JP2010024141A - Method for producing morphine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a useful compound for the efficient production method of morphine. <P>SOLUTION: This compound is expressed by general formula (I), (II), or (III) [wherein R<SP>1</SP>is a 1-6C alkyl; R<SP>2</SP>is an amino-protecting group without substantially being eliminated under a strongly acidic condition; and R<SP>3</SP>and R<SP>4</SP>are each a 1-6C alkyl]. Preferably the compound is expressed by any of general formulae (I) to (III), wherein R<SP>1</SP>is methyl and R<SP>2</SP>is a 2,4-dinitrobenzene sulfonic acid group. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to an efficient method for producing morphine.

  Morphine is a narcotic analgesic prescribed to patients with end-stage cancer for the purpose of alleviating strong pain such as cancer pain, and WHO has proposed a cancer pain treatment using morphine to avoid dependence formation. However, since the method of managing pain while spreading in the medical field, the amount of use has increased significantly in recent years. Morphine is extracted from opium, but an attempt has been made to stably supply morphine stably at low cost by chemical synthesis instead of a production method using natural opium as a raw material (in the following formula, Me is a methyl group). The same applies hereinafter).

  Various reports have been made on morphine synthesis methods (for review, see Synlett, 388, 2005, etc.). The most important point in the synthesis of morphine is the efficient construction of a pentacyclic skeleton containing a quaternary carbon. From this viewpoint, a number of excellent methods have been developed. However, these key reactions are often achieved using relatively simplified substrates. As a result, in order to construct the lower C ring allyl alcohol part of morphine at the end of the synthesis, it is necessary to perform complicated functional group conversion. For example, the method for synthesizing morphine described in Org. Lett., 8, 5311, 2006 has problems in terms of efficiency, such as the construction of C-ring allyl alcohol site requires 8 steps including oxidation reaction from ketone to enone. is there.

Further, a method is known in which a D ring is constructed by removing the protecting group from an intermediate compound in which a nitrogen atom is protected with trimethylsilylethyloxycarbonyl (Teoc) under acidic conditions (J. Org. Chem., 51, 2594, 1986; J. Org. Chem., 53, 4694, 1988). However, in order to produce an intermediate compound protected with this protecting group (Teoc), in order to avoid the cleavage of the protecting group, the reaction under acidic conditions (particularly the construction of the B ring) cannot be performed, and the construction The law requires multiple steps, leaving problems in terms of efficiency.
Synlett, 388, 2005 J. Org. Chem., 71, 449, 2006 J. Am. Chem. Soc., 127, 14785, 2005 Org. Lett., 8, 5311, 2006 J. Org. Chem., 51, 2594, 1986 J. Org. Chem., 53, 4694, 1988 Tetrahedron Lett., 49, 358, 2008 Synlett, 2859, 2007

  An object of the present invention is to provide an efficient production method of morphine and an intermediate for production that can be suitably used in the efficient production method of morphine.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors utilize a tricyclic production intermediate having A, C, and E rings and protected with a protecting group that is stable under acidic conditions. The ring B can be efficiently constructed under acidic conditions, and by carrying out the cyclization reaction under basic conditions by deprotecting the protecting group from the obtained tetracyclic compound, a very high yield of codeinone is obtained. It was found that it can be manufactured. Since conversion from codeinone to morphine can be easily carried out in a high yield, morphine can be completely synthesized in a highly efficient and high yield by this method. The present invention has been completed based on the above findings.

That is, according to the present invention, the following general formula (I), (II), or (III):
(Wherein R ¹ represents a C _1-6 alkyl group, R ² represents an amino protecting group that is not substantially eliminated under strongly acidic conditions; R ³ and R ⁴ are each independently C _{1 -6 represents} an alkyl group)
Is provided. According to a preferred embodiment, the compounds represented by the above general formulas (I) to (III) wherein R ¹ is a methyl group; the above general formula (I) wherein R ² is a 2,4-dinitrobenzenesulfonyl group Or a compound represented by the above general formula (III), wherein R ³ and R ⁴ are methyl groups.

