KR810001913B1 - Process for preparing 3-phenoxy n-substituted morphinan derivatives - Google Patents

Abstract

Title compds. (I; R = halogen, nitro, lower alkyl, lower alkoxy, hydroxy or H; R1 = H, lower alkyl, lower alkenly, or =CH2(CH2)pR2; R2 = arom. alkyl, cyclic lower alkyl; p = 0-3; n = 1-5) were prepd. by the reaction of II and III(X = halogen). Thus, 6.0 g (-)-3-hydroxy-N-methylmorphinan, 4.8 g potassium carbonate, 9.0 g hexafluorobenzene and 6.0 g Cu were reacted at 120≰C for 7 days in 60 ml pyridine to give I.

Description

Method for preparing 3-phenoxy N-substituted morphinan derivative

The present invention relates to 3-phenoxy N-substituted morphinan derivatives of the following formula (I), which are left-handed and pharmaceutically harmless salts thereof.

In the above formula

R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen,

(R₂는 헤테로 방향족알킬, 방향족알킬 또는 환상 저급알킬이며 p는 0에서 3까지의 정수이다)이며R ₁ is hydrogen, lower alkyl, lower alkenyl, —CH ₂ (CH ₂ ) _p R ₂ or

(R ₂ is heteroaromaticalkyl, aromaticalkyl or cyclic lower alkyl and p is an integer from 0 to 3)

n is an integer from 1 to 5.

및

이다.In the above description, “halogen” includes all halogens such as bromine, chlorine, fluorine and iodine, with fluorine and bromine being preferred. `` Lower alkyl '' is a saturated aliphatic hydrocarbon having 1 to 7 carbon atoms, straight or branched, including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, with methyl being preferred. Lower alkenyl is an aliphatic hydrocarbon having 2 to 7 carbon atoms, straight and branched, and contains one olefin double bond such as vinyl, allyl, or prop-2-en-1-yl. Preferred lower alkenyl groups are -CH ₂ -CH = CH ₂ ,

And

to be.

Monocyclic lower alkyl '' means a saturated cycloaliphatic hydrocarbon group having 3 to 6 carbon atoms. Among the preferred cyclic-lower alkyl groups are cyclopropyl, cyclobutyl, cyclohexyl and the like. "Lower alkoxy" is a lower alkoxy group having 1 to 7 carbon atoms, which includes methoxy, ethoxy, propoxy and isopropoxy.

Heteroaromatic means a hydrocarbon ring system containing a heteroatom selected from oxygen, nitrogen and sulfur and having a 5 or 6 atom cyclic structure. Preferred heteroaromatic ring structures are thienyl, pyryl, furyl, pyridyl, pyranyl.

"Aromatic" means hydrocarbon aromatic substituents such as phenyl and naphthyl, with phenyl being preferred.

The preparation method of the compound of the present invention is as follows.

The compound of formula (II) is then reacted with the compound of formula (III) and if necessary the compound of formula (I) is converted to its pharmaceutically toxic acid addition salt.

In the above formula

R ₁ , R and n are homologous and X is halogen.

When the compounds of formula (II) and (III) are reacted using a copper catalyst, compounds of formula (I) can be obtained. This reaction is carried out in the presence of an inorganic alkali metal base in an organic solvent. Preferred solvents for which conventional organic solvents are used in carrying out this reaction are nitrobenzene, collidine, diglyme and tertiary amine. Tertiary amines include cyclic tertiary amines such as pyridine and triloweralkyl amines such as trimethylamine and triethylamine. This reaction is also carried out in the presence of a base such as an alkali metal base. Preferred bases include alkali metal hydroxides such as potassium hydroxide and sodium hydroxide and alkali metal carbonates and bicarbonates such as sodium carbonate, potassium carbonate and sodium bicarbonate. Preferred inorganic bases for use in the present invention are weak bases such as potassium carbonate. Temperature and pressure in the practice of the present invention are not critical and can be carried out at actual and atmospheric pressures. However, high temperatures can be used if necessary. In general, it is preferred to carry out the reaction at 100 to 250 ° C. This reaction is carried out in the presence of a copper catalyst such as cupric chloride, cupric bromide, cupric sulfate, cuprous iodine, a mixture of copper and bronze and metal copper, of which copper particles are preferred.

