WO2021132637A1 - Method for producing cyclic secondary amine - Google Patents

Abstract

The present invention addresses the problem of providing a method for producing a high-purity N-dealkylated cyclic secondary amine via a simple and non-turbulent method. An N-dealkylated cyclic secondary amine can be obtained by reacting a cyclic tertiary amine, in which a substituent expressed by R¹-CH₂- (wherein R¹ is a hydrogen atom, an optionally substituted alkyl, a vinyl, a cyclopropyl, or an optionally substituted phenyl) is bonded to the nitrogen atom, and a dialkyl azodicarboxylate, and reacting a compound represented by EWG¹-CH₂-EWG² (wherein EWG¹ and EWG² represent identical or different electron-accepting groups) with the reaction product thereof.

Description

Method for producing cyclic secondary amine

The present invention relates to a method for N-dealkylation of an N-alkyl cyclic amine compound having various structures such as an alkaloid having a morphinan skeleton and an alkaloid having a tropane skeleton, and a method for producing an N-dealkylated cyclic amine compound. , And N-dealkylated cyclic amine compounds.

Naturally-derived alkaloids are often used as pharmaceuticals because they show a variety of physiological activities in trace amounts. Examples of such naturally occurring alkaloids include tropane alkaloids, opium alkaloids and the like.

Tropane alkaloids are a group of natural products having an azabicyclo [3.2.1] octane skeleton, and include cocaine, scopolamine, atropine, etc., which are used as pharmaceuticals. Cocaine, scopolamine and atropine commonly have a cyclic amine structure in which the 8-position of the azabicyclo [3.2.1] octane skeleton is N-methylated, and the substituent at the 8-position has a great effect on physiological activity. Therefore, drug discovery research aimed at developing new and useful drugs by converting the N-methyl group at the 8-position to other substituents is still being vigorously conducted.
On the other hand, opium alkaloids include morphine, codeine, thebaine and the like, which are also used as pharmaceuticals or raw materials for pharmaceuticals. Natural morphinan derivatives such as morphine, codeine and thebaine commonly have a cyclic amine structure in which the 17th position of the morphinan skeleton is N-methylated. As with the previous tropane alkaloid, the substituent at this position has a large effect on the bioactivity of the morphinan derivative. Therefore, various substituents are introduced at this position to confirm the structure-activity relationship and create new and more useful drugs. Drug discovery research has been conducted with the aim of achieving this. In fact, from such drug discovery research, levalophane (a morphinan derivative in which an allyl group was introduced instead of a methyl group as a substituent at the 17-position of the morphinan skeleton) and buprenorphine (a cyclone instead of a methyl group as a substituent at the 17-position of the morphinan skeleton) A morphinan derivative into which a propylmethyl group has been introduced) has been developed.

In the above drug discovery research, naturally-derived tropane alkaloids and opium alkaloids were used as starting materials, and the 8-position N-methyl group and the 17-position N-methyl group, respectively, were removed to form a no-form, and then newly substituted. The method of introducing a group is common. Many such N-demethylation methods have been reported so far, but the yield of the demethylation reaction at a sterically crowded position tends to be low, and in order to improve the yield. Various ideas have been applied so far. For example, it has been reported in the following patent documents and non-patent documents.
Among them, the N-demethylation method using dialkyl azodicarboxylate is a method widely used for producing morphinan derivatives, particularly buprenorphine derivatives having a sterically crowded skeleton.
For example, in Non-Patent Document 1: Journal of Medicinal Chemistry, 56 (8), 3207-16, 2013, diisopropyl azodicarboxylate (DIAD) and pyridine hydrochloride are allowed to act on buprenolfin derivative 6 to obtain the desired N. -It has been reported that the demethylation reaction was achieved in a yield of 77%.

In the above reaction, the reaction proceeds in two steps as in the following scheme, and in the first step, an aminal intermediate in which N-methylcyclic amine is added to dialkyl azodicarboxylate is produced, which occurs in the second step. It is known that the aminal intermediate is solvolyzed under acidic conditions to finally complete demethylation (Non-Patent Document 2: Targets in Heterocyclic Systems, 20, 113-138, 2016).
At this time, formaldehyde is produced as a by-product as the reaction progresses.

