Method for producing phenol derivatives

Abstract

The present invention provides: a method for producing a phenol derivative represented by general formula (B), or the like, by having lithium metal and liquid ammonia or a primary amine act on a compound represented by general formula (A), or the like; and the like. (In the formulae, Rp1 represents an optionally substituted C6-10 aryl group; Rp2 represents a lower alkyl group or the like; and each of Rq1, Rq2, Rq3 and Rq4 represents a hydrogen atom or an arbitrary substituent, or alternatively, adjacent two moieties among Rq1, Rq2, Rq3 and Rq4 may combine with each other to form a ring.)

Description

[Technical field]

[0001] The present invention relates to a method for producing a phenol derivative. This application claims priority based on Japanese Patent Application No. 2019-134083, filed on July 19, 2019, the contents of which are incorporated herein by reference. [Background technology]

[0002] Among the compounds having the morphinan skeleton represented by the following formula, some, such as morphine and buprenorphine, are known to bind to opioid receptors and exhibit excellent pharmacological activities such as analgesia and antitussive properties.

[0003] [ka] (In this specification, when only position numbers are stated, they refer to the position numbers in the above structural formula.) Many of these compounds are known to have an ether bridge (commonly known as a 4,5-epoxy ring) between the 4th and 5th positions of the morphinan skeleton. However, many semi-synthetic pharmaceutical derivatives that do not have an ether bridge between the 4th and 5th positions of the morphinan skeleton, such as butorphanol and levalophan, have also been reported.

[0004] [ka]

[0005] [ka] In the production of these derivatives, as shown below, a known morphinan derivative (i) having a 4,5-epoxy ring in the morphinan skeleton is used as a starting material, the 4,5-epoxy ring is opened in the first step to give a phenol (ii) at the 4th position, and then the phenolic hydroxyl group at the 4th position generated in the second step is converted to a phenoxy group by the Ullmann reaction or the like to give compound (iii)-1, and the phenoxy group at the 4th position is removed by the Birch reduction or Benkeser reduction using an alkali metal in the third step to give compound (iv) (Route 1). As an alternative method, a method has also been reported in which the phenolic hydroxyl group generated in the first step is triflated in the second step to give compound (iii)-2, and then the trifluoromethylsulfonyloxy group is removed by a palladium-catalyzed reaction in the presence of a nucleophilic agent serving as a hydride source such as triethylsilane in the third step to give compound (iv) (Route 2).

[0006] [ka]

[0007] [ka] These reactions are usually carried out with derivatives in which the phenolic hydroxyl group at the 3-position, which plays an important role in the expression of biological activity, is protected with an alkyl group (mainly a methyl group), etc. Therefore, in the production of the final biologically active substance (v), a process for removing the alkyl group introduced as a protecting group for the 3-position hydroxyl group is required. However, the removal of the methyl group in particular poses many challenges for application to industrial-scale production, such as the use of highly toxic and corrosive reagents such as boron tribromide. When the dehydroxylation reaction in the third step is carried out by Birch reduction or Benkeser reduction, there have been many reports of using sodium as the alkali metal. For example, Non-Patent Document 1 discloses a synthesis example of compound 2, in which compound 1 having a 2,4-diaminophenyloxy group on a benzene ring is dephenoxylated by reacting it with metallic sodium in liquid ammonia.

[0008] [ka] Furthermore, EXAMPLE 1 of Patent Document 1 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.

[0009] [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.

[0010] [ka] Non-Patent Document 3 also describes a dephenoxy reaction similar to that described in Non-Patent Document 2. That is, in Scheme 1, a three-step conversion reaction is carried out from compound 11 to obtain compound 12a, which is then converted into compound 13a, which is then subjected to a demethylation reaction with boron tribromide in methylene chloride to obtain compound 6a.

[0011] [ka] In addition, Scheme 1 of Non-Patent Document 4 discloses a synthesis example of dephenoxylated compound 16 by reacting compound 15 with metallic sodium at −78° C. in the presence of liquid ammonia.

[0012] [ka] Furthermore, Scheme 2 of Non-Patent Document 4 discloses an example in which Compound 21a is obtained from Compound 16 through several steps, and then demethylation reaction is carried out using boron tribromide to obtain Compound 22a.

[0013] [ka] Furthermore, Non-Patent Document 5 discloses an example in which compound (XVIII), in which a phenolic hydroxyl group at 4-position has been converted to a phenoxy group, is reacted with metallic sodium in toluene in the presence of liquid ammonia at −55° C. to carry out a dephenoxylation reaction to obtain compound (XIX), as in Patent Document 1.

[0014] [ka] In addition, Non-Patent Document 6 discloses a method for producing (+)-deoxynaltrexone by ring-opening 4,5-epoxy from (+)-naltrexone. In this method, a method is disclosed in which metallic sodium is reacted with compound 23 in liquid ammonia to obtain compound 24 from which the phenoxy group has been removed. Furthermore, the obtained compound 24 is treated with 2N hydrochloric acid to remove the acetal protecting group, leading to compound 25, which is then demethylated with boron tribromide to obtain (+)-deoxynaltrexone 4.

[0015] [ka] In addition, in Non-Patent Document 7, Compound 10 having a buprenorphine skeleton is reacted with liquid ammonia and metallic sodium in diethyl ether to obtain dephenoxylated Compound 11.

[0016] [ka] Non-Patent Document 8 discloses a method in which compound 7d is converted to a ketal-protected form in a conventional manner, followed by Birch reduction using metallic sodium in toluene to dephenoxylate the compound, followed by removing the ketal-protecting group, and then reacting the resulting compound 8d with pyridine hydrochloride at 170° C. to perform a 3-position demethylation reaction to obtain compound 9d.

[0017] [ka] Furthermore, the supplementary material of Non-Patent Document 9 describes a method in which compound S3 is reacted with metallic sodium in toluene in the presence of liquid ammonia to convert it into compound 1a.

[0018] [ka]

[0019] In these manufacturing methods, metallic sodium is used for the dephenoxylation reaction, but metallic sodium is highly reactive and easily reacts with even a small amount of moisture to generate hydrogen, which may pose the risk of ignition or even explosion due to the heat of reaction. In addition, low-temperature conditions such as -40°C or -78°C are required as reaction conditions, but when an intense exothermic reaction occurs with scale-up, it becomes difficult to control the temperature, making it difficult to apply to industrial-scale production. For these reasons, there is a need for the development of safer reagents or methods for dephenoxylation that can replace metallic sodium. To avoid these risks, a reagent in which metallic sodium is supported on a solid phase has been developed, and there have been reports of the use of this reagent in the removal of the phenoxy group at the 4-position of the morphinan skeleton. For example, Scheme 1 of Non-Patent Document 10 discloses a method in which compound 5 is reacted with silica gel-supported metallic sodium under Benkeser reduction conditions in THF to give compound 6, and then several functional group transformations are carried out. Then, boron tribromide is reacted with the resulting compound 8a to perform a demethylation reaction of the 3-position hydroxyl group, thereby giving compound 2a.

[0020] [ka] In addition, Non-Patent Document 11 discloses an example in which compound 6 is reacted with silica gel-supported metallic sodium in the same manner as Non-Patent Document 10 to obtain compound 7a (Scheme 1), which is then subjected to a demethylation reaction using boron tribromide to obtain compound 3a (Scheme 2). A similar conversion reaction is described in paragraphs

[0038] and

[0039] (Reference Example 3) of Patent Document 2, which describes a production method for compound 7a using silica gel-supported metallic sodium.

[0021] [ka] Furthermore, paragraph

[0025] of Patent Document 3 discloses a method in which compound (b-1) is subjected to an Ullmann reaction to obtain compound (m), which is then subjected to a dephenoxylation reaction with silica gel-supported metallic sodium under Benkesser reduction conditions to obtain compound (n), which is then subjected to a demethylation reaction with boron tribromide or the like to obtain compound (o). Furthermore, paragraph

[0024] of Patent Document 4 and paragraph

[0027] of Patent Document 5 disclose methods for producing compound (n) by a Benkesser reduction reaction using a similar silica gel-supported metallic sodium.

[0022] [ka] These methods for removing the 4-hydroxyl group using silica gel-supported metallic sodium have a lower risk of fire and are easier to carry out than previously reported methods using metallic sodium, and are therefore useful for laboratory-scale synthesis. However, silica gel-supported metallic sodium is an expensive reagent and difficult to obtain in large quantities, limiting the use of this reagent in industrial-scale production. In order to solve these problems, a method for dehydroxylating the triflate at the 4-position of the morphinan skeleton by a palladium catalyzed reaction has been reported in recent years. For example, Non-Patent Document 12 reports an example in which compound 15 is reacted with catalytic amounts of palladium acetate and 1,3-bis(diphenylphosphino)propane in the presence of triethylsilane to carry out a dehydroxylation reaction to obtain compound 18.

[0023] [ka] Furthermore, paragraph number

[0514] of Patent Document 6 shows an example in which compound 6 is dehydroxylated in THF under the same reaction conditions as in Non-Patent Document 12 to obtain compound 7.

[0024] [ka] A similar conversion reaction is disclosed in paragraphs

[0287] and

[0288] of Patent Document 7, in which DMF is used as a solvent. Furthermore, paragraphs

[0393] and

[0394] of Patent Document 8 disclose an example in which the 4-hydroxyl group of compound 1 is removed in DMF under the same reaction conditions as those of Patent Document 6 to obtain compound 2, which is then demethylated by the action of ethanethiol sodium salt in NMP at 150° C. to obtain compound 3.

[0025] [ka] Furthermore, paragraphs

[0160] to

[0165] of Patent Document 9 describe an example in which the 4-hydroxyl group of compound 1 is removed in DMF under the same reaction conditions as those of Patent Document 6 and the like, followed by ketal protection of the ketone moiety of compound 2 and removal of the benzyl group, which is the protecting group of the 3-hydroxyl group, to thereby lead to compound 3.

[0026] [ka] Moreover, Example 10 of Patent Document 10 reports an example in which the hydroxyl group at the 4-position of Compound AE is removed in DMF under the same reaction conditions as those in Patent Document 6 and the like to obtain Compound AF.

[0027] [ka] As an example of removing the 4-hydroxyl group without using triflate, Non-Patent Document 13 reports a method in which a 1-phenyl-tetrazolyl-5-yl group is introduced into the 4-hydroxyl group of compound 27, and the phenolic hydroxyl group is removed by catalytic hydrogenation in the presence of a palladium carbon catalyst to obtain compound 5.

[0028] [ka] A similar method for removing the 4-hydroxyl group has also been reported in Non-Patent Document 14 as a method for obtaining compound 21 from compound 28.

[0029] [ka] These methods, in which the 4-hydroxyl group is converted to a triflate and then removed by a palladium-catalyzed reaction, or the method in which the 4-hydroxyl group is converted to a 1-phenyl-1H-tetrazolyl-5-yloxy group and then removed by catalytic hydrogenation in the presence of a palladium-carbon catalyst, are both advantageous in that they do not use metallic sodium, which reacts violently with water and poses the risk of fire and explosion. However, there remain problems that the introduction of sodium is sometimes difficult, and furthermore, the palladium-catalyzed reaction, which is the removal reaction after introduction, does not proceed in derivatives that are highly sterically hindered, and there are currently few examples of their application. [Prior art documents] [Patent documents]

[0030] [Patent Document 1] U.S. Patent No. 5,504,208 [Patent Document 2] JP 2015-180605 A [Patent Document 3] International Publication No. 2013 / 035833 [Patent Document 4] International Publication No. 2014 / 136305 [Patent Document 5] International Publication No. 2014 / 021273 [Patent Document 6] International Publication No. 2014 / 102593 [Patent Document 7] International Publication No. 2014 / 102587 [Patent Document 8] International Publication No. 2016 / 182840 [Patent Document 9] US Patent Publication No. 2015 / 0072971 [Patent Document 10] International Publication No. 2013 / 167963 [Patent Document 11] International Publication No. 2016 / 148232 [Non-patent literature]

[0031] [Non-Patent Document 1] Journal of Organic Chemistry,30(6),1769-1773,1965 [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] Journal of Organic Chemistry, 73, 8093-8096,2008 [Non-Patent Document 10] Bioorganic & Medicinal Chemistry Letters, 27(12), 2742-2745,2017 [Non-Patent Document 11] Bioorganic & Medicinal Chemistry Letters, 27(15), 3495-3498,2017 [Non-Patent Document 12] Tetrahedron Letters, 51(17), 2359-2361,2010 [Non-Patent Document 13] Journal of Medicinal Chemistry, 33(4), 1200-1206,1990 [Non-Patent Document 14] Helvetica Chimica Acta, 72(6), 1233-1240,1989 [Non-Patent Document 15] Bioorganic & Medicinal Chemistry Letters, 22,7711-7714,2012 [Non-Patent Document 16] Bioorganic & Medicinal Chemistry Letters,22,5071-5074,2012 Summary of the Invention [Problem to be solved by the invention]

[0032] Under the above circumstances, the method for removing the 4-hydroxyl group using the Birch reduction or Benkeser reduction is based on an electron transfer reaction and is not easily affected by steric hindrance, so it can be applied to the production of derivatives with a wide range of structures. Although the strong reactivity of metallic sodium with water remains an issue, this is still an attractive method for removing the 4-hydroxyl group that is widely used today.

