KR800000061B1 - Process for the preparation of codeine from dihydrothebaine - Google Patents

Abstract

Codeines, useful as linitive and sedation, were prepd. Thus, 7-halo- or 1,7-dihalodihydro codeinones (I; R = C1-6 alkyl, X = H, Cl, Br, Y = Cl, Br) were dehalogen-hydrogenated in polar aprotic solvent to give codeinone ketal, and which was hydrolized to give codeinone and 1-halo codeinone, and the product was reduced to give the codeine.

Description

Method for preparing codeine from dehydrothevain

The present invention relates to a new method of dehydrohalogenation of several alpha-halo ketals, which are also known as intermediates in the synthesis of codeine from thebaine.

It is known to prepare 7-bromodihydrocodeinone by treating dihydrothebaine with N-bromoacetamide in methyl alcohol (Rapoport et al. J. Amer. Chem. Soc., 1956, 78, 5128; 1967, 89, 1942-47).

This alpha-bromo ketal substance can be dehydrobrominated with the corresponding alpha: beta unsaturation codeinone dimethyl ketal, which is a rare acid. If you process it as Codeinone (Codeinone). Codeineone itself is easily reduced by ringing agents, such as sodium borohydride, to become an important codeine as an analgesic and antitussive agent.

Therefore, 7-halodihydrocodeinone dimethyl ketal is intended to develop a commercially available method of synthesizing codeine, especially when the method starts with the opiate alkaloid thebaine. Must be a key step to dehalogenated).

In the dehydrobromination method described in the references cited above, alpha-bromoketal is converted to potassium tertiary amylate (2-methylbutane) in tert-amyl alcohol (2-methyl butan-2-ol). -2-oxide). This method has several disadvantages from a commercial point of view, especially since the reaction proceeds slowly, which takes 24 hours to complete.

Another factor that should be considered here is the use of expensive potassium potassium in the manufacture of potassium tertiary amide, which is also dangerous to handle due to its very high reactivity.

We have found that as a solvent used in the base catalysis dehydrobromination method described above, dialkyl sulfoxides (eg dimethylsulfoxide (DMSO)), dialkylformamides (eg dimethylformamide ( DMF)] and polar aprotic solvents such as cyclicamides (eg N-diethylphylloliden), dialkylacetamides [eg dimethylacetamide (DMA)], alkylphosphoramides (E.g. hexamethylphosphoramide), glycols such as digiyme (diethyleneglycol dimethyl ether) and ethers and polyglycol ethers and sulfolane (tetrahydrothiophene-1, 1-dioxide) We have seen some advantages of using sulphones. Here, the polar aprotic solvent means a solvent that is not a proton donor and preferably has a dielectric constant ε> 15. Therefore, when using potassium tertiary butoxide as an organic solvent and DMSO as a solvent, the reaction proceeds rapidly at room temperature and is completed within about half an hour.

On the other hand, when the same organic base is used in the solvent of the third butyl alcohol, only a slight reaction (less than 10%) proceeds. In addition, in the case of using DMSO as a solvent, potassium tertiary pentoxide or potassium tertiary pentoxide must not be used for the dehydrobromination reaction, and alkali metal hydroxides other than those mentioned above are required. Even with other bases such as alkali metal hydrides and alkoxides, Cordey also has very good yields of dimethyl ketal. Also, we have found that when using alkali metal hydroxides, a small amount of water, for example up to 20%, in particular 1-20% (v / v) of water, may cause hydrolysis of any of the solvents listed above. I found it effective in that.

It has also been found that the use of DMSO as a solvent has the same effect on promoting 1.7-dibromodihydrocodeinone dimethyl ketal to de-bromination of I-bromocoday with dimethyl ketal.

1-Bromocoday can be hydrolyzed to dimethyl ketal with acetic acid to form 1-bromocodeinone (1-bromocodeinone), which is then reduced to lithium aluminum hydride to make codeine. To lose.

