DE1938219A1 - Process for the preparation of 14-hydroxy-normorphinone derivatives - Google Patents

Description

Dlpk-lng. Kari Kiekeben Patent attorney ! •• rift 10,

July 24, 1969 P.5017

Sankyo Company, Limited Tokyo (Japan).

in

Process for the preparation of 14-hydroxy-normorphinone derivatives.

The invention relates to a new process for the preparation of 14-hydroxy-normorphinone derivatives. In particular, it relates to a new process for the preparation of 14-hydroxy-normorphinone derivatives formula

OH

(I)

where R _x and Rp can be the same or different and each represent a lower alkyl group, an allyl group or an aralkyl

pose a group.

909887/1711

So far it is known that 14-hydroxy-codeinone is produced by subjecting thebaine, which is obtained from natural products, to oxidation. Thebain can, however only obtained in small quantities from natural products » will.

The process for preparing 14-hydroxy-codeinone from codinone has been described in Journal of American Chemical Society, Volume 89, page 1942 (1967) and in Chemistry of the Morphine Alkaloids, Oxford London, 1954, page 251. According to that in these publications 14-hydroxy-codeinone is produced by reducing codeinone to obtain dihydro-codeinone, by reacting the latter compound with dimethyl sulfate in the presence of an alkali to obtain dihydrocodeinone-enol methyl ether, by reacting the latter compound with methyl hypobromite, to obtain 7-bromo dihydrocodeinone dimethyl ketal by reacting the latter compound with pyridine to obtain codeinone dimethyl ketal by reacting the latter compound with phosphorus trichloride to obtain thebaine with subsequent oxidation of the latter compound. However, this process is unsuitable for economic purposes because it requires a large number of process steps and the overall yield is only about 20 % .

It is therefore an object of the present invention to. to show a new process for the preparation of 14-hydroxy-normorphinone derivatives from a normorphinone derivative which is derived from codeine, which can be obtained in large quantities from natural products, by a small number of process steps and with good yield.,. , i ^ y '.: ■ ' - '' - ■ '■■■■■> ■ ";

As a result of investigations, it has now been found that 14-hydroxy-normorphinone derivatives a _ei? above, -, α ~. ■ -. Formula (I) can be prepared by a process which comprises (a) heating a normorphinone derivative of Formula

- 3 - 909887/1711

NO,

(II)

wherein R ^ and Rp have the meaning described above, with Pyrrolidine in a molar ratio of 1: 1 in the presence of an aprotic solvent to form a normorphinone pyrrolidinyl enamine the formula

(III)

to produce, wherein R ^, and I? 2 have the meaning described above and the oxidation of the latter compound, or (b) the reaction of a normorphinone derivative of the above Formula (II) with an alcohol of the formula

R _Z OH y

(IV)

wherein R ', * is a lower alkyl group or an alkoxyalkyl group represents, in the presence of an aprotic solvent Tö'ünd an aromatic sulfonic acid to produce a Normorphihoh-enolftther of the formula

9 0 9 8 8 7/1711

(ν)

to produce, wherein R ^, R ₂ and R, have the meaning described above, and the oxidation of the latter compound.

In the above formulas, the lower alkyl group can be a straight or branched chain alkyl group, such as Methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl and the same.

An example of the aralkyl group is the phenylalkyl group, such as benzyl or phenethyl.

Examples of the alkoxyalkyl group are methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like. All 14-hydroxy-normorphinone derivatives of formula (I) are useful as intermediate products for the synthesis of the known 14-hydroxymorphinone derivatives, such as N-phenethyl-14-hydroxydihydro-normorphinone, 14-hydroxy-dihydro-morphinone, N-allyl-14-hydroxy-dihydro-normorphinone Or 14-hydroxy-dihydro-6ß-thebainol-4-methyl ether, which are known as analgesic morphine antagonists and antitussives (Textbook of Organic Medicinal and Pharmaceutical Chemistry, 4th Ed. (1966), p. 662). For example, N-phenethyl-14-hydroxydihydro-normorphinone is used produced by N-phenethyl-14-hydroxy-normorphinon subject to catalytic reduction.