[0033] Therefore, the present inventors have proposed to use metallic lithium, which has a relatively low reactivity with water, in the removal reaction of the 4-position hydroxyl group, instead of metallic sodium, which reacts violently with water. Although metallic lithium reacts with water at room temperature, the reaction is relatively mild, making it less dangerous than metallic sodium, and an alkali metal that is easy to use on an industrial scale. In fact, while metallic sodium must be stored under water-free conditions, metallic lithium can be stored in brown bottles, without being immersed in mineral oil, like a normal reagent, without being blocked off from air and moisture. In addition, under the conditions of the Birch reduction, metallic sodium must be broken into small pieces in order to dissolve it in a solvent such as liquid ammonia before the reaction, which makes it difficult to use industrially due to the danger and labor involved in processing. As a means of compensating for these problems, finely granulated metallic sodium dispersed in mineral oil is also commercially available, but it is expensive, and there have been cases in which manufacturers have stopped supplying it recently due to low demand and safety concerns, making it difficult to continue obtaining it. In contrast, metallic lithium is relatively stable, so metallic lithium processed into granules can be easily obtained at low cost, and it is also a major advantage that it can be used on an industrial scale without pretreatment. Therefore, if the Birch reduction or Benkeser reduction, which dehydroxylates the 4-position of the morphinan skeleton, can be carried out using metallic lithium instead of metallic sodium, it will be possible to produce larger amounts of morphinan derivatives dehydroxylated at the 4-position on an industrial scale. However, there has been no report to date of the use of metallic lithium in the Birch reduction or Benkeser reduction aimed at removing the phenolic hydroxyl group at the 4-position of the morphinan skeleton. Two reports have been published in which the Birch reduction or Benkeser reduction using metallic lithium was applied to the synthesis of analogues having a morphinan skeleton (Non-Patent Documents 15 and 16). However, neither of these studies aimed to remove the phenolic hydroxyl group at the 4-position. In the example of Non-Patent Document 15, metallic lithium was reacted with compound 5 in ethanol-THF in the presence of liquid ammonia at -33°C, and it is reported that compound 6, in which the benzene ring of the morphinane skeleton is reduced, and compound 7, in which the reduction has progressed further, were obtained. Non-Patent Document 6 also describes a reaction for the same compound.

[0034] [ka] These reports suggest that "when a derivative having a morphinan skeleton is subjected to the Birch reduction or Benkeser reduction using metallic lithium, an undesirable reduction reaction of the benzene ring proceeds and complex by-products are generated, so that it is difficult to control the reaction for the purpose of producing a 4-dehydroxylated group shown in the scheme of paragraph number

[0006] of this specification." Therefore, it is presumed that metallic sodium has been used rather than metallic lithium in the Birch reduction or Benkeser reduction aimed at removing the phenolic hydroxyl group at the 4-position of morphinan skeleton derivatives.

[0035] Under these circumstances, the present inventors have conducted intensive research and have succeeded in finding conditions under which, when a specific morphinan derivative represented by the general formula (I) described below is reacted with metallic lithium in the presence of an amine, the reduction reaction of the benzene ring of the morphinan skeleton is controlled and the desired removal reaction of the phenolic hydroxyl group at the 4-position proceeds in high yield. Surprisingly, we also found that in this reaction, the methyl group protecting the phenolic hydroxyl group at the 3-position was simultaneously removed in addition to the dehydroxylation at the 4-position. This means that whereas the previous method of 4-position dehydroxylation by Birch reduction or Benkeser reduction using metallic sodium required two steps, (1) 4-position dehydroxylation, and (2) deprotection of the 3-position hydroxyl group (demethylation when the protecting group is a methyl group), in the production of derivatives having a phenolic hydroxyl group at the 3-position, the method of 4-position dehydroxylation by Birch reduction or Benkeser reduction using metallic lithium can achieve two functional group transformations, 4-position dehydroxylation and 3-position demethylation, in a single step, which can significantly shorten the industrial process. Furthermore, in the examples of 4-position dehydroxylation reaction by Birch reduction or Benkeser reduction using metallic sodium in Patent Documents 2 to 5 and Non-Patent Documents 10 and 11, for example, in paragraph number

[0025] [Chemical Formula 7] of Patent Document 3, the benzyl group, which is a protecting group on the nitrogen atom, remains unreacted and it was necessary to remove the benzyl group by a separate catalytic hydrogenation reaction in the presence of a palladium carbon catalyst, or the like. However, in the 4-position dehydroxylation reaction by Birch reduction or Benkeser reduction using metallic lithium in the present invention, it was found that the debenzylation reaction also proceeds simultaneously. In addition, for example, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (compound A) described in Patent Document 11 is an important synthetic intermediate for a morphinan derivative having excellent opioid δ receptor agonist activity. In order to obtain this compound A, for example, in Patent Document 3, Then, under the Benkeser reduction conditions described in paragraphs

[0283] to

[0285] (Example 65), a dehydroxylation reaction at the 4-position was carried out using silica gel-supported sodium to obtain compound 75, which was then debenzylated by a hydrogenation reaction described in paragraphs

[0289] to

[0291] (Example 67) to obtain compound 76, and then a demethylation reaction using boron tribromide described in paragraphs

[0023] to

[0025] (Reference Example 1-1) of Patent Document 11 was carried out in a total of three steps to obtain compound A.

[0036] [ka]

[0037] As a result of intensive research, the present inventors have found that the desired dephenoxylation reaction at the 4-position proceeds under Birch reduction or Benkeser reduction conditions using metallic lithium. Furthermore, when a compound has a methoxy group and an N-benzyl group at the 3-position, as in compound 74 in Example 64 of Patent Document 3, demethylation and N-debenzylation proceed simultaneously, and the three functional group transformations can be conveniently carried out in one pot, leading to the completion of the present invention. One object of the present invention is to provide a method for producing a monophenol derivative, which is a method for converting a biphenyl ether having an ortho-methoxy group into a monophenol derivative in one step. The method provided by the present invention can be applied to a compound having a morphinan skeleton. In one embodiment, the present invention provides a highly versatile method for producing a morphinan derivative that can be applied to a dephenoxylation reaction of a morphinan derivative having a phenoxy group at the 4-position. [Means for solving the problem]

[0038] [1] That is, one embodiment of the present invention is The following general formula (A):

[0039] [ka] (In the formula, R p1 C may have a substituent 6-10 represents an aryl group, R p2 represents a lower alkyl group, an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, or a silyl protecting group, And R q1 , R q2 , R q3 and R q4 are the same or different and represent a hydrogen atom or any substituent, or R q1, R q2 , R q3 and R q4 Of these, two adjacent ones may form a ring.) or a tautomer, stereoisomer, or isotope of the compound, is reacted with metallic lithium, and liquid ammonia or a primary amine, The following general formula (B):

[0040] [ka] (In the formula, R q1 , R q2 , R q3 and R q4 has the same meaning as above.) or a salt, tautomer, stereoisomer or isotope of the phenol derivative. [2] Also, one embodiment of the present invention is a compound represented by the formula: q3 and R q4 is a hydrogen atom, and R q1 and R q2 are combined with each other to form a ring. [3] Also, one embodiment of the present invention is a compound represented by the formula: p1 wherein is a phenyl group. [4] Also, one embodiment of the present invention is a compound represented by the formula: p2 The present invention relates to the process according to any one of the above [1] to [3], wherein [5] Also, one embodiment of the present invention is a compound represented by the following general formula (I):

[0041] [ka] (In the formula, R 1 ~R 15 , R a and R b are the same or different and each represents a hydrogen atom or an arbitrary substituent, Here, R 8 , R 10 and R14 any two groups selected from these may be bonded to each other to form an alkylene chain, the alkylene chain may be substituted with a substituent, the alkylene chain may have a carbon atom constituting the alkylene chain replaced with a heteroatom, may have a double bond or an amide bond in the middle, and the remainder other than the two selected groups may be bonded to the alkylene chain, R 16 C may have a substituent 6-10 represents an aryl group or an optionally substituted heteroaryl group, R 17 is C 1-10 represents an alkyl group, an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, or a silyl protecting group, X represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, or an oxygen atom which may have a substituent, A double line consisting of a solid line and a dashed line represents a single bond or a double bond. Where: If the double line consisting of a solid line and a dashed line is a double bond, X is N or CR 01 where R 01 is a hydrogen atom or any substituent, and in this case, R 11 does not exist, If the double line consisting of a solid line and a dashed line is a single bond, X is O, NR 02 , C.R. 03 R 04 , C=CR c0 R d0 Or C=NC x and Here, R 02 , R 03 and R 04 are the same or different and each is a hydrogen atom or an arbitrary substituent, R c0 and R d0 are the same or different, and each may be a hydrogen atom or a C 1-10 Alkyl group, optionally substituted C 3-10an alkenyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group; C x C may have a substituent 1-10 represents an alkyl group, And R 10 and R 11 together with the carbon atom to which they are attached form C=CR c R d (R c and R d are the same or different, and each may be a hydrogen atom or a C 1-10 Alkyl group, optionally substituted C 3-10 C═NC represents an alkenyl group, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. y (C y C may have a substituent 1-10 represents an alkyl group; or may form a cyclic ketal which may have a substituent, and further, X represents NR 02 In the case of R 10 and R 11 may be taken together with the carbon atom to which they are attached a carbonyl or thiocarbonyl group; R 01 and R 10 may be bonded to each other to form an optionally substituted unsaturated hydrocarbon ring, an optionally substituted unsaturated heterocycle, or an optionally substituted lactam ring, and these rings may be further condensed with an optionally substituted saturated hydrocarbon ring, an optionally substituted saturated heterocycle, an optionally substituted unsaturated hydrocarbon ring, or an optionally substituted unsaturated heterocycle, R 02 or R 03 And, R 10may be bonded to each other to form a saturated hydrocarbon ring which may have a substituent, a saturated hetero ring which may have a substituent, an unsaturated hydrocarbon ring which may have a substituent, an unsaturated hetero ring which may have a substituent, or an optionally substituted lactam ring, and these rings may be further condensed with a saturated hydrocarbon ring which may have a substituent, a saturated hetero ring which may have a substituent, an unsaturated hydrocarbon ring which may have a substituent, or an optionally substituted unsaturated hetero ring, R c0 and R c may form an unsaturated hydrocarbon ring or an unsaturated heterocycle together with the C=C to which they are attached, R c0 and C. y may form an unsaturated heterocycle together with the C=C and C=N to which they are attached, Said C x and C. y may form an unsaturated heterocycle together with the C=N to which they are attached, And k represents 1 or 2. or a tautomer, stereoisomer or isotope of the morphinan derivative, isoform or derivative thereof, is reacted with metallic lithium and an amine in the presence or absence of an organic solvent. The following general formula (II):

[0042] [ka] (In the formula, R 1 ~R 15 , R a , R b , X, k and the double line consisting of a solid line and a dashed line have the same meanings as above.) or a salt, tautomer, stereoisomer or isotope of said morphinan derivative. [6] Also, one embodiment of the present invention is a compound in which k is 1 and X is CH 2 and the double line consisting of a solid line and a dashed line is a single bond. [7] Also, one embodiment of the present invention is a compound represented by the formula: R 1 wherein is a hydrogen atom, a methyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a benzyl group, or an allyl group. [8] Also, one embodiment of the present invention is a compound represented by the formula: 1 is a hydrogen atom. [9] Also, one embodiment of the present invention is a compound represented by the formula: 2 ~R 7 , R 9 , R 11 ~R 13 , R 15 , R a and R b and are the same or different and are a hydrogen atom, a methyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a benzyl group, or an allyl group.

[10] Also, one embodiment of the present invention is a compound represented by the formula: 8 , R 10 and R 14 are taken together to form a bicyclic ring including the carbon atom to which they are bonded.