Intermediates of formula (II) can be prepared by known or analogous methods to known compounds.

Formula (I) compounds together with inorganic acids form pharmaceutically toxic acid addition salts. Accordingly, the compounds of the present invention are suitable for inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and tartaric acid, oxalic acid, citric acid, camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, ascorbic acid, valeric acid, succinic acid, formic acid, acetic acid. Reacts with the same organic acid to form pharmaceutically toxic acid addition salts.

Formula (I) compounds and their pharmaceutically harmless salts are used as analgesics or anesthetic drugs. These compounds relieve pain by codeine-like action when administered orally or parenterally.

Moreover, the compounds of the present invention do not decompose chemically to produce compounds with addiction such as dromoran.

Formula (I) compounds and salts may be prepared in pharmaceutical formulations, for example, they may be administered orally or parenterally with adjuvant. Auxiliary materials include organic and inorganic inert carriers such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkylene glycols and the like. Pharmaceutical formulations are in solid form, tablets, suppositories, capsules or liquid forms, ie solutions, suspensions and emulsions. Pharmaceutical aids may be added, including preservatives, stabilizers, wetting agents or emulsifiers or salts that alter or buffer osmotic pressure. Pharmaceutical formulations may contain substances with other therapeutic actions.

The daily dosage of a compound varies depending on the particular new compound used because of the potency of the compound, the method of administration and the size of the container. The dosage is not limited but should be pharmacologically effective. Typical administration of the compound of formula (I) is oral administration. Tablets containing the compound of formula (I) may be administered orally from 0.01 μg to 0.15 μg per kg of body weight per day.

The compound of general formula (I) and salts thereof eliminate pain by analgesic action. This analgesic activity was tested by the standard phenyl quinone writhing test [Sigmund et al., Proc. soc. Exp. Biol. Med. 95, 729 (1957). The compounds of the present invention exhibit an analgesic action in mice that significantly reduce pain and cause chemical pain in the abdomen. ED ₅₀ represents a dose that reduces the number of twists by 50%. When the following compound of formula (1) is used as a test substance, analgesic action is expressed by the following ED ₅₀ when compared with the standard painkiller codeine.

(-)-3-phenoxy-N-methylmorphinantrate-ED ₅₀ 2.0 mg / kg (subcutaneous injection),

(-)-3-p-methyl) -phenoxy-N-methylmorphinan hydrochloride ED _5o 23 mg / kg (subcutaneous injection),

(-)-3-p-methoxy) -phenoxy-N-methylmorphinan hydrochloride ED ₅₀ 2.lmg / kg (subcutaneous injection),

(-)-3-N-phenoxy-N-cyclobutylmethylmorphinan hydrochloride ED ₅₀ l5mg / kg (subcutaneous injection)

(-)-3-phenoxy-N-phenethylmorphinan oxalate ED ₅₀ 2.6 mg / kg (subcutaneous injection),

0.94 mg / kg (subcutaneous injection) of (-)-3-phenoxy-N- [2- (2-furyl) ethyl] morphinan oxalate ED ₅₀ ,

(-)-3-phenoxy-N- [2- (2-thienyl) ethyl] morphinan sulfate ED ₅₀ 9.6 mg / kg (subcutaneous injection),

-플루오로)페녹시-N-메틸모르피난-d-타트레이트 ED₅₀1.85mg(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan-d-tartrate ED ₅₀ 1.85 mg

/ kg (subcutaneous injection),

(-)-3- (0-methoxy) phenoxy-N-cyclopropyl methylmorphinan hydrochloride ED ₅₀ 1.17 mg / kg (subcutaneous injection),