Accordingly, the present invention provides a method for dehalogenating a 7-halo- or 1.7-dihalodihydrocodeinone dialkyl ketal of the following general formula (I).

(Ⅰ)

(Ⅰ)

Wherein R represents an alkyl group having 1 to 6 carbon atoms, X represents halogen or chlorine or bromine, and Y represents a base in which ketal is present in the presence of a polar aprotic solvent Mark chlorine or bromine to act on.

Particularly preferred bases for the reaction of the present invention include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkali metal hydrides such as sodium hydride, alkali metal amides such as sodamide, sodium piperidide, or especially sodium methoxide and alkali metal alkoxides having 1 to 6 carbon atoms, such as sodium methoxide and sodium ethoxide.

Instead of sodium alkoxide, potassium alkoxides such as ethoxide, ethoxide, butoxide or pentoxide may also be used. However, these bases are not used relatively much. The reason for this is that in order to improve these substances, metal potassium is used, which, as mentioned above, is expensive and risky to handle. In particular, when preparing lower alkoxides using potassium and lower alcohols, very vigorous reactions may occur.

Dialkyl sulfoxides are preferred as polar aprotic solvents, preferably lower dialkyl sulfoxides, in particular diethyl sulfoxide. Other suitable polar aprotic solvents include those noted above. Preferably, the reaction proceeds in near anhydrous state or, if the base is an alkali metal hydroxide, a small amount of water (eg up to 20% (v / v)) is advantageous.

In the general formula (I) indicated above, it is preferred that R is ethyl. In addition, X is preferably hydrogen or bromine.

X is hydrogen, Y is chlorine and R is a ketal which is an alkyl group having 1 to 6 carbon atoms, and the present invention can also produce such a new compound, ketal. A new kind of ketal of this kind is described in Example 18, which is polar 7-chlorodihydrocodeinonedimethyl ketal.

Therefore, a preferable feature of the present invention is to provide a method for dehydrobromizing 7-bromodihydrocodeinone dimethyl ketal or 1.7-dibromodihydrodinone dimethyl ketal, in which the ketal is a solvent. In the presence of dimethyl sulfoxide, in the presence of anhydrous or a constant amount of water (eg, up to 20% (v / v) water relative to dimethyl sulfoxide), and at a temperature between room temperature and the reflux temperature of this solvent. After treatment with sodium or potassium hydroxide, this dehydrobrominated product is separated. If alkali metal hydroxide is used as the base, a temperature of 70-120 degrees Celsius is preferable.

In carrying out the method of the present invention, an appropriate amount of base may be used for convenience, but it is generally preferable to use an excess of about 1 mol relative to haloketal. However, when using sodium hydride, which acts as a very strong base in solvents such as DMSO, side reactions can occur, so avoid using excess.

When using an alkali metal hydroxide, it is good to use an excess of hydroxide with respect to the quantity with respect to the compound in which a dehalogenation reaction takes place. Thus, the molar ratio of hydroxide to haloketal should be greater than 1: 1 hydroxide: haloketal, more specifically 1.5: 1 to 10: 1, more specifically 1.5: 1 to 4: 1 It is good to do.

The present invention also relates to a process for preparing codeine from 7-bromodihydrocodeinone dimethyl ketal or 1: 7-dibromodihydrocodeinone dimethyl ketal, wherein the hydrocracked liquor is dehydrobrominated by the method described herein. Provide a process. It is surprising that haloketal dehydrochlorination or dehydrochlorination occurs with alkali metal hydroxides and small amounts of water, because under these conditions other reactions, such as substitution reactions, are expected to occur. Because it is done.

In preparing codeine from dehydrodevine using the method of the present invention, it is not necessary to separate various intermediates and the whole process proceeds without such separation. In this case in particular, DMSO, alkali metal hydroxides and small amounts of water as indicated above are used as solvents.

This method is described in particular for dehydrochlorination but can also be used for dehydrochlorination. Ketals used as starting materials can be prepared by the methods generally described in the following Examples 16-18.

The following examples illustrate the invention.

