JP2010111656A - Method for producing thebaine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing a thebaine derivative which is important compound as an intermediate for synthesizing pharmaceuticals. <P>SOLUTION: The method for producing the thebaine derivative (I) is provided, including the following process: a codeinone derivative is subjected to (i) an acetalization step, (ii) a solvent-distilling-out step and (iii) a dealcoholization step. A thebaine/methanesulfonate salt crystal having characteristic(s) in peaks 10 or greater in relative intensity in the powder X-ray diffractometry (CuKα, λ=1.54 Å). In the formula (I), R<SP>1</SP>and R<SP>2</SP>are each independently 1-6C alkyl, 1-6C alkylcarbonyl or 7-11C aralkyl; and R<SP>3</SP>is 1-6C alkyl. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an efficient method for producing a thebaine derivative, which is an important compound as a pharmaceutical intermediate.

Oxycodone is a kind of alkaloid-type analgesic that acts on opioid receptors and exhibits analgesic action, and is synthesized from thebaine, a component contained in opium. Oxycodone is used to relieve moderate to high pain in clinical practice, and is said to have less affinity for μ2 receptors than morphine, and is considered to have fewer side effects such as constipation and nausea.
In addition, it is known that oxymethebanol, which is clinically used as a narcotic antitussive, is synthesized according to Scheme 1 below. In this case, thebaine is an important synthetic intermediate. Become.
As described above, since thebaine is an important synthetic intermediate for pharmaceuticals, development of an efficient production method that can be used industrially is desired.

  So far, research on the production method of thebaine has been reported. For example, according to US Pat. No. 6,958,398, codeinone is converted into trimethyl orthoformate, methanesulfonic acid as shown in Scheme 2 below. A method for producing by heating in the presence has been reported (see Patent Document 1).

US Pat. No. 6,958,398

  The problem is to provide an efficient production method for industrially available thebaine, which is an important synthetic intermediate for pharmaceuticals.

The present inventor is a compound having the general formula (I)

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group or a C7-C11 aralkyl group, and R ³ represents a C1-C6 alkyl group. ]
We have conducted extensive research on the production methods of thebaine derivatives. As a result, the present inventors have completed the present invention by overcoming the drawbacks that have been problematic so far and finding a method for producing an excellent thebaine derivative that can be used industrially. That is, according to the present invention, a reaction temperature as high as about 90 ° C. is usually required, but the reaction can be rapidly advanced even at a temperature that is considered to be more practical. Further, according to the present invention, since the reaction is completed at a lower temperature and in a shorter time, it is possible to suppress decomposition or the like which is usually a concern under high temperature conditions and improve the yield. In addition, due to the above improvements, production efficiency can be expected to be reduced by reducing energy required for heating during industrial production, shortening the manufacturing period, and increasing yield.

The present invention
(1): Compound having general formula (I)

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group or a C7-C11 aralkyl group, and R ³ represents a C1-C6 alkyl group. A process for producing

Compound having general formula (II)

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, or a C7-C11 aralkyl group. ]
(I) an acetalization step which is a step of heating in alcohol in the presence of one acetalization reagent selected from trimethyl orthoformate, triethyl orthoformate, dimethoxypropane or diethoxypropane and methanesulfonic acid;
(Ii) a solvent distillation step, which is a step of adding a solvent and then concentrating;
(Iii) by adding a carboxylic acid anhydride selected from acetic anhydride, propionic anhydride, benzoic anhydride or trifluoroacetic anhydride, followed by a dealcoholization step which is a step of heating in a solvent,
A process for producing a compound having the general formula (I)
Preferably,
(2): A method for producing a compound having the general formula (I) according to (1), wherein R ¹ , R ² and R ³ are each independently a methyl group or an ethyl group,
(3): A method for producing a compound having the general formula (I) according to (1), wherein R ¹ , R ² and R ³ are methyl groups,
(4): A method for producing a compound having the general formula (I) according to (1), wherein the acetalizing reagent in the acetalization step is trimethyl orthoformate,
(5): A method for producing a compound having the general formula (I) according to (1), wherein the alcohol in the acetalization step is methanol,
(6): A method for producing a compound having the general formula (I) according to (1), wherein the solvent in the solvent distillation step and the dealcoholization step is acetonitrile, and
(7): A method for producing a compound having the general formula (I) according to (1), wherein the carboxylic acid anhydride in the dealcoholization step is acetic anhydride,
(8): In the dealcoholization step of (iii), methanesulfonic acid is further added, The method for producing the compound having the general formula (I) according to claim 1,

(9): Compound having general formula (I) as described in (1)