According to the present invention, the 14 ^ -hydroxynormorphinone derivatives can be prepared in only two steps and the total yield is about 20 to 40 % _f, so that the process of the present invention is suitable as a commercial process.

- 5 - 909887/1711

When carrying out the step for the preparation of the compound (III) from the compound (II) of the invention In the process, the reaction can preferably be carried out by heating the compound (II) with pyrrolidine in a molar ratio of 1: 1 in the presence of an aprotic solvent.

The use of more than one mole of pyrrolidine per mole of said compound (II) in this stage is not desirable because of the formation of 7-pyrrolidine dihydronormorphinone.

As the aprotic solvent, any organic solvent other than none can be used satisfactorily Has protons. It is advisable to use an organic solvent which forms an azeotropic mixture with water, to use, for example a hydrocarbon such as benzene or toluene, halogenated hydrocarbons such as Methylene chloride, chloroform or carbon tetrachloride.

The reaction temperature is generally above room temperature and is preferably about 60 to 80 ^° C. The removal of the water generated in the reaction by azeotropy results in a shortening of the reaction time and an improvement in the yield.

It is advantageous to carry out the reaction at the reflux temperature of an aprotic solvent which boils at about 60 to 80 ⁰ C while the water formed in the reaction by azeotropy is removed. The reaction time is usually from about 1 hour to 3 hours.

It has been found that the addition of a catalytic amount of an aromatic sulfonic acid, ie p-toluenesulfonic acid or benzenesulfonic acid, the reaction of this stage is accelerated favorably.

After the reaction has ended, the desired product (III) can easily be obtained from the reaction mixture by one of the customary methods. For example, will

909887/1711

1933219

the reaction mixture washed with water and dried over anhydrous Dried sodium sulfate.

If an aromatic sulfonic acid is used as a catalyst, the reaction mixture is vepdünaten with a aqueous alkali solution and water, and dried over anhydrous sodium sulfate.

The dried reaction mixture is concentrated after it was decolorized with activated charcoal or active aluminum oxide, and then the solvent was distilled off.

If desired, the crude product thus obtained can be obtained by recrystallization from a suitable solvent, v / ie isopropanol. The reaction is carried out in quantitative yields and does not produce any Byproducts. Therefore, "the crude product can be used in the next step without further purification.

In carrying out the step for producing the compound (I) from the compound (III) of the present invention In the process, the reaction can preferably be carried out by subjecting the compound (III) to oxidation in the presence subjected to a solvent.

The oxidation is carried out by using an oxidizing agent such as hydrogen peroxide, chromic acid, Potassium permanganate or an organic peracid, for example peracetic acid or perbenzoic acid. Most convenient is a 30 # aqueous hydrogen peroxide solution used. An acid can be used satisfactorily as a solvent, for example phosphoric acid, Formic acid, acetic acid, halogenated acetic acid such as chloroacetic acid, and an organic solvent such as Acetone.

It is advantageous to carry out the reaction of this stage in the presence of as little water as possible, because this good yields can be obtained. The reaction temperature in this stage is not critical, but it is useful to carry out the reaction at a temperature of about 40 to 60.degree. The reaction time is also not

^iiv; 90 98 8 7/1711 ~ ⁷ ""

critical, and it may vary depending on the Type of solvent used in the reaction.

Generally "the reaction time is from about 30 minutes to 2 hours.

After the reaction has ended, the desired product (I) can be obtained from the reaction mixture by one of the customary Methods are obtained. For example, the reaction mixture is diluted with water and with an aqueous ammonia solution made alkaline. The alkaline mixture is extracted with a suitable solvent such as chloroform, and the extract is washed with water and poured over water- (( dried free sodium sulfate. The extraction solvent is then distilled off. If desired, the thus obtained crude product can be purified by washing with ethanol or recrystallization from ethanol.

When performing the stage for making the Compound (V) from the compound (IT) of the invention Procedure, the reaction can be carried out preferentially by reaction of the compound (II) with the compound (IV) in the presence of an aprotic solvent and an aromatic sulfonic acid.

