Method for producing morphinan derivatives

Abstract

Provided is a method for producing a morphinan derivative represented by general formula (II), etc., by causing metallic sodium and ethylenediamine to act on a morphinan derivative represented by general formula (I) in the presence of an auxiliary solvent. (In the formula, R1 represents a hydrogen atom or an optionally substituted C1-10 alkyl group, C3-6 cycloalkyl group, C2-6 alkenyl group, C6-10 aryl group or heteroaryl group, R2 represents an amino protecting group, R3 represents a methoxy group, R4 and R5 represent a hydrogen atom or a hydroxy group, R6 and R7 represent a hydrogen atom or an electron-donating group; here, R6 and R7 are not simultaneously hydrogen atoms, and X represents O or CH2.)

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of morphinan derivatives and to novel morphinan derivatives which can be used as starting materials in said process. This application claims priority based on Japanese Patent Application No. 2019-134051, filed on July 19, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] There are three types of opioid receptors known: μ, δ, and κ. Morphine, which has a strong affinity for μ receptors, has long been used as an analgesic. Although morphine has a strong analgesic effect, it is known to cause adverse events such as dependence, respiratory depression, and constipation via the μ receptor. On the other hand, it is known that δ receptors also have analgesic effects, but δ receptor agonists are not involved in the adverse events seen with morphine. Therefore, it is believed that agonists selective for δ receptors may be better analgesics than morphine, and research into their creation is being actively conducted. However, there are no δ receptor agonists approved as therapeutic or preventive drugs yet.

[0003] Patent Documents 1 and 2 disclose morphinan derivatives having excellent δ receptor agonist activity, which are represented by the following formula.

[0004] [ka]

[0005] The production of these derivatives requires a multi-step synthesis, and therefore it is desirable to have a high yield in each reaction and a high purity of the target compound obtained in each reaction. For example, paragraph

[0025] of Patent Document 1 discloses a method in which a phenyl group is introduced into a phenol (b-1) at the 4-position of a morphinan derivative by Ullmann reaction to obtain compound (m), and the oxygen functional group at the 4-position is removed using commercially available silica gel-supported sodium, sodium silica gel stage I, and ethylenediamine to obtain compound (n).

[0006] [ka] However, the silica gel-supported sodium used in the above reaction is expensive and difficult to obtain in large quantities, making it difficult to utilize industrially. On the other hand, many examples of similar dephenoxylation reactions using metallic sodium have been reported. For example, Non-Patent Document 1 discloses a synthesis example of compound 2, which is dephenoxylated by reacting compound 1, which has a 2,4-diaminophenyloxy group on the benzene ring of the morphinane skeleton, with metallic sodium in liquid ammonia.

[0007] [ka] Furthermore, EXAMPLE 1 of Patent Document 3 discloses an example in which 14β-hydroxy-3-methoxymorphinan (IV) is synthesized by reacting 4-phenoxy-14β-hydroxy-3-methoxymorphinan (III) with metallic sodium in liquid ammonia at −40° C.

[0008] [ka] In addition, Non-Patent Document 2 discloses a synthesis example of dephenoxylated compound 12 by reacting compound 11 having a phenoxy group with metallic sodium in liquid ammonia at −78° C. to room temperature.

[0009] [ka] In addition, similar reactions have been reported in Non-Patent Documents 3 to 9. [Prior art documents] [Patent documents]

[0010] [Patent Document 1] International Publication No. 2013 / 035833 [Patent Document 2] International Publication No. 2016 / 148232 [Patent Document 3] U.S. Patent No. 5,504,208 [Non-patent literature]

[0011] [Non-Patent Document 1] Journal of Organic Chemistry,1965,30(6),1769-1773 [Non-Patent Document 2] Bioorganic & Medicinal Chemistry Letters,19(16),4603‐4606; 2009 [Non-Patent Document 3] Chemical Biology & Drug Design,74(4),335-342;2009 [Non-Patent Document 4] Journal of Medicinal Chemistry,50(11),2747-2751; 2007 [Non-Patent Document 5] Tetrahedron,24(20),6185-96;1968 [Non-Patent Document 6] Journal of Medicinal Chemistry,58(12),5038-5052;2015 [Non-Patent Document 7] Recueil des Travaux Chimiques des Pays-Bas,107(6),449-54;1988 [Non-Patent Document 8] Helvetica Chimica Acta,73(2),326-36;1990 [Non-Patent Document 9] J. Org. Chem.2008,73,8093-8096 Summary of the Invention [Problem to be solved by the invention]

[0012] The present inventors have found that in the production of a morphinan derivative (n) which is a dephenoxylated diaryl ether derivative (m) shown in paragraph number

[0025] of Patent Document 1, as shown in the diagram below, the cleavage position of the bond between the oxygen atom and the two aryl groups cannot be controlled, and in addition to the desired dephenoxylated product (n), cleavage occurs at an undesired position to produce the raw material compound (b-1) as a by-product. The by-product compound (b-1) is structurally similar to the desired dephenoxylated product (n), making it difficult to separate from the desired product (n), and chromatographic purification is required. Furthermore, they have found that in an industrialized process, purification by chromatography is undesirable and poses a major problem. Furthermore, in the production of compound (n) from compound (m), the inventors carried out a reaction similar to that described in Patent Document 1 using metallic sodium pieces that are applicable to industrialized processes instead of silica gel-supported sodium, which has problems in application to industrialized processes. However, they found a problem in that the reaction was not completed even when metallic sodium pieces were used in large excess relative to compound (m), resulting in the raw material remaining.

[0013] [ka] Therefore, one object of the present invention is to provide a method for highly selectively producing a morphinan derivative (n) from a diaryl ether derivative (m) while suppressing the production of a by-product, that is, a phenol (b-1), which can be applied to an industrial production process.