Example 1

Codeinone dimethyl ketal

7-bromodihydrocodeinone dimethyl ketal (8.48 g) was added to dimethyl sulfoxide (110 ml) and treated with potassium hydroxide fillet (5.6 g) ground at room temperature.

The mixture was exchanged and then heated in an oil bath to 80-90 degrees Celsius and maintained at this temperature for 4 hours and 30 clouds (thin layer chromatography indicated that the dehydrobromination reaction was complete after 3 hours and 45 minutes). ).

The reaction mixture was cooled at room temperature, diluted well with water and then extracted with ether. The etel extract was evaporated to give 6.35 g of crude codeinone dimethyl ketal, with a melting point (m.p.) of 135-137.5 degrees Celsius (after recrystallization from aqueous methanol).

Example 2

Codeinone

Dehydrobromination was carried out as in Example 1, but 1.76 g of ground sodium hydroxide pellets were used instead of potassium hydroxide.

Thin layer chromatography shows complete reaction after 4 hours 30 minutes. Instead of separating cordinone dimethyl ketal as in Example 1, the reaction mixture was cooled to room temperature and treated with N-hydrochloric acid (74mI) to hydrolyze the ketal. After stirring for 1 hour and 15 minutes at room temperature, the mixture was poured into iced water (25 ml) containing some excess ammonia. The precipitated cordinone precipitate was filtered off, washed with water and dried at 50 degrees Celsius. The yield was 4.91 g and the melting point was 179-182.5 degrees Celsius (after recrystallization from ethyl acetate).

Example 3

1-Bromocodeinone dimethyl ketal

A mixture of 1.7-dibromodihydrocodeinone dimethyl ketal (5.03 g) and potassium tertary butoxide (5.60 g) was treated with dimethyl sulfoxide (30 ml) and stirred at room temperature for 1 hour 30 minutes (thin layer croissant). Matography showed that the debromination reaction was complete after 30 minutes).

Next, the reaction mixture was slowly added to ice water (300 ml), and the precipitated 1-bromocodeinone dimethyl ketal was filtered off, washed with water, and dried at 50 degrees Celsius. Yield was 2.95 g and melting point was 123-124 degrees Celsius (after recrystallization from alcohol).

For comparison purposes, instead of using diethylsulfoxide at room temperature, an experiment was conducted using tertiary butyl alcohol at reflux (82.8 degrees Celsius) as a solvent. Under these preloads, thin-bromography showed that the dehydrobromination reaction only proceeded very slowly and less than 10% of the reaction was completed after 24 hours.

Example 4

1-Bromocodeinone dimethyl ketal

1: 7-dibromodihydrocodeinone dimethyl ketal (10 g) and ground potassium hydroxide pellets (5.6 g) were stirred with dimethyl sulfoxide (65 ml) and then heated to 70-80 degrees Celsius.

Thin layer chromatography showed that the dehydrobromination reaction was complete after 3 hours. The reaction mixture was cooled down and diluted well with water and extracted as ether.

After evaporation of this ether extract, 5.34 g of 1-bromocodeinone dimethyl ketal was obtained, with the next melting point of recrystallization from alcohol being 121-124 degrees Celsius.

Example 5

1-Bromocodeinone

1: 7-dibromohydrocodeinone dimethyl ketal (22.56 g) and ground sodium hydroxide pellets (5.28 g) were stirred with dimethyl sulfoxide (330 ml) at a temperature of 70-80 degrees Celsius. Thin layer chromatography showed little reaction after l hour and 30 minutes.