  These compounds are useful as intermediates for the production of morphine or related compounds such as morphine, codeinone, or codeine. Therefore, according to the present invention, a compound represented by the above general formula (I), (II), or (III) for use as an intermediate for the production of morphine or a similar compound, and the above general formula (I) , (II), or (III) is used as an intermediate for producing morphine or a related compound thereof.

  Another aspect of the present invention is a method for producing a compound represented by the above general formula (II), wherein the hydroxyl group of the compound represented by the above general formula (III) is oxidized to convert it into a ketone, and then subjected to acidic conditions. A method comprising a step of cyclizing with a compound represented by the general formula (I), the method comprising a step of subjecting the compound represented by the general formula (II) to a dehydration reaction; A method for producing the compound represented by the general formula (I), wherein (a) the hydroxyl group of the compound represented by the general formula (III) is oxidized to be converted to a ketone, and then the reaction mixture is cyclized under acidic conditions. And a step of producing a compound represented by the above general formula (II) and (b) subjecting the compound represented by the general formula (II) obtained in the above step (a) to a dehydration reaction. A method is provided by the present invention.

  A method for producing codeinone, the method comprising a step of cyclizing by deprotecting the amino protecting group of the compound represented by the general formula (I) and treating with a base; and a method for producing codeinone (A) oxidizing the hydroxyl group of the compound represented by the above general formula (III) to convert it to a ketone, and then cyclizing under acidic conditions to produce the compound represented by the above general formula (II) (B) a step of subjecting the compound represented by the general formula (II) obtained in the step (a) to a dehydration reaction, and (c) a general formula (I) obtained in the step (b). The present invention provides a method comprising the step of cyclization by deprotecting the amino protecting group of the compound represented by) and treating with a base. Furthermore, according to the present invention, there is provided a method for producing morphine, which comprises a step of reducing a ketone of codeinone and a step of demethylation in addition to the steps (a) to (c).

  Further, according to the present invention, there is provided a method for producing morphine or an analogous compound thereof, the method comprising at least one step selected from the group consisting of the above step (a), step (b), and step (c) according to the present invention. Provided.

Further, according to the present invention, the following general formulas (IV) and (V):
(Wherein R ¹ , R ² , R ³ , and R ⁴ are as defined above). These compounds are also useful as intermediates for the production of morphine or related compounds. In particular, the compound represented by the general formula (IV) is useful as an intermediate for producing the compound represented by the general formula (I). In addition, since the compound represented by the general formula (V) is a compound produced by the conversion to the ketone in the step (a) in the above production method, this compound is used as a starting material, and the step (a In place of), the above compound (V) may be cyclized under acidic conditions to produce a compound represented by the above general formula (II). The above embodiments are also included in the scope of the present invention.

  The compounds provided by the present invention are useful as intermediates for the production of morphine or its related compounds. By using these compounds, morphine or its related compounds can be easily produced with a very high yield.

  The notation of configuration in the chemical formulas shown in the present specification is the same as the notation normally used, and the configuration in the general formula indicates a relative configuration or an absolute configuration, preferably an absolute configuration. The wavy line in the formula indicates that the bond is either an α bond or a β bond, or a combination of both (in which case the compound is a mixture of diastereomers).

As the C _1-6 alkyl group represented by R ¹ , R ³ , and R ⁴ , an alkyl group composed of linear, branched, cyclic, or a combination thereof can be used. A chain or branched alkyl group can be used, and a linear or branched C _1-4 alkyl group can be more preferably used. A methyl group or an ethyl group can be particularly preferably used, and a methyl group is most preferable.

R ² represents an amino protecting group that does not substantially leave under strongly acidic conditions. For the amino protecting group, reference can be made, for example, to Green et al., Protective Groups in Organic Synthesis, 3rd Edition, 1999, John Wiley & Sons, Inc. The strongly acidic conditions are not particularly limited, but it is preferable to select a protecting group that does not substantially desorb in the presence of an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid, trifluoromethanesulfonic acid, and the like. The protecting group is preferably a protecting group that can be easily removed under reaction conditions other than acidic conditions, for example, under basic conditions or in the presence of other reagents. For example, 2,4-dinitrobenzenesulfonyl group (DNs), 2-nitrobenzenesulfonyl group (Ns), 4-nitrobenzenesulfonyl group (Ns), allyloxycarbonyl group (Alloc), 2,2,2-trichloroethylcarbonyl group (Troc), 9-fluorenylmethyl group (Fmoc), 2-chloroethylcarbonyl group and the like can be mentioned, but are not limited thereto. Particularly preferably, a 2,4-dinitrobenzenesulfonyl group can be used.