[0014] The present inventors have intensively studied the method for producing the morphinan derivative (n) described in paragraph

[0025] of Patent Document 1, and have found that by using a compound in which a substituent has been introduced into a specific position of the phenyl group introduced into compound (b-1) by the Ullmann reaction as a starting material for the dearyloxy reaction instead of compound (m), it becomes possible to highly control the cleavage position between oxygen and the aryl group, and the target compound (n) can be obtained with high selectivity. In addition, the present inventors have found that the target compound (n) can be obtained with high yield by using a sodium dispersion that can also be applied to industrial production methods, and have completed the present invention. [Means for solving the problem]

[0015] That is, the present invention provides [1] The following general formula (I): [ka] (In the formula, R 1 is a hydrogen atom, optionally substituted C 1-10 Alkyl group, optionally substituted C 3-6 Cycloalkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 6-10 represents an aryl group or an optionally substituted heteroaryl group, R 2 represents an amino protecting group, R 3 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-10 represents an alkoxy group, R 4 and R 5 are the same or different and each represents a hydrogen atom or a hydroxy group, R 6 and R 7 are the same or different and each represents a hydrogen atom or an electron-donating group, Here, R 6 and R 7 is not a hydrogen atom at the same time, and X represents O or CH2. A morphinan derivative represented by the formula: The following general formula (II): [ka] (In the formula, R 1 ~R 5 and X are as defined above. [2] The present invention also provides R 1 The present invention relates to a method for producing the morphinan derivative according to the above [1], wherein [3] The present invention also provides R 1 C may have a substituent 3-6 Cycloalkyl-substituted C 1-10 The present invention relates to a method for producing the morphinan derivative described in the above [1], which is an alkyl group. [4] The present invention also provides R 1 The present invention relates to a method for producing the morphinan derivative according to the above [1] or [3], wherein [5] The present invention also provides R 2 The present invention relates to a method for producing a morphinan derivative according to any one of the above [1] to [4], wherein [6] The present invention also provides R 3 C 1-10 The present invention relates to a method for producing the morphinan derivative according to any one of the above [1] to [5], wherein the alkoxy group is an alkoxy group. [7] The present invention also provides R 3 The present invention relates to a method for producing a morphinan derivative according to any one of the above [1] to [6], wherein [8] The present invention also provides R 4 and R 5 The present invention relates to a method for producing a morphinan derivative according to any one of the above [1] to [7], wherein [9] The present invention also provides R 6 C 1-10 Alkyl group, OR 8 (R 8 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 9 R 10 (R 9 and R 10 are the same or different, and may have a hydrogen atom or a substituent. 1-10 represents an alkyl group.) The present invention relates to a method for producing a morphinan derivative according to any one of the above items [1] to [8].

[10] The present invention also provides R 6 C may have a substituent 1-10 The present invention relates to a method for producing the morphinan derivative according to any one of the above [1] to [9], wherein the morphinan derivative is an alkyl group.

[11] The present invention also provides R 6 The present invention relates to a method for producing a morphinan derivative according to any one of the above [1] to

[10] , wherein

[12] The present invention also provides R 6 The method for producing a morphinan derivative according to any one of the above [1] to [8], wherein

[13] The present invention also provides R 7 The present invention relates to a method for producing a morphinan derivative according to any one of the above [1] to

[11] , wherein

[14] The present invention also provides R 7 C may have a substituent 1-10 Alkyl group, OR 11 (R 11 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 12 R 13 (R 12 and R 13 are the same or different, and may have a hydrogen atom or a substituent. 1-10represents an alkyl group.) The present invention relates to a method for producing a morphinan derivative according to any one of the above items [1] to

[12] .

[15] The present invention also provides R 7 C may have a substituent 1-10 The present invention relates to a method for producing the morphinan derivative according to any one of the above items [1] to

[12] and

[14] , wherein the alkoxy group is selected from the group consisting of alkoxy groups.

[16] The present invention also provides R 7 The present invention relates to a method for producing a morphinan derivative according to any one of the above items [1] to

[12] ,

[14] and

[15] , wherein

[17] The present invention also relates to a method for producing a morphinan derivative according to any one of the above [1] to

[16] , wherein metallic sodium is used in an amount of 1 to 10 equivalents based on the morphinan derivative of the above general formula (I).

[18] The present invention also relates to the method for producing a morphinan derivative according to any one of the above [1] to

[17] , wherein the metallic sodium is a metallic sodium dispersion.

[19] The present invention also relates to a process for producing a morphinan derivative according to any one of the above [1] to

[18] , wherein the auxiliary solvent is an aromatic hydrocarbon-based or ether-based solvent.

[20] The present invention also relates to a method for producing a morphinan derivative according to any one of the above [1] to

[19] , wherein the reaction temperature is from -30°C to 150°C. [twenty one] The present invention also relates to a method for producing a morphinan derivative according to any one of [1] to

[20] , wherein the reaction temperature is 0°C to 30°C. [twenty two] The present invention also relates to a compound represented by the following general formula (I): [ka] (In the formula, R 1 is a hydrogen atom, optionally substituted C 1-10 Alkyl group, optionally substituted C 3-6Cycloalkyl group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 6-10 represents an aryl group or an optionally substituted heteroaryl group, R 2 represents an amino protecting group, R 3 is a hydrogen atom, a halogen atom, or an optionally substituted C 1-10 represents an alkoxy group, R 4 and R 5 are the same or different and each represents a hydrogen atom or a hydroxy group, R 6 and R 7 are the same or different and each represents a hydrogen atom or an electron-donating group, Here, R 6 and R 7 is not a hydrogen atom at the same time, and X represents O or CH2. The present invention relates to a morphinan derivative represented by the formula: [twenty three] The present invention also provides R 1 wherein R is a hydrogen atom. [twenty four] The present invention also provides R 1 C may have a substituent 3-6 Cycloalkyl-substituted C 1-10 The morphinan derivative according to the above

[22] , wherein the alkyl group is an alkyl group. [twenty five] The present invention also provides R 1 wherein R is a cyclopropylmethyl group.

[26] The present invention also provides R 2 The morphinan derivative according to any one of the above

[22] to

[25] , wherein is a benzyl group.

[27] The present invention also provides R 3 C 1-10 The present invention relates to the morphinan derivative according to any one of the above

[22] to

[26] , wherein the alkoxy group is an alkoxy group.

[28] The present invention also provides R 3 The morphinan derivative according to any one of the above

[22] to

[27] , wherein is a methoxy group.

[29] The present invention also provides R 4 and R 5 The morphinan derivative according to any one of the above

[22] to

[28] , wherein is a hydrogen atom.

[30] The present invention also provides R 6 C 1-10 Alkyl group, OR 8 (R 8 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 9 R 10 (R 9 and R 10 are the same or different, and may have a hydrogen atom or a substituent. 1-10 represents an alkyl group.

[31] The present invention also provides R 6 C may have a substituent 1-10 The present invention relates to the morphinan derivative according to any one of the above

[22] to

[30] , which is an alkyl group.

[32] The present invention also provides R 6 The morphinan derivative according to any one of the above

[22] to

[31] , wherein

[33] The present invention also provides R 6 The morphinan derivative according to any one of the above

[22] to

[29] , wherein is a hydrogen atom.

[34] The present invention also provides R 7 The morphinan derivative according to any one of the above

[22] to

[32] , wherein is a hydrogen atom.