-메톡시)페녹시-N-사이클로프로필 메틸모르피난 염산염 ED_5o1.15mg/kg (피하주사),(-)-3- (

-Methoxy) phenoxy-N-cyclopropyl methylmorphinan hydrochloride ED _5o 1.15 mg / kg (subcutaneous injection),

-메톡시)페녹시-N-메틸모르피난 옥살레이트 ED_5o2.5mg/kg (피 하주사),(-)-3- (

-Methoxy) phenoxy-N-methylmorphinan oxalate ED _5o 2.5 mg / kg (subcutaneous injection),

-메톡시)페녹시-N-메틸모르피난 옥살레이트 ED_5o0.49mg/kg (피 하주사),(-)-3- (

-Methoxy) phenoxy-N-methylmorphinan oxalate ED _5o 0.49 mg / kg (subcutaneous injection),

-하이드록시)페녹시 -N-메틸모르피난 염산염 ED_5o1.3mg/kg (피 하주사),(-)-3- (

-Hydroxy) phenoxy-N-methylmorphinan hydrochloride ED _5o 1.3 mg / kg (subcutaneous injection),

-하이드록시)페녹시-N-에틸모르피난 d-타트레이트 ED_5o9.0mg/kg (피하주사),(-)-3- (

-Hydroxy) phenoxy-N-ethylmorphinan d-tartrate ED _5o 9.0 mg / kg (subcutaneous injection),

-하이드록시)페녹시-N-메틸모르피난 d-타트레이트 ED_5o1.8mg/kg (피하주사),(-)-3- (

-Hydroxy) phenoxy-N-methylmorphinan d-tartrate ED _5o 1.8 mg / kg (subcutaneous injection),

-니트로)페녹시-N-메틸모르피난 염산염 ED_5o2.8mg/kg (피하주사),(-)-3- (

-Nitro) phenoxy-N-methylmorphinan hydrochloride ED _5o 2.8 mg / kg (subcutaneous injection),

-플루오로)페녹시-N-메틸모르피난 염산염 ED_5oI.0mg/kg (피하주사),(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan hydrochloride ED _5o I.0 mg / kg (subcutaneous injection),

-플루오로)페녹시-N-메틸모르피난 옥살레이트 ED_5o3.0mg/kg (피하주사)(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan oxalate ED _5o 3.0 mg / kg (subcutaneous injection)

(-)-3-pentafluorophenoxy-N-methylmorphinan oxalate ED _5o 9.2 mg / kg (subcutaneous injection),

(-) - 3-phenoxy -N- cyclopropyl methyl formate evacuation hydrochloride (17) ED _5o 1.7mg / kg subcutaneous injection) and codeine -ED _5o 3.9mg / kg (subcutaneous injection)

The general formula (I) compound antagonizes morphine analgesic action. This action can be demonstrated by mouse tail hitting tests. This test is used to measure narcotic antagonism. This compound is injected subcutaneously 10 minutes before morphine sulfate. 10 mg / kg of morphine sulfate can be determined as a percentage with response time in the subcutaneous injection test and a substantial increase percentage is used to calculate the percentage of morphine analgesics for the antagonist. Percentage of cancellation is J. pharmacol. Calculated according to Harris and Pearson's formula in Exp Ther., 143: 141, 1964. Among the compounds of the present invention, the following representatives are used as test substances, and the morphine canceling action can be represented by the following ED _5o . (-)-3-phenoxy-N-cyclopropylmethylmorphinan hydrochloride ED _5o 40.28 mg / kg (subcutaneous injection)

The following examples illustrate the invention but do not limit the invention. Temperature is Celsius. The ether used is diethyl ether. Mm used here is mmHg.