[11] Also, one embodiment of the present invention is a compound represented by the formula: 16 C may have a substituent 6-10 The present invention relates to the method for producing a compound according to any one of the above items [5] to

[10] , wherein the compound is an aryl group.

[12] Also, one embodiment of the present invention is a compound represented by the formula: 16 The present invention relates to the process according to any one of the above items [5] to

[10] , wherein

[13] Also, one embodiment of the present invention is a compound represented by the formula: R 17 The present invention relates to the process according to any one of the above items [5] to

[12] , wherein

[14] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[13] , wherein the amines are liquid ammonia, a primary amine or a secondary amine.

[15] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[13] , wherein the amines are primary amines.

[16] Also, in one embodiment of the present invention, the amines are represented by the following general formula (III):

[0043] [ka] (In the formula, R g , R h and R i are the same or different, and may have a hydrogen atom or a substituent. 1-6 represents an alkyl group or R g , R h and R i Any two of may be combined together to form a ring, and m represents an integer of 1 to 5. The present invention relates to the process for producing a primary amine represented by any one of the above items [5] to

[13] .

[17] Furthermore, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[16] , in which metallic lithium is used in an amount of 2 to 20 equivalents per functional group to be reduced in the morphinan derivative represented by the above general formula (I).

[18] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[17] , wherein the organic solvent is an aromatic hydrocarbon-based, alcohol-based or ether-based solvent.

[19] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[17] , wherein the organic solvent is an ether solvent.

[20] Furthermore, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[17] , in which the morphinan derivative represented by the above general formula (I) is reacted with metallic lithium and an amine in the absence of an organic solvent.

[21] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[20] , wherein the reaction temperature is -10°C to 120°C.

[22] Moreover, one embodiment of the present invention relates to the production method according to any one of the above [5] to

[20] , wherein the reaction temperature is -5°C to 105°C.

[23] Another embodiment of the present invention relates to the process according to any one of the above [5] to

[22] , wherein a metal hydride is present in the reaction system.

[24] Moreover, one embodiment of the present invention relates to the production method according to the above

[23] , wherein the metal hydride is selected from lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, and lithium aluminum hydride.

[25] Also, one embodiment of the present invention is a compound represented by the following general formula (IV):

[0044] [ka] (In the formula, R 1 represents a hydrogen atom or an arbitrary substituent, R 16 C may have a substituent 6-10 represents an aryl group or an optionally substituted heteroaryl group, R 17 is C 1-10 represents an alkyl group, an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, or a silyl protecting group, k represents 1 or 2; X 0 represents a carbon atom which may have a substituent, a nitrogen atom which may have a substituent, or an oxygen atom which may have a substituent, A 1 represents CH or N, B 1 represents an alkylene chain having 1 to 3 carbon atoms which may have a substituent, and the alkylene chain is represented by NR 0 may form an amide bond together with D 1 CH 2 , N.R. 05 , O or S, where R 05 represents a hydrogen atom or an arbitrary substituent, and R 0 represents a hydrogen atom, an aralkyl group which may have a substituent, or a heteroarylalkyl group which may have a substituent. or a tautomer, stereoisomer or isotope of the morphinan derivative, reacting with metallic lithium and amines in the presence or absence of an organic solvent; The following general formula (V):

[0045] [ka] (In the formula, R 1 , k, X 0 , A 1 , B 1 and D. 1 has the same meaning as above.) or a salt, tautomer, stereoisomer or isotope of said morphinan derivative.

[26] Also, one embodiment of the present invention is a compound in which k is 1 and X 0 CH 2 The present invention relates to the production method according to the above

[25] ,

[27] Also, one embodiment of the present invention is a method for producing a medicament comprising the steps of: 1 and D. 1 CH 2 And, A 1 The present invention relates to the production method according to the above

[25] or

[26] , wherein

[28] Also, one embodiment of the present invention is a compound represented by the formula: 1 The present invention relates to the process according to any one of the above items

[25] to

[27] , wherein

[29] Also, one embodiment of the present invention is a compound represented by the formula: R 1 is a hydrogen atom.

[30] Also, one embodiment of the present invention is a compound represented by the formula: 16 C may have a substituent 6-10The present invention relates to the method for producing a compound according to any one of the above items

[25] to

[29] , wherein the compound is an aryl group.

[31] Also, one embodiment of the present invention is a compound represented by the formula: R 16 The present invention relates to the process according to any one of the above items

[25] to

[29] , wherein

[32] Also, one embodiment of the present invention is a compound represented by the formula: R 17 The present invention relates to the process according to any one of the above items

[25] to

[31] , wherein

[33] Also, one embodiment of the present invention is a compound represented by the formula: R 0 The present invention relates to the process according to any one of the above items

[25] to

[32] , wherein

[34] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[33] , wherein the amines are liquid ammonia, a primary amine or a secondary amine.

[35] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[33] , wherein the amines are primary amines.

[36] Also, one embodiment of the present invention is that the amines are represented by the following general formula (III):

[0046] [ka] (In the formula, R g , R h and R i are the same or different, and may have a hydrogen atom or a substituent. 1-6 represents an alkyl group or R g , R h and R i Any two of may be combined together to form a ring, and m represents an integer of 1 to 5. The present invention relates to the process for producing a primary amine represented by any one of the above items

[25] to

[33] .

[37] Furthermore, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[36] , in which metallic lithium is used in an amount of 2 to 20 equivalents per functional group to be reduced in the morphinan derivative represented by the above general formula (IV).

[38] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[37] , wherein the organic solvent is an aromatic hydrocarbon-based solvent, a lower alcohol-based solvent or an ether-based solvent.

[39] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[37] , wherein the organic solvent is an ether solvent.

[40] Furthermore, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[37] , in which metallic lithium and an amine are reacted with the morphinan derivative represented by the above general formula (IV) in the absence of an organic solvent.

[41] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[40] , wherein the reaction temperature is -10°C to 120°C.

[42] Moreover, one embodiment of the present invention relates to the production method according to any one of the above

[25] to

[40] , wherein the reaction temperature is -5°C to 105°C.

[43] Another embodiment of the present invention relates to the process according to any one of the above

[25] to

[42] , wherein a hydrogenation metal is present in the reaction system.

[44] Moreover, one embodiment of the present invention relates to the process according to the above

[43] , wherein the metal hydride is selected from lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, and lithium aluminum hydride.

[45] Also, one embodiment of the present invention is a compound represented by the following general formula (VI):

[0047] [ka] (In the formula, R 1 represents a hydrogen atom or an arbitrary substituent, R 16 C may have a substituent 6-10 represents an aryl group or an optionally substituted heteroaryl group, R 17 is C 1-10represents an alkyl group, an aralkyl group which may have a substituent, an alkenyl group which may have a substituent, or a silyl protecting group. or a tautomer, stereoisomer or isotope of said morphinan derivative.

[46] Also, one embodiment of the present invention is a compound represented by the formula: R 1 is a hydrogen atom, a methyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a benzyl group, or an allyl group, or a tautomer, stereoisomer, or isotope of the morphinan derivative according to the above

[45] .

[47] Also, one embodiment of the present invention is a compound represented by the formula: R 1 is a hydrogen atom, or a tautomer, stereoisomer, or isotope of the morphinan derivative according to the above

[45] or

[46] .

[48] ​​Also, one embodiment of the present invention is a compound represented by the formula: R 16 C may have a substituent 6-10 The present invention relates to the morphinan derivative according to any one of the above

[45] to

[47] , which is an aryl group, or a tautomer, stereoisomer, or isotope of the morphinan derivative.

[49] Also, one embodiment of the present invention is a compound represented by the formula: R 16 The present invention relates to the morphinan derivative according to any one of the above

[45] to

[47] , wherein is a phenyl group, or a tautomer, stereoisomer, or isotope of the morphinan derivative.

[50] Furthermore, one embodiment of the present invention is a compound comprising R 17 The present invention relates to the morphinan derivative according to any one of the above

[45] to

[49] , wherein is a methyl group, or a tautomer, stereoisomer, or isotope of the morphinan derivative. Effect of the Invention

[0048] According to the present invention, a method for converting a biphenyl ether having an ortho-methoxy group into a monophenol derivative in one step can be provided. The method provided by the present invention can be applied to compounds having a morphinan skeleton. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0049] One embodiment of the present invention relates to a method for producing a phenol derivative, which can be applied to, for example, the compound represented by the above general formula (A), biphenyl ethers having an alkoxy group or the like at the ortho position, and morphinan derivatives having a phenoxy group or the like that may be substituted at the 4-position, and the present invention will be described in more detail below. Note that, in the present specification, "isotope" means a compound labeled with a radioisotope element in each compound.

[0050] <1.> A compound represented by general formula (A) or general formula (B) R in the above general formulas (A) and (B) q1 , R q2 , R q3 and R q4 are each independently a hydrogen atom or a C which may have a substituent such as a halogen atom. 1-10 Alkyl group; halogen atom; optionally substituted amino group; optionally substituted C 6-10 and optionally substituted alkenyl groups. Also, R q1 , R q2 , R q3 and R q4 Among these, an example in which two adjacent units form a ring is R q1 and R q2 are joined together to form a six-membered ring, and R q1 and R q2 is bonded to a benzene ring that constitutes part of a morphinane ring. R in the above general formula (A) p1 C, which may have the following substituent: 6-10 The aryl group may be a halogen atom, an alkyl group having 1 to 6 carbon atoms, an amino group which may have a substituent, an alkoxy group having 1 to 6 carbon atoms, or the like. 6-10 An aryl group is exemplified, and a phenyl group is preferred. R in the above general formula (A) p2The lower alkyl group in R is an alkyl group having 1 to 6 carbon atoms, preferably a methyl group, an aralkyl group which may have a substituent such as a benzyl group, an alkenyl group which may have a substituent such as an allyl group, an example of a silyl protecting group such as a t-butyldimethylsilyl group, and the like. p2 A preferred example of the alkyl group is a methyl group.

[0051] <2.> A compound represented by general formula (I), general formula (II) or general formula (III) R in the above general formula (I) and general formula (II) 1 ~R 15 , R a and R b is a hydrogen atom or any substituent, and preferably includes the following: R 1 is a hydrogen atom, a C 1-10 Alkyl group, optionally substituted C 3-6 Cycloalkyl groups, cycloalkylalkyl groups which may have a substituent (the cycloalkyl portion has 3 to 6 carbon atoms, and the alkylene portion has 1 to 5 carbon atoms), aralkyl groups which may have a substituent (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 5 carbon atoms), heteroarylalkyl groups which may have a substituent (heteroaryl contains 1 to 4 heteroatoms which may be the same or different and selected from N, O and S as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms), C groups which may have a substituent, 2-6 Alkenyl group, optionally substituted C 6-10 Examples of the group include an aryl group, an optionally substituted heteroaryl group, and an amino-protecting group.

[0052] R in the above general formulas (I) and (II) 2 ~R 15 are the same or different, and each may be a hydrogen atom, a C 1-10 Alkyl group, optionally substituted C 1-10Alkoxy group, halogen atom, optionally substituted amino group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 6-10 An aryl group or a hydroxy group can be mentioned. R in the above general formulas (I) and (II) a and R b are the same or different, and each may be a hydrogen atom, a C 1-10 Alkyl group, halogen atom, optionally substituted amino group, optionally substituted C 2-6 Alkenyl group, optionally substituted C 6-10 Examples of such groups include aryl groups.

[0053] In the above general formulas (I) and (II), X is C=CR c0 R d0 R in c0 and R d0 , and R 10 and R 11 is formed with the carbon to which it is bonded, C=CR c R d R in c and R d are the same or different, and each may be a hydrogen atom, a C 1-10 Alkyl group, optionally substituted C 3-10 Examples of the alkyl group include an alkenyl group, an aryl group which may have a substituent, and a heteroaryl group which may have a substituent.

[0054] R in the above general formulas (I), (II) and (III) 1 ~R 15 , R a , R b , R 17 , R c , R d , R i , C x , and C y C, which may have the following substituent: 1-10 C in alkyl groups 1-10Examples of the alkyl group include 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, and a hexyl group, and preferred are linear or branched C alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, and a tert-butyl group. 1-6 An alkyl group is preferable, and a methyl group is more preferable.

[0055] R in the above general formulas (I) and (II) 1 C, which may have the following substituent: 3-6 C in cycloalkyl groups 3-6 Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group, and preferably a cyclopropyl group.