[35] The present invention also provides R 7 C may have a substituent 1-10Alkyl group, OR 11 (R 11 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 12 R 13 (R 12 and R 13 are the same or different, and may have a hydrogen atom or a substituent. 1-10 represents an alkyl group.

[36] The present invention also provides R 7 C may have a substituent 1-10 The present invention relates to the morphinan derivative according to any one of the above

[22] to

[33] and

[35] , wherein the alkoxy group is an alkoxy group.

[37] The present invention also provides R 7 The morphinan derivative according to any one of the above

[22] to

[33] ,

[35] and

[36] , wherein

[38] Furthermore, the present invention relates to a method for producing a (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole, (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(3-methoxyphenoxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole and (1S,3aR,5aS,6R,11bS,11cS)-3-Benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(p-toluyloxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole The present invention relates to a morphinan derivative selected from the group consisting of Effect of the Invention

[0016] According to the present invention, there can be provided a method for producing a morphinan derivative (n) with high selectivity from a diaryl ether derivative (m) while suppressing the production of a by-product, that is, a phenol (b-1), which can be applied to an industrial production process. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The present invention will now be described in more detail. In the above general formula (I), R 1 C, which may have the following substituent: 1-10 The alkyl group may be a halogen atom, a hydroxyl group, or a C 1-10 C which may have a substituent selected from an alkoxy group, an amino group, etc. 1-10 Alkyl group; optionally substituted C 3-6 Cycloalkyl-substituted C 1-10 Examples of the group include an alkyl group, an aralkyl group which may have a substituent, and a heteroarylalkyl group which may have a substituent. R 1 C, which may have the following substituent: 1-10 Alkyl C 1-10 The alkyl group may be a straight or branched C alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group. 1-10 Examples of the alkyl group include an alkyl group, preferably a methyl group, an ethyl group, or a propyl group, and more preferably a methyl group.

[0018] R 1 C, which may have the following substituent: 3-6 Cycloalkyl-substituted C 1-10 The alkyl group may be a halogen atom, a hydroxyl group, or a C 1-10 C aryl such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, which may have a substituent selected from an alkoxy group, an amino group, and the like;3-6 Examples of the cycloalkyl group include a methyl group or an ethyl group substituted with a cycloalkyl group. Preferred examples include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group or a cyclobutylethyl group, and more preferred examples include a cyclopropylmethyl group. R 1 The aralkyl group which may have a substituent is a halogen atom, a hydroxy group, C 1-10 The number of carbon atoms in the aryl portion may be C, which may have a substituent selected from an alkoxy group, an amino group, and the like. 6-10 The number of carbon atoms in the alkylene portion is C 1-5 Preferred are methyl or ethyl groups substituted with phenyl or naphthyl, and more preferred are methyl groups substituted with phenyl (that is, benzyl groups). R 1 The optionally substituted heteroarylalkyl group includes a halogen atom, a hydroxyl group, 1-10 The heteroaryl moiety, which may have a substituent selected from an alkoxy group, an amino group, and the like, contains 1 to 4 heteroatoms, which may be the same or different, selected from a nitrogen atom, an oxygen atom, and a sulfur atom, as ring-constituting atoms, and the alkyl moiety is a C group such as a methyl group, an ethyl group, or a propyl group. 1-6 Examples of the heteroarylalkyl group include an alkyl group, and preferably include monocyclic heteroarylalkyl groups such as a (pyridin-2-yl)methyl group, a (pyridin-3-yl)methyl group, a (pyridin-4-yl)methyl group, a 2-(pyridin-2-yl)ethyl group, a (furan-2-yl)methyl group, a (furan-3-yl)methyl group, a (imidazol-2-yl)methyl group, a (imidazol-4-yl)methyl group, a (imidazol-5-yl)methyl group, a (thiazol-2-yl)methyl group, a (thiazol-4-yl)methyl group, a (thiazol-5-yl)methyl group, a (thiophene-2-yl)methyl group, or a 2-(thiophene-2-yl)ethyl group, and bicyclic heteroarylalkyl groups such as a (quinolin-3-yl)methyl group or an (indol-3-yl)methyl group.

[0019] In the above general formula (I), R 1 C, which may have the following substituent: 3-6 Cycloalkyl groups include halogen atoms, hydroxy groups, C 1-10 Examples of the aryl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, each of which may have a substituent selected from an alkoxy group, an amino group, and the like, and preferably a cyclopropyl group. In the above general formula (I), R 1 C, which may have the following substituent: 2-6 The alkenyl group may be a halogen atom, a hydroxyl group, or a C 1-10 Examples of alkenyl groups include an allyl group, a vinyl group, a 1-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, and a 5-hexenyl group, which may have a substituent selected from an alkoxy group, an amino group, and the like. In the above general formula (I), R 1 C, which may have the following substituent: 6-10 The aryl group includes a halogen atom, a hydroxyl group, and C 1-10 Examples of the group include a phenyl group or a naphthyl group, which may have a substituent selected from an alkoxy group, an amino group, and the like, and a phenyl group is preferred. In the above general formula (I), R 1 The optionally substituted heteroaryl group includes a halogen atom, a hydroxyl group, 1-10 Examples of heteroaryl groups include heteroaryl groups containing 1 to 4 heteroatoms, which may be the same or different, selected from a nitrogen atom, an oxygen atom and a sulfur atom as ring-constituting atoms, and which may have a substituent selected from an alkoxy group, an amino group, etc., and preferred examples include monocyclic heteroaryl groups such as a pyridyl group, a furyl group, an imidazolyl group, a pyrimidinyl group, a pyrazinyl group, or a thiazolyl group; and bicyclic heteroaryl groups such as a quinolyl group, or an indolyl group.

[0020] R 2Examples of the amino-protecting group represented by the formula (I) include a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-methoxybenzylcarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, and a 3,5-dimethoxybenzyloxycarbonyl group. carbamate-based protecting groups such as 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, and 9-fluorenylmethyloxycarbonyl group; sulfonamide-based protecting groups such as p-toluenesulfonyl group and 2-nitrobenzenesulfonyl group; acyl-based protecting groups such as acetyl group and trifluoroacetyl group; imide-based protecting groups such as phthaloyl group; C-type protecting groups such as benzyl group, trityl group, and naphthylmethyl group 7-19 and the like, and preferably C 7-19 Of these, an aralkyl group represented by the formula (I) is preferable, and a benzyl group is more preferable.

[0021] R 3 C, which may have the following substituent: 1-10 The alkoxy group includes a halogen atom, a hydroxyl group, and C 1-10 A linear or branched C alkyl group such as a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group, or a hexyloxy group, which may have a substituent selected from an alkoxy group, an amino group, or the like. 1-10 Examples of the alkyl group include an alkoxy group, preferably a methoxy group, an ethoxy group, or a propoxy group, and more preferably a methoxy group.