Then water (6.6 ml) was added and further heated to a temperature of 70-80 degrees Celsius for 1 hour and 15 minutes, and then the reacted mixture was irradiated with thin layer chromatography, at which time the dehydrobromination reaction was about 50%. It turned out to be enough. After that, the reaction proceeded smoothly and stopped. After 6.6 ml more water was added, the reaction started again, and after heating for 6 hours and 15 minutes at 70-80 degrees Celsius, the reaction was actually completed. The reaction mixture was cooled down and poured into three volumes of ice water with stirring. Precipitated 1-bromocodeinone dimethyl ketal was filtered off and then enacted with water and dried as dry as possible. The wet solid was dissolved in 2N hydrochloric acid (110 ml) and hydrolyzed by stirring at room temperature for 1 hour 30 minutes. The 1-bromocodeinone thus prepared was precipitated by pouring the solution into ice water (400 ml) containing a little excess of ammonia. The precipitated solid was filtered off, washed with water and dried at 50 degrees Celsius. . The yield was 11.5 g and the melting point was 191-192.5 degrees Celsius after recrystallization from methanol.

Example 6

Codeine

If desired, 7-bromodihydrocodeinone dimethyl ketal can be converted to codeine without separating the intermediate codeinone dimethyl ketal and codeinone.

Dimethyl sulfoxide containing 7-bromodihydrocodeinone dimethyl ketal (84.8 g) and granular sodium hydroxide (17.64 g) containing 5% (v / v) water at 90-100 degrees Celsius. 175 ml).

The dehydrobromination reaction was completed after 3 hours by thin layer chromatography. After 1 hour of heating at the same temperature, the thermal reaction mixture was slowly poured into 0 degree Celsius water (500 ml) with good stirring.

2N sulfuric acid (230 ml) was added at 20 degrees Celsius without isolation of the crude crude cotenone methyl ketal, followed by hydrolysis by stirring for 1 hour. At this time, thin layer chromatography was completely converted to codeineone. At the end of the gas cracking, crude crude sulfate was crystallized as an unisolated dark brown solid.

The reaction mixture became alkaline by the addition of 2N sodium hydroxide (120 ml) and methanol (200 ml), and sodium borohydride over 15 minutes while adding the same amount of water and maintaining the reaction temperature at 20 degrees Celsius by external cooling. Hydride (sodium borohydride) (3.8 g) was added. The reaction mixture was stirred for 1 hour and 30 minutes, and then examined by thin layer chromatography, indicating that the reaction of reducing codeinone to codeine was completed.

The reaction mixture was extracted several times with chloroform (6 × 200 ml) and then the solvent extract was washed once with water (200 ml) and shaken with 1N hydrochloric acid (3 × 100 ml). Ammonium hydroxide was added to this aqueous acid extract to give a basic pH of 9, and extracted with chloroform (300 ml, 200 ml, 2 x 100 ml) and dried. This solvent was removed in vacuo to afford the zocodein base (57.12 g). The base was dissolved in 74o.p. alcohol (81ml) and water (100ml). The solution was filtered and treated with sulfuric acid solution (50% v / v) .The pH was about 4.5 (10.5ml). Became.

The solution was cooled to about 5 degrees Celsius, and crystallized codeine sulfate was filtered off and washed with ice-cold 50% aqueous alcohol.

The product was then dried at 50 degrees Celsius until the weight remained unchanged to produce anhydrous codeine sulfate (56.36 g). This material, when quantified by non-aqueous titration, showed a purity of 99.6% and, when basified with excess ammonia, produced a codeine alkaloid with a melting point of 155.5 degrees Celsius.

Example 7

Codeinone

7-bromodihydrocodeinone dimethyl ketal (2.12 g) was stirred in hexamethylphosphoramide (10 ml) at room temperature and treated with solid potassium terbutoxide (1.23 g). Thin layer chromatography indicated that the debromination reaction was complete after 1 hour and 15 minutes.

The reaction mixture was poured into cold water (75 ml) while stirring, and the precipitated cordinone dimethyl ketal was extracted with chloroform (3 × 20 ml). The chloroform solution was extracted with l / 4N sulfuric acid (20,2 × 5 ml), and the solution obtained was left at 20 degrees Celsius for 1 hour to allow the hydrolysis to proceed completely [a small amount of codeinone sulfate during this time. Precipitated into white needles; The mixture was then cooled in an ice / water bath and basified by addition of an aqueous solution of sodium hydroxide (0.4 g) of water (5 ml) while stirring. The white fine solid separated by filtration was washed twice with ice cold water and vacuum dried at room temperature. The yield was 1.38 g and the melting point was 179-183 degrees Celsius (after recrystallization with ethyl acetate).