[0056] R in the above general formulas (I) and (II) 1 The cycloalkyl group in the cycloalkylalkyl group (wherein the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms) which may have a substituent is preferably a C cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group. 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 is a cyclopropylmethyl group.

[0057] R in the above general formulas (I), (II) and (III) 1 ~R 15 , R a , R b , R 17 , R c , R d , R i , C x , and C y C, which may have the following substituent: 1-10 Alkyl group, R 1 C, which may have the following substituent: 3-6The substituents in the cycloalkyl group and the cycloalkylalkyl group which may have a substituent include linear or branched C alkyl groups such as a methyl group, an ethyl group, a propyl group, or an isopropyl group. 1-6 Examples of the alkyl group include halogenated methyl groups such as an alkyl group, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group, halogen atoms such as a fluorine atom and a chlorine atom, a hydroxy group, an amino group which may have a substituent, and an acyl group such as an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group.

[0058] R 1 and R 17 The aralkyl group in the aralkyl group which may have a substituent is an aralkyl group having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and examples thereof include a methyl group or an ethyl group substituted with phenyl or naphthyl, and preferably a methyl group (i.e., a benzyl group) or an ethyl group (i.e., a phenethyl group) substituted with phenyl.

[0059] R 1 Examples of the heteroaryl group in the heteroarylalkyl group which may have a substituent and is represented by the following formula (I) include a heteroaryl group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom as ring-constituting atoms. Examples of the heteroarylalkyl group include 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, Examples of heteroarylalkyl groups include monocyclic heteroarylalkyl groups such as an (imidazol-2-yl)methyl group, an (imidazol-4-yl)methyl group, an (imidazol-5-yl)methyl group, a (thiazol-2-yl)methyl group, a (thiazol-4-yl)methyl group, a (thiazol-5-yl)methyl group, a (thiophen-2-yl)methyl group, or a 2-(thiophen-2-yl)ethyl group; and bicyclic heteroarylalkyl groups such as a (quinolin-3-yl)methyl group or an (indol-3-yl)methyl group.

[0060] R1 and R 17 The alkenyl group in the alkenyl group which may have a substituent is C 3-6 Examples of such alkenyl groups include an allyl 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.

[0061] R 1 and R 16 C, which may have the following substituent: 6-10 C in aryl groups 6-10 The aryl group includes a phenyl group or a naphthyl group, and preferably a phenyl group.

[0062] R 1 and R 16 Examples of the heteroaryl group in the heteroaryl group which may have a substituent include a furyl group, a thienyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group, and a tetrazolyl group, and preferably a thienyl group, a pyridyl group, or a tetrazolyl group.

[0063] R 2 ~R 15 C, which may have the following substituent: 1-6 C in alkoxy group 1-6 Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an iso-propoxy group, a butoxy group, an iso-butoxy group, and the like, and preferably a methoxy group.

[0064] R 2 ~R 15 , R a and R b The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

[0065] R 17 Examples of the silyl protecting group include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, and a tert-butyldiphenylsilyl group, and preferably a tert-butyldimethylsilyl group or a triisopropylsilyl group.

[0066] R 1 Examples of the amino-protecting group 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, a 3,5-dimethoxybenzyloxycarbonyl group, a 3,4,5-trimethoxybenzyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, a p-chlorobenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a p-phenylazobenzyloxycarbonyl group, a p-methoxyphenylazobenzyloxycarbonyl group, a 3,5-dimethoxybenzyloxycarbonyl group, a 2,2,2-trichloroethoxycarbonyl group, a carbamate-based protecting groups such as p-toluenesulfonyl group or 2-nitrobenzenesulfonyl group; imide-based protecting groups such as phthaloyl group; acyl-based protecting groups such as acetyl group or trifluoroacetyl group; C-type protecting groups such as benzyl group, phenylethyl group, phenylpropyl group, trityl group or naphthylmethyl group; 7-19 and the like.

[0067] R in the above general formulas (I) and (II) 03 and R 10 Examples of the saturated hydrocarbon ring formed by bonding to each other and which may have a substituent include those having 3 to 8 carbon atoms such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane, and preferably cyclopentane or cyclohexane.

[0068] R in the above general formulas (I) and (II)03 and R 10 Examples of the saturated heterocycle formed by bonding to each other and which may have a substituent include 4- to 6-membered cyclic amines such as azetidine, pyrrolidine, piperidine, piperazine, and morpholine, cyclic ethers such as tetrahydrofuran, tetrahydrothiophene, and dioxane, and cyclic thioethers, and are preferably cyclic amines, and more preferably pyrrolidine or piperidine.

[0069] R in the above general formulas (I) and (II) 01 and R 10 Examples of the unsaturated hydrocarbon ring formed by bonding to each other and which may have a substituent include cycloalkenes having 5 to 8 carbon atoms, such as cyclopentene and cyclohexene, and aromatic hydrocarbons having 6 to 10 carbon atoms, such as benzene and naphthalene, and preferably benzene.

[0070] R in the above general formulas (I) and (II) 01 and R 10 Examples of unsaturated heterocycles which may have a substituent and are formed by bonding to each other include five-membered rings such as pyrrole, furan, imidazole, oxazole, isoxazole, oxadiazole, thiophene, thiazole, isothiazole, and thiadiazole, and six-membered rings such as pyridine, pyrimidine, pyridazine, and pyrazine, and preferred examples include furan, thiophene, thiazole, and pyridine.

[0071] R in the above general formulas (I) and (II) 02 and R 10 Examples of the saturated heterocycle formed by bonding to each other and which may have a substituent include 4- to 6-membered cyclic amines such as azetidine, pyrrolidine, piperidine, piperazine, and morpholine, and preferably pyrrolidine or piperidine.

[0072] R in the above general formulas (I) and (II) 03 and R 10Examples of the unsaturated hydrocarbon ring formed by bonding together and which may have a substituent include cycloalkenes having 5 to 8 carbon atoms such as cyclopentene and cyclohexene.

[0073] R in the above general formulas (I) and (II) 03 and R 10 Examples of the unsaturated heterocycle formed by bonding to each other and which may have a substituent include tetrahydropyridine and dihydropyran.

[0074] R in the above general formulas (I) and (II) 01 , R 02 or R 03 And, R 10 a lactam ring which may have a substituent formed by bonding together, and R 8 ,R 10 and R 14 Among these, the ring formed together with the alkylene chain formed by bonding any two groups together, and the ring formed together with the remaining group may contain δ-lactam or γ-lactam.

[0075] R in the above general formulas (I) and (II) 01 , R 02 or R 03 And, R 10 Examples of rings that can be condensed with a saturated hydrocarbon ring, a saturated hetero ring, an unsaturated hydrocarbon ring, an unsaturated hetero ring, and a lactam ring which may have a substituent, which are formed by bonding to each other, include a saturated hydrocarbon ring, a saturated hetero ring, an unsaturated hydrocarbon ring, and an unsaturated hetero ring, and preferably, the condensed ring is quinoline, indole, benzofuran, or benzothiophene.

[0076] R 01 , R 02 or R 03 And, R 10are bonded to each other to form a saturated hydrocarbon ring which may have a substituent, a saturated hetero ring which may have a substituent, an unsaturated hydrocarbon ring which may have a substituent, an unsaturated hetero ring which may have a substituent, or a lactam ring which may have a substituent, as well as the above-mentioned condensed rings, preferred are an unsaturated hetero ring which may have a substituent and a condensed unsaturated hetero ring. As the compound represented by the above general formula (I), for example, a compound represented by the following chemical formula is preferred.

[0077] [ka] (In the formula, R 1 , R 16 , R 17 , R a , R b and k have the same meaning as above.

[0078] R 8 , R 10 and R 14 As the alkyl group, any two groups selected from these may be bonded to each other to form C 1-4 An alkylene chain may be formed, and the alkylene chain may be substituted with a substituent. In addition, the alkylene chain may have a carbon atom constituting the alkylene chain replaced with a heteroatom such as a sulfur atom, an oxygen atom, or a nitrogen atom, and may further have a double bond or an amide bond in the middle, and the remainder other than the two selected groups may be bonded to the alkylene chain.

[0079] R 8 , R 10 and R 14 In R 10 and R 14 or R 10 and R 14 The group formed by bonding is further joined by R 8 Examples of the morphinan derivatives to which are linked include, but are not limited to, the following (a) and (b):

[0080] (a)R 10 and R 14 Compounds in which are bonded to each other to form a 5- to 8-membered ring

[0081] [ka] (In the formula, R 1 ~R 9 , R 11 ~R 13 , R 15 ~R 17 , R a , R b , k, and X have the same meanings as above. A and C are CH 2 , N.R. t (In the formula, R t represents an amino-protecting group, an aralkyl group which may have a substituent, or a heteroaryl group which may have a substituent), or an oxygen atom, and B represents a bond or an alkylene chain having 1 to 3 carbon atoms which may have a substituent). Specific examples include the following compounds. Note that descriptions of substituents other than those shown are omitted.

[0082] [ka]

[0083] (b)R 8 , R 10 and R 14 Compounds with

[0084] [ka] (In the formula, R 1 ~R 7 , R 9 , R 11 ~R 13 , R 15 ~R 17 , R a , R b , k and X have the same meanings as above. 2 represents CH or N, C 2 and D.2 CH 2 , N.R. t , O or S; B 2 and E 2 represents an alkylene chain having 1 to 3 carbon atoms which may have a bond or a substituent, and examples of the substituent include C 1-6 Alkyl group, C 1-6 an alkoxy group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, a halogen atom, a hydroxy group, C 1-6 Examples of the substituent include an amino group which may have a substituent such as an alkylamino group, ═O, and ═S. Specific examples include the following compounds. Note that descriptions of substituents other than those shown are omitted.

[0085] [ka]

[0086] From another viewpoint of the present invention, in the case of a morphinan derivative having a nitrogen atom as a constituent atom of the ring and protected with an aralkyl group or a heteroarylalkyl group (particularly preferably a benzyl group) as in the derivative described in Patent Document 11, the present invention can be applied to carry out all deprotection reactions in one step, including the dephenoxylation reaction at the 4-position and the removal of the alkyl protecting group of the phenol at the 3-position (particularly preferably removal of the benzyl group or methyl group). More specifically, the applicable morphinan derivatives in general formula (I) include derivatives represented by the following general formula (c).

[0087] [ka] (In the formula, R 1 , R 16 , R 17 , A 1 , B 1 , D 1 , k and X have the same meanings as in formula (IV). b1The group may be an aralkyl group which may have a substituent or a heteroarylalkyl group which may have a substituent, and preferably an aralkyl group which may have a substituent. Specific examples include the following compounds. Note that descriptions of substituents other than those shown are omitted.

[0088] [ka]

[0089] Of the derivatives represented by the above general formula (a), (b) or (c), preferred are derivatives of formula (b) and (c), more preferred is (c). The compound represented by the above general formula (I) can be obtained by referring to the method described in Patent Document 3, or the methods described in Patent Documents 1, 2, 4 to 11, and Non-Patent Documents 1 to 16.

[0090] R 10 and R 11 Examples of the cyclic ketal in the optionally substituted cyclic ketal group formed by combining with the carbon to which it is bonded include dioxolane and dioxane.

[0091] k represents an integer of 1 or 2, with 1 being preferred.

[0092] m represents an integer of 1 to 5, with 1 or 2 being preferred.

[0093] A double line consisting of a solid line and a dashed line represents a single bond or a double bond, with a single bond being preferred.

[0094] The amino group which may have a substituent is an amino group, a linear or branched C 1-10 Alkylamino group, N-(straight or branched C 1-10 Alkyl group)-N-(linear or branched C 1-10 (alkyl)amino group, acylamino group, protected amino group, etc. Unless otherwise specified in the present specification, the substituents include linear or branched C alkyl groups such as methyl, ethyl, propyl, or isopropyl groups. 1-6 Alkyl groups; halogenated C such as fluoromethyl, difluoromethyl, and trifluoromethyl groups 1-10 Alkyl groups; linear or branched C such as methoxy, ethoxy, propoxy or isopropoxy groups 1-6 Alkoxy groups; halogenated C such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy groups 1-10 Alkoxy groups; halogen atoms such as fluorine or chlorine; amino groups which may have a substituent; acyl groups such as acetyl, cyclopropylcarbonyl or benzoyl; C groups such as 2-propenyl; 2-6 Examples include an alkenyl group, a cyano group, or a hydroxy group.