[0022] R 6 The electron donating group represented by the formula (I) is a halogen atom, a hydroxyl group, 1-10 C which may have a substituent selected from an alkoxy group, an amino group, etc. 1-10Alkyl group, OR 8 (R 8 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 9 R 10 etc., where R 9 and R 10 are the same or different, and may have a hydrogen atom or a substituent. 1-10 Represents an alkyl group. R 8 C, which may have the following substituent: 1-10 The alkyl group may be a straight or branched C alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, or a hexyl group. 1-10 Examples of the alkyl group include an alkyl group, and a preferred example is a tert-butyl group. R 9 and R 10 Examples of the amino group include an amino group, a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, and a propylamino group. R 6 As the ion exchange agent, preferably C 1-10 An alkyl group is preferable, and a tert-butyl group is more preferable.

[0023] R 7 The electron donating group represented by the formula (I) is a halogen atom, a hydroxyl group, 1-10 C which may have a substituent selected from an alkoxy group, an amino group, etc. 1-10 Alkyl group, OR 11 (R 11 is a hydrogen atom or an optionally substituted C 1-10 represents an alkyl group, or NR 12 R 13 (R 12 and R 13 are the same or different, and may have a hydrogen atom or a substituent. 1-10 represents an alkyl group. R 11 C, which may have the following substituent: 1-10 The alkyl group is R 8C, which may have the following substituent: 1-10 The same as the alkyl group can be mentioned, and R 12 and R 13 As for R 9 and R 10 The following are some examples:

[0024] X may be an oxygen atom or CH2, with CH2 being preferred.

[0025] In the present specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom, preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom. In this specification, C 1-10 The alkoxy group is a straight-chain or branched C alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, a tert-butoxy group, a pentyloxy group, or a hexyloxy group. 1-10 Examples of the alkyl group include an alkoxy group, preferably a methoxy group, an ethoxy group, or a propoxy group, and more preferably a methoxy group. In the present specification, the amino group is NR d R e where R d and R e are the same or different, and may have a hydrogen atom or a substituent. 1-10 Examples of the alkyl group include an alkyl group, and preferred examples include an amino group, a dimethylamino group, and a diethylamino group.

[0026] Preferred combinations of these substituents include: R 1 C may have a substituent 1-10 C which may have an alkyl group or a substituent 3-6 Cycloalkyl-substituted C 1-10 is an alkyl group; R 2 is an amino protecting group; R 3 is a methoxy group; R 4and R 5 is a hydrogen atom; R 6 is a hydrogen atom or C 1-10 is an alkyl group; R 7 is a hydrogen atom or a methoxy group; However, R 6 and R 7 and X is CH2.

[0027] The compound represented by the above general formula (I) can be produced by known methods, for example, the method described in Patent Document 1. The morphinan derivative represented by the general formula (II) can be produced by reacting the compound of the general formula (I) with metallic sodium in the presence of ethylenediamine.

[0028] [ka]

[0029] As the sodium reagent used in the above reaction, commercially available products such as metallic sodium and metallic sodium dispersions can be used, with metallic sodium dispersions being preferred. In this specification, the metallic sodium dispersion refers to a dispersion obtained by dissolving sodium in an inert solvent having a boiling point of 100° C. or higher, gradually cooling the solution while vigorously stirring the solution to solidify the sodium. The particle size of the metallic sodium dispersion used is, for example, 1 to 100 μm, preferably 1 to 75 μm, more preferably 1 to 50 μm, and even more preferably 1 to 25 μm. The amount of the sodium reagent used in the above reaction is 1 to 50 equivalents relative to the raw materials, preferably 1 to 30 equivalents, more preferably 1 to 20 equivalents, further preferably 1 to 10 equivalents, preferably 2 to 10 equivalents, and preferably 5 to 10 equivalents.

[0030] Instead of the ethylenediamine used in the above reaction, other primary amines (eg, ethylamine, propylamine, etc.) may be used, but it is preferable to use ethylenediamine. The amount of ethylenediamine or other primary amine used is 1 to 100 mol, preferably 1 to 50 mol, more preferably 1 to 30 mol, further preferably 1 to 20 mol, more preferably 1.5 to 20 mol, per mol of the sodium reagent.

[0031] The auxiliary solvent used in the above reaction includes aromatic hydrocarbon or ether solvents. Examples of the aromatic hydrocarbon solvent include benzene, toluene, xylene, etc., preferably toluene. Examples of the ether solvent include tetrahydrofuran, 1,4-dioxane, etc., preferably tetrahydrofuran. Of these solvents, tetrahydrofuran is preferable. The amount of the auxiliary solvent to be used is not particularly limited, but is preferably in the range of 1 to 50 parts by mass, more preferably 1 to 20 parts by mass, per part by mass of the morphinan derivative represented by the above general formula (I). These organic solvents are preferably purified by a known method such as distillation before use.

[0032] The above reaction is preferably carried out under an inert gas such as nitrogen or argon, and the reaction temperature can be in the range of -30 to 150°C, preferably -10 to 120°C, and more preferably -5 to 115°C. The target compound can be obtained by reacting for 1 to 16 hours. The morphinan derivative represented by the general formula (II) produced by the above-mentioned method can be isolated and / or purified by applying a method known per se, such as solvent extraction, concentration, crystallization, precipitation, filtration, chromatography, etc. When the production method of the present invention is applied as an industrial production method, it is preferable not to use chromatography as a purification method from the viewpoint of production efficiency. Therefore, one embodiment of the present invention is the above-mentioned production method, which includes at least one step selected from solvent extraction, concentration, crystallization, precipitation, and filtration as a step for isolating and / or purifying the morphinan derivative represented by general formula (II), and does not include a chromatography step. By applying the above-mentioned isolation and / or purification process, the morphinan derivative represented by the general formula (II) can be obtained, for example, with a purity of 75% or more, preferably 80% or more, more preferably 90% or more, and even more preferably 94% or more, and with a yield of 75% or more, preferably 80% or more, more preferably 85% or more, even more preferably 90% or more, and particularly preferably 95% or more. In addition, the content of the phenol body (b-1) which is a by-product in the target product can be 5% by mass or less, preferably 3% by mass or less, more preferably 1% by mass or less, and even more preferably 0% by mass, i.e., none, relative to the mass of the target product. EXAMPLES

[0033] The present invention will be described in more detail below with reference to Examples, Reference Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. The names of the compounds of the Examples, Reference Examples, and Comparative Examples were derived by converting the structural formulas drawn using ChemDraw ver.15 (CambridgeSoft) into English names using the naming algorithm built into the software, and then translating them into Japanese.