That is, in the step of hydrolyzing the aminal intermediate, formaldehyde and a benzene ring having an electron-donating substituent of the morphinan derivative coexist under acidic conditions. Since it is well known that the hydroxymethylation reaction to the benzene ring proceeds when formaldehyde is allowed to act on a benzene derivative having an electron-donating substituent under acidic conditions (for example, Non-Patent Document 3: Journal). Of Heterocyclic Chemistry, 17 (2), 315-20, 1980), in the reaction of Non-Patent Document 1 described above, a hydroxymethylated product of formaldehyde produced by acid hydrolysis of an aminal intermediate may be generated as an impurity.
In the examples of demethylation reactions from many known morphinan derivatives, in order to suppress such side reactions, a weak acid such as pyridine hydrochloride is allowed to act at room temperature. There have been reports of cases where the reaction was not completed after a long reaction, and it is hard to say that this is a satisfactory method. Further, even under the condition of such a weak acid, the addition reaction of formaldehyde to the benzene ring is still observed in a small amount, and the contamination of these impurities becomes a big problem in the quality of the drug substance in the manufacture of pharmaceutical products.

Patent Document 1 describes that DIAD is allowed to act on oxymorphone having a hydroxy group at the 14-position, and the produced aminal is hydrolyzed with methanol to obtain a secondary amine and formaldehyde-dimethyl acetal.

The demethylation of cyclic N-methylamine having a tropane skeleton is described in Non-Patent Document 4: Bioorganic & Medical Chemistry Letters, 14 (7), 1775-8, 2004, as in the following scheme. After the action of diethyl azodicarboxylate (DEAD), the resulting aminal intermediate is hydrolyzed using an ethanol solution of hydrogen chloride.

In the example of demethylation of tropane alkaloids, since the molecule does not have a benzene ring having an electron-donating group, the aminal intermediate is solvolyzed under relatively severe acidic conditions. Often stays moderate.

As described above, although the demethylation reaction using dialkyl azodicarboxylate is widely used in the field of medicinal chemistry, it often produces by-products during post-treatment, and has high purity by a simple method. Since it was difficult to obtain the desired product, it was difficult to apply it on an industrial scale.

European Patent Publication 2062897

An object of the present invention is that in the dealkylation reaction of an N-alkyl cyclic amine compound using dialkyl azodicarboxylate, the desired dealkylated product can be obtained with a simple and mild operation and with high purity. The purpose is to provide an industrially applicable method.

As a result of diligent studies to solve the above problems, the present inventor reacts an N-alkylated cyclic tertiary amine compound having various structures with a dialkyl azodicarboxylate, and EWG ^1- a compound represented by CH ^₂ -EWG ₂ (here, EWG ¹ and EWG ² are the same or different exhibits an electron withdrawing group) by reacting, simple and mild operating at high purity N- dealkylation The present invention has been completed by finding that a modified cyclic secondary amine compound can be produced.

The present invention is as follows:
[1]
i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
R ^a OOC-N = N-COOR ^a
(Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Including the step of reacting the compound represented by
A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, wherein R 1} is a hydrogen atom or a substituent not involved in the reaction;
[2]
EWG ¹ and EWG ² are the same or different and represent -C (= O) -R ^b , -NO ₂ , Rx-SO _2- , -CN or Rx- (Rx'-) P (= O)-. ,
Here, R ^b , Rx and Rx'are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon. The method according to [1], which represents a heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms in addition to atoms;
[3]
EWG ¹ or EWG ² is -C (= O) -R ^b ,
Here, R ^b has C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and is selected from N, O, and S in addition to carbon atoms. The method according to [1] or [2], which is a heteroaryl containing 1 to 4 heteroatoms to be formed as a ring-constituting atom;
[4]
i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
R ^a OOC-N = N-COOR ^a
(Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Including the step of reacting the compound represented by
A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, and R 1} is a hydrogen atom or a substituent not involved in the reaction.
Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
The method is a NO ₂ -CH ₂ -COOC ₂ H ₅ or _CN-CH 2 -COOCH _3;
[5]
i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
R ^a OOC-N = N-COOR ^a
(Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Including the step of reacting the compound represented by
A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, and R 1} is a hydrogen atom or a substituent not involved in the reaction.
Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
R ^c- C (= O) -CH _2- C (= O) -R ^d
(In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
Method which is 1,3-diketo compound represented by;
[6]
Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
R ^c- C (= O) -CH _2- C (= O) -R ^d
(In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
It is a 1,3-diketo compound represented by
1,3-Diketopiperazine

