [a] £ ⁵ -18.61 ° (c = 1.03 in methanol).

Example 29

To a solution of 1.7 g (0.005 mol) (-) - 3- (o-methoxy) -phenoxy-N-methylmorphinane in 25 ml of toluene is a solution of dropwise at room temperature with stirring and nitrogen 2.5 g of cyclopropanecarboxylic acid chloride in 15 ml of toluene were added.

The reaction mixture is refluxed for 13 days. The residue obtained after removing the solvent in vacuo between ether (500 ml) and 4N hydrochloric acid (200 ml) distributed. The ethereal solution is washed with dilute ammonium hydroxide and water and then dried. By Removal of the solvent gives crude (-) - 3- (o-methoxy) -phenoxy-N-cyclopropylcarbonylmorphinane, which is reduced without further purification.

A suspension of 0.2 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran is added dropwise Solution of 1.0 g (0.002 mol) of (-) - 3- (o-methoxy) phenoxy-N-cyclopropylcarbonylmorphinane added in 10 ml of anhydrous tetrahydrofuran. The reaction mixture is kept under nitrogen during Heated to reflux for 15 hours, cooled to room temperature and then added dropwise with water. The received The suspension is filtered. The residue obtained after concentrating the filtrate is between ether and 4N hydrochloric acid

809823/0906

distributed. The aqueous solution is made alkaline with 10N sodium hydroxide and extracted with ether. The ethereal solution is washed with water and dried. By removing the solvent in vacuo, crude (-) - 3- (o-methoxy) phenoxy-N-cyclopropylmethylmorphinane is obtained. A sample of this compound is distilled for analytical purposes. Boiling point 210-220 ° (0.1 mm Hg), M ^ ⁵ -57.34 ° (c = 0.52 in methanol).

By treating 0.5 g (0.001 mol) of the above base with anhydrous hydrogen chloride in ethyl acetate, crude hydrochloride is obtained, which after crystallization from ethanol / ether (-) - 3- (o-methoxy) phenoxy-N-cyclopropylmethylmorphinane hydrochloride from Melting point 226-227 ° (dec.) Gives [a] ^ ⁵ -71.18 ° (c = 1.00 in methanol).

Example 30

To a solution of 1.9 g (0.005 mol) of (-) - 3- (p-methoxy) -phenoxy-N-methylmorphinane a solution of 2.9 g is added dropwise in 25 ml of toluene at room temperature under nitrogen Cyclopropanecarboxylic acid chloride in 12 ml of toluene was added. The reaction mixture is stirred for 13 days Heated to reflux. The residue obtained after removing the solvent under reduced pressure is between Ether and 4-N hydrochloric acid distributed. The essential solution is washed with dilute ammonium hydroxide and water and then dried. Obtained by removing the solvent an oily residue, which after distillation <-) - 3- (p-MethoxyJphenoxy-N-cyclopropylcarbonylmorphinan from boiling

point delivers 170 ° (0.05 mm Hg). This compound is used for the reduction without further purification.

A suspension of 0.4 g of lithium aluminum hydride in 20 ml of anhydrous tetrahydrofuran is added dropwise Solution of 2.2 g (0.005 mol) (-) - 3- (p-methoxy) phenoxy-N-cyclopropylcarbonyl

8G9B23 / G9GS

275-062

morphinan in 10 ml of anhydrous tetrahydrofuran.

The reaction mixture is refluxed under nitrogen for 15 hours, cooled to room temperature and then water was added dropwise. The suspension obtained is filtered. The one obtained after concentrating the filtrate The residue is partitioned between ether and 4N hydrochloric acid. The aqueous solution becomes alkaline with 10N sodium hydroxide placed and extracted with ether. The ethereal solution is washed with water and dried. By removing the A solvent in vacuo gives crude (-) - 3- (p-methoxy) -phenoxy-N-cyclopropylmethylmorphinane. A sample of this compound is distilled for analytical purposes. Boiling point 215-220 ° (0.25 mm Hg), Mp ⁵ -77.78 ^ (c = 0.45 in methanol).

Treatment of 1.5 g (0.004 mol) of the above base with anhydrous hydrogen chloride in ethyl acetate gives crude hydrochloride. By recrystallization from ethanol / Ether is obtained (-) - 3- (p-methoxy) phenoxy-N-cyclopropylmethylmorphinane hydrochloride with a melting point of 204-206 °. [σ] _ -60.50 ° (c = 0.99 in methanol).

809623/0906

1. 2. 3. 4.

10 5.

6th

Example A tablet is made as follows:

Components mg / tablet (-) - 3-Phenoxy-N-methylmorphinan 5.0 Lactose 99.0 Pre-gelatinized starch 10.0 Cornstarch 15.0 Modified starch 10.0 Magnesium stearate 1.0 Weight of the tablet 140 mg procedure

15 1. The ingredients 1, 2, 3, 4 and 5 are mixed in a suitable mixer and granulated with water. It will Oven dried overnight and then ground in a grinder. 2. Component 6 is mixed in, followed by a suitable one

20 press is pressed into tablets.