[0034] 1. Starting material: Preparation of diaryl ether derivatives An example of the production of a diphenyl ether derivative by Ullmann coupling of bromobenzene with (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-ol is shown below.

[0035] (Reference example 1) Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-phenoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0036] [ka] In a 300 mL round-bottom flask, (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-ol dihydrochloride (5 g, 1 eq.) was dissolved in pyridine (50 mL) under a nitrogen atmosphere. Potassium carbonate (3.8 g, 6 eq.), bromobenzene (4.8 mL, 5 eq.) and copper powder (0.6 g, 1 eq.) were added to the resulting solution and heated to reflux with vigorous stirring. After 16 hours, the disappearance of the raw materials was confirmed by mass spectrometry (MS) and thin layer chromatography. After cooling the reaction mixture to room temperature, the reaction mixture was filtered through a Celite pad to remove insoluble matter. The pad was washed with ethyl acetate (50 mL) and methanol (50 mL), and 6% aqueous ammonia (50 mL) was added to the combined filtrate and washings. The organic layer and the aqueous layer were separated using a separatory funnel, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (50 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off, followed by concentration under reduced pressure to obtain the title compound as a crude product. The obtained crude product was dissolved in a 1:1 mixture (100 mL) of n-heptane and ethyl acetate, and the solution was filtered through a short column packed with silica gel (35 g) using the same mixed solvent as an elution solvent. The obtained filtrate was concentrated under reduced pressure to obtain the title compound (free form). The obtained free form was dissolved in a 1:4 mixture of n-heptane and ethyl acetate (50 mL), and then a 4N hydrogen chloride / ethyl acetate solution (5 mL) was slowly added thereto at 0 to 5° C. with stirring to obtain a suspension. The resulting solid was collected by filtration to give the hydrochloride salt of the title compound (5 g). The obtained hydrochloride of the title compound was desalted with 4N aqueous sodium hydroxide solution (20 mL) to obtain the title compound (4.4 g, yield 88%).

[0037] 1 H-NMR (400MHz, CDCl3): δ7.10-7.35(m,7H),6.90-7.05(m,2H),6.70-6.85(m,3H),6.72(d ,1H,J=13Hz),3.68(s,3H),3.58(d,1H,J=13Hz),2.90-3.25(m,6H),2.60-2.75(m,3H),2.4 5(dd,1H,J=5,12Hz),2.29(d,2H,J=6Hz),1.99(dt,1H,J=3,13Hz),1.50-1.80(m,3H),1.10 -1.25(m,1H),1.00-1.10(m,2H),0.70-0.85(m,2H),0.40-0.55(m,2H),0.00-0.15(m,2H).

[0038] Below are examples of the preparation of diaryl ether derivatives by Ullmann coupling of other haloaryls with (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-ol.

[0039] [ka]

[0040] Example 1 Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0041] [ka] In a 2000 mL round bottom flask, (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-ol dihydrochloride (30 g, 1 equiv.) was dissolved in pyridine (300 mL) under nitrogen atmosphere. Potassium carbonate (22.9 g, 3 equiv.), 4-tert-butylbromobenzene (47 mL, 5 equiv.) and copper powder (3.5 g, 1 equiv.) were added to the resulting solution and heated to reflux with vigorous stirring. After 16 hours, the reaction was analyzed by MS and thin layer chromatography, and a small amount of raw material was confirmed to remain. The reaction mixture was cooled to room temperature, potassium carbonate (22.9 g, 3 equivalents), 4-tert-butylbromobenzene (47 mL, 5 equivalents), copper powder (3.5 g, 1 equivalent) and pyridine (300 mL) were added to the reaction mixture, and the mixture was heated to reflux again with vigorous stirring. After 24 hours, the reaction mixture was analyzed by MS and thin layer chromatography to confirm the complete disappearance of the raw materials. After cooling the reaction mixture to room temperature, the reaction mixture was filtered through a Celite pad to remove insoluble matter. The pad was washed with ethyl acetate (300 mL) and methanol (100 mL), and 6% aqueous ammonia (300 mL) was added to the combined filtrate and washings. The organic layer and the aqueous layer were separated using a separatory funnel, and the aqueous layer was extracted with ethyl acetate (300 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off, followed by concentration under reduced pressure to obtain the title compound as a crude product. The obtained crude product was dissolved in a 1:1 mixture (300 mL) of n-heptane and ethyl acetate, and filtered through a short column packed with silica gel (210 g) using the same mixed solvent as the elution solvent (2100 mL), and the obtained filtrate was concentrated under reduced pressure to obtain the title compound (free form). The obtained free form was dissolved in a 1:4 mixture (150 mL) of n-heptane and ethyl acetate, and then a 4N hydrogen chloride / ethyl acetate solution (30 mL) was slowly added at 0-5°C with stirring to obtain a suspension. The resulting solid was collected by filtration to give the title compound (33 g) as the hydrochloride salt. The obtained hydrochloride salt of the title compound was desalted with 4N aqueous sodium hydroxide solution (20 mL) to obtain the title compound (29.2 g, yield 88%).

[0042] 1 H-NMR (400MHz, CDCl3): δ7.10-7.35(m,7H),6.97(d,1H,J=8Hz),6.77(d,1H,J=8Hz),6.67(d,2H,J=8Hz),3.70 (d,1H,J=13Hz),3.68(s,3H),3.55(d,1H,J=13Hz),2.90-3.20(m,6H),2.60-2.70(m,1H),2.46(dd,1H,J=4,12H z),2.29(d,2H,J=6Hz),1.99(dt,1H,J=3,13Hz),1.75(dt,1H,J=5,13Hz),1.50-1.65(m,3H),1.30(s,9H),1.2 0-1.35(m,1H),1.10-1.20(m,1H),1.00-1.10(m,2H),0.70-0.85(m,2H),0.40-0.50(m,2H),0.00-0.15(m,2H).

[0043] Example 2 Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(3-methoxyphenoxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0044] [ka] The title compound (0.12 g, yield 99%) was obtained in the same manner as in Example 1, except that 3-bromoanisole was used as the halobenzene.

[0045] 1H-NMR (400MHz, CDCl3): δ7.15-7.30(m,5H),7.11(t,1H,J=8Hz),6.97(d,1H,J=8Hz),6.78(d,1H,J=8Hz),6.52(dd,1H,J=2 ,8Hz),6.38(t,1H,J=2Hz),6.32(dd,1H,J=2,8Hz),3.75(s,3H),3.72(d,1H,J=13Hz),3.68(s,3H),3.58(d,1H,J=13Hz),2. 90-3.25(m,6H),2.60-2.75(m,3H),2.47(dd,1H,J=4,12Hz),2.29(d,2H,J=6Hz),1.99(dt,1H,J=3,13Hz),1.76(dt,1H,J=5 ,13Hz),1.50-1.70(m,2H),1.10-1.20(m,1H),1.00-1.10(m,2H),0.70-0.85(m,2H),0.40-0.50(m,2H),0.00-0.15(m,2H).