An example of a typical and preferred method of the present invention is shown in the scheme. Hereinafter, these methods will be specifically described, but the method of the present invention is not limited to the following methods, and is not limited to the specific reaction conditions and reagents shown in the following scheme. .

The compound represented by the above general formula (II) is produced by oxidizing the hydroxyl group of the compound represented by the above general formula (III) to convert it to a ketone, and then cleaving the ketal under acidic conditions to cyclize. can do. In the compound represented by the general formula (II), the hydroxyl group indicated by the wavy line has an α bond, a β bond, or a configuration of either of them. In the above scheme, a case where R ¹ , R ³ , and R ⁴ are methyl groups and R ² is a 2,4-dinitrobenzenesulfonyl group (DNs) is shown as a particularly preferred embodiment of the present invention. The first step of the cyclization reaction is a reaction in which a hydroxyl group is oxidized to a ketone, and this reaction can be performed with high yield using, for example, Dess-Martin periodinane (DMP). However, the oxidizing agent is not limited to DMP, and it is easily understood by those skilled in the art that an appropriate oxidizing agent can be selected.

  The ring B can be efficiently constructed by subjecting the obtained ketone compound to acid treatment to cleave the ketal after or without isolation. The cleavage of the ketal can be performed in the presence of an acid such as acetic acid, trifluoroacetic acid, hydrochloric acid or trifluoromethanesulfonic acid, and the reaction can be particularly preferably performed in the presence of trifluoroacetic acid. The oxidation reaction and the cyclization reaction by ketal cleavage can be preferably carried out in the presence of an inert solvent. The former reaction is carried out in a solvent such as dichloromethane, and the latter is carried out in a solvent such as toluene in the presence of water. The reaction can be carried out in the presence, and can generally be carried out at a temperature ranging from room temperature to about 60 ° C. Without being bound by any particular theory, the above scheme shows a reaction mechanism that is reasonably assumed.

  After the construction of the B ring, the compound represented by the above general formula (I) is produced by dehydrating the obtained compound represented by the general formula (II) (generally obtained as a diastereomer mixture). can do. The dehydration reaction can be performed, for example, by reacting a hydroxyl group with methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base. As the base, for example, an organic amine compound such as triethylamine is preferably used. This reaction can be performed, for example, in the presence of an inert solvent such as dichloromethane. Usually, the reaction can be performed under ice cooling to about 50 ° C., preferably from room temperature to 50 ° C.

By removing the protecting group from the compound represented by the general formula (I), a codeinone in which the D ring is closed can be obtained. When DNs is used as a protecting group, a reagent such as a thiol compound, such as HSCH ₂ COOH, can be used in the presence of a base for the removal of the protecting group. As the base, for example, an organic amine compound such as triethylamine can be used. This reaction can be carried out in the presence of an inert solvent such as dichloromethane, and is generally carried out in the presence of an inert gas such as argon at a temperature of about room temperature to 40 ° C., preferably at room temperature. it can. In this reaction, neopinone which is a structural isomer in addition to codeinone may be obtained as a by-product, but it is well known to those skilled in the art that neopinone can be efficiently converted to cordinone by treating with acid. In this conversion reaction, for example, hydrochloric acid can be used as the acid, and the reaction is preferably performed in the presence of an inert solvent such as ethyl acetate.

The obtained ketone of codeinone can be converted into codeine by reducing it, and the target product morphine can be produced by converting the methoxy group of codeine into a hydroxyl group. Is well known. Examples of morphine-related compounds that can be produced by the method of the present invention include heroin, dihydrocodeine, naloxone, nalolphine and the like in addition to codeinone and codeine shown below, but are not limited thereto. Methods for converting codeinone to these related compounds are well known to those skilled in the art.

The compound represented by the general formula (III) is obtained, for example, by ether-bonding an upper unit corresponding to the A ring and a lower unit corresponding to the C ring by Mitsunobu reaction according to the method shown in the following scheme. The ether compound is cyclized by intramolecular Heck reaction to construct E ring, and if necessary, the amino protecting group can be converted to R ² (in the scheme, Cbz represents benzyloxycarbonyl group). , TBS represents a tert-butyldimethylsilyl group).