In this step, the same aprotic solvent and the same aromatic sulfonic acid can be used, such as those which the above-mentioned t at stage \ for the preparation of the compound (III) from the compound ^l (II) were used. It is appropriate to use more than one mole of the alcohol compound (IV) per mole of the aforementioned normorphinone (II) at this stage. ;

The reaction temperature is suitably more than> about 60 ⁰ C. It is convenient to conduct the reaction under a reflux temperature of an aprotic solvent which boils at 60 to 80 * C ⁰ perform.

The removal of the reaction by azeotropy ^■: water produced results in a shortening of the reaction time and better yields.

909887/1711 BAD ORIGINAL

"* ■ ö ■"

The reaction time is usually from about 3 hours to 15 hours.

After the reaction has ended, the desired product (V) can be removed from the reaction equipment by one of the customary Methods are easily obtained. For example, the reaction mixture by adding an aqueous alkali solution, such as aqueous sodium hydroxide, neutralized with ice cooling and the organic phase separated. The organic Phase is washed with water, and the desired product is dissolved in a dilute aqueous acetic acid extracted. The extract is made with hydroxylamine hydrochloride treated to convert a by-product (keto compound) which contaminates the extract into the corresponding oxime compound convict. The extract obtained is made strongly alkaline, if necessary after decolorization with activated charcoal by adding a concentrated aqueous caustic alkali solution and extracted with benzene. The benzene extract is washed with water, dried over anhydrous sodium sulfate, and then the solvent is distilled off. Of the The residue is recrystallized from a suitable solvent such as ethanol and, if desired, with the aid purified by chromatography. _

When performing the stage for making the. Compound (I) from the compound (V) of the process of the present invention can preferentially carry out the reaction _: in the same manner as that in the above-mentioned step for the preparation of the compound (I) from the compound (III).

The presence of water is advisable at this stage, because this allows easy control of the dxothermal reaction.

The compounds of formula (II) in which both R ^. as well as R _{2 represent} the groups given above, with the exception of the methyl group, are new and can be made by a known method hp-r », for example by

- 9 909887/1711

Normorphinone of alkylation, or benzylation Subjects to aralkylation.

The invention is illustrated by the following examples, but is not restricted to them.

example 1 14-Hydroxy-codeinone

(1) -1 To a solution of 1.5 g codeinone in 20 ml benzene | 0.5 ml of pyrrolidine was added. The resulting mixture was refluxed for 1.5 hours, during which time the water produced by the means of formation of a azeotropic mixture was distilled off with benzene.

After the completion of the reaction, the reaction mixture was cooled, washed twice with water and over dried anhydrous sodium sulfate. The reaction solvent was distilled off, leaving an oily orange color Received residue.

The residue dissolved in benzene was chromatographed through a column charged with 30 g of active alumina and eluted with benzene. >

The eluates were collected and the solvent was distilled off. The residue was washed with isopropanol and recrystallized from isopropanol to give 2.0 g of pale yellow crystals of codeinone-pyrrolidinyl-enamine obtained, the melt-in 126'bis 128 ⁰ C. Analysis values ·.

Calculated for C ₂₂ H ₂₆ N ₂ O ₂ : C = 75.40 #; H = 7, W; N = 7.99 # Found: C = 75.14 #; H = 7.74 #; N = 7.9O #

IH (Nudol) x V _c = ^c 6.35 / fc

UV: X ethyl alcohol ^ _{(£ = 8} ^ ₀₎

max - '

- 10 -909887/1711

(Ό-2 To a solution of 9 g of codeinone in 80 ml of benzene were 3 ml of pyrrolidine and 0.3 g of p-toluenesulfonic acid monohydrate added. The resulting mixture was refluxed for 1.5 hours, during which time. the water produced is distilled off by azeotropic with benzene became. After completion of the reaction, the reaction mixture was cooled, with two portions of 15 ml a 10 # aqueous sodium carbonate solution and then washed with two 20 ml portions of water and dried over anhydrous sodium sulfate.