[0046] Example 3 Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(p-toluyloxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0047] [ka] The title compound (0.11 g, yield 90%) was obtained in the same manner as in Example 1, except that 4-bromotoluene was used as the halobenzene.

[0048] 1H-NMR (400MHz, CDCl3): δ7.15-7.30(m,5H),7.02(d,2H,J=8Hz),6.97(d,1H,J=8Hz),6.77(d,1H,J=8Hz),6.65 (d,2H,J=8Hz),3.73(d,1H,J=13Hz),3.67(s,3H),3.59(d,1H,J=13Hz),2.90-3.25(m,6H),2.60-2.75(m,3H),2 .47(dd,1H,J=4,12Hz),2.35(d,2H,J=6Hz),2.29(s,3H),1.99(dt,1H,J=3,13Hz),1.76(dt,1H,J=5,13Hz),1.5 0-1.70(m,2H),1.10-1.20(m,1H),1.00-1.10(m,2H),0.70-0.85(m,2H),0.40-0.50(m,2H),0.00-0.15(m,2H).

[0049] Comparative Example 1 Synthesis of ethyl 3-(((1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-yl)oxy)benzoate

[0050] [ka] The title compound (0.19 g, yield 73%) was obtained in the same manner as in Example 1, except that ethyl 3-iodobenzoate was used as the halobenzene.

[0051] 1H-NMR (400MHz, CDCl3): δ7.65(d,1H,J=8Hz),7.48(s,1H),7.15-7.35(m,6H),7.00(d,1H,J=8Hz),6.91(dd,1H,J=3,8Hz), 6.78(d,1H,J=8Hz),4.46(q,2H,J=7Hz),3.71(d,1H,J=13Hz),3.65(s,3H),3.57(d,1H,J=13Hz),2.90-3.20(m,6H),2.60- 2.80(m,2H),2.46(dd,1H,J=4,12Hz),2.29(d,2H,J=6Hz),2.00(dt,1H,J=3,13Hz),1.76(dt,1H,J=5,13Hz),1.50-1.70(m ,3H),1.38(t,3H,J=7Hz),1.10-1.25(m,1H),1.00-1.10(m,2H),0.70-0.85(m,2H),0.40-0.50(m,2H),0.00-0.15(m,2H).

[0052] Comparative Example 2 Synthesis of 3-(((1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-yl)oxy)benzonitrile

[0053] [ka] The title compound (0.05 g, yield 44%) was obtained in the same manner as in Example 1, except that 3-bromobenzonitrile was used as the halobenzene.

[0054] 1H-NMR (400MHz, CDCl3): δ7.15-7.40(m,7H),6.90-7.05(m,3H),6.78(d,1H,J=8Hz),3.71(d,1H,J=13H z),3.67(s,3H),3.58(d,1H,J=13Hz),2.95-3.15(m,6H),2.65-2.80(m,2H),2.48(dd,1H,J=4,12Hz), 2.25-2.35(m,2H),2.00(dt,1H,J=3,13Hz),1.76(dt,1H,J=5,13Hz),1.50-1.70(m,3H),1.15-1.30(m ,1H),1.00-1.05(m,1H),0.85-0.95(m,1H),0.65-0.85(m,2H),0.40-0.55(m,2H),0.00-0.15(m,2H).

[0055] Comparative Example 3 Synthesis of 4-(((1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-yl)oxy)benzonitrile

[0056] [ka] The title compound (0.085 g, yield 75%) was obtained in the same manner as in Example 1, except that 4-bromobenzonitrile was used as the halobenzene.

[0057] 1H-NMR (400MHz, CDCl3): δ7.52(d,2H,J=8Hz),7.15-7.30(m,5H),7.02(d,1H,J=8Hz),6.81(d,2H,J=8Hz),6.77(d,1H ,J=8Hz),3.70(d,1H,J=13Hz),3.66(s,3H),3.56(d,1H,J=13Hz),2.90-3.15(m,6H),2.70-2.80(m,1H),2.60-2.70(m ,1H),2.47(dd,1H,J=4,12Hz),2.20-2.35(m,2H),1.95(dt,1H,J=3,13Hz),1.76(dt,1H,J=5,13Hz),1.50-1.70(m,3H ),1.15-1.30(m,1H),1.00-1.10(m,1H),0.90-0.95(m,1H),0.65-0.85(m,2H),0.40-0.55(m,2H),0.00-0.15(m,2H).

[0058] Comparative Example 4 Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(pyridin-3-yloxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0059] [ka] The title compound (0.14 g, yield 80%) was obtained in the same manner as in Example 1, except that 3-iodopyridine was used as the heteroaryl halide.

[0060] 1H-NMR (400MHz, CDCl3): δ8.15-8.25(m,2H),7.15-7.35(m,6H),7.02(d,2H,J=8Hz),6.78(d,1H,J=8Hz),3. 72(d,1H,J=13Hz),3.67(s,3H),3.56(d,1H,J=13Hz),2.95-3.15(m,6H),2.65-2.80(m,2H),2.47(dd,1H,J= 4,12Hz),2.29(d,2H,J=6Hz),2.00(dt,1H,J=3,13Hz),1.76(dt,1H,J=5,13Hz),1.55-1.70(m,2H),1.15-1 .30(m,2H),1.00-1.10(m,1H),0.90-1.00(m,1H),0.70-0.85(m,2H),0.45-0.55(m,2H),0.00-0.15(m,2H).

[0061] Comparative Example 5 Synthesis of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(thiophen-3-yloxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0062] [ka] The title compound (0.081 g, yield 71%) was obtained in the same manner as in Example 1, except that 3-bromothiophene was used as the heteroaryl halide.

[0063] 1H-NMR (400MHz, CDCl3): δ7.10-7.40(m,6H),6.96(d,1H,J=8Hz),6.70-6.80(m,2H),6.05(dd, 1H,J=2,3Hz),3.72(s,3H),3.70(d,1H,J=13Hz),3.57(d,1H,J=13Hz),2.90-3.20(m,6H),2.60 -2.80(m,2H),2.40-2.50(m,1H),2.28(d,2H,J=6Hz),1.90-2.00(m,1H),1.70-1.75(m,1H),1 .50-1.70(m,3H),1.00-1.20(m,3H),0.65-0.85(m,2H),0.40-0.50(m,2H),0.00-0.15(m,2H).