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group or a C7-C11 aralkyl group, and R ³ represents a C1-C6 alkyl group. ] After the completion of the heating reaction,
(I) Concentrate under reduced pressure,
(Ii) After adding the C1-C6 alkyl ester to the residue,
(Iii) by precipitating crystals,
A method for producing thebaine / methanesulfonate crystals,
(10): C1-C6 alkyl ester is methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl butanoate, ethyl butanoate and propyl butanoate A method for producing the thebaine / methanesulfonate crystals according to (9),
(11): The method for producing thebaine / methanesulfonate crystals according to (9), wherein the C1-C6 alkyl ester is methyl acetate, ethyl acetate or propyl acetate,
(12): A method for producing thebaine having a purity of 98% or more using the thebaine / methanesulfonate crystal obtained in (9), and (13): powder X-ray diffraction (Cu Kα, λ = 1.54 Å) Thebaine / methanesulfonate crystals with a relative intensity of 10 or higher

である。

It is.

  The “C1-C6 alkyl group” of the present invention is a linear or branched alkyl group having 1-6 carbon atoms, preferably a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. , An isobutyl group, a sec-butyl group or a tert-butyl group, more preferably a methyl group or an ethyl group, and particularly preferably a methyl group.

  The “C1-C6 alkylcarbonyl group” of the present invention is a group in which a carbonyl group is bonded to the above-mentioned C1-C6 alkyl group or a formyl group, preferably a formyl group or an acetyl group, more preferably An acetyl group.

  The “C7-C11 aralkyl group” of the present invention is a group in which a methyl group is bonded to a phenyl group or a naphthalene group, and is preferably a benzyl group.

  The “C1-C6 alkyl ester” of the present invention is an ester of a C1-C6 alkyl group and a C1-C6 alkyl carboxylic acid, preferably methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, propion Ethyl acid, propyl propionate, butyl propionate, methyl butanoate, ethyl butanoate or propyl butanoate, more preferably methyl acetate, ethyl acetate or propyl acetate, particularly preferably ethyl acetate .

(1) About the (i) acetalization process of this invention The alcohol which is a solvent to be used is preferably methanol or ethanol, and more preferably methanol.
The amount of alcohol to be used is 1 to 10 times, preferably 1 to 5 times that of the raw material compound, by volume.
The amount of the acetalizing reagent used is preferably 1-10 equivalents, more preferably 2-4 equivalents.
The amount of methanesulfonic acid used is preferably 1-5 equivalents, and more preferably 1.1-1.3 equivalents.
The reaction temperature is preferably 20-80 ° C, more preferably 40-50 ° C.
The reaction time is usually about 5 hours, and the progress of the reaction can be confirmed by HPLC.

(2) (ii) Solvent distillation step of the present invention The solvent used is not particularly limited as long as it is not a protic solvent, but is preferably acetonitrile, tetrahydrofuran, acetone, ethyl acetate, toluene, dimethylformamide or dimethyl. Sulfoxide, more preferably acetonitrile.
Concentration is 7 times or less, preferably 5 times or less, of the raw material compound by volume.

(3) Regarding the (iii) dealcoholization step of the present invention, the solvent used is not particularly limited as long as it is not a protic solvent, but is preferably acetonitrile, tetrahydrofuran, acetone, ethyl acetate, toluene, dimethylformamide or dimethyl sulfoxide. More preferably, it is acetonitrile.

The amount of the solvent to be used is 1-5 times, preferably 1-3 times that of the raw material compound by volume.
The amount of acetic anhydride used is preferably 1-10 equivalents, more preferably 3-5 equivalents.
The reaction temperature is preferably 40-100 ° C, more preferably 60-70 ° C.
The reaction time is usually about 3 hours, and the progress of the reaction can be confirmed by HPLC.

According to the present invention, a reaction temperature as high as about 90 ° C. is usually required, but the reaction can proceed rapidly even at a temperature that is considered to be more practical. Further, according to the present invention, since the reaction is completed at a lower temperature and in a shorter time, it is possible to suppress decomposition or the like which is usually a concern under high temperature conditions and improve the yield. In addition, the present invention is useful because the above-described improvements are expected to reduce the energy required for heating during industrial production, shorten the production period, and improve production efficiency by increasing yield.
Further, when thebaine is produced from codeinone, it is useful since thebaine is converted into thebaine after the thebaine is converted into a crystal of a salt of methanesulfonic acid to obtain a high-purity thebaine.

  The present invention will be specifically described below with reference examples and examples, but the present invention is not limited thereto.