809823/0906

Example A tablet is made as follows:

Components mg / tablet 1. (-) - 3-Phenoxy-N-methylmorphinan 10.0 2. Lactose anhydrous 103.0 3. Avicel 45.0 4th Modified starch 10.0 5. Cornstarch 30.0 6th Magnesium stearate 2.0 Weight of the tablet 200 mg procedure

15 1. Components 1, 2, 3, 4 and 5 are taken for 10-15 min.

mixed in a suitable mixer.

2. The magnesium stearate (ingredient 6) is mixed in, followed by mixing for an additional 4 minutes. the Tablets are pressed on a suitable press.

809823/0906

Example A capsule is made as follows:

Components mg / capsule 1. (-) - 3-Phenoxy-N-methylmorphinan 10.0 2. Lactose 218.0 3. Cornstarch 50.0 4th Magnesium stearate 2.0 5. Talk 10.0 Filling weight of the capsule 220 mg procedure

1. Ingredients 1, 2 and 3 are mixed in a suitable mixer and then in a suitable mill marry.

2. The ingredients 4 and 5 are mixed in, whereupon the mixture is filled into capsules by machine.

809823/0906

example

A capsule is made as follows:

Components

mg / capsule

1. (-) - 3- (p-Methoxy) phenoxy-N-methyl- 25.0 morphinan 257.0 2. Lactose 70.0 3. Cornstarch 3.0 4th Magnesium stearate 15.0 5. Talk 370 mg Filling weight of the capsule procedure

1. Ingredients 1, 2 and 3 are mixed in a suitable mixer and then in a suitable mill marry.

2. The ingredients 4 and 5 are mixed in, whereupon the mixture is filled into capsules by machine.

809823/0906

DJj

1 example

A capsule is produced in a manner similar to that in Example, but using (-) - (p-methyl) phenoxy-5 as the active ingredient N-methylmorphinan is used.

example

A tablet (wet granulation) is produced as follows:

Ingredients mg / tablet

1. (-) - 3- (p-Methoxy) phenoxy-N-methyl- 0.5 morphinan 186.5 2. Lactose 35 3. Modified starch 4th Pre-gelatinized starch q. s. 5. Distilled water 4th 6th Magnesium stearate 250 mg Weight of the tablet procedure

1. Ingredients 1-4 are mixed in a suitable mixer

mixed. 25 2. The granules are mixed with enough water to make one

to maintain clean consistency. This is followed by grinding. 3. It is dried in a suitable oven. It will

mixed with magnesium stearate for 3 minutes. 5. It is turned into tablets on a suitable tablet press 30 pressed.

809823/0906

example

A tablet (wet granulation) is made as follows:

Components mg / tablet 1. (-) - 3-Pentafluorophenoxy ~ N-methyl- morphinan 2.0 2. Lactose 253.0 3. Modified starch 55 4th Pre-gelatinized starch 35 5. Distilled water q.s. 6th Magnesium stearate 5 Total weight of the tablet 350 mg procedure

1. Ingredients 1-4 are mixed in a suitable mixer.

2. The granules are distilled with enough

Add 20 water to get a clean consistency. This is followed by grinding.

3. It is dried in a suitable oven. It is mixed with magnesium stearate for 3 minutes.

5. The tablets are pressed on a suitable tablet press 25.

809823/0906

Claims (87)