[0064] 2. Preparation of ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole) using the diaryl ether derivative prepared in 1 above as a starting material.

[0065] Example 4 Synthesis of (1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole dihydrochloride

[0066] [ka] In a 200mL round-bottom flask, tetrahydrofuran (25mL) was dissolved in ethylenediamine (25mL) under a nitrogen atmosphere. Metallic sodium (5g, 40wt% dispersion in oil Alfa Aesar) was added to the obtained solution under ice bath. After stirring for 10 minutes, a tetrahydrofuran (25mL) solution of (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (5g, 1 equivalent) obtained in Example 1 above was added dropwise to the obtained reaction solution while stirring. After 1 hour, the reaction was analyzed by MS and thin layer chromatography to confirm the remaining raw materials. The reaction solution was warmed to room temperature. After 1 hour, the reaction was analyzed by MS and thin layer chromatography to confirm the disappearance of the raw materials. While stirring the reaction solution in an ice bath, ethanol (25 mL) was added dropwise, and then a mixture (25 mL) of ethanol / water = 4 / 1 was added. Finally, water (25 mL) was added dropwise, and the mixture was stirred for 1 hour. This was used as reaction solution 1. 1 mL of reaction solution 1 was dispensed, and the amounts of the target product and by-products produced were confirmed by HPLC. The remaining reaction solution 1 was concentrated under reduced pressure, and 6NHCl aqueous solution was added to the resulting residue in an ice bath to adjust the reaction solution to pH 2. The resulting reaction solution was washed with heptane (100mL x 3 times), and the aqueous layer was adjusted to pH 12 with 4N NaOH aqueous solution. This aqueous layer was extracted with ethyl acetate (200mL x 3 times). The combined organic layers were dried over anhydrous sodium sulfate, and the anhydrous sodium sulfate was filtered off, followed by concentration under reduced pressure to obtain a crude product of the title compound. The obtained crude product was dissolved in a mixed solvent (25 mL) of ethyl acetate / heptane=1 / 4, and a 4N hydrogen chloride / ethyl acetate solution (5 mL) was slowly added thereto at 0 to 5° C. with stirring to obtain a suspension. The resulting solid was collected by filtration to obtain the title compound (4.18 g, 96%, purity 94%). The yield (%) of the target product and the content (%) of the by-product corresponding to (b-1) in the reaction mixture are shown in Table 1. The target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole) and the by-product ((1S,3aR,5aS, The amount of 6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-11-ol (hereinafter referred to as by-product A) produced was determined by HPLC area percentage (%). No by-product A was observed, and the yield of the target product was a high 94%. This result indicates that no dephenylation reaction was observed, and that the dephenoxylation reaction occurred highly selectively.

[0067] 1 H-NMR(400MHz,DMSO-d6):δ10.40-10.65(m,1H),9.29(brs,1H),7.70-7.80(m,1H),7.60-7. 70(m,1H),7.40-7.55(m,3H),7.18(d,0.5H,J=8Hz),7.13(d,0.5H,J=8Hz),6.70-6.90(m,2H) ,4.20-4.40(m,2H),4.00-4.10(m,2H),3.73(s,1.5H),3.72(s,1.5H),2.85-4.00(m,11H),1. 80-2.10(m,2H),1.30-1.75(m,4H),1.00-1.25(m,2H),0.50-0.75(m,3H),0.30-0.45(m,1H).

[0068] (Reference example 2) Using the diaryl ether derivative produced in Reference Example 1 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was 79%, with 5% by-product A. This result indicates that the dephenoxylation reaction was predominant, but dephenylation also occurred.

[0069] Example 5 Using the diaryl ether derivative produced in Example 2 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions according to the method of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was high at 89%, with 1% of by-product A produced. This result indicates that although a small amount of dephenylation reaction occurred, the dephenoxy reaction occurred more selectively than in Reference Example 2.

[0070] Example 6 Using the diaryl ether derivative produced in Example 3 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. No by-product A was observed, and the yield of the target product was a high 93%. This result indicates that no dephenylation reaction was observed, and that the dephenoxylation reaction occurred highly selectively.

[0071] Comparative Example 6 Using the diaryl ether derivative produced in Comparative Example 1 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was 30%, with 3% by-product A. This result indicates that the dephenoxylation reaction was predominant, but the dephenylation reaction also occurred, and the selectivity of the dephenoxylation reaction was lower than that in Reference Example 2.

[0072] Comparative Example 7 Using the diaryl ether derivative produced in Comparative Example 2 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was 42%, with 6% of by-product A produced. This result indicates that the dephenoxylation reaction was predominant, but the dephenylation reaction also occurred, and the selectivity of the dephenoxylation reaction was lower than that in Reference Example 2.

[0073] Comparative Example 8 Using the diaryl ether derivative produced in Comparative Example 3 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the desired product was 2%, with 35% of by-product A produced. This result indicates that the dephenylation reaction occurred more predominantly than the dephenoxylation reaction.

[0074] Comparative Example 9 Using the diaryl ether derivative produced in Comparative Example 4 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was 76%, with 10% by-product A. This result indicates that the dephenoxylation reaction was predominant, but the dephenylation reaction also occurred, and the selectivity of the dephenoxylation reaction was lower than that in Reference Example 2.

[0075] Comparative Example 10 Using the diaryl ether derivative produced in Comparative Example 5 as a starting material, a dephenoxylation reaction was carried out under Na-Benkeser reaction conditions in a manner similar to that of Example 4 to produce the target product ((1S,3aR,5aS,6R,11bR,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole). Table 1 shows the yield (%) of the target product and the content (%) of by-product A obtained. The yield of the target product was 67%, with 3% by-product A produced. This result indicates that the dephenoxylation reaction was predominant, but the dephenylation reaction also occurred, and the yield of the dephenoxylation reaction was lower than that of Reference Example 2.

[0076] The test results of the above-mentioned Reference Example 2, Examples 4 to 6, and Comparative Examples 6 to 10 are shown in Table 1 below.

[0077] [Table 1] [Industrial Applicability]

[0078] According to the present invention, there is provided a method for producing a morphinan derivative highly selectively from a diaryl ether derivative while suppressing the production of a phenol by-product, which can be applied to an industrial production process.