Example 1

(-) -3-pentafluorophenoxy-N-methylmorphinan

6.0 g of (-)-3-hydroxy-N-methylmorphinan (0.023 mol), 60 ml of freshly distilled pyridine, 4.8 g of potassium carbonate, 9.0 g of hexafluorobenzene and 6.0 g of copper (particles) in a stainless container Heat at 120 ° C. for 7 days. After cooling, open the vessel and filter the mixture. The filtrate is concentrated under reduced pressure and the residue is partitioned between 700 ml of ether and 5N aqueous sodium hydroxide solution. The ether is removed and the residue is extracted with hexane (200 ml). The residue (5.0 g) obtained from the hexane extract was chromatographed on neutral alumina (75 g) and extracted with methylene chloride, diethyl ether and ethyl acetate. The fractions are collected and the solvent is removed under reduced pressure to give crude (-)-3-pentafluoro phenoxy-N-methylmorphinan. Samples of this compound are distilled off for analysis. Boiling point 150 to 160 ° / 0.1 mm, [α] ₂₅ D-39.69 ° (C 1.21, MeOH).

To 3.6 g (0.01 mol) of the base in 20 ml of diethyl ether is added a solution of 0.8 g of oxalic acid in 20 ml of ether. Crude oxalate was recrystallized from ethyl acetate to give (-)-3-pentafluorophenoxy-N-methylmorphinan oxalate half-hydrate with a melting point of 157 to 160 ° [α] ²⁵ D-24.50 ° (C 1.00, MeOH).

Example 2

(-)-3-phenoxy-N-methylmorphinan

A solution of 10.2 g (0.04 mol) of (-)-3-hydroxy-N-methylmorphinan in 240 ml of freshly distilled pyridine was added to a nitrogen stream with 18.5 g of bromobenzene, 13.8 g of potassium carbonate and 13.0 g of copper (particles). Reflux under stirring for 8 days. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is partitioned between 500 ml of ether and 200 ml of 5N sodium hydroxide. The ether solution is washed with water and dried. The ether is removed and the residue is distilled off to give a boiling point of 180 to 185 ° / 0.1 mmHg (-)-3-phenoxy-N-methylmorphinan. Recrystallization from ether has a melting point of 87 to 88 ° [α] ²⁵ D -60.10 ° (C 1.01, MeOH).

To 10.0 g (0.03 mol) of the base in 50 ml of ether is added a solution of 3.2 g of oxalic acid in 100 ml of ether. Recrystallization of crude oxalate crystals in ethanol gave (-)-3-phenoxy-N-methylmorphinan oxal having a melting point of 184 to 185 ° (d) [α] ²⁵ D-35.47 ° (C 1.00, MeOH). Get rate.

To 7.0 g of base (0.02 mol) in 25 ml of acetone is added with stirring a warm solution of 3.5 g of d-tartaric acid in 75 ml of acetone. The mixture is stirred for 0.5 h at room temperature and again for 4 h at 0 ° to 5 ° C. The tartrate salt is isolated by filtration and recrystallized from ethanol (40 ml) to obtain (-)-3-phenoxy-N-methylmorphinan d-tartrate. 131 to 133 ° [α] ²⁵ D-20.08 ° (C 0.99, MOH).

Example 3

-메틸)페녹시-N-메틸 모르피난(-) -3- (

-Methyl) phenoxy-N-methyl morphinan

-메틸)페녹시-N-메틸모르피난을 얻는다. 이 화합물의 샘플을 에테르에서 재결정하면 융점 94내지 96°, [α]²⁵D-55.98° (C 1.00, MeOH)이다.In 20 ml of freshly distilled pyridine, 5.0 g of (-)-3-hydroxy-N-methylmorphinan (0.019 mol) was added together with 6.4 g of p-bromo-toluene, 4.0 g of potassium carbonate and 0.2 g of copper (particles). It is refluxed under stirring for 9 days under a stream of nitrogen. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is extracted with 200 ml of ether and the ether solution is washed with 100 ml of 2N sodium hydroxide, again with water and dried. The ether is removed and the residue is distilled to give a boiling point of 125 to 140 ° / 0.15 mmHg (-)-3- (

-Methyl) phenoxy-N-methylmorphinan is obtained. Recrystallization of a sample of this compound in ether has a melting point of 94-96 °, [α] ²⁵ D-55.98 ° (C 1.00, MeOH).