Example 8

Cadeinone

A solution of 7-bromodihydrocoinone dimethyl ketal (2.12 g) in N, N-dimethyl formamide (20 ml) was stirred at room temperature and treated with solid potassium terburoxide (1.23 g). Thin layer chromatography showed the reaction to be complete after 4 hours 30 minutes. The reaction solution was poured into cold water (150 ml) and extracted with chloroform (3 x 20 ml).

The chloroform reactions were extracted with 1/3 N sulfuric acid (2 x 15 ml), after which the acidic extract was left at room temperature for 2 hours and then washed with chloroform (2 x 20 ml). After basification with a slight excess of ammonia and extraction with chloroform (2 × 20,10 ml), the extract was dried over sodium sulfate and the solvent removed in vacuo. Crystal residues of jocotanone were obtained, which had a melting point of 183.5-186.5 degrees Celsius (after recrystallization with ethyl acetate).

Example 9

Codeinone

A solution of 7-bromodihydrocodeinone diethyl ketal (2.12 g) in N, N-dimethylacetamide (20 ml) was stirred at room temperature and treated with solid potassium tert-butoxide (1.23 g). Dehydrobromination was observed to be complete after 1 hour by thin layer chromatography. The reaction mixture was diluted with water (150 ml) and proceeded as in the case of the dimethylformamide of Example 8 to obtain 1.29 g of codeinone, which had a melting point of 181-185 degrees Celsius after recrystallization with ethyl acetate.

Example 10

Codeinone dimethyl ketal

7-bromodimethylcodeinone dimethyl ketal (4.24 g) and sodium hydride (0.5 g, 50% oily dispersion) were stirred in dimethyl sulfoxide dried over calcium hydride at 90 degrees Celsius. The dehydrobromination reaction was completed after nearly 6 hours (t. L. C.). The thermal reaction mixture was slowly poured into ice-cold water (50 ml) while stirring. At this time, the precipitated cordinone dimethyl ketal was filtered off, rinsed with water (20 ml) and vacuum dried at 25 degrees Celsius. Yield was 2.87 g and melting point was 133-136.5 degrees Celsius (after recrystallization from a solution with a methanol to water ratio of 2: 1 v / v).

Example 11

1-Bromocodeinone

1.7-Thebromodihydrocodeinone dimethyl ketal (2.52 g) was stirred with sodium ethoxide (0.75 g) in dimethyl sulfoxide at room temperature. The dehydrobromination reaction was complete after 3 hours but stirring was continued overnight. After 21 hours had elapsed, the reaction mixture was poured slowly into ice cold water (75 ml) with stirring, and the precipitate formed there was filtered and washed.

This wash was dissolved in N hydrochloric acid (15 ml) in a humid state and stirred at 20 degrees Celsius for 3 hours. The acidic solution was then slowly poured into ice cold water (50 ml) containing some excess ammonia. The precipitated 1-bromocodeinone was filtered off, washed with water and dried at 50 degrees Celsius. Yield was 1.0 g and melting point was 187-l89 degrees Celsius (after recrystallization from methanol).

Example 12

Codeinone dimethyl ketal

7-bromodihydrocodeinone dimethyl ketal (2.12 g) and solid potassium tert-butoxide (1.23 g) were stirred in sul-pholane (10 ml) and then heated at 50 degrees Celsius. Thin layer chromatography showed that the reaction was complete after 3 hours 45 minutes. The reaction mixture was poured into ice cold water (100 ml) with slow stirring. At this time, the precipitated cordinone dimethyl ketal was filtered off, washed with water and vacuum dried at 40 degrees Celsius.

The yield was 1.32 g and the melting point was 133-l38 degrees Celsius (after recrystallization of the ethanol to water in a 2: 1 v / v solution).