[0095] <3.> A compound represented by general formula (IV) or general formula (V) R in the above general formulas (IV) and (V) 1 and k have the same meaning as described in <2.> above, and the same specific examples are also included. R in the above general formula (IV) 16 and R 17 has the same meaning as described in <2.> above, and the specific examples thereof are similar. X in the above general formulas (IV) and (V) 0 As for CR 21 R 22 , N.R. 23 or an oxygen atom (R 21 ~R 23 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, etc.), preferably CH 2 Examples include: A in the above general formulas (IV) and (V) 1 As the alkyl group, CH is preferable. B in the above general formulas (IV) and (V) 1 represents an alkylene chain having 1 to 3 carbon atoms which may have a substituent such as a halogen atom, and the alkylene chain is NR 0may form an amide bond together with 2 Examples include: D in the above general formulas (IV) and (V) 1 As for the CH 2 , N.R. 05 , O or S, where R 05 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, etc.), preferably CH 2 Examples include: And, R in the above general formula (IV) 0 Examples of the aryl group include a hydrogen atom; an aralkyl group which may have a substituent such as a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms (for example, 6-10 Aryl-substituted C 1-3 alkyl group; heteroarylalkyl group which may have a substituent such as a halogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkoxy group having 1 to 6 carbon atoms (for example, a C substituted with a 5- to 7-membered heterocycle such as thiazole, 1-3 alkyl group), preferably a hydrogen atom or a benzyl group. The compound represented by the above general formula (IV) can be obtained by referring to the method described in Patent Document 3, or the methods described in Patent Documents 1, 2, 4 to 11, and Non-Patent Documents 1 to 16.

[0096] <4.> A compound represented by general formula (VI) R in general formula (VI) 1 , R 16 and R 17 has the same meaning as described in <2.> above, and the specific examples thereof are similar. Here, the compound represented by the general formula (VI) can be, for example, (i) a compound represented by the above general formula (IV) (wherein R 0 represents a benzyl group.) is subjected to catalytic reduction in the presence of Pd / C to debenzylate, or (ii) a compound represented by general formula (IV) is reacted with phenyl chloroformate to produce a phenyl carbamate, which is then reacted with a base to obtain the phenyl carbamate.

[0097] <5.> Reduction reaction conditions The morphinan derivative represented by the above general formula (II) can be produced by reacting the morphinan derivative represented by the above general formula (I) with metallic lithium under the conditions of Birch reduction or Benkeser reduction.

[0098] The metallic lithium used in the method of the present invention may be commercially available, for example, in wire, granular or chip form. From the viewpoint of safety and ease of use, the granular or chip form is preferred. In the method of the present invention, examples of the organic solvent include aromatic hydrocarbons such as benzene, toluene, or xylene; ethers such as diethyl ether, tert-butyl methyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or ethylene glycol dimethyl ether; alcohols such as methanol, ethanol, isopropanol, or tert-butyl alcohol; and solvents such as acetone, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, or ethyl acetate, preferably aromatic hydrocarbons or ethers, more preferably tetrahydrofuran, benzene, toluene, or xylene. It is also possible to carry out the reaction under solvent-free conditions, that is, in the absence of an organic solvent. When an organic solvent is used, there is no particular restriction on the amount of the organic solvent used, but it is preferably in the range of 1 to 50 times by weight relative to 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 because metallic lithium is used. The reaction is usually carried out at a temperature between −30° C. and the boiling point of the organic solvent used, for example, at a temperature between 150° C., preferably −10° C. to 120° C., more preferably −5° C. to 105° C., and even more preferably 70 to 95° C. The reaction is completed in 30 minutes to 24 hours, preferably 1 hour to 20 hours. In addition, in the method of the present invention, three functional group transformations, namely, dephenoxylation reaction at the 4-position, dealkylation reaction of the alkoxy group at the 3-position, and N-debenzylation reaction of the N-benzyl group, can be carried out in a one-pot manner under Birch reduction or Benkeser reduction conditions using metallic lithium. The amount of metallic lithium used per functional group transformation is 2.0 to 50 equivalents, preferably 2.0 to 20 equivalents, relative to the morphinan derivative represented by the above general formula (I).

[0099] The amines used in the method of the present invention include ammonia (e.g., liquid ammonia), primary amines, and secondary amines. Primary amines include alkylamines such as methylamine, ethylamine, propylamine, isopropylamine, butylamine, isobutylamine, sec-butylamine, and tert-butylamine; primary amines represented by the above general formula (III) such as ethylenediamine and propylenediamine; and polyamines such as spermine. Secondary amines include dialkylamines such as dimethylamine, diethylamine, and methylethylamine; and cyclic amines such as pyrrolidine, piperidine, piperazine, and morpholine. Primary amines are preferred, primary amines are more preferred, primary amines represented by the above general formula (III) are even more preferred, and ethylenediamine or propylenediamine are the most preferred. The amount of the amines used, for example, in the reaction in the presence of an organic solvent, can be 1 to 20 mol, preferably 1 to 15 mol, and more preferably 1 to 10 mol, per mol of lithium. In the reaction in the absence of an organic solvent, 5 to 50 mol, preferably 5 to 30 mol, more preferably 5 to 20 mol, and further preferably 5 to 15 mol can be used per mol of lithium.

[0100] The metal hydride used in the method of the present invention includes lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, and the like. The amount of the metal hydride used may be 0.1 to 20% by weight, preferably 1 to 10% by weight, based on the amines used. The method of the present invention can be carried out in an open system, but is preferably carried out in an atmosphere of an inert gas such as nitrogen or argon.

[0101] As an example of one-pot conversion of three functional groups, the compound represented by the above general formula (IV) (e.g., R 0 The compound represented by the general formula (V) can be produced by the above-mentioned method of the present invention, which can be applied to the compound represented by the general formula (V). The derivative represented by the general formula (V) can be produced by the above-mentioned method of the present invention. 0 The compound can also be effectively produced by applying the method of the present invention to a compound in which R is a hydrogen atom. Furthermore, the reduction reaction from the compound represented by the above general formula (A) to the compound represented by the above general formula (B) can also be carried out in a manner similar to the method for obtaining the morphinan derivative represented by the above general formula (II) from the morphinan derivative represented by the above general formula (I). The phenol derivative represented by the general formula (B), or a salt, tautomer, stereoisomer, or isotope of the phenol derivative; the morphinan derivative represented by the general formula (II), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative; or the morphinan derivative represented by the general formula (V), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative, can be isolated and / or purified by applying a method known per se, such as solvent extraction, concentration, crystallization, precipitation, filtration, or chromatography. 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 production method, which includes at least one step selected from solvent extraction, concentration, crystallization, precipitation, and filtration as an isolation and / or purification step of a phenol derivative represented by general formula (B), or a salt, tautomer, stereoisomer, or isotope of the phenol derivative; a morphinan derivative represented by general formula (II), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative; or a morphinan derivative represented by general formula (V), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative, and does not include a chromatography step. By applying the above-mentioned isolation and / or purification steps, a phenol derivative represented by general formula (B), or a salt, tautomer, stereoisomer, or isotope of the phenol derivative; a morphinan derivative represented by general formula (II), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative; or a morphinan derivative represented by general formula (V), or a salt, tautomer, stereoisomer, or isotope of the morphinan derivative, 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 95% or more, and with a yield of 30% or more, preferably 40% or more, more preferably 50% or more, and even more preferably 60% or more. In this specification, the salt of a phenol derivative represented by general formula (B), the salt of a morphinan derivative represented by general formula (II), or the salt of a morphinan derivative represented by general formula (V) refers to a salt commonly used in the field of organic chemistry, such as a base addition salt at a phenolic hydroxyl group when the compound has a phenolic hydroxyl group, or an acid addition salt at an amino group or a basic heterocyclic group when the compound has an amino group or a basic heterocyclic group. Examples of base addition salts include alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; ammonium salts; and organic amine salts such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, and N,N'-dibenzylethylenediamine. Examples of acid addition salts include inorganic acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and perchloric acid; organic acid salts such as acetic acid, formic acid, maleic acid, fumaric acid, tartaric acid, citric acid, ascorbic acid, and trifluoroacetic acid; and sulfonate salts such as methanesulfonic acid, isethionic acid, benzenesulfonic acid, and p-toluenesulfonic acid. The salts can be mutually converted between free forms and salts, or between different salts, by a method known per se before or after the isolation and / or purification step. EXAMPLES

[0102] The present invention will be described in more detail below with reference to Examples, Comparative Examples, and Test Examples, but the present invention is not limited thereto. The compounds of the Examples and Reference Examples were named by converting the structural formulas drawn using ChemDraw ver.15 (Cambridge Soft) into English names using the naming algorithm built into the software, and then translating the names into Japanese.

[0103] (Reference example 1) (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 Preparation of free form and dihydrochloride salt

[0104] [ka] (Manufacturing method using copper powder) In a 1000mL 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 (27g, 1 equivalent) was dissolved in pyridine (270mL) under a nitrogen atmosphere. Cesium carbonate (97g, 6 equivalents), bromobenzene (39g, 5 equivalents) and copper powder (3.2g, 1 equivalent) were added to the resulting solution and heated to reflux with vigorous stirring. After 6 hours, the reaction was confirmed by HPLC and the conversion rate was 85%. Pyridine (270 mL), cesium carbonate (97 g, 6 equivalents), bromobenzene (39 g, 5 equivalents) and copper powder (3.2 g, 1 equivalent) were added to the reaction solution, and the mixture was heated to reflux overnight with vigorous stirring. The conversion rate was confirmed by HPLC and was 98%. 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 (500 mL) and methanol (500 mL), and the combined filtrate and washings were concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (400 mL), washed twice with a saturated aqueous ammonium chloride solution (150 mL), and then washed twice with 6% aqueous ammonia (100 mL). The separated aqueous layer was washed twice with ethyl acetate (80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound in crude free form (28 g, 103%). The obtained crude free form was dissolved in a 1:1 mixture (3.5 L) of n-heptane and ethyl acetate, and the solution was filtered through a short column packed with silica gel (140 g) using the same mixed solvent as an elution solvent, and then concentrated under reduced pressure to obtain the title compound free form (21.6 g). The NMR spectrum was consistent with that reported for compound 74 in Example 64 of Patent Document 3. The obtained free form was dissolved in ethyl acetate (150 mL), and then a 4N hydrogen chloride / ethyl acetate solution (20 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 title compound dihydrochloride (21.6 g, 79%) as a light brown amorphous solid. Purity: 83%

[0105] 1 H-NMR (400MHz, CD 3 OD) δ7.50-7.59(m,5H),6.77-7.36(m,7H),4.27-4.43(m,1H),4.24-4.26(m,1H),4.07-4.14(m,1H),2.79-2 .88(m,14H),1.85-2.11(m,4H),1.69-1.72(m,1H),1.15-1.60(m,1H),0.70-0.80(m,2H),0.48-0.67(m,2H).

[0106] (Production method using catalytic amount of copper iodide) Pyridine (1600 mL) was added to a reaction vessel filled with nitrogen at room temperature, and nitrogen gas was passed through the pyridine for 10 minutes to replace the oxygen in the solvent with nitrogen. Next, (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 (173.9 g, 0.32 mol, 1 equivalent) and potassium phosphate (305.7 g, 1.44 mol, 4.5 equivalents) were added at room temperature under a nitrogen atmosphere, and the mixture was heated to 95-105 °C and stirred for 60 minutes. Cuprous iodide (12.2 g, 64 mmol, 0.2 equivalents) and bromobenzene (226.1 g, 151.7 mL, 1.44 mol, 4.5 equivalents) were added to the reaction solution while stirring at the same temperature, and the mixture was stirred at 110-120°C under a nitrogen atmosphere. After 6 hours, HPLC analysis showed that the conversion rate was 85%, so bromobenzene (8.4 mL, 0.25 equivalents) was added and the mixture was stirred for 14 hours. HPLC analysis showed that the conversion rate was 99.4%. After cooling the reaction solution to room temperature, unnecessary materials were filtered off using a Seitz-type filter and washed with ethyl acetate (450 mL). The collected filtrate and washings were concentrated under reduced pressure. Ethyl acetate (1800 mL) was added to the residue to dissolve it, and 8% aqueous ammonia (1000 mL) was slowly added to adjust the pH to 10. The resulting two-layer solution was stirred for 20 minutes, and the deep purple aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (800 mL), and the combined organic layers were washed with water (1200 mL, 1000 mL). The aqueous layer was filtered through a filter filled with silica gel 60 (125 g), and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1000 mL) and cooled to 5°C. A 15% hydrogen chloride / ethyl acetate solution (220 mL, 4 equivalents) was slowly added to the resulting solution. Heptane (2000 mL) was added to the resulting suspension, and the mixture was stirred at 0-10°C for 30 minutes. The resulting solid was collected by filtration, washed with a mixed solution of ethyl acetate and heptane (1:2, 200 mL x 2), and dried at 40 °C for 12 hours under reduced pressure to obtain the dihydrochloride salt of the title compound (177.9 g, 89.7%) as a light brown amorphous solid. Purity: 92.4% The NMR spectrum was consistent with that of the above-mentioned production method using copper powder.