-메틸)페녹시-N-메틸모르피난 염산염을 얻는데 융점 223내지 224°, [α]²⁵D-37.85°(C 0.69, MeOH)이다.Treatment of 3.3 g (0.01 mol) of the base with hydrogen chloride (anhydrous) in ethyl acetate (5 ml) yielded 3.3 g of crude hydrochloride. Recrystallization from ethyl acetate gives (-)-3- (

It has a melting point of 223 to 224 °, [α] ²⁵ D-37.85 ° (C 0.69, MeOH) to obtain -methyl) phenoxy-N-methylmorphinan hydrochloride.

Example 4

-메톡시)페녹시-N -메틸모르피난(-) -3- (

-Methoxy) phenoxy-N-methylmorphinan

-브로모아니솔 7.5g, 탄산칼륨 4.01g 및 구리(입자) 0.2g과 함께 질소 기류하에서 7일동안 교반하면서 환류시킨다. 혼합물을 여과하고 여액을 감압하에서 농축시킨다. 잔사를 에테르 400ml와 10N 수산화나트륨 100ml사이에 분배시킨다. 에테르 응액을 물로 세척하고 건조시킨다. 에테르를 제거하고 잔사를 증류시켜서 비점 139내지 155°/0.15mmHg인 (-)-3-(P-메톡시)페녹시-N-메틸모르피난을 얻는다. 이 화합물을 에테르에서 재결정시켜서 융점 130내지 132°[α]²⁵D- 51.59° (C 0.99, MeOH)인 순수한 생성물을 얻는다.A solution of 5.1 g of (-)-3-hydroxy-N-methylmorphinan (0.02 mol) in 20 ml of freshly distilled pyridine

Reflux with 7.5 g bromoanisole, 4.01 g potassium carbonate and 0.2 g copper (particles) with stirring for 7 days under a stream of nitrogen. The mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is partitioned between 400 ml of ether and 100 ml of 10N sodium hydroxide. The ether coagulum is washed with water and dried. The ether is removed and the residue is distilled to give (-)-3- (P-methoxy) phenoxy-N-methylmorphinan having a boiling point of 139 to 155 ° / 0.15 mmHg. This compound is recrystallized in ether to give a pure product having a melting point of 130 to 132 ° [α] ²⁵ D- 51.59 ° (C 0.99, MeOH).

]²⁵D-34.22° (C 0.99, MeOH)인 (-)-3-(P-메톡시)페녹시-N-메틸모르피난 염산염을 얻는다.2.0 g (0.006 mole) of the product was treated with anhydrous hydrogen chloride in ethyl acetate to obtain crude hydrochloride crystals. When recrystallized from ethyl acetate, the melting point was 170 to 172 °, [

²⁵ -(-)-3- (P-methoxy) phenoxy-N-methylmorphinan hydrochloride which is D-34.22 ° (C 0.99, MeOH).

Example 5

-메톡시)페녹시-N-메틸모르피난(-)-3- (

-Methoxy) phenoxy-N-methylmorphinan

-메톡시)페녹시-N-메틸모르피난을 얻는다. 분석용으로, 이 화합물의 샘플을 에테르에서 재결정하면 융점 88내지 90°[α]²⁵D-61.81°(C 1.00, MeOH)이다.A solution of 5.1 g of (-)-3-hydroxy-N-methylmorphinan (0.02 mol) in 20 ml of freshly distilled pyridine, together with 7.5 g of m-bromoanisole, 4.1 g of potassium carbonate and 0.2 g of copper (particles) It is refluxed under stirring for 10 days under a stream of nitrogen. The reaction mixture is filtered by adding ether (double volume). The filtrate is concentrated under reduced pressure to decompose the residue between ether and 5N sodium hydroxide. The ether solution is washed with water and dried. The ether is removed and the residue is distilled to give (-)-3- (boiling point of 145 to 160 ° / 0.1 mmHg.