Example 13

Codeinone dimethyl ketal

7-bromodihydrocodeinone dimethyl ketal (2.12 g) and solid potassium tert-butoxide (1.23 g) were stirred in didiglyme (12.5 ml) and then heated to 55-60 degrees Celsius. The thin layer chromatography test showed that the reaction was completed after 2 hours and 30 minutes. The thermal reaction mixture was slowly poured into ice-cold water (110 ml) while stirring. The precipitated cordinone dimethyl ketal was filtered off, washed with water, and dried in vacuo at 30 degrees Celsius. Yield was 1.36 g and point was 136-138 degrees Celsius (after recrystallization from a solution of methanol to water of 2: 1v / v).

Example 14

Codeinone

Sodium hydride (1.40 g of 50% dairy acid solution) was stirred with piperidine (3.4 g) at room temperature under dry nitrogen gas. After 5 minutes excess piperiton was removed under pressure to form a light gray sodium piperidide residue. Next, 7-bromodihydrocodeinone dimethyl ketal (4.24 g) and hexamethylphosphoramide (20 ml) were added, followed by stirring and heating to 90 degrees Celsius. This dehydrobromination reaction was completed after 3 hours (t. L. C.).

Next, the thermal reaction solution was slowly poured into water (70 ml) while stirring, and the formed codeinenon dimethyl ketal was extracted in chloroform (3 × 20 ml). The chloroform solution was extracted with 1N sulfuric acid and stirred at room temperature for 1 hour 30 minutes to complete hydrolysis.

During this reaction, codeinone sulfate was separated into white crystals. The slurry was cooled to 5 degrees Celsius, and then treated with sodium hydroxide (0.8 g) dropwise into water (5 ml) one by one. Then, the precipitated cotenone was filtered off and washed with water and vacuum oven at 30 degrees Celsius. Dried. Yield was 2.I6 g and melting point was 178-l84 degrees Celsius (after recrystallization with ethyl acetate).

Example 15

Codeinone dimethyl ketal

7-bromodihydrocodeinone dimethyl ketal (4.24 g) and sodium amide (0.86 g) were stirred in hexamethylphosphoramide (15 ml) and heated to 85-90 degrees Celsius. Thin layer chromatography (t.l.c.) test showed that the reaction was complete after 4 hours. Next, the thermal reaction solution was squeezed drop by drop while stirring in ice cold water to precipitate codeine dimethone ketal. The precipitate was filtered off, washed with water and dried in a vacuum oven at 30 degrees Celsius. Yield was 1.66 g and melting point was 136-139 degrees Celsius (after recrystallization from methanol).

Example 16

Codeinone

7-bromodihydrocodeinone methyl n-propyl ketal (9.02 g) was added to a mixed solution of dimethyl sulfoxide and water mixed at 19: 1 (v / v), followed by granular sodium hydroxide (1.76 g). Heated to 90-100 degrees Celsius. Dehydrobromination reaction was completed after 4 hours by thin layer chromatography (t. 1. c.) Test. The mixture was then cooled to 15 degrees Celsius, stirred and acidified by addition of 2N sulfuric acid (23 ml) and stirring continued at room temperature for 2 hours to complete hydrolysis. Next, while cooling the reaction solution, an aqueous sodium hydroxide solution (1.6 g) was added and basified, which was extracted with chloroform (3 x 20 ml). The chloroform extract was washed with water (25 ml), dried over sodium sulfate, and the solvent was removed under reduced pressure to give a brown residue. It was crystallized from ethyl acetate to give cordinone (2.15 g), which had a melting point of 179-184 degrees Celsius.

These starting materials were prepared by the following method.