The upper unit corresponding to the A ring can be produced, for example, by the method shown in the following scheme (in the scheme, MOM represents a methoxymethyl group).

Further, the lower unit corresponding to the C ring can be produced, for example, by the method shown in the following scheme.

  In the examples of the present specification, each reaction in the above scheme is shown more specifically. Accordingly, those skilled in the art will refer to the general description shown in these schemes and the specific description of the examples, select appropriate reagents and reaction conditions as necessary, and further modify or modify these methods as appropriate. By adding, the compound represented by the general formulas (I) to (III) and the target product, morphine or its related compounds, can be easily produced. The production method of the compound represented by the general formula (III) is not limited to the details shown in these general explanations and the details of the concrete explanations of the examples, and those skilled in the art can use any method. Needless to say, it can be adopted.

Hereinafter, the present invention will be described more specifically with reference to examples. However, the scope of the present invention is not limited to the following examples. In the following examples, Ac represents an acetyl group.
Example 1
2-cyclohexen-1-one (1) (3.06 g, 30.0 mmol) was dissolved in 60 ml of toluene, and Pb (OAc) ₄ (28.0 g, 60.0 mmol) was added thereto, followed by heating to reflux. After 4 hours, ether and 1 M HCl aqueous solution were added, and solids were removed by Celite filtration. The organic layer was washed with H ₂ O and then dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 2.80 g (yield 82%) of acetate 2.
^{1 H NMR (400 MHz, CDCl} 3) δ 6.97 (m, 1 H), 6.07 (d, J = 10.1 Hz, 1 H), 5.37 (dd, J = 4.6 Hz, 13.7 Hz, 1 H), 2.58 ( m, 2 H), 2.29 (m, 1 H), 2.19 (s, 3 H), 2.16 (m, 1 H)

Acetate 2 1.02 g (6.61 mmol) and DMAP 162 mg (1.32 mmol) were dissolved in pyridine 8 ml and carbon tetrachloride 22 ml, and I ₂ 2.51 g (9.92 mmol) was added thereto. The mixture was stirred at room temperature for 30 minutes and then neutralized with 3 M aqueous HCl. After extraction with dichloromethane, the organic layer was washed with saturated aqueous Na ₂ S ₂ O ₃ and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to obtain 1.67 g (yield 90%) of α-iodoenone.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69 (dd, J = 2.8 Hz, 4.9 Hz, 1 H), 5.47 (dd, J = 5.5 Hz, 13.7 Hz, 1 H), 2.58 (m, 2 H) , 2.26 (m, 2 H), 2.18 (s, 3 H)

α-iodoenone 3 14.1 g (50.2 mmol) was dissolved in 100 ml of tetrahydrofuran and 150 ml of pH 7.41 phosphate buffer, and 3.5 g of lipase AK was added thereto. The mixture was stirred at room temperature for 6 hours, extracted with ether, and dried over Na ₂ SO ₄ . After filtration and concentration, 14.1 g of a mixture of alcohol 4 and acetate 5 was obtained as a crude product.

14.1 g of a mixture of alcohol 4 and acetate 5 was dissolved in 200 ml of dichloromethane, and cooled to 0 ° C., 5.85 ml (50.2 mmol) of 2,6-lutidine and 5.76 ml (25.1 ml of TBSOTf (tert-butyldimethylsilyl trifluoromethanesulfonate) mmol) was added. After stirring at 0 ° C. for 30 minutes, the mixture was neutralized with 1 M HCl aqueous solution. After extraction with dichloromethane, it was dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 6.89 g (yield 45%) of TBS ether 6 and 7.17 g (yield 51%) of acetate 5.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (t, J = 4.4 Hz, 1 H), 4.30 (dd, J = 4.8 Hz, 10.8 Hz, 1 H), 2.51 (m, 2 H), 2.18 ( m, 2 H), 0.90 (s, 9 H), 0.16 (s, 3 H), 0.08 (s, 3 H)