Claims

1. The following general formula (I): 【Chemistry 1】 (In the formula, R １ is a halogen atom, a hydroxyl group, C １－１０ C which may have a substituent selected from an alkoxy group and an amino group ３－６ Cycloalkyl-substituted C １－１０ represents an alkyl group, R ２ is a carbamate protecting group, a sulfonamide protecting group, an acyl protecting group, an imide protecting group, and C ７－１９ represents an amino-protecting group selected from the group consisting of aralkyl groups R ３ is a hydrogen atom, a halogen atom, or a halogen atom, a hydroxyl group, C １－１０ C which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkoxy group, R ４ and R ５ are the same or different and each represents a hydrogen atom or a hydroxy group, R ６ is a hydrogen atom, OR ８ , N.R. ９ R １０ , or a hydroxy group, C １－１０ C, which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkyl group, R ７ is a hydrogen atom, OR １１ , N.R. １２ R １３ , or a hydroxy group, C １－１０ C, which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkyl group, Here, R ６ and R ７ is not a hydrogen atom at the same time, R ８ is a hydrogen atom or C １－１０ represents an alkyl group, R ９ and R １０ are the same or different and each represents a hydrogen atom or C １－１０ represents an alkyl group, R １１ is a hydrogen atom or C １－１０ represents an alkyl group, R １２ and R １３ are the same or different and each represents a hydrogen atom or C １－１０ represents an alkyl group, and X is O or CH ２ Represents.) A morphinan derivative represented by the formula: The following general formula (II): 【Chemistry 2】 (In the formula, R １ ~R ５ and X has the same meaning as above.

2. R ２ In the above, the carbamate protecting group is a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-methoxybenzylcarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, a 3,5-dimethoxybenzyloxy carbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2-(trimethylsilyl)ethoxycarbonyl group, or 9-fluorenylmethyloxycarbonyl group; the sulfonamide protecting group is p-toluenesulfonyl group or 2-nitrobenzenesulfonyl group; the acyl protecting group is acetyl group or trifluoroacetyl group; the imide protecting group is phthaloyl group; and ７－１９ 2. The method for producing a morphinan derivative according to claim 1, wherein the aralkyl group is a benzyl group, a trityl group, or a naphthylmethyl group.

3. R ２ The method for producing a morphinan derivative according to claim 1 or 2, wherein is a benzyl group.

4. R ３ The method for producing a morphinan derivative according to any one of claims 1 to 3, wherein is a methoxy group.

5. R ６ and R ７ are the same or different and are a hydrogen atom, a methoxy group, a methyl group, or a tert-butyl group, and R ６ and R ７ The method for producing a morphinan derivative according to any one of claims 1 to 4, wherein is not simultaneously a hydrogen atom.

6. R ６ The method for producing a morphinan derivative according to any one of claims 1 to 5, wherein is a hydrogen atom.

7. R ７ The method for producing a morphinan derivative according to any one of claims 1 to 5, wherein is a hydrogen atom.

8. Metallic sodium is used in an amount of 1 to 10 equivalents relative to the morphinan derivative of the above general formula (I). A method for producing the morphinan derivative according to any one of claims 1 to 7.

9. The method for producing a morphinan derivative according to any one of claims 1 to 8, wherein the metallic sodium is a metallic sodium dispersion.

10. The method for producing a morphinan derivative according to any one of claims 1 to 9, wherein the auxiliary solvent is an aromatic hydrocarbon-based or ether-based solvent.

11. The method for producing a morphinan derivative according to any one of claims 1 to 10, wherein the reaction temperature is from -30°C to 150°C.

12. The method for producing a morphinan derivative according to any one of claims 1 to 11, wherein the reaction temperature is 0°C to 30°C.

13. The following general formula (I): 【Chemistry 3】 (In the formula, R １ is a halogen atom, a hydroxyl group, C １－１０ C which may have a substituent selected from an alkoxy group and an amino group ３－６ Cycloalkyl-substituted C １－１０ represents an alkyl group, R ２ is a carbamate protecting group, a sulfonamide protecting group, an acyl protecting group, an imide protecting group, and C ７－１９ represents an amino-protecting group selected from the group consisting of aralkyl groups R ３ is a hydrogen atom, a halogen atom, or a halogen atom, a hydroxyl group, C １－１０ C which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkoxy group, R ４ and R ５ are the same or different and each represents a hydrogen atom or a hydroxy group, R ６ is a hydrogen atom, OR ８ , N.R. ９ R １０ , or a hydroxy group, C １－１０ C, which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkyl group, R ７ is a hydrogen atom, OR １１ , N.R. １２ R １３ , or a hydroxy group, C １－１０ C, which may have a substituent selected from an alkoxy group and an amino group １－１０ represents an alkyl group, Here, R ６ and R ７ is not a hydrogen atom at the same time, R ８ is a hydrogen atom or C １－１０ represents an alkyl group, R ９ and R １０ are the same or different and each represents a hydrogen atom or C １－１０ represents an alkyl group, R １１ is a hydrogen atom or C １－１０ represents an alkyl group, R １２ and R １３ are the same or different and each represents a hydrogen atom or C １－１０ represents an alkyl group, wherein the carbamate protecting group in R 2 is a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group, a tert-amyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-methoxybenzylcarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, a 3,5-dimethoxybenzyloxycarbonyl group, a 3,4,5-trimethoxybenzyloxycarbonyl group, a p-biphenylisopropyloxycarbonyl group, a diisopropylmethyloxycarbonyl group, a 2-(trimethylsilyl)ethoxycarbonyl group, or a 9-fluorenylmethyloxycarbonyl group; the sulfonamide protecting group is a p-toluenesulfonyl group or a 2-nitrobenzenesulfonyl group; the acyl-based protecting group is an acetyl group or a trifluoroacetyl group; the imide-based protecting group is a phthaloyl group, and X is O or CH ２ Represents.) A morphinan derivative represented by the formula:

14. R ２ In C ７－１９ The morphinan derivative according to claim 13, wherein the aralkyl group is a benzyl group, a trityl group, or a naphthylmethyl group.

15. R ２ The morphinan derivative according to claim 13 or 14, wherein is a benzyl group.

16. R ３ The morphinan derivative according to any one of claims 13 to 15, wherein is a methoxy group.

17. R ６ and R ７ are the same or different and are a hydrogen atom, a methoxy group, a methyl group, or a tert-butyl group, and R ６ and R ７ The morphinan derivative according to any one of claims 13 to 16, wherein is not simultaneously a hydrogen atom.

18. R ６ The morphinan derivative according to any one of claims 13 to 17, wherein is a hydrogen atom.

19. R ７ The morphinan derivative according to any one of claims 13 to 17, wherein is a hydrogen atom.

20. (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole, (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(3-methoxyphenoxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole and (1S,3aR,5aS,6R,11bS,11cS)-3-benzyl-14-(cyclopropylmethyl)-10-methoxy-11-(p-toluyloxy)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole A morphinan derivative selected from:

Images