(Reference Example 1) Synthesis of codeine from codeine Ethyl acetate (600 mL) and cyclohexanone (150 mL) were added to codeine (50.0 g, 167 mmol) and concentrated, and then aluminum isopropoxide (8.5 g, 42 mmol) was added and heated to reflux. did. After stirring for 2 hours, water (200 mL) and concentrated hydrochloric acid (20.3 g) were added to separate the aqueous layer, lactic acid (19.5 g) and chloroform (250 mL) were added, and then an aqueous sodium hydroxide solution was added to adjust the pH to 7 Adjusted to ~ 9. After separating the organic layer, isopropyl alcohol (250 mL) was added, concentrated under reduced pressure, and cooled to 0-5 ° C. The suspension was filtered and washed with isopropyl alcohol (100 mL), and the obtained crystals were dried at 40 ° C. under reduced pressure to obtain codeinone (38.4 g) (yield 77%).

Example 1 Synthesis of Thebaine / Methanesulfonate Crystal from Codeinone

Methanesulfonic acid (12.4 g, 129 mmol) was added to a suspension of codeinone (32.0 g, 108 mmol) in methanol (32 mL) and trimethyl orthoformate (22.8 g, 215 mmol) and heated to 40-50 ° C. After stirring for 6 hours, toluene (96 mL) was added, and the mixture was concentrated under reduced pressure. Acetonitrile (160 mL), methanesulfonic acid (1.0 g, 10 mmol) and acetic anhydride (8.2 g, 80 mmol) were added to the residue and heated to 70-75 ° C. After stirring for 4 hours, the mixture was concentrated under reduced pressure, and ethyl acetate (320 mL) was added to the residue. After further concentration under reduced pressure, ethyl acetate (320 mL) was added to the residue, and the mixture was heated to 35 to 45 ° C. and stirred for 30 minutes. The suspension was cooled to 0-5 ° C., filtered and washed with ethyl acetate (64 mL). The obtained crystals were dried at 40 ° C. under reduced pressure to give thebaine / methanesulfonate crystals (38.6 g). (Yield 88%).

(1-1) Powder X-ray diffraction measurement of thebaine / methanesulfonate crystals obtained in Example 1 Table 2 shows peaks with relative intensities of 10 or more in powder X-ray diffraction (Cu Kα, λ = 1.54 Å). Show.

(1-2) NMR measurement of thebaine / methanesulfonate crystals obtained in Example 1
¹ H-NMR (CDCl ₃ , 500 MHz) δ: 1.97 (1H, dd, J = 14.0, 3.1 Hz), 2.30-2.35 (1H, m), 2.85 (3H, s), 3.00 (3H, s), 3.16 -3.21 (1H, m), 3.31 (1H, dd, J = 19.5, 7.1 Hz), 3.64-3.76 (5H, m), 3.87 (3H, s), 4.30 (1H, d, J = 7.4 Hz), 5.11 (1H, d, J = 6.7 Hz), 5.35 (1H, s), 5.91 (1H, d, J = 6.7 Hz), 6.73 (2H, dd, J = 23.3, 8.2 Hz), 11.40 (1H, s ).

(Example 2) Synthesis of thebaine from thebaine / methanesulfonate crystals

Water (224 mL) and methanol (96 mL) were added and dissolved in thebaine / methanesulfonate crystals (36.2 g), and then an aqueous ammonia solution was added to adjust the pH to 7.5 to 8.5. After stirring at room temperature for 1.5 hours, the suspension was filtered and washed with 30% aqueous methanol (64 mL), and the resulting crystals were dried at 40 ° C. under reduced pressure to give thebaine (27.4 g) (yield) 99%).

(2-1) Impurity qualitative analysis of thebaine obtained in Example 2 Thebaine obtained in Example 2 was analyzed under the following conditions. The area percent of thebaine obtained via thebaine / methanesulfonate crystals was 98.2%. Table 3 shows a comparison of the quality of the peak of 0.1% or more with thebaine that does not pass through the methanesulfonate crystal.
Sample solution: phosphate buffer (pH 3.0) / tetrahydrofuran (240/70)
About 0.050 g of thebaine was dissolved in the sample diluent to make exactly 50 mL. This solution was accurately weighed in 5 mL, and a sample solution was added to make exactly 50 mL. Using 5 μL of this as a sample solution, high performance liquid chromatography analysis was performed under the following conditions. (Thebaine shows a retention time of 10-11 minutes under these conditions)
Column: L-Column ODS 3.0mmI.D. × 100mm 3μm
Mobile phase: Dissolved by adding diluted phosphoric acid (1/1000, 500 mL) to sodium lauryl sulfate (1.0 g), adjusted to pH 3.0 with sodium hydroxide test solution, and then adding tetrahydrofuran (70 mL) to this solution (240 mL) ) Added and mixed Flow rate: Constant flow rate of about 0.5 mL / min (adjusted so that thebaine is 10.5 minutes)
Detector: UV absorptiometer (measurement wavelength 210nm)
Column temperature: Constant temperature around 40 ° C Calculation method: Each peak area / total peak area x 100%