Claims Process for the preparation of levorotatory 3-phenoxy-N-substituted morphinane derivatives of the general formula N-R1 10 (R) in which R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen; R is hydrogen, lower alkyl, lower alkenyl, the group -CH2 (CH2) R2 or -CO- (CH2) R2; R- denotes a heteroaromatic or aromatic radical or cyclo-lower alkyl; A is an even number from 0-3; and η denotes an even number from 1-5, as well as pharmaceutically acceptable salts thereof, characterized in that a) a compound of the formula Jl in which R, has the meaning mentioned above, with a compound of the general formula ί R> " III OFnGINAL INSPECTED 809823/0906 - Aft '- 10 15 20 25 30 35 275A062 in which R and η are as defined above and X is halogen, or b) for the preparation of a compound of the formula I in which R is hydroxy, a Ethers of the formula (R3O) n I — R IA in which η and R, have the abovementioned meaning and R3 is lower alkyl, cleaves, or c) for the preparation of a compound of the formula I in which R, -CO- (CH2) - R- denotes a compound of the formula IN C H3 \ RI in which η and R have the meanings mentioned above, with a compound of the formula X — CO- (CH2) p — R2 in which R-, ρ and X have the meanings mentioned above , reacts, or 809823/0906 3 275A062 d) for the preparation of a compound of the formula I in which R, -CH2 (CH2) R2 denotes a compound of the formula I -CO- (CH2Ip-R2 IE in which R, R2 and ρ have the meanings mentioned above, reduced, or e) for the preparation of a compound of the formula I in which R, denotes hydrogen, a compound of Formula 0-OCH2-CCI- in which R and η have the meaning mentioned above, treated with zinc in a lower alkanecarboxylic acid, or f) for the preparation of a compound of the formula I in which R.) is R2, a compound of the formula 809823/0906 in which R and η have the abovementioned meaning, with a compound of the formula X-CH2- (CH2) p-R2 X 5 in which X, R_ and ρ have the abovementioned meaning, or g) for the preparation of a compound of the formula I, in which R 1 is hydrogen, ie a compound of the formula VII, a compound of the formula IC is dealkylated, or h) for the preparation of a compound of the formula I in which R 1 is -CH2 (CH2) R2, a compound of the formula VII with converts a compound of the formula IV, or i) for the preparation of a verb indung of the formula I, in which R is lower alkyl or lower alkenyl, a compound of the formula VII with a compound of the formula X-R. wherein X has the abovementioned meaning and R_ denotes lower alkyl or lower alkenyl, or k) a compound of the formula R) n XIII 809823/0906 - 46 - in which R, R, and η have the abovementioned meaning, cyclized and if desired 1) a compound of the formula I is converted into a pharmaceutically acceptable acid addition salt. 2. The method according to claim 1, characterized in that R- is cyclo-lower alkyl. 3. The method according to claim 1, characterized in that R 1 is lower alkyl. 4. The method according to claim 3, characterized in that R 1 is methyl. 5. The method according to claim 1, characterized in that R _{1 is} -CO- (CH ₂ JR ₂ . 6. The method according to claim 5, characterized in that ρ is Ο. 7. The method according to claim 6, characterized in that R "is cyclopropyl. 8. The method according to claim 5, characterized in that ρ is 1. 9. The method according to claim 8, characterized in that R- is phenyl. 10. The method according to claim 8, characterized in that R _{2 is} 2-furyl. 11. The method according to claim 1, characterized in that R _{1 is} -CH ₂ (CH ₂ ) R ₂ . 809823/0906 C 275-062 12. The method according to claim 11, characterized in that ρ is Ο. 13. The method according to claim 12, characterized in that R_ is cyclopropyl. 14. The method according to claim 1, characterized in that R is hydrogen. 15. The method according to claim 1, characterized in that that R is lower alkyl. 16. The method according to claim 14, characterized in that R is methyl. 17. The method according to claim 16, characterized in that η is 1. 18. The method according to claim 1, characterized in that R is lower alkoxy. 19. The method according to claim 18, characterized in that R is methoxy. 20. The method according to claim 19, characterized in that η is 1. 21. The method according to claim 1, characterized in that R is hydroxy. 22. The method according to claim 21, characterized in that η is 1. 23. The method according to claim 1, characterized in that R denotes nitro. 809823/0906 24. The method according to claim 23, characterized in that η is 1. 25. The method according to claim 1, characterized in that R is halogen. 26. The method according to claim 25, characterized in that R is fluorine. 27. The method according to claim 26, characterized in that that η is 1 or 5. 28. The method according to claim 1, characterized in that that one produces (-) - 3-phenoxy-N-methylmorphinan. , 29. The method according to claim 1, characterized in that (-) - 3- (p-methyl) phenoxy-N-methylmorphinan is produced. 30. The method according to claim 1, characterized in that (-) - 3-phenoxy-N-phenethylmorphinan is produced. 