[0107] (Reference example 2) (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 Preparation of free form and dihydrochloride salt

[0108] [ka] (Manufacturing method using copper powder) Pyridine (45 L) was added to a 100 L reaction vessel at room temperature, (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 (2.2 kg, 1 equivalent) and potassium carbonate (2.8 kg, 5 equivalents) were added, and the mixture was stirred for 60 minutes at 95 to 105 °C under a nitrogen atmosphere. Copper powder (259 g, 1 equivalent) and 1-bromo-4-(tert-butyl)benzene (4.31 kg, 5 equivalents) that had just been distilled and purified were added to the reaction mixture at the same temperature, and the mixture was heated to reflux under a nitrogen stream for 24 hours. The reaction solution was cooled from 95°C to 105°C, and the reaction was confirmed by HPLC, but raw materials remained. Copper powder (259g, 1 equivalent) was added, and the mixture was heated under reflux for 20 hours. The reaction solution was cooled from 95°C to 105°C, and the reaction was confirmed by HPLC, but raw materials remained. Copper powder (259g, 1 equivalent) was added again, and the mixture was heated under reflux for 20 hours. At this time, the conversion rate of the reaction was 98.7%. The reaction solution was cooled to room temperature and then filtered through a short column packed with silica gel (100-200 mesh, 6.5 kg). The short column was washed with ethyl acetate (44 L) and methanol (22 L). The collected filtrate and washings were concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (22 L). 6% aqueous ammonia (11 L) was added to the resulting solution, and the mixture was stirred for 20 minutes. The organic layer was separated, and the aqueous layer was extracted three times with ethyl acetate (11 L). The collected organic layer was dried over anhydrous sodium sulfate (1.0 kg), and the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent (11 L) of ethyl acetate and heptane (1:4), and cooled to 0-10°C. A 4N hydrochloric acid / ethyl acetate solution (2.2 L, 2.2 equivalents) was added to the resulting solution with stirring, and then the mixture was stirred for 1 hour. The resulting solid was collected by filtration, washed with a mixed solvent (11 L) of ethyl acetate and heptane (1:4), and the dihydrochloride salt of the title compound was obtained.

[0109] 1 H-NMR (400MHz, CD 3OD) δ7.51-7.62(m,5H),7.40(d,1H,J=12Hz),7.25-7.37(m,2H),7.14(d,1H,J=8.4Hz),6.78(d,1H,J=12Hz),6.71 (d,1H,J=12Hz),4.09-4.47(m,5H),2.79-3.88(m,11H),1.15-2.10(m,21H),0.70-0.90(m,2H),0.47-0.69(m,2H).

[0110] The dihydrochloride obtained above was transferred to a 100 L reaction vessel, and ethyl acetate (11 L), water (11 L), and concentrated aqueous ammonia (about 4.5 L) were added thereto, and the pH of the aqueous layer was adjusted to 10-11. After separating the organic layer, the aqueous layer was extracted three times with ethyl acetate (11 L). The collected organic layer was concentrated under reduced pressure and filtered through a short column packed with silica gel (100-200 mesh, 5.5 kg). The short column was washed with ethyl acetate (44 L) and methanol (22 L). The collected filtrate and washings were concentrated under reduced pressure, and the resulting residue was dissolved in 2-propanol (16.5 L), and the resulting solution was slowly added dropwise to vigorously stirred water (66 L) at room temperature. The resulting solid was collected by filtration and washed with water (500 mL). The obtained solid was dried under reduced pressure at 25°C for 72 hours to obtain the free form of the title compound (1.85 kg, 75.9%, purity 90.5%) as a white solid.

[0111] 1 H-NMR (400MHz, CD 3 OD) δ7.20-7.30(m,7H),7.03(d,1H,J=8.4Hz),6.88(d,1H,J=8.4Hz),6.59-6.63(m, 2H),3.58-3.64(m,4H),2.93-3.32(m,7H),2.65-2.75(m,2H),2.45-2.49(m,1H),2.2 6-2.35(m,2H),1.98-2.05(m,1H),1.69-1.78(m,2H),1.44-1.57(m,1H),1.22-1.34 (m,1H),1.01-1.16(m,2H),0.72-0.82(m,2H),0.40-0.51(m,2H),0.08-0.18(m,2H).

[0112] (Production method using catalytic amount of cuprous iodide) Pyridine (175 mL) was added to a 250 mL reaction vessel at room temperature, and (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 (10.87 g, 20.0 mmol, 1 equivalent) and potassium phosphate (19.1 g, 90 mmol, 4.5 equivalents) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 95 to 105 ° C. for 60 minutes. Then, copper iodide (0.95g, 5.0mmol, 0.25 equivalents) and 1-bromo-4-(tert-butyl)benzene (17.1g, 80mmol, 4.0 equivalents) were added at the same temperature, and the reaction temperature was raised to 110-120°C, and the mixture was stirred under a nitrogen atmosphere for 4 hours. As a result of HPLC analysis, the conversion rate was 54%. Stirring was continued for 14 hours, and after confirming the disappearance of the raw materials by HPLC analysis, the reaction solution was cooled to room temperature. The reaction solution was filtered through a Seitz-type filter, and after filtering out the insoluble matter, the filter was washed with ethyl acetate (260mL). The combined filtrate and washings were concentrated under reduced pressure to obtain a residue (24.7g). Ethyl acetate (300mL) and 6% aqueous ammonia (160mL) were added to the residue, the pH was adjusted to 10, and the mixture was stirred for 20 minutes. After separating the aqueous layer, it was extracted with ethyl acetate (300 mL), and the combined ethyl acetate layer was washed with water (400 mL) and filtered with a Pall-Carbon filter, and the filtrate was concentrated under reduced pressure to obtain a residue (19.8 g). After dissolving the residue in ethyl acetate (80 mL), the resulting solution was cooled to 0-10°C, and a 1M hydrogen chloride / ethyl acetate solution was slowly added. Heptane (33 mL) was then added and stirred at 0-10°C for 30 minutes. The resulting suspension was filtered and washed with a mixed solvent of ethyl acetate and heptane (1:2, 100 mL x 2), and the dihydrochloride salt of the title compound (12.0 g, 88.5%) was obtained as a light brown amorphous powder (purity 94.7%). The NMR spectrum was consistent with that produced using copper powder, as described above.

[0113] The dihydrochloride salt (6.72 g, 0.01 mol, 1 equivalent) obtained above was added to a reaction vessel and dissolved in water (220 mL) while stirring for 20 minutes. 25% aqueous ammonia (2.7 g, 0.04 mol, 4 equivalents) was added to the obtained solution while stirring over 30 minutes, and then stirred at room temperature for 30 minutes. The obtained suspension was stirred at 0-5°C for 2 hours, and the solid was filtered, washed with water (200 mL x 2), and dried at 40°C under reduced pressure to obtain the free form of the title compound (5.2 g, 87%) as a light brown amorphous solid (purity 90.3%). The NMR spectrum was consistent with that produced using copper powder, as described above.

[0114] (Example 1-1) Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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

[0115] [ka] (Produced by debenzylation through hydrogenation) (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 dihydrochloride was dissolved in ethanol (230mL) and 10% palladium-carbon (6.87g) was added, and the mixture was stirred under a hydrogen atmosphere (50psi) at 40°C. After 32 hours, the remaining raw material was confirmed by HPLC analysis, so the reaction solution was filtered, and 10% palladium-carbon (6.97g) was added to the filtrate, and the mixture was stirred under a hydrogen atmosphere (50psi) at 40°C for another 56 hours (conversion rate 92%). Since HPLC analysis confirmed the remaining raw materials, stirring was continued for another 3 days. The reaction solution was filtered and washed with ethanol (100 mL), and the filtrate was concentrated under reduced pressure to obtain the title compound (19.5 g, 85%).

[0116] 1 H-NMR (400MHz, CD 3 OD)δ6.75-7.21(m,7H),2.83-3.91(m,13H),0.60-2.51(m,12H),0.35-0.58(m,2H),0.02-0.10(m,2H).

[0117] (Example 1-2) Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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

[0118] [ka] (Prepared by debenzylation via phenylcarbamate) First step: Preparation of phenyl (1S,3aR,5aS,6R,11bS,11cS)-14-(cyclopropylmethyl)-10-methoxy-11-phenoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate hydrochloride

[0119] THF (50mL, 10v / w) was added to a 100mL reaction vessel, and (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 dihydrochloride (5.0g, 8.1mmol, 1eq) was suspended at room temperature, followed by the addition of water (1.5mL, 0.3v / w) and potassium carbonate (5.6g, 40.4mmol, 5eq). The reaction mixture changed from a suspension to a clear solution. The reaction mixture was stirred under heating to reflux, and then phenyl chloroformate (2.54 g, 16.2 mmol, 2 equivalents) was added, followed by stirring for 2 hours at 60° C. The disappearance of the raw materials was confirmed by HPLC analysis. After the reaction solution was cooled to room temperature, ethyl acetate (50 mL, 10 v / w) and water (25 mL, 5.0 v / w) were added, and the mixture was stirred at room temperature for 30 minutes. The two layers were separated, and the organic layer was washed twice with water (50 mL, 10 v / w) and concentrated under reduced pressure. The residue was dissolved in a mixed solvent of ethyl acetate and heptane (1:8, 100 mL, 20 v / w), and the resulting solution was cooled to 0-10°C, and 4N hydrogen chloride / ethyl acetate solution (8.1 mL, 32.4 mmol, 4 equivalents) was slowly added with stirring, and the mixture was stirred for 1 hour. The resulting solid was collected by filtration and washed with a mixed solvent of ethyl acetate and heptane (1:8, 25 mL, 5 v / w). The resulting solid was added to a 100 mL reaction vessel, suspended in MTBE (25 mL, 5 v / w), stirred under heated reflux for 1 hour, and then cooled to 0-10°C. The solid was collected by filtration, washed with MTBE (10 mL, 2.0 v / w), and dried under reduced pressure at 45-50°C for 3 hours to obtain the title compound (4.5 g, 93.9%) as a pale yellow powder (purity 91%).

[0120] 1 H-NMR (400MHz, CD 3 OD)δ6.75-7.21(m,12H),4.35-4.63(m,1H),4.20(d,1H,J=6.4Hz),2.71-3.95(m,10H),0.71-1.88(m,14H),0.43-0.60(m,2H).

[0121] Second step: Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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 Add tert-butanol (86mL, 20v / w) to a 250mL reaction vessel, add the phenyl (1S,3aR,5aS,6R,11bS,11cS)-14-(cyclopropylmethyl)-10-methoxy-11-phenoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate hydrochloride (4.3g, 7.0mmol, 1 equivalent) obtained above, and distill off the solvent at 50-55°C under reduced pressure while stirring. Add tert-butanol (43mL, 10v / w) again, and distill off the solvent in the same manner. Repeat the above operation once more, and cool to room temperature. The resulting residue was suspended in tert-butanol (43 mL, 10 v / w), potassium hydroxide (3.9 g, 70.2 mmol, 10 eq) was added, and the reaction solution was stirred under heating and refluxing for 2 hours. HPLC analysis showed that the raw materials were completely consumed. After cooling the reaction solution to room temperature, MTBE (86 mL, 20.0 v / w) was added and washed with water (86 mL, 20.0 v / w). The aqueous layer was extracted twice with MTBE (43 mL, 10.0 v / w), and the collected organic layer was concentrated under reduced pressure. The residue was suspended in MTBE (86 mL, 20.0 v / w), and water (86 mL, 20.0 v / w) and 12N hydrochloric acid were added to adjust the pH to 3. The aqueous layer was separated and washed twice with MTBE (43 mL, 10.0 v / w). The aqueous layer was transferred to a 250 mL reaction vessel and stirred under reduced pressure to distill off MTBE. The remaining aqueous layer was heated to 50°C and stirred for 1 hour, then aqueous ammonia was added at the same temperature to adjust the pH to 9-10, and the mixture was stirred for another 1 hour, and then cooled to room temperature to obtain a suspension. The solid was collected by filtration, washed with water (4 mL, 1.0 v / w), and dried under reduced pressure at 45-50°C for 3 hours to obtain the title compound (2.4 g, 74.9%) as a pale yellow powder (purity 99.7%). The NMR spectrum was consistent with that prepared by hydrogenation debenzylation.