(Comparative Example 1) Synthesis of thebaine from codeinone
J. Am. Chem. Soc. 1951, 73, 4001. To codeinone (1.0 g, 3.4 mmol) synthesized by a known method, acetonitrile (9 mL), methanol (1 mL), trimethyl orthoformate ( 714 mg, 6.7 mmol) was added, and finally methanesulfonic acid (423 mL, 4.4 mmol) was added. The solution was heated to reflux for 2 hours. Methanol (2 mL) was added and refluxed for 2 hours, and methanol (2 mL) was further added and refluxed for 2 hours. Trimethyl orthoformate (361 mg, 3.4 mmol) was added, and the mixture was further refluxed for 1 hour. After concentration and evaporation of methanol, the mixture was refluxed intermittently for 3 hours. Methanesulfonic acid (0.066 ml, 1.0 mmol) was added and the mixture was further refluxed for 3 hours, and then N, N-dimethylformamide (0.25 mL) was added and refluxed for 1 hour. After cooling to room temperature, water (10 mL) was added, and a 25% aqueous sodium hydroxide solution was added until the pH was 11 or more, followed by stirring for 30 minutes. The precipitated crystals were filtered, and the separated crystals were washed with water (2 mL). The obtained crystals were dried at 40 ° C. under reduced pressure to obtain pale yellow thebaine (0.59 g, yield 56%).

Claims (13)

Compound having general formula (I)

[Wherein, R ¹ and R ² each independently represents a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group or a C7-C11 aralkyl group, and R ³ represents a C1-C6 alkyl group. A process for producing
Compound having general formula (II)

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group, or a C7-C11 aralkyl group. ]
(I) an acetalization step which is a step of heating in alcohol in the presence of one kind of acetalization reagent selected from trimethyl orthoformate, triethyl orthoformate, dimethoxypropane or diethoxypropane and methanesulfonic acid;
(Ii) a solvent distillation step, which is a step of adding a solvent and then concentrating;
(Iii) by adding a carboxylic acid anhydride selected from acetic anhydride, propionic anhydride, benzoic anhydride or trifluoroacetic anhydride, followed by a dealcoholization step, which is a step of heating in a solvent,
A process for producing a compound having the general formula (I). The method for producing a compound having the general formula (I) according to claim ¹ , wherein R ¹ , R ² and R ³ are each independently a methyl group or an ethyl group. The method for producing a compound having the general formula (I) according to claim ¹ , wherein R ¹ , R ² and R ³ are methyl groups. The method for producing a compound having the general formula (I) according to claim 1, wherein the acetalizing reagent in the acetalization step is trimethyl orthoformate. The method for producing a compound having the general formula (I) according to claim 1, wherein the alcohol in the acetalization step is methanol. The method for producing a compound having the general formula (I) according to claim 1, wherein the solvent in the solvent distillation step and the dealcoholization step is acetonitrile. The method for producing a compound having the general formula (I) according to claim 1, wherein the carboxylic acid anhydride in the dealcoholization step is acetic anhydride. The method for producing a compound having the general formula (I) according to claim 1, wherein methanesulfonic acid is further added in the dealcoholization step of (iii). Compound having general formula (I) according to claim 1

[Wherein, R ¹ and R ² each independently represent a C1-C6 alkyl group, a C1-C6 alkylcarbonyl group or a C7-C11 aralkyl group, and R ³ represents a C1-C6 alkyl group. ] After the completion of the heating reaction,
(I) Concentrate under reduced pressure,
(Ii) After adding the C1-C6 alkyl ester to the residue,
(Iii) by precipitating crystals,
A method for producing thebaine / methanesulfonate crystals. Any of C1-C6 alkyl ester consisting of methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, propyl propionate, butyl propionate, methyl butanoate, ethyl butanoate and propyl butanoate The method for producing thebaine / methanesulfonate crystals according to claim 9. The method for producing thebaine / methanesulfonate crystals according to claim 9, wherein the C1-C6 alkyl ester is methyl acetate, ethyl acetate or propyl acetate. A method for producing thebaine having a purity of 98% or more, using the thebaine / methanesulfonate crystals obtained in claim 9. A thebaine / methanesulfonate crystal in which a peak of relative intensity 10 or more in powder X-ray diffraction (Cu Kα, λ = 1.54 Å) is represented by the following table.