The method according to any one of [1], [2], and [5], which is a compound having a structure represented by.
[7]
The method according to [6], wherein the 1,3-diketo compound is dimedone or Meldrum's acid;
[8]
The method according to any one of [1] to [7], wherein R ¹ is a hydrogen atom, an alkyl, vinyl, cyclopropyl, which may have a substituent, or a phenyl, which may have a substituent. ;
[9]
The method according to any one of [1] to [8], wherein R ¹ is an alkyl, vinyl, cyclopropyl or phenyl which may have a hydrogen atom and a substituent;

[10]
Step ii) the result of, removing a compound represented by-product aldehyde ^EWG 1 _-CH ² -EWG 2 above, according to any one of [1] to [9] The method;
[11]
Step ii) is carried out in the presence of a solvent selected from hydrocarbons, amides, nitriles, ethers, hydrogen halides, aprotic polar solvents, alcohols, water and acetic acid [1]. The method according to any one of [10];
[12]
The method according to any one of [1] to [11], wherein step i) and step ii) are performed in the presence of the same solvent;
[13]
The method according to any one of [1] to [12], wherein step ii) is performed at a temperature of 30 ° C. to 150 ° C.;

[14]
The method according to any one of [1] to [13], wherein step ii) is performed at a temperature of 40 ° C. to 100 ° C.;
[15]
The method according to any one of [1] to [14], wherein the dialkyl azodicarboxylate is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditert-butyl azodicarboxylate or dibenzyl azodicarboxylate. ;
[16]
Further, the reaction solution or the reaction solvent obtained in step ii) was distilled off, the obtained reaction residue was dissolved in an organic solvent insoluble in water, and then treated with a neutral or basic solution and separated. [1] to [1] to [1] to [1], which comprises a step of treating the organic layer with an acid and ^{isolating a cyclic secondary amine in which the substituent represented by R 1-} CH _{2- is substituted with a hydrogen atom as an acid addition salt.} 15] The method according to any one of;
[17]
Further, the reaction solution or reaction solvent obtained in step ii) was distilled off, and the reaction residue obtained was dissolved in an organic solvent insoluble in water, and then treated with an acid instead of being treated with a basic solution. The method according to any one of [1] to [15], which comprises a step of isolating a cyclic secondary amine in which the substituent represented by ^{R 1-} CH _{2- is substituted with a hydrogen atom as an acid addition salt.} Method;
[18]
Further, the reaction solution or reaction solvent obtained in step ii) is distilled off, and the reaction residue obtained is dissolved in an organic solvent insoluble in water, and then the aqueous layer is represented by R ^1- CH _{2- with an acidic aqueous solution.} [1] to [15], which comprises a step of extracting a cyclic secondary amine in which the substituent is substituted with a hydrogen atom, separating the organic layer, and then extracting the aqueous layer into the organic layer again as basic. The method described in any of the above;

[19]
The cyclic tertiary amine is represented by the following general formula (I):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
R ² and R ³ represent the same or different hydrogen atoms, hydroxy or C _1-6 alkoxy, or R ² and R ³ together represent = O or ethylenedioxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R ⁷ represents a hydrogen atom or hydroxy, or, ^{R 7,} together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - may be formed, ^{R 8} and R ⁹ is a hydrogen atom, or one of R ⁸ and R ⁹ is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, and a substituent. Represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent)
A morphinan derivative represented by or an optical isomer thereof.
The cyclic secondary amine is the following general formula (II):

(In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above)
The method according to any one of [1] to [18], which is a morphinan derivative represented by (1), an optical isomer thereof, or a salt thereof;
[20]
The method according to [19], wherein R ^{1 represents a hydrogen atom or phenyl;}
[21]
R ² and ^{R 3} are the same or different, a hydrogen atom, or a hydroxy or _{C 1-6} alkoxy, ^{R 2} and ^{R 3} together represent ethylenedioxy, in [19] or [20] Method of description;
[22]
The method according to any one of [19] to [21], wherein R ⁴ and R ^{5 both represent a hydrogen atom;}
[23]
R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of [19] to [21], which represents (may be benzyl);
[24]
The method according to any one of [19] to [21], wherein R ⁴ and R ^{5 together represent an epoxy;}
[25]
The method according to any one of [19] to [24], wherein R ⁶ _{represents C 1-6 alkoxy;}
[26]
The method according to any one of [19] to [25], wherein R ^{7 represents a hydrogen atom;}
[27]
R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, ^{R 8} and ^{R 9} are both hydrogen, [19] - [25 ] The method described in any of the above;
[28]
R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, a one hydrogen atom of ^{R 8} and ^{R 9,} the other is substituted with hydroxy Represents an alkyl which may be, a carbamoyl which may have a substituent, an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent, [19] to [25]. ] The method described in any of the above;
[29]
R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, one of ^{R 8} and ^{R 9} is a hydrogen atom, the other substituents The method according to any one of [19] to [25], which represents a carbamoyl that may be possessed;