[0122] (Example 2-1) Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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

[0123] [ka] (Produced by debenzylation through hydrogenation) Ethanol (4.5L) was added to a 10L autoclave, and (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 (435g, 0.73mol) and 10% palladium-carbon (87g) were added at room temperature. The reaction vessel was replaced with nitrogen three times, then replaced with hydrogen three times, the internal pressure was set to 0.3 to 0.35MPa, and the mixture was stirred at 50°C for one day and night. At this time, the raw material still remained, so the reaction temperature was cooled to 25°C to 30°C, and the reaction vessel was purged with nitrogen three times. Palladium-carbon was filtered off and washed with ethanol (150mL). The collected filtrate and washings were transferred to a 10L autoclave, 10% palladium-carbon (87g) was added, the reaction vessel was purged with nitrogen three times, and then with hydrogen three times, and the internal pressure was set to 0.3 to 0.35MPa, and the mixture was stirred at 50°C for 72 hours. The reaction vessel was purged with nitrogen three times, and the palladium-carbon was filtered off and washed with THF (1.0L). The collected filtrate and washings were concentrated under reduced pressure to obtain the title compound (330g, 89.2%) as a brown syrup-like substance (purity 89.8%).

[0124] 1 H-NMR (400MHz, CD 3OD) δ7.26-7.30(m,2H),7.10(d,1H,J=8.8Hz),6.97(d,1H,J=8.4Hz),6.64 -6.68(m,2H),3.84-3.88(m,1H),2.88-3.44(m,8H),2.51-2.55(m,2H),2.3 0-2.40(m,2H),2.06-2.12(m,1H),1.71-1.87(m,2H),1.46-1.54(m,1H),1 .02-1.24(m,1H),0.75-0.80(m,1H),0.49-0.51(m,2H),0.01-0.02(m,2H).

[0125] (Example 2-2) Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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

[0126] [ka] (Prepared by debenzylation via phenylcarbamate) First step: Preparation of phenyl (1S,3aR,5aS,6R,11bS,11cS)-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate hydrochloride THF (10.0L, 10.0v / w) was added to a 20L reaction vessel, and (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 dihydrochloride was added at room temperature and suspended. Water (300mL, 0.3v / w) and potassium carbonate (1022.0g, 7.39mol, 5eq) were added to the resulting mixture at room temperature and stirred under heating and reflux conditions. Phenyl chloroformate (464.0 g, 2.96 mol, 2 equivalents) was added to the reaction solution over 10 minutes at 60° C. After the dropwise addition was completed, the mixture was stirred for 2 hours. The conversion rate was 99.8% by HPLC analysis. After cooling the reaction solution to room temperature, ethyl acetate (10.0L, 10v / w) and water (5.0L, 5v / w) were added and stirred at room temperature for 30 minutes. The two layers were separated, and the organic layer was washed twice with water (10.0L, 10v / w). The organic layer was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of ethyl acetate and heptane (1:8, 20.0L, 20v / w). The resulting solution was cooled to 0-10°C, and 4N hydrogen chloride / ethyl acetate solution (1.48L, 4.0 equivalents) was slowly added and stirred for 1 hour. The resulting suspension was filtered, and the solid was filtered off, then washed with a mixed solvent of ethyl acetate and heptane (1:8, 5.0L, 5v / w) to obtain a yellow solid. The obtained solid was transferred to 10 L of reaction solution, suspended in MTBE (5.0 L, 5 v / w), and stirred under heating and refluxing conditions for 1 hour. The reaction solution was cooled to 0-10°C, and the solid was collected by filtration, washed with MTBE (1.0 L, 1 v / w), and then dried under reduced pressure at 45-50°C for 12 hours to obtain the title compound (947.0 g, 95.6%) as a yellow solid (purity 92.9%).

[0127] 1 H-NMR (400MHz, CD 3OD) δ7.03-7.38(m,11H),4.19-4.47(m,2H),2.72-3.97(m,10H),1.90-2.02(m,2H),1.40- 1.80(m,4H),1.21-1.39(m,11H),1.00-1.20(m,2H),0.70-1.00(m,4H),0.45-0.59(m,2H).

[0128] Second step: Preparation of (1S,3aR,5aS,6R,11bS,11cS)-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 Tert-butanol (13.0L, 10v / w) was added to a 20L reaction vessel, and phenyl (1S,3aR,5aS,6R,11bS,11cS)-11-(4-(tert-butyl)phenoxy)-14-(cyclopropylmethyl)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate hydrochloride (1.3kg, 1.94mol, 1 equivalent) was added and suspended. The resulting mixture was concentrated to 5.0-6.5L at 50-55°C while stirring. Tert-butanol (6.5L, 5v / w) was added to the residue at room temperature, and the solvent was distilled off again. This operation was repeated once more. After cooling the reaction solution to room temperature, tert-butanol (6.5 L, 5 v / w) and potassium hydroxide (1.09 kg, 19.4 mol, 10 equivalents) were added and stirred for 2 hours under heating and refluxing conditions. After confirming the disappearance of the raw materials by HPLC analysis, the reaction solution was cooled to room temperature. MTBE (13.0 L, 10.0 v / w) was added to the reaction vessel and washed with water (13.0 L, 10.0 v / w). The aqueous layer was extracted twice with MTBE (6.5 L, 5 v / w), and the collected organic layer was concentrated under reduced pressure. The residue was dissolved in MTBE (13.0 L, 10.0 v / w), and water (26.0 L, 20.0 v / w) was added, followed by the addition of 36% hydrochloric acid (450 mL) to adjust the pH to 3-4. The two layers were separated, and the aqueous layer was washed twice with MTBE (6.5 L, 5 v / w), and then concentrated under reduced pressure to remove MTBE. The remaining aqueous layer was heated to 50°C, and 25% aqueous ammonia (380.0 g) was added to adjust the pH to 9 to 10. The resulting suspension was filtered, and the solid was separated by filtration, washed with water (13 L, 10 v / w), and then dried under reduced pressure at 55 to 60°C for 6 days to obtain the title compound (895.0 g, 90.0%) as a pale yellow solid (purity 94.3%). The NMR spectrum was consistent with that prepared by debenzylation by hydrogenation.

[0129] (Experimental Results) The diphenyl ether derivatives (starting materials) obtained in Reference Examples 1 and 2 and Examples 1-1 to 2-2 below were subjected to Benkeser reaction conditions using lithium metal, and the yield and purity of the compound ([Chemical Formula 6] of

[0024] ) described in Reference Example 1-1 of Patent Document 11 obtained were shown in Table 1.

[0130] [ka]

[0131] [Table 1]

[0132] Example 3 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0133] [ka] THF (5mL) and lithium (70mg, 5eq) were added to a 50mL three-neck flask and cooled to 0℃, after which a solution of ethylenediamine (5mL, 41eq) and (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 (1g, 1eq) in THF (5mL) was added at the same temperature and stirred for 1 hour. The reaction solution was warmed to room temperature and stirred for 2 hours, after which lithium (70mg, 5eq) was added and stirred for 1 hour at the same temperature. HPLC analysis showed that all raw materials were consumed. Ethanol (5 mL) and water (5 mL) were added to the reaction solution, and the pH of the reaction solution was adjusted to 7 with 1N hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the ethanol was distilled off, and the residue containing water was extracted twice with ethyl acetate (20 mL). The aqueous layer was adjusted to pH 11-12 using 1M aqueous sodium hydroxide solution, and then extracted three times with ethyl acetate (20 mL). The organic layer was concentrated under reduced pressure to obtain the title compound (0.3 g, 47%). Purity: 82% The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0134] Example 4 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0135] [ka] Ethylenediamine (40mL, 353 equivalents) and calcium hydride (2.0g, 5.0%) were added to the reaction vessel, and the mixture was heated to reflux for 1 hour, and then cooled to 60°C. (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 (1.0g, 1 equivalent) was added to the resulting suspension at 60°C, and the mixture was stirred at 60°C for 15 minutes. Lithium chips (512mg, 40 equivalents) were added to the reaction solution, and the mixture was stirred at 60°C for 30 minutes. During this time, the internal temperature of the reaction solution rose to 80°C. After confirming the disappearance of the raw materials by HPLC, the reaction solution was cooled to 0°C to 10°C. THF (20mL) and methanol (3mL) were added to the reaction vessel at the same temperature, and then 6N hydrochloric acid (10mL) was added at the same temperature to adjust the pH of the reaction solution to 10 to 11. The resulting suspension was filtered, and insoluble matter was removed by filtration and washed with THF (20mL). The filtrate was extracted three times with a mixed solvent (20mL) of isopropyl acetate and THF (2:1). The collected organic layer was washed with 15% saline (40mL) and then concentrated under reduced pressure. The residue was dissolved by adding isopropyl acetate (6mL) and water (6mL). The resulting mixture of two layers was stirred at room temperature for one day and night to obtain a suspension. The resulting solid was washed with isopropyl acetate (2.0mL) to obtain the title compound (0.2g, 31%, purity 95.4%) as a yellow solid. The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0136] Example 5 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0137] [ka] Ethylenediamine (40mL, 353 equivalents) and calcium hydride (2.0g, 5.0%) were added to the reaction vessel, and the mixture was heated to reflux for 1 hour, and then cooled to 60°C. (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 (1.0g, 1 equivalent) was added to the resulting suspension at 60°C, and the mixture was stirred at 60°C for 15 minutes. Lithium chips (465mg, 40 equivalents) were added to the reaction solution, and the mixture was stirred at 60°C for 30 minutes. During this time, the internal temperature of the reaction solution rose to 80°C. After confirming the disappearance of the raw materials by HPLC, the reaction solution was cooled to 0°C to 10°C. THF (20mL) and methanol (3mL) were added to the reaction vessel at the same temperature, and then 6N hydrochloric acid (10mL) was added at the same temperature to adjust the pH of the reaction solution to 10 to 11. The resulting suspension was filtered, and insoluble matter was removed by filtration and washed with THF (20mL). The filtrate was extracted three times with a mixed solvent (20mL) of isopropyl acetate and THF (2:1). The collected organic layer was washed with 15% saline (40mL) and then concentrated under reduced pressure. The residue was dissolved by adding isopropyl acetate (60mL) and water (60mL). The resulting mixture of two layers was stirred at room temperature for one day and night to obtain a suspension. The resulting solid was washed with isopropyl acetate (2.0mL) to obtain the title compound (0.18g, 31%, purity 96.7%) as a yellow solid. The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0138] Example 6 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0139] [ka] THF (50mL), lithium chips (760mg, 10 equivalents), and ethylenediamine (12.5mL, 17 equivalents) were added to a 500mL three-neck flask and heated to reflux for 30 minutes. A solution of (1S,3aR,5aS,6R,11bS,11cS)-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 (5g, 1 equivalent) in THF (10mL) was added to the resulting solution and heated to reflux for 2.5 hours. Consumption of the raw material was confirmed by HPLC analysis. The reaction solution was cooled to 0-10°C, and ethanol (20mL) and water (20mL) were added to quench the reaction. The reaction solution was concentrated under reduced pressure, and after distilling off the ethanol, concentrated hydrochloric acid was added to the residue containing water to adjust the pH to 1-2. The aqueous layer was washed twice with ethyl acetate (50mL), and then a 4N aqueous solution of sodium hydroxide was added to the aqueous layer to adjust the pH to 11-12, followed by extraction three times with ethyl acetate (50mL). The collected organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off and dried under reduced pressure to obtain the title compound (3.6gg, 94%, purity 79.3%) as a yellow solid. The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0140] Example 7 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0141] [ka] Ethylenediamine (33mL, 15v / w) and calcium hydride (1.65g, 5wt%) were added to a 250mL reaction vessel at room temperature and stirred for 30 minutes at 100-120°C. After cooling the reaction solution to 60-70°C, (1S,3aR,5aS,6R,11bS,11cS)-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 (2.2g, 4.82mmol, 1 equivalent) was added at the same temperature and stirred for 30 minutes. Lithium (101 mg, 14.4 mmol, 3 eq.) was added and stirred for 10 minutes, after which lithium (101 mg, 14.4 mmol, 3 eq.) was added again and stirred for 10 minutes, after which lithium (136 mg, 19.4 mmol, 4 eq.) was added and stirred for 60 minutes. As a result of HPLC analysis, the disappearance of the raw materials was confirmed, the reaction solution was cooled to 0-5°C, THF (33 mL, 15 v / w) and methanol (7 mL, 3 v / w) were added at the same temperature, and then 6N hydrochloric acid (22 mL, 10 v / w) was added to adjust the pH to 10-11. After separating the aqueous layer, it was extracted three times with a mixed solvent of isopropyl acetate and THF (44 mL, 20 v / w). 4N hydrochloric acid was added to the collected organic layer to adjust the pH to 1-2. After separating the aqueous layer, the organic layer was extracted twice with 4N hydrochloric acid (22 mL, 10 v / w). Isopropyl acetate (22 mL, 10 v / w) was added to the collected aqueous layer, and the pH was adjusted to 10 with 6N aqueous sodium hydroxide. The resulting mixture of two layers was stirred at room temperature for 1 hour, and then at 0-5°C for 2 hours. The resulting suspension was filtered, and the collected solid was washed with a mixture of isopropyl acetate and water (4 mL, 2 v / w), and after drying, the title compound (0.86 g, 51%) was obtained as a pale yellow solid. Purity 99.1% The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0142] Example 8 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0143] [ka] (1S,3aR,5aS,6R,11bS,11cS)-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 (1440g, 1 equivalent) was dissolved in THF (21.6L) at room temperature in a 100L reaction vessel, lithium chips (157g, 8 equivalents) were added, and the mixture was stirred at 40-50°C for 20 minutes. Ethylenediamine (2529g, 15 equivalents) was added to the reaction mixture at the same temperature, and the mixture was stirred at 60-70°C for 120 minutes. The disappearance of the raw material was confirmed by HPLC, and the reaction vessel was cooled to 0-10°C. Ethanol (3.6 L) was added to the reaction mixture, and the mixture was stirred for 30 minutes. Water (3.6 L) was added and the mixture was stirred for another 30 minutes. The resulting suspension was filtered, the solid was washed twice with THF (3 L), and the combined filtrate and washings were transferred to a 50 L reaction solution. Water (15 L) was added to the reaction vessel, and the organic and aqueous layers were separated. The aqueous layer was extracted twice with a mixed solvent (7.5 L) of isopropyl acetate and THF (2:1). 4N hydrochloric acid (9 L) was added to the collected organic layer. At this time, the pH of the aqueous layer was 1 to 2. The organic and aqueous layers were separated, and the organic layer was extracted with 4N hydrochloric acid (3 L). The collected aqueous layer was washed with isopropyl acetate (6 L), and then isopropyl acetate (6 L) and 6N aqueous sodium hydroxide solution (9 L) were added to the aqueous layer. At this time, the pH of the aqueous layer was 10. The resulting mixture of two layers was stirred at room temperature for one day and night to obtain a suspension. The resulting solid was collected by filtration, washed twice with isopropyl acetate (3 L), and then dried under reduced pressure at 40 to 45° C. for 4 hours to obtain the title compound (460 g, 47%, purity 94%) as a pale yellow solid. The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ).