Improvement of 7-bromodihydrocodeinone methyl n-propyl ketal

Dihydrothebaan (6.26 g) and p-toluenesulphonic acid monohydrate (3.80 g) were stirred in n-propanol (35 ml) at room temperature to dihydrolevane p- A slurry of toluenesulfonate (dihydrothebainep-toluenesulphonate) was made. Next, a drop of 1,3-dibromo-5,5-dimethylhydantoin (1.3-dibromo-5,5-dimethylhydantoin) (2.95 g) in acetone (20 ml) was dropped over half an hour. The addition was continued followed by stirring for half an hour. Next, while stirring this reaction solution, sodium hydroxide (1.6g) was added to the solution which melt | dissolved in 5 degreeC water (180ml).

Here, a white sticky solid precipitated out, which was not suitable for filtration, and this material was extracted with chloroform (30,25 ml). The chloroform extract was washed with water (30 ml) and dried over sodium sulfate, and the solvent was removed under reduced pressure, and the crude 7-bromodihydrocodeinone methyl n-propyl ketal (brown gum) was removed. 9.02 g). This was used for the dehydrobromination step without purification.

Example 17

Codeinone

7-bromodihydrocodeinone methyl n-pentyl ketal (2.5 g) and potassium tert-butoxide (1.46 g) were stirred in dimethyl sulfoxide (20 ml) at about 35 degrees Celsius.

Thin layer chromatography showed that the dehydrobromination reaction was complete after 2 hours. The reaction solution was diluted with water (100 ml), extracted with chloroform (6 × 20 ml), washed with water (20 ml), and extracted again with N / 4 sulfuric acid (2 × 20, 2 × 10 ml).

The hydrolysis was completed after almost 1 hour at room temperature. The acidic solution was added with ammonia to give a basic pH of 9 and extracted with chloroform (3 x 40 ml). The extract was dried over sodium sulfate and the solvent was removed under reduced pressure to obtain a crystalline codeine residue. Yield was 0.95 g and melting point was l80-185 degrees Celsius (after recrystallization with ethyl acetate). This product was tested by i.r. spectrum and was identical to the spectrum of pure codeinone sample. Starting materials were made in the following manner.

Preparation of 7-bromodihydrocodeinone methyl n-penal ketal

Dihydrothebaine (6.26 g) and p-toluenesulfonic acid monohydrate (3.8 g) were added to n-pentanol (20 ml) at 21 degrees Celsius and stirred, and the resulting slurry was dropped dropwise for at least 30 minutes and acetone (19 ml). ) Was treated with a 1,3-dibromo-5,5-dimethylhytantoin (2.95 g) solution. The reaction solution was stirred for at least 30 minutes and filtered to separate the white solid, which was mainly dihydrothevain p-toluenesulfonate unreacted water. The filtrate was concentrated to a volume of 20 ml under reduced pressure, and then toluene (20 ml) was removed and washed with N / 2 sulfuric acid (17 ml). The weaning solution was then washed with water (20 ml) and dried over sodium sulfate, and the solvent was removed under reduced pressure to give crude 7-bromodihydrocodeinone methyl n-pentyl ketal (7.18 g) on brown gum. Got. This material was purified by column chromatography using silica (Sorbsil, in which 5% methane of chloroform was washed with a solution before dehydrobromination).

Example 18

Codeinone

7-chlorodihydrocodeinone dimethyl ketal (7.66 g) and granular sodium hydroxide (1.76 g) were stirred together with a mixed solution (17.5 ml) in which the dimethyl sulfoxide and water were mixed in a volume ratio of 19: 1 and 90 degrees Celsius. Heated to -100 degrees.

Thin layer chromatography test showed that the reaction was completed after 16 hours. The reaction mixture was poured into ice cold water (70 ml) with stirring, extracted with chloroform (3 x 20 ml) and washed with water (25 ml). The chloroform solution was extracted with IN sulfuric acid (20,2 × 5ml), continued stirring at 20 ° C for 1 hour, cooled to 5 ° C and basified by addition of a solution of sodium hydroxide (1.6g) water (5ml). lost. The chloroform extract (3 × 20 ml) was washed with water, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was recrystallized with ethyl acetate to obtain cordinone having a melting point of 177-I80 degrees Celsius. This material is i.r. And n.m.r. It was confirmed by comparison with a pure sample of the base by the spectra.