[30]
The cyclic tertiary amine is the following general formula (III):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
R ² and R ³ _{represent the same or different hydrogen atoms, hydroxy or C 1-6} alkoxy when the double bond consisting of a solid line and a broken line is a single bond, or ^{R 2} and R ³ are combined. = O or ethylenedioxy, where the double bond consisting of a solid line and a broken line is a double bond, R ³ does not exist and R ² represents a hydrogen atom or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group)
A morphinan derivative represented by or an optical isomer thereof.
The cyclic secondary amine is represented by the following general formula (IV):

(In the formula, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above)
The method according to any one of [1] to [18], which is a morphinan derivative represented by (1), an optical isomer thereof, or a salt thereof;
[31]
The method according to [30], wherein R ^{1 represents a hydrogen atom or phenyl;}
[32]
In the case where the double line consisting of a solid line and a broken line is a single bond, R ² and R ³ represent the same or different hydrogen atom, hydroxy or C _1-6 alkoxy, in [30] or [31]. Method of description;
[33]
The method according to [30] or [31], wherein the double line consisting of a solid line and a broken line is a single bond, and R ² and R ^{3 together represent O or ethylenedioxy;}
[34]
The method according to [30] or [31], wherein the double line consisting of a solid line and a broken line is a double bond, R ³ does not exist, and R ² represents a hydrogen atom or C _{1-6 alkoxy.} ;
[35]
The method according to any one of [30] to [34], wherein R ⁴ and R ^{5 both represent a hydrogen atom;}
[36]
R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of [30] to [34], which represents (may be benzyl);
[37]
The method according to any one of [30] to [34], wherein R ⁴ and R ^{5 together represent an epoxy;}

[38]
The cyclic tertiary amine is represented by the following formula (V):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
Both m and n represent 1 or 2.
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by or an optical isomer thereof.
The cyclic secondary amine is represented by the following formula (VI):

(In the equation, R ² , R ⁴ , R ⁵ , R ⁶ , R ^p , R ^q , m, n, and the double line consisting of a solid line and a broken line are the same as above)
The method according to any one of [1] to [18], which is a morphinan derivative represented by (1), an optical isomer thereof, or a salt thereof;
[39]
The method according to [38], wherein R ^{1 represents a hydrogen atom or phenyl;}
[40]
The method according to [38] or [39], wherein R ² represents a hydrogen atom or C _{1-6 alkoxy;}
[41]
The method according to any one of [38] to [40], wherein R ⁴ and R ^{5 both represent a hydrogen atom;}
[42]
R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of [38] to [40], which represents (may be benzyl);
[43]
The method according to any one of [38] to [40], wherein R ⁴ and R ^{5 together represent an epoxy;}
[44]
The method according to any of [38] to [43], wherein R ⁶ represents hydrogen or C _{1-6 alkoxy;}
[45]
The method according to any one of [38] to [44], wherein R ^p and R ^{q both represent a hydrogen atom;}
[46]
One of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, an alkoxyalkyl optionally comprising a substituent, or The method according to any one of [38] to [44], which represents an alkanoyl which may have a substituent;
[47]
R ^p and R ^q both represent hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other represents a carbamoyl which may have a substituent, [38] to [44]. The method described in any of the above;
[48]
The method according to any one of [38] to [47], wherein the double line consisting of a solid line and a broken line represents a single bond;
[49]
The method according to any one of [38] to [47], wherein the double line consisting of a solid line and a broken line represents a double bond;
[50]
The method according to any one of [1] to [49], wherein R ^{1 is hydrogen;}

[51]
The cyclic tertiary amine is represented by the following formula (VII):

(In the formula, m and n both represent 1 or 2,
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by or an optical isomer thereof.
The cyclic secondary amine is represented by the following formula (VIII):