The dried mixture was treated in the same manner as in (1) -1 above to obtain 9.8 g of codeinone pyrrolidinyl enamine received.

(2) 1 ml of a 30% aqueous hydrogen peroxide solution was added to a solution of 2.5 g of codeinone pyrrolidinylenamine in 5 »5 ml of 98% aqueous formic acid. The temperature of the mixture rose to about 46 C and then slowly fell to room temperature. After about 50 minutes, the reaction mixture was diluted with 20 ml of ice water, ^{cooled to 0 °} C. and neutralized by adding anhydrous sodium carbonate. The mixture was made alkaline by adding ammonia and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue was washed with methanol, giving 0.35 g of crystals of 14-hydroxy-codeinone, which melts at 270 to 275 ° C. The product thus obtained was identified with an authentic sample by means of the mixed melting point and the infrared spectrum.

- 11 -

90 9887/1711

Example 2 14-Hydroxy-benzylmorphinone -

(1) To a solution of 2.0 g of benzylmorphinone in 60 ml of benzene, 0.56 ml of pyrrolidine and 0.08 g of p-toluenesulfonic acid monohydrate were added. The resulting mixture was refluxed for 1.5 hours, during which time the water generated was distilled off by forming an azeotropic mixture with benzene. After the completion of the reaction, the reaction mixture was treated in the same manner as in Example 1 (1) -2 above to obtain 1.85 U of benzylmorphinone-pyrrolidinyl-enamine as a yellow oil.
Analysis values:

Calculated for C ₂₈ H ₅₀ N 1 O ₂ : C = 78.84 $; H = 7.09 #; N = 6.57 # Found: C = 78.95 #; H = 7.17 #; N = 6

IR (NUjOl): I) ₀ = C '6,? =. / *

UV: - ^ ethyl alcohol ^. _{nÄ (} 9375)

max ^y

By the same procedure as in Example 2 (1), the following normorphinone-pyrrolidinyl-enamine compounds were obtained Obtained with good yields from the corresponding Normorphinone derivatives. "

N-phenethyl-norcodeinön-pyrrölidinyl-ehamin

^; . - ^ - '■ Melting point 153.5 to 155.5 ° C.' Allylmorphinon-pyrrolidinyl-enamine

■ · " - ^x: ' ■" ■ "" ■ pale red oil

UV: X ethyl alcohol ^ ₅

Max
K-Allyl-norcodeinone-pyrrolidinyl-enamine

pale orange oil

IR (Nuüol): l ^ _c = C 6.5 / 1 UV: X ethyl alcohol 909887/1711 T

SAD ORIGINAL

(2) To a solution of 1.6 g of benzylmorphonon-pyrrolidinyl-enamine in 3j2 ml of a 98 # aqueous formic acid solution were 0.6 ml of a 30 # aqueous hydrogen peroxide solution added. The resulting mixture was allowed to stand at room temperature for about 1 hour. After completion the reaction, the reaction mixture was treated in the same manner as in the above Example 1 (2), 0.5 g of crystals of 14-hydroxy-benzylmorphinone, which melts at 244 to 245 ° C., were obtained. Analysis values:

Calculated for C ₂₄ H ₂₃ NO ₄ : C = 74.02 #; H = 5.95 #; N = 3.60 # Found: C = 73.62 #; H = 6.41%; N = 3.58 #

By the same procedure as in Example 2 (2), the following 14-hydroxy-normorphinone derivatives were obtained from the corresponding normorphinon-pyrrolidinyl-enamine produced in good yields.

14-Hydroxy-N-phenethyl norcodeinone tartrate

Melting point 198 ⁰ C (with decomposition)

14-hydroxy-allylmorphinone

Melting point 222-22 ⁰ $ C

14-Hydroxy-N-allyl-norcodeinone

Melting point 133-135 ° C

Example 3

14-hydroxy-ethy-morphinone

(1) To a solution of 4.5 g of codeinone in 60 ml of benzene were 2.0 ml of pyrrolidine and 0.2 g of p-toluenesulfonic acid added. The resulting mixture was refluxed for 1.5 hours, during which time the water generated was distilled off by forming an azeotropic mixture with benzene. After the reaction was over, it became

90 9887/1711 - 13 -

Reaction solvent is distilled off, 3 * 3 g of an oily crude ethylmorphinone-pyrrolidinyl-enamine received,.