7.83 g (22.2 mmol) of ketone 6 and 20.8 mmol (28.9 mmol) of CeCl ₃ · 7H ₂ 0 were dissolved in 111 ml of methanol, and 1.09 g (28.9 mmol) of NaBH ₄ was slowly added little by little while cooling at 0 ° C. After stirring at 0 ° C. for 30 minutes, the mixture was neutralized with 1 M aqueous HCl and methanol was removed under reduced pressure. After extraction with dichloromethane, it was dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: dichloromethane = 1: 1) to obtain 77.76 g of alcohol (yield 99%). The optical purity of alcohol 7 was determined to be 100% ee by measurement using chiral column HPLC.
¹ H NMR (400 MHz, CDCl ₃ ) δ 6.50 (t, J = 3.9 Hz, 1 H), 4.10 (dd, J = 4.1 Hz, J = 4.1 Hz, 1 H), 3.97 (ddd, J = 4.1 Hz , J = 4.1 Hz, J = 9.8 Hz, 1 H), 2.76 (d, J = 4.1 Hz, 1 H), 2.21 (m, 1 H), 2.05 (m, 1 H), 1.85 (m, 1 H ), 1.67 (m, 1 H), 0.91 (s, 9 H), 0.11 (s, 3 H), 0.11 (s, 3 H)

A tetrahydrofuran 11 ml solution containing 1.58 g (8.90 mmol) of vinylcarbamic acid benzyl ester was freeze-degassed, and 1.08 g (4.45 mmol) of 9 (BBN) ₂ was added under an argon atmosphere. After stirring at room temperature for 30 minutes, 5.6 ml of 3 M NaOH solution containing 1.97 g (5.56 mmol) of alcohol and 227 mg (0.28 mmol) of PdCl ₂ dppfCH ₂ Cl ₂ and 11 ml of tetrahydrofuran were frozen and degassed. added. After stirring at room temperature for 2 hours, the mixture was diluted with ether and phosphate buffer, and 30% aqueous H ₂ O solution was added dropwise at 0 ° C. The organic layer and the aqueous layer were separated, and the aqueous layer was extracted with dichloromethane and then dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 1.85 g (82% yield) of carbamate 8.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (m, 5 H), 5.59 (br, 1 H), 5.38 (br, 1 H), 5.09 (s, 2 H), 3.85 (br, 1 H) , 3.75 (ddd, J = 3.6 Hz, J = 3.6 Hz, J = 11.2 Hz, 1 H), 3.35 (m, 2 H), 2.80 (d, J = 3.6 Hz, 1 H), 2.41 (m, 1 H), 2.17 (m, 2 H), 1.97 (m, 1 H), 1.75 (m, 1 H), 1.54 (m, 1 H), 0.91 (s, 9 H), 0.10 (s, 6 H)

In a 19.7 ml solution of tetrahydrofuran containing 1.60 g (3.94 mmol) of alcohol 8 and 1.33 g (3.94 mmol) of phenol, 1.97 ml (7.88 mmol) of ⁿ Bu ₃ P (7.88 mmol) and 3.58 ml (7.88) of diethyl azodicarboxylate under an argon atmosphere mmol) was added. After stirring at room temperature for 30 minutes, the mixture was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 102.75 g (yield 96%) of aryl ether.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34 (m, 5 H), 6.99 (d, J = 8.2 Hz, 1 H), 6.83 (d, J = 8.2 Hz, 1 H), 5.81 (br, 1 H), 5.07 (s, 2 H), 4.91 (br, 1 H), 4.57 (br, 1 H), 4.54 (t, J = 5.5 Hz, 1 H), 4.02 (br, 1 H), 3.82 ( s, 3 H), 3.46 (m, 1 H), 3.34 (s, 3 H), 3.34 (s, 3 H), 3.27 (m, 1 H), 3.06 (d, J = 5.5 Hz, 2 H) , 2.46 (m, 1 H), 2.33 (m, 1 H), 2.25 (m, 2 H), 2.05 (m, 1 H), 1.64 (m, 1 H), 0.75 (s, 9 H),- 0.14 (s, 3 H), -0.18 (s, 3 H)