31. The method according to claim 1, characterized in that (-) - 3-phenoxy-N- [2- (2-furyl) ethyl] morphinan is prepared, 32. The method according to claim 1, characterized in that (-) - 3- (o-MethoxyJphenoxy-N-cyclopropylmethylmorphinan manufactures. 33. The method according to claim 1, characterized in that that one (-) - 3- (p-methoxy) phenoxy-N-cyclopropylmethylmorphinan manufactures. 34. The method according to claim 1, characterized in that (-) - 3- (m-methoxy) phenoxy-N-methylmorphinan is prepared. 35. The method according to claim 1, characterized in that that (-) - 3- (o-methoxy) phenoxy-N-methylmorphinan is produced. 809823/0906 1 36. The method according to claim 1, characterized in that (-) - 3- (p-hydroxy) phenoxy-N-methylmorphinan is produced. 37. The method according to claim 1, characterized in that 5 that (-) - 3- (o-hydroxy) phenoxy-N-methylmorphinan is produced. 38. The method according to claim 1, characterized in that (-) - 3- (o-nitro) phenoxy-N-methylmorphinan is produced. 39. The method according to claim 1, characterized in that (-) - 3- (p-fluoro) phenoxy-N-methylmorphinan is prepared. 40. The method according to claim 1, characterized in that that one produces (-) - 3- (o-fluoro) phenoxy-N-methylmorphinan. 41. The method according to claim 1, characterized in that (-) - 3-pentafluorophenoxy-N-methylmorphinan is produced. 42. The method according to claim 1, characterized in that 20 that (-) - S-phenoxy-N-cyclopropylmethylmorphinan is produced. 43. The method according to claim 1, characterized in that (-) - S-phenoxy-IT-cyclopropylcarbonyLmorphinan is produced. 809823/0906 - "9O - 44. Process for the preparation of preparations with analgesic and / or narcotic-antagonistic properties, characterized in that a morphinane derivative according to general formula I of claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient with non-toxic, inert, solid and conventional in such preparations suitable for therapeutic administration liquid carriers and / or excipients mixed. 45. Preparation with analgesic and / or narcotic antagonistic properties, characterized in that it is a compound of the general formula I according to claim or a pharmaceutically usable acid addition salt thereof together with a suitable carrier material. 809823/0906 46. Left-rotating 3-phenoxy-N-substituted morphinan derivatives of the general formula wherein R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen; R, hydrogen, lower alkyl, lower alkenyl, -CO- (CH ₂ JR ₂ or -CH ₂ (CH ₂ ) R ₂ ; R _{2 is} a heteroaromatic or aromatic radical or cyclone-lower alkyl; ρ is an even number from 0-3; and η means an even number from 1-5 as well as pharmaceutically acceptable acid addition salts thereof. 47. A compound according to claim 46, wherein R _{2 is} cyclonic lower alkyl. 48. A compound according to claim 46, wherein R 1 is lower alkyl. 49. A compound according to claim 48, wherein R _{1 is} methyl. 50. A compound according to claim 46, wherein R 1 is -CO- (CH ₂ ) -R ₂ . 51. The compound of claim 50, wherein ρ is zero. 52. The compound of claim 51, wherein R- is cyclopropyl. 53. The compound of claim 50, wherein ρ is 1. 35 54. A compound according to claim 53, wherein R- is phenyl. 809823/0906 55 · Compound according to claim 54, wherein R- is 2-furyl, 56 · Compound according to claim 46, wherein R 1 is -CO- (CH ₂ ) -R_. 57. The compound of claim 56, wherein ρ is zero. 58. The compound of claim 57, wherein R ~ is cyclopropyl. 59 · The compound of claim 46, wherein R is hydrogen. 6O. The compound of Claim 46 wherein R is lower alkyl means. 61 · Compound according to Claim 6O, in which R is methyl. 62 · The compound of claim 61, wherein η is 1. 63. The compound of claim 46, wherein R is lower alkoxy means. 64. A compound according to claim 6 2 ^ wherein R is methoxy. 65. The compound of claim 64, wherein η is 1. 25th 66 · Compound according to claim 46, wherein R is hydroxy. 67. The compound of claim 66, wherein η is 1. 68 · Compound according to claim 46, wherein R is nitro. 69. The compound of claim 68, wherein η is 1. 7O A compound according to claim 46, wherein R is halogen. 36 809823/0906 -ys- 71. A compound according to Claim 70 _f wherein R is fluorine. 72. The compound of claim 71, wherein η is 1 or 5. 73. (-) - 3-Phenoxy-N-methylmorphinan. 74. (-) - 3- (p-Methyl) phenoxy-N-methylmorphinan. 75. (-) - 3-Phenoxy-N-phenäthyimorphinan. 76. (-J-S-Phenoxy-N-U-iZ-FuryDäthyllmorphinan. 77. (-) - 3- (o-Methoxy) phenoxy-N-cyclopropylmethylmorphinane. 78. (-) - 3- (p-Methoxy / phenoxy-N-cyclopropylmethylmorphinane. 79. (-) - 3- (m-Methoxy) phenoxy-N-methylmorphinane. 80. (-) - 3- (o-Methoxy) phenoxy-N-methylmorphinan. 20th 81. (-) - 3- (p-Hydroxy) phenoxy-N-methylmorphinan. 82. (-) - 3- (o-Hydroxy) phenoxy-N-methylmorphinan. 83. (-) - 3- (o-Nitro) phenoxy-N-methylmorphinan. 84. (-) - 3- (p-Fluoro) phenoxy-N-methylmorphinan. 85. (-) - 3- (o-Fluoro) phenoxy-N-methylmorphinan. 30th 86 · (-) - 3-Pentafluorophenoxy-N-methylmorphinane. 87. (-) - S-Phenoxy-N-cyclopropylmethylmorphinan. 88 · (-J-S-phenoxy-IT-cyclopropylcarbonylmorphinane. 809823/0906