IR (Nujol): y _c = C

ÜVi ■) ethyl alcohol ₃₃₅

^ max ⁷

(2) To a solution of 3J3 g of the crude Äthylmorphinonpyrrolidihyl enamine in 7> 8 nil a 98 #igen aqueous Ämeisensäurelösung were 1 ^ $ 4 ml of 30 $ aqueous hydrogen peroxide solution added, and the resulting ¹ mixture would be about 1 hour at room temperature ditched. After the end of the reaction, the reaction mixture would be treated in the same way as in the above example Ϊ (2) * whereby 1 _f 0 g of crystals of 14-hydroxyethylmorphine were often obtained, at 236 to 23? ° Ö melts, analysis valuesί

Reconciled for Ö ^ gH ^ NÖ ^ i 0 = 69.70 ^ 5 H = 6.47 ^; Ν = 4 found.: 0 ^ 69 ^ 84 ^; H = S, 37 ^ 5 Ν = 4

Follow the same procedure as Ift. Example 3 (1) and (2) the following wilideü ⁱ 14-Hydröxy-normörphinondex ^f iVäte auö the approaches speaking Wormorphinonderivaten with good yields "

Melting point 218 to 219 ° Ö 14 ^ Hydröxy «n * isöpröpylfflorphinön

Öchifielzpunkt 237 to 239 ⁰ C *

Example 4

14 ^ hydroxy "benzylmorphinone
(1) A mixture of 3.3 g of p-iolüoläülfonsäure-monohydrate

00.8-807 / 171.1 ■ " ¹

and 160 ml of benzene was heated Λ $ reflux for 5 hours, to complete the water through the formation of a azeotr.open mixture; to remove"

After the mixture obtained had cooled, 4-0 ml of n-propanol and 8 g of benzylmorphinone were dissolved therein.

The resulting mixture was refluxed for 3> 5 hours heated, during which time the produced water was distilled off *

After the completion of the reaction, the reaction mixture was cooled mixed with bis and washed twice with a mixture of 5 ml of a 30% aqueous sodium hydroxide solution and 25 ml of water, washed twice with water and then extracted with 10% aqueous acetic acid. After the extract was washed with benzene is rooted * were 0.5 g of hydroxylamine hydro-chloride added to the extract and heated for 10 minutes 50 to 60 G ^0, the keto compound which contaminates the extract, into the corresponding oxime compound to convert.

The extract was decolorized with activated charcoal, the pH up above 12.0 by adding a 30% aqueous solution Sodium hydroxide solution adjusted and extracted with benzene » The benzene extract was washed with water, dried over anhydrous sodium sulfate and the solvent was removed

Of? The residue was dissolved in a small amount of benzene and adsorbed on an aluminum oxide column. The pillar was eluted with benzene. The benzene eluate was collected and the "solvent is distilled off *

The * residue was dissolved in a mixture of 20 ml of ethanol and 1 ml of water. To the solution, 1 g of tartaric acid was added with shaking to give 1 g ^ 4- Benzylmorphinon-eflol-n-propyläthertartrat as crystals, melting at 118-123 ⁰ C (with decomposition).

- 15 - BAD ORIGINAL

909887/1711

Analysis values:

Calculated for C ^ H _currently -NO _Q · 1.5 H ₀ O

31 35 9 2

C = 62.83 ^;
Found C = 62.95 #; H = 6.48%; N = 2.23 #

By the same procedure as in Example 4 (1), the following normorphinone enol ethers were obtained from the respective ones Normorphinone derivatives prepared in good yields.