Iodobenzene 10 1.98 g (2.73 mmol) and the _{Pd 2 (dba) 3 250 mg} (0.27 mmol) and P (o-tol) acetonitrile 18.2 ml solution containing ₃ 166 mg (0.55 mmol), under an argon atmosphere Et ₃ N 1.13 ml (8.19 mmol) was added and heated to reflux. After 2 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to obtain 1.64 g (yield 100%) of carbamic acid ester 11.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (m, 5 H), 6.71 (s, 2 H), 5.97 (d, J = 10.1 Hz, 1 H), 5.69 (m, 1 H), 5.05 ( s, 2 H), 4.75 (br, 1 H), 4.56 (t, J = 4.8 Hz, 1 H), 4.48 (d, J = 7.3 Hz, 1 H), 3.96 (dd, J = 7.3 Hz, J = 12.2 Hz, 1 H), 3.82 (s, 3 H), 3.35 (s, 3 H), 3.31 (s, 3 H), 3.21 (m, 1 H), 3.13 (m, 1 H), 2.88 ( d, J = 4.8 Hz, 2 H), 2.25 (m, 1 H), 2.29 (m, 1 H), 1.98 (m, 2 H), 0.89 (s, 9 H), 0.13 (s, 6 H)

Lithium aluminum hydride (LAH) 226 mg (6.02 mmol) was added little by little to a 10.0 ml tetrahydrofuran solution containing 1.20 g (2.01 mmol) of carbamate 11 and refluxed under heating. After 1 hour, the mixture was diluted with ether, and H ₂ O, 3 M NaOH aqueous solution was added dropwise at 0 ° C. The solid was removed by Celite filtration and then concentrated. The obtained crude product was dissolved in 10.0 ml of dichloromethane and 10.0 ml of a saturated aqueous NaHCO ₃ solution, and 643 mg (2.41 mmol) of 2,4-dinitrobenzenesulfonyl chloride (DNsCl) was added. The mixture was stirred at room temperature for 30 minutes, extracted with dichloromethane, and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to obtain 1.77 g of sulfonamide 12 as a crude product.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 9.1 Hz, 1 H), 8.43 (s, 1 H), 8.04 (d, J = 9.1 Hz, 1 H), 6.75 (s, 2 H), 5.98 (d, J = 9.8 Hz, 1 H), 5.75 (m, 1 H), 4.56 (t, J = 5.7 Hz, 1 H), 3.89 (m, 1 H), 3.82 (s, 3 H), 3.37 (s, 3 H), 3.35 (m, 1 H), 3.33 (s, 3 H), 2.98 (m, 1 H), 2.92 (s, 3 H), 2.86 (d, J = 5.7 Hz, 2 H), 2.27 (m, 1 H), 2.06 (m, 3 H), 0.89 (s, 9 H), 0.12 (s, 6 H)

The sulfonamide 12 1.77 g (22.2 mmol) obtained as a crude product was dissolved in 10.0 ml of methanol, and 140 mg (0.60 mmol) of CSA was added. After stirring for 3 hours, the mixture was neutralized with a saturated aqueous NaHCO ₃ solution, extracted with dichloromethane, and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to obtain 905 mg of alcohol (76% yield).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.44 (d, J = 8.5 Hz, 1 H), 8.44 (s, 1 H), 8.07 (d, J = 8.5 Hz, 1 H), 6.78 (d, J = 8.5 Hz, 1 H), 6.75 (d, J = 8.5 Hz, 1 H), 6.02 (d, J = 11.2 Hz, 1 H), 5.83 (m, 1 H), 4.53 (t, J = 4.8 Hz , 1 H), 4.37 (d, J = 8.5 Hz, 1 H), 3.85 (s, 3 H), 3.85 (m, 1 H), 3.37 (s, 3 H), 3.35 (m, 1 H), 3.32 (s, 3 H), 2.97 (m, 1 H), 2.92 (s, 3 H), 2.87 (d, J = 4.8 Hz, 2 H), 2.65 (br, 1 H), 2.41 (m, 1 H), 2.15 (m, 2 H), 1.97 (m, 1 H)

Alcohol 13 402 mg (0.677 mmol) was dissolved in dichloromethane 6.7 ml, and Dess-Martin periodinane 430 mg (1.02 mmol) was added. After stirring at 40 ° C. for 10 minutes, a saturated aqueous Na ₂ S ₂ O ₃ solution was added, extracted with dichloromethane, and dried over Na ₂ SO ₄ . After filtration and concentration, β, γ-unsaturated ketone 14 442 mg was obtained as a crude product.