(In the formula, m and n both represent 1 or 2,
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
The method according to [38], which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof;

[52]
The cyclic tertiary amine is represented by the following formula (IX):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, have a phenyl which may have a substituent or substituents Is also a good benzyl)
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
R _aa represents a hydrogen atom or hydroxy and represents
R _bb is a hydrogen atom;
_{C 1-10} alkyl which may have a substituent;
_{C 3-6} cycloalkyl which may have a substituent;
_{C 6-10} aryl, which may have a substituent;
Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
Y represents CH ₂ , C = O or bond)
A morphinan derivative represented by or an optical isomer thereof.
The cyclic secondary amine is represented by the following formula (X):

(In the equation, R ⁵ , R ⁶ , R _y , R _z , R _aa , R _bb and Y are the same as above)
The method according to any one of [1] to [18], which is a morphinan derivative represented by (1), an optical isomer thereof, or a salt thereof;
[53]
The method according to [52], wherein R ¹ represents a hydrogen atom, vinyl, cyclopropyl or phenyl;
[54]
The method according to [52] or [53], wherein R ^{1 represents a hydrogen atom or cyclopropyl;}
[55]
The method according to any of [52] to [54], wherein R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
[56]
The method according to any of [52] to [55], wherein R ^{6 represents hydroxy or methoxy;}
[57]
The method according to any one of [52] to [56], wherein R _y and R _z both represent a hydrogen atom, or R _y and R _{z together represent = O;}
[58]
The method according to any one of [52] to [57], wherein R _{aa represents a hydrogen atom;}
[59]
The method according to any of [52] to [58], wherein Y represents C = O or a bond;
[60]
_{The method according to any of [52] to [59], wherein Rbb} represents a hydrogen atom, phenyl, benzyl or 6-oxo-1,6-dihydropyridine-2-yl;
[61]
R ^1- CH _2- is R ^1a- CH _2- , and the cyclic tertiary amine is the following general formula (XI) :.

(In the formula, R ^1a represents a hydrogen atom, vinyl, alkyl, cyclopropyl, which may have a substituent, or phenyl, which may have a substituent.
R ^2a , R ^3a , R ^11a and R ^12a represent the same or different hydrogen atom or alkoxycarbonyl, and R ^4a and R ^5a are the same or different.
Hydrogen atom;
Hydroxy;
Alkanoyloxy which may have a substituent;
Alkyl which may have a substituent;
Alkoxycarbonyl;
Amino which may have protecting groups;
-OR ^10a (where R ^10a is an alkyl, aryl, silyl or heteroaryl optionally having a substituent);
-NR'R'' (where R'and R'' are the same or different, alkyl, aryl, acyl, alkoxycarbonyl, heteroaryl or sulfonyl);
Cyano;
Aryl which may have a substituent (here, the number of carbon atoms of the aryl is 6 to 10); or a heteroaryl which may have a substituent (where, the ring-constituting atom of the heteroaryl) The number is 6 to 10, and in addition to the carbon atom, 1 to 4 heteroatoms selected from N, O, and S are included as ring-constituting atoms of the heteroaryl).
R ^4a and R ^5a together form an olefin that may have = O, ethylenedioxy or a substituent, or R ^4a and R ^5a are attached to have a substituent. Heterocycle (here, the heterocycle is a non-aromatic ring which may contain a double bond, the heterocyclic portion has 1 to 10 carbon atoms, and 1 to 4 selected from N, O and S. Heteroatoms may be included as ring-constituting atoms of the heterocycle).
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
When the double line consisting of a solid line and a broken line is a single bond,
R ^6a and R ^7a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 6a} nor R ^7a represents hydroxy).
R ^8a and R ^9a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 8a} nor R ^9a represents hydroxy), or
R ^6a and R ^8a may be combined to form an epoxy (where R ^7a and R ^9a are hydrogen).
If the double line consisting of a solid line and a broken line is a double bond,
R ^7a and R ^9a do not exist, and ^{both R 6a} and R ^8a represent hydrogen atoms)
It is a tropane derivative represented by, or an optical isomer thereof.
The cyclic secondary amine is represented by the following formula (XII):