-Methoxy) phenoxy-N-methylmorphinan is obtained. For analysis, a sample of this compound is recrystallized from ether at melting point 88-90 ° [α] ²⁵ D-61.81 ° (C 1.00, MeOH).

-메톡시)페녹시-N-메틸모르피난 옥살레이트를 얻는다.To 1.5 g of the above product (0.004 mol) in ether is added 0.4 g solution of oxalic acid in ether. Crude oxalate was recrystallized from ethanol-ether to give a melting point of 148 to 150 ° [α] ²⁵ D-39.60 ° (C 1.00, MeOH) (-)-3- (

-Methoxy) phenoxy-N-methylmorphinan oxalate is obtained.

Example 6

-메톡시)페녹시-N-메틸모르피난(-)-3- (

-Methoxy) phenoxy-N-methylmorphinan

(-)-3-hydroxy-N-methylmorphinan (0.02 mol) in 20 ml of freshly distilled pyridine. Reflux with 5.0 g for 3 days. The mixture is filtered and the filtrate is filtered under reduced pressure. The residue is partitioned between ether and 5N sodium hydroxide. The ether solution is washed with water and dried. After the solvent was removed, the residue was distilled off so that the boiling point was 165 ° / 0.2mmHg.

Obtain 3- (0-methoxy) phenoxy-N-methylmorphinan. Recrystallized samples of this compound for analysis in ethyl acetate have a melting point of 87-89 ° [α] ²⁵ D-59.32 °. (C 1.16, MeOH).

-메톡시) -페녹시-N-메틸모르피난 옥살레이트를 얻는다.To 2.7 g of the product (0.01 mol) in ether is added 0.7 g solution of oxalic acid in ether. Melting point by re-crystallization from ether 185 to 187 ° (d) [α] 25 D-37.19 ° (C 0.99, MeOH) in-crude ethanol oxalate (-) - 3- (

-Methoxy) -phenoxy-N-methylmorphinan oxalate is obtained.

Example 7

-니트로)페녹시-N-메틸모르피난(-)-3- (

-Nitro) phenoxy-N-methylmorphinan

A solution of (-)-3-hydroxy-N-methylmorphinan (0.02 mol) in 30 ml of freshly distilled pyridine was 1.00 g of 1-bromo-2-nitrobenzene, 6.0 g of potassium carbonate, and 0.3 g of copper (particles). And reflux with stirring under nitrogen stream for 3 days. The mixture is filtered, the filtrate is concentrated under reduced pressure and partitioned between residue 릍 ether and 5N sodium hydroxide. The ether solution is washed with water and dried to remove the ether and the residue is redistributed between chloroform and 5N sodium hydroxide. After removal of chloroform in vacuo, the residue was crystallized from ether to give (-)-3- (0-nitro) phenoxy-N-methylmor having a melting point of 158 to 160 ° [α] ²⁵ D-53.16 ° (C 0.99, MeOH). Evacuation is obtained.

]²⁵D-32.62°(C 0.99, MeOH)인 (-)-3-(

-니트로)페녹시-N-메틸모르피난 염산염 1/2수화물이 수득된다.2.0 g of the product (0.005 mol) was treated with anhydrous hydrogen chloride in ethyl acetate to give crude hydrochloride, which was determined at ethyl acetate to have a melting point of 155 to 157 ° (d), [

] ^25- (-)-3- (C 0.99, MeOH)

-Nitro) phenoxy-N-methylmorphinan hydrochloride half hydrate is obtained.