442 mg of β, γ-unsaturated ketone 14 was dissolved in 6.7 ml of toluene, and 2.3 ml of 50% aqueous trifluoroacetic acid (TFA) solution was added. After stirring at 50 ° C. for 3 hours, the mixture was neutralized with saturated aqueous NaHCO ₃ solution, extracted with ethyl acetate, and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to obtain 15282 mg of alcohol (77% yield) as a mixture of diastereomers.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (m, 2 H), 8.45 (m, 2/3 H), 8.13 (d, J = 8.3 Hz, 1/3 H), 8.04 (d, J = 10.1 Hz, 1 H), 7.09 (dd, J = 11.0 Hz, J = 4.4 Hz, 1/3 H), 7.06 (dd, J = 11.0 Hz, J = 4.4 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 4/3 H), 6.70 (d, J = 8.3 Hz, 4/3 H), 6.24 (d, J = 11.0 Hz, 1/3 H), 6.14 (d, J = 11.0 Hz, 1 H), 4.83 (s, 1 H), 4.78 (s, 1/3 H), 3.87 (s, 3 H), 3.85 (s, 3/3 H), 3.62 (m, 4/3 H), 3.48 (m, 4/3 H), 3.14 (m, 4/3 H), 3.04 (m, 4/3 H), 2.94 (s, 3/3 H), 2.92 (s, 3 H), 2.88 (m , 2 H), 2.85 (m, 2/3 H), 2.53 (d, J = 9.2 Hz, 4/3 H),
2.21 (m, 4/3 H), 2.12 (m, 4/3 H)

Diastereomeric alcohols 15 3.2 mg a-mer mixture (0.0059 mmol) and triethylamine _{(Et 3 N) 4.1 μl (} 0.0295 mmol) in dichloromethane 0.2 ml solution methanesulfonyl chloride (MsCl) and 1.3 [mu] l was added containing, stirred for 10 minutes at room temperature did. The temperature was raised from room temperature to 50 ° C. and stirred for 30 minutes. A saturated aqueous NH ₄ Cl solution was added, and the mixture was extracted with ethyl acetate, and then dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by preparative thin layer chromatography to obtain 16 2.5 mg (80%) of dienone.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.45 (d, J = 10.1 Hz, 1 H), 8.44 (s, 1 H), 8.07 (d, J = 10.1 Hz, 1 H), 7.28 (d, J = 10.1 Hz, 1 H), 6.76 (d, J = 8.3 Hz, 1 H), 6.70 (d, J = 8.3 Hz, 1 H), 6.41 (d, J = 4.6 Hz, 1 H), 5.98 (d , J = 10.1 Hz, 1 H), 5.00 (s, 1 H), 3.87 (s, 3 H), 3.59 (d, J = 20.2 Hz, 1 H), 3.43 (d, J = 20.2 Hz, 1 H ), 3.42 (m, 1 H), 3.11 (m, 1 H), 2.91 (s, 3 H), 2.16 (m, 2 H)

HSCH ₂ CO ₂ H 0.8 μl (0.0091 mmol) was added to a dichloromethane 0.2 ml solution containing dienone 16 4.0 mg (0.0076 mmol) and triethylamine 3.2 μl (0.0227 mmol) under an argon atmosphere. After stirring at room temperature for 5 minutes, a saturated aqueous NaHCO ₃ solution was added, and the mixture was further stirred for 30 minutes. After extraction with chloroform, and dried over Na ₂ SO _4. After filtration, the filtrate was concentrated and purified by preparative thin layer chromatography to obtain 1.8 mg (yield 80%) of a mixture of neopinone (17) and codeinone (18).