(In the formula, R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^11a , R ^12a and the double line consisting of the solid line and the broken line are the same as above)
The method according to any one of [1] to [18], which is a tropane derivative represented by (1), an optical isomer thereof, or a salt thereof;
[62]
The method according to [61], wherein R ^{1a is a hydrogen atom or phenyl;}
[63]
The method according to [61] or [62], wherein one of R ^2a and R ^{3a represents a hydrogen atom and the other represents an alkoxycarbonyl;}
[64]
R ^4a and R ^5a are the same or different,
Hydrogen atom;
Hydroxy;
Alkanoyloxy which may have a substituent;
Alkyl which may have a substituent;
Alkoxycarbonyl;
Amino which may have protecting groups;
-OR ^10a (where R ^10a is alkyl, aryl, silyl or heteroaryl);
-NR'R'' (where R'and R'' are the same or different, alkyl, aryl, acyl, alkoxycarbonyl, heteroaryl or sulfonyl);
Cyano;
Aryl which may have a substituent (here, the number of carbon atoms of the aryl is 6 to 10); or a heteroaryl which may have a substituent (where, the ring-constituting atom of the heteroaryl) The number is 6 to 10, and any of [61] to [63] representing (including 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms of heteroaryl) in addition to carbon atoms. Method described in Crab;
[65]
The method according to any of [61] to [63], wherein R ^4a and R ^5a are combined to form an olefin which may have an O, ethylenedioxy or a substituent;
[66]
A ^{heterocycle in which R4a} and ^R5a are bonded and may have a substituent (here, the heterocycle is a non-aromatic ring which may contain a double bond, and the number of carbon atoms in the heterocyclic portion is 1. The method according to any one of [61] to [63], wherein 1 to 4 heteroatoms selected from N, O and S are formed as ring-constituting atoms of a heterocycle.
[67]
The double line consisting of a solid line and a broken line is a single bond,
R ^6a and R ^7a represent a hydrogen atom.
The method according to any one of [61] to [66], wherein R ^8a and R ^{9a represent a hydrogen atom;}
[68]
Any of [61] to [66], wherein the double line consisting of a solid line and a broken line is a single bond, R ^6a and R ^8a together form an epoxy, and R ^7a and R ^{8a represent hydrogen.} Method described in Crab;
[69]
Described in any of [61] to [68], wherein the double line consisting of a solid line and a broken line is a double bond, R ^7a and R ^9a do not exist, and ^{both R 6a} and R ^{8a represent hydrogen atoms.} the method of;
[70]
The method according to any one of [61] to [69], wherein R ^{1a is hydrogen;}
[71]
The method according to any one of [61] to [70], wherein R ^11a and R ^{12a are hydrogen atoms;}
[72]
The method according to [61], wherein the cyclic tertiary amine is atropine, scopolamine or cocaine;

[73]
The following general formula (VI):

(In the formula, R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
Both m and n represent 1 or 2.
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by, an optical isomer thereof, or a salt thereof;
[74]
R ² represents hydrogen atom or _{C 1-6} alkoxy, morphinan derivatives or optical isomers thereof, or salts thereof according to [73];
[75]
The morphinan derivative according to [73] or [74], an optical isomer thereof, or a salt thereof, wherein R ⁴ and R ^{5 both represent a hydrogen atom;}
[76]
R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The morphinan derivative according to [73] or [74], an optical isomer thereof, or a salt thereof, which represents (may be benzyl);
[77]
The morphinan derivative according to [73] or [74], an optical isomer thereof, or a salt thereof, wherein R ⁴ and R ^{5 together represent an epoxy;}
[78]
The morphinan derivative according to any one of [73] to [77], an optical isomer thereof, or a salt thereof, wherein R ⁶ represents a hydrogen atom or C _{1-6 alkoxy;}
[79]
The morphinan derivative according to any one of [73] to [78], an optical isomer thereof, or a salt thereof, wherein R ^p and R ^{q both represent a hydrogen atom;}
[80]
One of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, an alkoxyalkyl optionally comprising a substituent, or The morphinan derivative according to any one of [73] to [78], an optical isomer thereof, or a salt thereof, which represents an alkanoyl which may have a substituent;

[81]
The following general formula (VIII):

(In the formula, m and n both represent 1 or 2,
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by, an optical isomer thereof, or a salt thereof;
[82]
The following general formula (X):