[0144] Example 9 Preparation of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0145] [ka] Ethylenediamine (675.0g, 115.1 equivalents) and calcium hydride (37.5g, 5%) were added to a 5L reaction vessel at room temperature. The resulting mixture was heated to reflux for 1 hour. After cooling the reaction solution to 60-65°C, (1S,3aR,5aS,6R,11bS,11cS)-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 (50g, 1 equivalent) was added at the same temperature and stirred for 15 minutes. Lithium chips (684mg, 1 equivalent) were added to the reaction mixture and stirred for 20 minutes. A small amount of foaming was observed, but when the foaming subsided, lithium chips (1.368 g, 2 equivalents) were added to the reaction mixture again and stirred for 20 minutes. Similarly, after the foaming subsided, lithium chips (1.368 g, 2 equivalents) were added to the reaction mixture and stirred for 20 minutes. Similarly, after the foaming subsided, lithium chips (1.368 g, 2 equivalents) were added to the reaction mixture and stirred for 20 minutes. Similarly, after the foaming subsided, lithium chips (2.052 g, 3 equivalents) were added to the reaction mixture and stirred for 1 hour. The internal temperature of the reaction solution spontaneously rose from 60 ° C to 70 ° C due to heat generation. Since the disappearance of the starting material was confirmed by HPLC, the reaction solution was cooled to 0-10 ° C. At the same temperature, THF (750 mL), methanol (150 mL) and 6N hydrochloric acid (300 mL) were added, and the pH of the reaction solution was adjusted to 10-11 to obtain a suspension. The resulting suspension was filtered, and the residue was washed with THF (300 mL). The aqueous and organic layers of the filtrate were separated, the aqueous layer was extracted three times with a mixed solvent (300 mL) of isopropyl acetate and THF (2:1), and the collected organic layer was concentrated under reduced pressure. The residue was dissolved in toluene (100 mL), stirred at 50-60°C for 1 hour, and then cooled to 0-10°C to obtain a suspension. The resulting solid was collected by filtration, washed with toluene (5.0 mL), and dried to obtain the title compound (23.8 g, 69.5%, purity 98.4%) as a pale yellow solid. The structure of the obtained (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol was confirmed by the fact that the retention time by HPLC analysis was consistent with that of the compound described in Reference Example 1-1 of Patent Document 11 ([Chemical Formula 6] in

[0024] ). [Industrial Applicability]

[0146] According to the present invention, a method for converting a biphenyl ether having an ortho-methoxy group into a monophenol derivative in one step can be provided. The method provided by the present invention can be applied to compounds having a morphinan skeleton.

Claims

1. The following general formula (IV): 【Chemistry 1】 (Where R １ is a hydrogen atom; a C 1-10 alkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group; a C 3-6 cycloalkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group; a cycloalkylalkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group;C 6-10 aryl-C 1-5 alkyl group, (pyridin-2-yl)methyl group, (pyridin-3-yl)methyl group, (pyridin-4-yl)methyl group, 2-(pyridin-2-yl)ethyl group, (furan-2-yl)methyl group, (furan-3-yl)methyl group, (imidazol-2-yl)methyl group, (imidazol-4-yl)methyl group, (imidazol-5-yl)methyl group, (thiazol-2-yl)methyl group, (thiazol-4-yl)methyl group, (thiazol-5-yl)methyl group, (thiophene-2-yl)methyl group, 2-(thiophene-2-yl)ethyl group, (quinolin-3-yl)methyl group, (indol-3-yl)methyl group, C 2-6 alkenyl group, C 6-10 An aryl group, a furyl group, a thienyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group, a tetrazolyl group, 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-phenyl ... a nylazobenzyloxycarbonyl 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, a 9-fluorenylmethyloxycarbonyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, or a trityl group; R １６ is C ６－１０ represents an aryl group, a furyl group, a thienyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group or a tetrazolyl group, R １７ is C １－１０ an alkyl group, a C 6-10 aryl-C 1-5 alkyl group, a C 3-6 alkenyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group or a tert-butyldiphenylsilyl group; k represents 1 or 2; X ０ represents CR 21 R 22 , NR 23 or an oxygen atom, where R 21 to R 23 each represents a hydrogen atom or a C 1-6 alkyl group; A １ represents CH or N, B １ represents an alkylene chain having 1 to 3 carbon atoms which may have a halogen atom, and the alkylene chain is represented by NR ０ may form an amide bond together with D １ is CH ２ , N.R. ０５ , O or S, where R ０５ represents a hydrogen atom or a C 1-6 alkyl group, and R ０ represents a hydrogen atom; a C 6-10 aryl-C 1-3 alkyl group which may have a substituent selected from a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group, or a C 1-3 alkyl group substituted by a 5- to 7-membered heteroaryl which may have a substituent selected from a halogen atom, a C 1-6 alkyl group and a C 1-6 alkoxy group. or a tautomer, stereoisomer or isotope of the morphinan derivative represented by the following general formula (III): 【Chemistry 2】 (In the formula, R g , R h and R i are the same or different and represent a hydrogen atom or a C 1-6 alkyl group optionally having a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group and a benzoyl group, and m represents an integer of 1 to 5.) or a secondary amine selected from dimethylamine, diethylamine, methylethylamine, pyrrolidine, piperidine, piperazine and morpholine in the presence or absence of an organic solvent, The following general formula (V): 【Chemistry 3】 (In the formula, R １ , k, X ０ , A １ , B １ and D. １ represents the same meaning as above.) or a salt, tautomer, stereoisomer or isotope of said morphinan derivative.

2. R １ The process according to claim 1, wherein is a hydrogen atom, a methyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a benzyl group, or an allyl group.

3. R １６ C ６－１０ The method according to claim 1 or 2, wherein the group is an aryl group.

4. R １７ The method according to any one of claims 1 to 3, wherein is a methyl group.

5. R ０ The method according to any one of claims 1 to 4, wherein is a hydrogen atom or a benzyl group.

6. The method according to any one of claims 1 to 5, wherein metallic lithium is used in an amount of 2 to 20 equivalents per functional group to be reduced in the morphinan derivative represented by the above general formula (IV).

7. A manufacturing method described in any one of claims 1 to 6, wherein the organic solvent is an aromatic hydrocarbon, a lower alcohol or an ether solvent.

8. The method according to any one of claims 1 to 6, comprising reacting a morphinan derivative represented by the above general formula (IV) with metallic lithium, liquid ammonia, a primary amine represented by the above general formula (III), or a secondary amine selected from dimethylamine, diethylamine, methylethylamine, pyrrolidine, piperidine, piperazine and morpholine in the absence of an organic solvent.

9. A method for producing a compound according to any one of claims 1 to 8, wherein the reaction temperature is from -10°C to 120°C.

10. A method for producing a compound according to any one of claims 1 to 9, wherein a hydrogenation metal is present in the reaction system.

11. The method of claim 10, wherein the metal hydride is selected from lithium hydride, sodium hydride, potassium hydride, calcium hydride, lithium borohydride, sodium borohydride, diisobutylaluminum hydride or lithium aluminum hydride. Claim 12: A compound of the following general formula (VI): 【Chemistry 4】 (Where R １ is a hydrogen atom; a C 1-10 alkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group; a C 3-6 cycloalkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group; a cycloalkylalkyl group which may have a substituent selected from a C 1-6 alkyl group, a halogenated methyl group, a halogen atom, a hydroxy group, an amino group, an acetyl group, a cyclopropylcarbonyl group, and a benzoyl group;C 6-10 aryl-C 1-5 alkyl group, (pyridin-2-yl)methyl group, (pyridin-3-yl)methyl group, (pyridin-4-yl)methyl group, 2-(pyridin-2-yl)ethyl group, (furan-2-yl)methyl group, (furan-3-yl)methyl group, (imidazol-2-yl)methyl group, (imidazol-4-yl)methyl group, (imidazol-5-yl)methyl group, (thiazol-2-yl)methyl group, (thiazol-4-yl)methyl group, (thiazol-5-yl)methyl group, (thiophene-2-yl)methyl group, 2-(thiophene-2-yl)ethyl group, (quinolin-3-yl)methyl group, (indol-3-yl)methyl group, C 2-6 alkenyl group, C 6-10 An aryl group, a furyl group, a thienyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group, a tetrazolyl group, 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-phenyl ... a nylazobenzyloxycarbonyl 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, a 9-fluorenylmethyloxycarbonyl group, a p-toluenesulfonyl group, a 2-nitrobenzenesulfonyl group, a phthaloyl group, an acetyl group, a trifluoroacetyl group, or a trityl group; R １６ represents a C 6-10 aryl group, a furyl group, a thienyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, an oxazolyl group, an oxadiazolyl group, a pyridyl group, a pyrimidyl group, a pyridazyl group, a pyrazinyl group or a tetrazolyl group; R １７ is C １－１０ an alkyl group, a C 6-10 aryl-C 1-5 alkyl group, a C 3-6 alkenyl group, a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, or a tert-butyldiphenylsilyl group. or a tautomer, stereoisomer or isotope of said morphinan derivative.

13. R １ The morphinan derivative according to claim 12, wherein is a hydrogen atom, a methyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a benzyl group, or an allyl group, or a tautomer, stereoisomer, or isotope of said morphinan derivative.

14. R １６ C ６－１０ 14. The morphinan derivative of claim 12 or 13, which is an aryl group, or a tautomer, stereoisomer or isotope of said morphinan derivative.

15. R １７ The morphinan derivative according to any one of claims 12 to 14, wherein is a methyl group, or a tautomer, stereoisomer or isotope of the morphinan derivative.

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