A mixture of neopinone (17) and codeinone (18) (1.8 mg, 0.0061 mmol) was dissolved in 4 M HCl acetic acid solution. After stirring at room temperature for 30 minutes, a saturated aqueous NaHCO ₃ solution was added to neutralize. After extraction with dichloromethane, it was dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated to obtain 1.8 mg of codeinone (18) as a crude product. 1.8 mg of the resulting codeinone (18) was dissolved in 0.2 ml of methanol, 0.3 mg of NaBH ₄ was added, and the mixture was stirred at room temperature for 10 minutes. H ₂ O was added, extracted with dichloromethane, and dried over Na ₂ SO ₄ . After filtration, the filtrate was concentrated and purified by preparative thin layer chromatography to obtain 1.8 mg (99%) of codeine (19).
¹ H NMR (400 MHz, CDCl ₃ ) δ 6.66 (d, J = 8.0 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 5.72 (d, J = 11.0 Hz, 1 H), 5.29 (d, J = 11.0 Hz, 1 H), 4.91 (d, J = 6.6 Hz, 1 H), 4.18 (s, 1 H), 3.85 (s, 3 H), 3.36 (m, 1 H), 3.05 (d, J = 18.8 Hz, 1 H), 2.87 (br, 1 H), 2.67 (s, 1 H), 2.60 (s, 1 H), 2.42 (s, 3 H), 2.38 (s, 1 H), 2.30 (s, 1 H), 2.07 (s, 1 H), 1.88 (d, J = 10.8 Hz, 1 H)

Claims (11)

The following general formula (I), (II), or (III):
(Wherein R ¹ represents a C _1-6 alkyl group, R ² represents an amino protecting group that is not substantially eliminated under strongly acidic conditions; R ³ and R ⁴ are each independently C _{1 -6 represents} an alkyl group)
A compound represented by The compound represented by any one of formulas (I) to (III) according to claim 1, wherein R ¹ is a methyl group and R ² is a 2,4-dinitrobenzenesulfonyl group. R ¹ is a methyl group, R ² is 2,4-nitrobenzenesulfonyl group, compounds wherein R ³ and R ⁴ is represented by the general formula of claim 1 is a methyl group (III). The compound represented by the general formula (I), (II), or (III) according to any one of claims 1 to 3, for use as an intermediate for the production of morphine or a related compound thereof. The compound according to claim 4, wherein the morphine or a related compound thereof is morphine, codeinone, or codeine. A method for producing a compound represented by the general formula (II) according to claim 1, wherein the hydroxyl group of the compound represented by the general formula (III) according to claim 1 is oxidized and converted into a ketone. , Cyclization under acidic conditions. A method for producing a compound represented by the general formula (I) according to claim 1, comprising a step of subjecting the compound represented by the general formula (II) according to claim 1 to a dehydration reaction. It is a manufacturing method of the compound represented by general formula (I) of Claim 1, Comprising: The following processes:
(a) The hydroxyl group of the compound represented by the general formula (III) according to claim 1 is oxidized to be converted to a ketone, and then cyclized under acidic conditions to give the general formula (II) according to claim 1 Producing the compounds represented; and
(b) A method comprising a step of subjecting the compound represented by the general formula (II) according to claim 1 obtained in the step (a) to a dehydration reaction. A method for producing morphine or a related compound thereof, comprising the following steps:
(a) The hydroxyl group of the compound represented by the general formula (III) according to claim 1 is oxidized to be converted to a ketone, and then cyclized under acidic conditions to give the general formula (II) according to claim 1 Producing the compound represented;
(b) subjecting the compound represented by the general formula (II) according to claim 1 obtained in the step (a) to a dehydration reaction; and
(c) at least one selected from the group consisting of a step of cyclization by deprotecting the amino protecting group of the compound represented by the general formula (I) obtained in the step (b) and treating with a base A method comprising the steps. A method for producing morphine or a related compound thereof, comprising the following steps:
(a) The hydroxyl group of the compound represented by the general formula (III) according to claim 1 is oxidized to be converted to a ketone, and then cyclized under acidic conditions to give the general formula (II) according to claim 1 Producing the compound represented;
(b) subjecting the compound represented by the general formula (II) according to claim 1 obtained in the step (a) to a dehydration reaction; and
(c) A method comprising a step of producing codeinone by cyclization by deprotecting the amino protecting group of the compound represented by the general formula (I) obtained in the step (b) and treating with a base. A method for producing morphine, which comprises the following steps in addition to steps (a) to (c) of claim 10:
(d) A method comprising a step of reducing the codeinone ketone obtained in the step (c) and a step of demethylation.