(Wherein, R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents Represents (which is a benzyl that may have)
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
R _aa represents a hydrogen atom or hydroxy and represents
R _bb is a hydrogen atom;
_{C 1-10} alkyl which may have a substituent;
_{C 3-6} cycloalkyl which may have a substituent;
_{C 6-10} aryl, which may have a substituent;
Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
Y represents CH ₂ , C = O or bond)
A morphinan derivative represented by, an optical isomer thereof, or a salt thereof;
[83]
R ⁵ is a hydrogen atom, an optionally phenoxy which may have a hydroxy or a substituent, a morphinan derivative or its optical isomer, or a salt thereof according to [82];
[84]
R ⁶ is a hydroxy or methoxy, [82] or [83] morphinan derivative or an optical isomer thereof or a salt thereof according to;
[85]
The morphinan derivative or optical isomer thereof according to any one of [82] to [84], wherein R _y and R _z both represent a hydrogen atom, or R _y and R _{z together represent = O.} Those salts;
[86]
The morphinan derivative according to any one of [82] to [85], or an optical isomer thereof, or a salt thereof, wherein R _{aa represents a hydrogen atom;}
[87]
The morphinan derivative according to any one of [82] to [86], an optical isomer thereof, or a salt thereof, wherein Y represents C = O or a bond;
[88]
R _bb is a hydrogen atom, a phenyl, a benzyl or 6-oxo-1,6-dihydropyridin-2-yl, [82] - [87] morphinan derivatives or optical isomers or their thereof of any salt;
[89]
R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
R ⁶ represents hydroxy or methoxy;
R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
R _aa represents a hydrogen atom;
Y represents C = O or bond;
R _bb is a hydrogen atom, a phenyl, a benzyl or 6-oxo-1,6-dihydropyridin-2-yl, morphinan derivatives or optical isomers thereof, or salts thereof according to [82];
[90]
R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
R ⁶ represents hydroxy or methoxy;
R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
R _aa represents a hydrogen atom or hydroxy;
Y represents the bond;
The morphinan derivative according to [82] or an optical isomer thereof or a salt thereof, wherein R _{bb represents a hydrogen atom or benzyl;}
[91]
R ⁵ represents a phenoxy which may have a substituent;
R ⁶ represents methoxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents the bond;
The morphinan derivative according to [82] or an optical isomer thereof or a salt thereof, wherein R _{bb represents benzyl;}
[92]
R ⁵ represents a hydrogen atom;
R ⁶ represents hydroxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents C = O;
R _bb is represents 6-oxo-1,6-dihydropyridin-2-yl, morphinan derivatives or optical isomers thereof or their salts, according to [82].

The present invention provides an industrially applicable production method capable of producing a high-purity N-dealkylated cyclic secondary amine compound by a simple and mild operation.

Hereinafter, the present invention will be described in detail.
In the present specification, the abbreviations "Et", "Bn" and "Ph" represent "ethyl", "benzyl" and "phenyl", respectively.
As used herein, "alkyl" includes straight-chain or branched-chain alkyls. Examples of "alkyl" include, but are not limited to, straight-chain or branched-chain "C _1-6 alkyl" and straight-chain or branched chain "C _1-10 alkyl".
Examples of straight or branched "C _1-6 alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl. Examples of straight or branched "C _1-10 alkyl" are, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl. , Nonyl, decyl.
In the present specification, examples of "cycloalkyl" include, but are not limited to, include a C _3-6 cycloalkyl group, examples of C _3-6 cycloalkyl groups include, but are not limited to, cyclopropyl group , Cyclobutyl group, cyclopentyl group, cyclohexyl group and the like, preferably cyclopropyl group.
As used herein, "alkoxy" includes straight-chain or branched-chain alkoxy. Examples of "alkoxy" includes, but is not limited to, include "C _1-6 alkoxy" linear or branched, examples of "C _1-6 alkoxy" linear or branched, but are Although not, methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy can be mentioned.
In the present specification, examples of "aryl" include, but are not limited to, include "C _6-10 aryl", examples of "C _6-10 aryl" includes, but is not limited to, phenyl and naphthyl Can be mentioned.
In the present specification, the example of "hydroxyl which may have a protecting group" is not limited to the following protecting groups:
An aralkyl group which may have a substituent such as a benzyl group, a 4-methoxybenzyl group and a trityl group, an alkanoyl group such as an acetyl group, a silyl group having a substituent such as a trimethylsilyl group and a tert-butyldimethylsilyl, etc. Examples thereof include hydroxy, which may have.
In the present specification, the example of "alkylenedioxy which may have a substituent" is not limited, but methylene which may have _{one or two C 1-6 alkyls as a substituent.} Examples include dioxy and ethylenedioxy, which may have _{one or two C 1-6 alkyl as substituents.}
In the present specification, the example of "alkylene having a substituent may be" is not limited to methylene, which may have _{one or two C 1-6 alkyl as a substituent.} Examples thereof include ethylene which may have 1 or 2 C _1-6 alkyl as a group and propylene which may have _{1 or 2 C 1-6 alkyl as a substituent.}