Example 8

-플루오로)페녹시-N-메틸모르피난(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan

-플루오로-브로모벤젠 17.0g, 탄산칼륨 4.1g 및 구리(입자) 0.2g와 함께 5일동안 교반하면서 환류시킨다. 반응혼합물에, 에테르(2배용량)을 가하고 여과시킨다. 여액을 진공에서 농축시키고 잔사를 뜨거운 헥산 150ml중에 현탁시켜서 여과시킨다. 여액을 5N수산화나트륨으로 세척한 뒤 물로 세척하고 건조시킨다. 용매를 제거하고, 잔사를 헥산에서 결정시켜서 융점 102내지 104° [

]²⁵D-53.36°(C 1.00, MeOH)인 (-)-3-(

-플루오로)페녹시-N-메틸모르피난을 수득한다.A solution of 5.1 g of (-)-3-hydroxy-N-methylmorphinan (0.02 mol) in 20 ml of freshly distilled pyridine was placed under nitrogen stream.

Reflux with 17.0 g of fluoro-bromobenzene, 4.1 g of potassium carbonate and 0.2 g of copper (particles) with stirring for 5 days. To the reaction mixture is added ether (double volume) and filtered. The filtrate is concentrated in vacuo and the residue is filtered by suspending in 150 ml of hot hexane. The filtrate is washed with 5N sodium hydroxide, followed by water and dried. The solvent is removed and the residue is crystallized from hexane to give a melting point of 102 to 104 ° [

(-)-3- ( ²⁵ D-53.36 ° (C 1.00, MeOH)

-Fluoro) phenoxy-N-methylmorphinan is obtained.

]²⁵D-34.83° (C 0.98, MeOH)인 (-)-3-(

-플루오로)페녹시-N-메틸모르피난 염산염 1/2수화물을 얻는다.4.0 g of the product (0.01 mol) are treated with anhydrous hydrogen chloride in ethyl acetate to produce crude hydrochloride. Recrystallized from ethyl acetate, melting point 162 to 164 ° [

(-)-3- (C at ²⁵ D-34.83 ° (C 0.98, MeOH)

-Fluoro) phenoxy-N-methylmorphinan hydrochloride half hydrate is obtained.

Example 9

-플루오로)페녹시-N-메틸모르피난(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan

-플루오로)페녹시-N-메틸모르피난을 생성시킨다. 분석용으로 화합물의 샘플을 에테르에서 결정시키면 융점이 113내지 115°[

]²⁵D-48.67°(C 0.95, MeOH)이다.A solution of 2.0 g of (-)-3-hydroxy-N-methylmorphinan (0.007 mol) in 10 ml of freshly distilled pyridine was added under a stream of nitrogen to 3.5 g of 0-fluoro-bromobenzene, 2.0 g of potassium carbonate and copper ( Particles) and reflux with stirring for 2 days. To the reaction mixture is added ether (double volume) and filtered. The filtrate is concentrated in vacuo, the residue is treated with ether (200 ml) and washed with 5N sodium hydroxide. The ether solution is washed with water and dried. Remove the ether to give crude (-)-3- (

-Fluoro) phenoxy-N-methylmorphinan is produced. For analysis, a sample of the compound was determined in ether and the melting point was 113 to 115 ° [

²⁵ D-48.67 ° (C 0.95, MeOH).

]²⁵D-30.98°(C 1.00, MeOH)인 (-)-3-(

-플루오로)페녹시-N-메틸모르피난옥살레이트를 생성시킨다.To 2.5 g of the product (0.007 mole) in ether is added 0.7 g solution of oxalic acid in ether (25 ml). Recrystallization of crude oxalate from ethanol has a melting point of 180 to 182 ° [

(-)-3- (C at ²⁵ D-30.98 ° (C 1.00, MeOH)

-Fluoro) phenoxy-N-methylmorphinanoxalate is produced.