Codeinone enol n-butyl ether

Melting point IO3 to 104 ⁰ C ' _and much more. \ Ethyl alcohol ^ _{(<f = 8228)} ^ max, '

Codeinone enol n-propyl ether

Melting point 155.5 to 156.6 ⁰ C

UV: I ethyl alcohol _{2QQ m} " ( _£ , ₇₈₇ 0)

iilBX

Codeinone enol ethyl ether

Melting point 123 to 124 ^W C UV: ^ ethyl alcohol _{285 m} ^ _{ r _{β? 819)} ^JX max ^J

Codeinori enol isopropyl ether

Melting point 131 to 132 ^° C

UV

Max

Codeinone-2-methoxyethyl ether

: \ _Ethyl alcohol 2Q6 ~ ^ _{= 811Q)}

Melting point 140 to 142 ⁰ g

: \ Ethyl alcohol _2m ^J \ max '

UV

1 1

Max

, (2) To a solution of 2.9 g of benzylmorphinone-enol-n-propyl ether tartrate in a mixture of 1.75 oil of an 85 # aqueous formic acid solution and 2.5 ml of water became 0.7 ml added to a 30 # aqueous hydrogen peroxide solution.

- 16 909887/1711

The mixture obtained was left to stand at 50 ^° C. for 1.5 hours. After the completion of the reaction, ice water was added to the reaction mixture, and the mixture was made alkaline by adding an aqueous ammonia solution and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off. The pale-brown residue was washed with methanol to obtain 1.7 g of 14-hydroxy-benzylmorphinon as crystals, melting at 244 to 24-5 ^0C.
Analysis values;

Calculated for C ₂₄ H ₂₅ NO ₄ : C = 74-02 #; H = 5.95 #; N = 3.60 # Found: C = 73.62 #; H = 6.4-1 #; N = 3.58 #.

Using the same procedure as in Example 4- (2), 14-hydroxy-codeinone was obtained from codeinone-enol-n-butyl ether, Codeinon-enol-n-propylether, Codeinon-enol-ethylether, Codeinone enol isopropyl ether and codeinone 2-methoxyethyl ether produced with good yields.

Claims;

- 17 909887/1711

Claims (5)

Godparent throws 1. Process for the preparation of 14-hydroxy-normorphinone derivatives the formula OH where R ^ and R _? may be the same or different and each represent a lower alkyl group, an allyl group or an aralkyl group, characterized by (a) the heating of a Normörphinonderivates of the formula H - where R ^, and have the meaning described above »with pyrrolidine in a molar ratio of 1; 1 in the present an aprotic solvent to form a normorphinone pyrrolidinyl enamine the formula 90 9 8 87/1711 .- 18 - - R, produce, wherein R _x , and R _{2 has} the meaning described above, and by oxidation of the latter compound, or (b) the reaction of the normorphinone derivative with an alcohol of the formula R ₂ OH wherein R, a lower alkyl group or an alkoxyalkyl-. group represents, in the presence of an aprotic solvent and an aromatic sulfonic acid, to a Normorphinone enol ether of the formula MR, to produce, wherein R ^, Rp and R ₁ , have the meaning described above, and the oxidation of the latter compound. 2. The method according to claim 1, characterized in that the aprotic solvent used is benzene. 909887/171 1 - 19 BAD ORIGINAL 3. The method according to claim 1, characterized in that that the aromatic sulfonic acid used is p-toluenesulfonic acid is. 4-. Method according to claim 1, characterized in that that the oxidation stage is carried out using hydrogen peroxide. 5. Process for the preparation of 14-hydroxy-normorphinone derivatives the formula MR ₂ where R. * and R _{2 can be} identical or different and each represent a lower alkyl group, an allyl group or an aralkyl group, characterized by the heating of a normorphinone derivative of the formula where R- and Rp have the meaning described above, with pyrrolidine in a molar ratio of 1 ι 1 in the presence of an aprotic solvent and one aromatic sulfonic acid to a normorphinone-pyrrolidinylenamine the formula 909887/1711 NO, to produce, wherein R- and Rp are those described above Has meaning, and by oxidation of the latter compound. 909887/171 1