Starting materials were prepared in the following manner.

Preparation of 7-chlorodihydrogodinone dimethyl ketal

Dihydrothebaine (6.26 g) and p-toluenesulfonic acid monohydrate (3.80 g) were dissolved in methanol at 17 degrees Celsius with stirring. A 1,3-dichloro-5,5-dimethylhydantoin (3.98 g) solution dissolved in acetone (45 ml) was added dropwise for 1 hour, and stirring was continued for at least 30 minutes. Examination of the reactants at this stage resulted in complete chlorination. The solvent was removed under reduced pressure, and the residue was partitioned between toluene and aqueous sodium hydroxide (1.6 g) dissolved in 35 ° C. water (20 ml).

After separating these phases, the liquid portion was reextracted with toluene and the toluene extract was dried over sodium sulfate.

The solvent was removed under reduced pressure to give crude 7-chlorodihydrocotenone dimethyl ketal (7.66 g) on a yellow gum. This was used for the debromination hydrogenation step without purification again.

Example 19

Codeinone

7-bromodihydrocodeinone dimethyl ketal (2.12 g) and granular sodium hydroxide (2.0 g) were added to hexamethylphosphoramide (10 ml) with stirring to heat to 95 degrees Celsius. Thin layer chromatography results showed that this dehydrobromination was completed after nearly 1 hour. The thermal reaction mixture was cooled to room temperature and poured into water (100 ml) with stirring. The resulting cordinone dimethyl ketal precipitate was extracted with chloroform (3 × 20 ml), washed with water (20 ml) and then extracted with 1 / 4N sulfuric acid (20, 2 × 5 ml).

The acidic solution was stirred at 20 degrees Celsius for 1 hour and 15 minutes to complete hydrolysis (slight white needles of cordinone sulfate crystals were produced during this reaction). Next, the mixture was cooled in an ice cold water bath and basified by slowly adding an aqueous solution of sodium hydroxide (0.4 g) in water (5 ml).

This was filtered to separate the cordinone, a white microsolid, and then cold water (2 × 5ml) and vacuum dried at 40 degrees Celsius. Yield was 1.38 g and melting point was 176-182 degrees Celsius (after recrystallization with ethyl acetate), the product was t.l.c. And i.r. compared with pure codeinone.

Example 20

Codeinone

7-bromodihydrocodeinone dimethyl ketal (2.12 g) and granular sodium hydroxide (2.0 g) were stirred with N, N-dimethyl-formamide (25 ml) and heated to 120 degrees Celsius. t.l.c. The test showed that the debromination reaction was completed after 10 hours. The reaction mixture was then cooled to room temperature and added to water (150 ml) at 0 degrees Celsius with stirring. The precipitated cotenone dimethyl ketal was extracted with chloroform (3 × 20 ml), washed with water (30 ml) and extracted with N / 3 sulfuric acid (2 × 15 ml) to hydrolysis, which was then stirred at room temperature ( Some white needle cordinone sulfate soon began to form). After 1 hour and 30 minutes had elapsed, the mixture was cooled in an ice-cold water bath, and cooled and stirred, and slowly basified by dropwise addition of an aqueous solution of sodium hydroxide (0.4 g) in water (5 ml). The white microsolid was separated by filtration, washed with cold water and vacuum dried at 30 degrees Celsius. Yield was 1.04 g and melting point was 180-184 degrees Celsius (after recrystallization with ethyl acetate).

Claims (1)

As described above in the text, dehalogenation of 7-halo- or 1.7-dihalodihydrocodeinone dialkyl ketals having the following general formula by the action of a base in the presence of a polar aprotic solvent Hydrogenation to form codeinone ketal and then hydrolysis to form codeinone or 1-halocodeinone and to reduce it to produce codeine, wherein the process for producing coderine with dihydrolevein.

Where R is an alkyl group having 1-6 carbon atoms, X is hydrogen, chlorine or bromine and Y is chlorine or bromine.