Example 10

-플루오로)페녹시-N-메틸모르피난(-)-3- (

-Fluoro) phenoxy-N-methylmorphinan

]²⁵D=-56.79°, (C 1.04, MeOH)인 (-)-3-(

-플루오로)페녹시-N-메틸모르피난이 생긴다.A mixture of 3.0 g of (-)-3-hydroxy-N-methylmorphinan (0.011 mol), 2.2 g of 3-bromofluorobenzene, 2.4 g of potassium carbonate and 3.0 g of copper (particles) in 50 ml of freshly distilled pyridine Heated to 120 ° C. in a stainless steel container for 8 days. After cooling, the vessel is obtained and the mixture is filtered. The filtrate is concentrated under reduced pressure and the residue is partitioned between ether and 10N sodium hydroxide. The ether solution is washed with water and dried. Removal of the solvent in vacuo gives a dark residue, which is distilled off to a boiling point of 131 to 140 ° (0.15 mmHg) [

] (-)-3- (with ²⁵ D = -56.79 °, (C 1.04, MeOH)

-Fluoro) phenoxy-N-methylmorphinan is produced.

]²⁵D-18.61°(C 1.03, MeOH)인 (-)-3-(

-플루오로)페녹시-N-메틸모르피난 d-타트레이트 1/2수화물을 수득한다.0.2 g of d-tartar solution dissolved in 10 ml of acetone is added to a solution of 0.4 g (0.001 mol) of the base in 2 ml of acetone. Recrystallization of zotarate from acetone, melting point 121-123 DEG C, [

] Of ^{25 D-18.61 ° (C 1.03} , MeOH) (-) - 3- (

-Fluoro) phenoxy-N-methylmorphinan d-tartrate half-hydrate is obtained.

Example 11

Tablets are formulated as follows.

Way

(1) Paragraphs 1,2,3,4 and 5 are mixed in a suitable mixer and granulated with water. Dry overnight in the oven. Grind through Pitts Patrick Mill.

(2) Mix with Paragraph 6 and tablet on a suitable compressor.

Example 12

Tablets are formulated as follows.

Way

(1) Paragraphs 1,2,3,4 and 5 are mixed for 10 to 15 minutes in a suitable mixer.

(2) Magnesium stearate (paragraph 6) is added to the premix and mixed for 4 minutes. Tablet on a suitable compressor.

Example 13

Capsule composition

Way

(1) Paragraphs 1,2 and 3 are mixed in a suitable mixer. Crush through a suitable base. (2) Mix with 4 and 5 and fill on capsule machine.

Example 14

Capsules are formulated as follows.

Way

(1) Paragraphs 1,2 and 3 are mixed in a suitable mixer. Crush through a suitable base. (2) Mix with 4 and 5 and fill in capsule machine.

Example 15

-메틸)페녹시-N-메틸모르피난인 것을 제외하고는 실시예 14의 방법으로 조성된다.Capsule is a component (-)-(

Except for -Methyl) phenoxy-N-methylmorphinan, it was prepared by the method of Example 14.

Example 16

Tablets are formulated by wet granulation as follows.

Way

(1) Paragraphs 1 to 4 are mixed in a suitable mixer.

(2) Sufficient distilled water is added and granulated at an appropriate density. Crush.

(3) Dry in a suitable oven.

(4) Grind and mix with magnesium stearate for 3 minutes.

(5) Tableting on a suitable compressor equipped with a suitable punch.

Example 17

Tablets (wet granulation) are prescribed as follows.

Way

1. Mix items 1 to 4 in a suitable mixer.

2. Add enough distilled water to make proper density. Crush.

3. Dry in a suitable oven;

4. Grind and mix with magnesium stearate for 3 minutes.

5. Tablet on a suitable compressor equipped with a suitable punch.

Claims (1)

The following compound of formula (II) is reacted with a compound of formula (III) to form a phenomena of 3-phenoxy-N-substituted morphinane derivatives of the general formula (I) How to manufacture.

In the above formula R is halogen, nitro, lower alkyl, lower alkoxy, hydroxy or hydrogen R ₁ is hydrogen, lower alkyl, lower alkenyl, —CH ₂ (CH ₂ ) PR ₂ or

Where R ₂ is heteroaromaticalkyl, aromatic alkyl or cyclic lower alkyl and P is an integer from 0 to 3 n is an integer from 1 to 5 X is halogen.