In the present specification, "alkyl optionally substituted" means an alkyl group substituted with one or more hydroxy groups. Examples of "alkyls optionally substituted with hydroxy" include, but are not limited to, hydroxymethyl groups, hydroxyethyl groups, hydroxypropyl groups, hydroxybutyl groups, dihydroxypropyl groups, dihydroxybutyl groups, 1-hydroxy-1. , 2,2-trimethyl-propyl and the like, preferably a hydroxymethyl group or a hydroxyethyl group, and more preferably a hydroxymethyl group.

As used herein, the term "carbamoyl" refers to a substituent represented by _{-C (O) NH 2.}
In the present specification, examples of "carbamoyl which may have a substituent" are not limited to, but are limited to, alkyl-NHC (O)-, (alkyl) ₂ NC (O)-, and aryl-NHC ( O)-, alkyl (aryl) -NC (O)-, heteroaryl-NHC (O)-, alkyl (heteroaryl) -NC (O)-, aralkyl-NHC (O)-, alkyl (aralkyl) -NC (O)-can be mentioned.
In the present specification, examples of "aralkyl" include, but are not limited to, include "C _7-16 aralkyl group", examples of "C _7-16 aralkyl group" include, but are not limited to, benzyl, Examples include phenethyl, naphthylmethyl and phenylpropyl.

In the present specification, examples of "alkoxyalkyl" include, but are not limited to, benzyloxymethyl, methoxyethyl, 2-benzyloxy-2 methylethyl and the like.
In the present specification, "alkanoyl" refers to a group in which a carbonyl (C = O) is bonded to the above-mentioned "alkyl", "aryl" or "heteroaryl" described later, and the example of "alkanoyl" is limited. Although not, acetyl, propionyl, butyryl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C (= O) Ph), benzylcarbonyl (-C (= O) CH ₂ Ph) can be mentioned.

As used herein, examples of "alkoxycarbonyl" are not limited to, but are limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl. And benzyloxycarbonyl.

In the present specification, the example of "alkanoyloxy" is not limited to, but is not limited to, acetyloxy, propionyloxy, butyryloxy, isobutylyloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, acryloyloxy, methacryloxy , Crotonoyloxy, isocrotonoyloxy and benzoyloxy, and further, heteroarylcarbonyloxy in which COO is bound to heteroaryl such as indole may be used.

In the present specification, the example of "amino which may have a protecting group" is not limited, but the following protecting groups:
Methoxycarbonyl group, ethoxycarbonyl group, tert-butoxycarbonyl group, tert-amyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, p-chlorobenzyloxycarbonyl group, p-methoxybenzylcarbonyl Group, p-nitrobenzyloxycarbonyl group, p-phenylazobenzyloxycarbonyl group, p-methoxyphenylazobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group Carbamate protecting group such as group, p-biphenylisopropyloxycarbonyl group, diisopropylmethyloxycarbonyl group, 2- (trimethylsilyl) ethoxycarbonyl group or 9-fluorenylmethyloxycarbonyl group; p-toluenesulfonyl group or 2-nitrobenzene Symphonamide protecting group such as sulfonyl group; Iimide protecting group such as phthaloyl group; Acyl protecting group such as acetyl group or trifluoroacetyl group; C _7-19 aralkyl such as benzyl group, trityl group or naphthylmethyl group Examples thereof include an amino group which may have a system protecting group.

In the present specification, examples of "acyl" are not limited to, but are limited to C _1-6 alkanoyl groups such as formyl group, acetyl group, propionyl group, butanoyl group, pentanoyl group, hexanoyl group; cyclopropylcarbonyl group, cyclo. _{C 4-7} cycloalkanoyl groups such as butylcarbonyl group and cyclopentylcarbonyl group; alloyl groups such as benzoyl group and naphthoyl group; 5- to 6-membered heteroaroyl groups such as floyl group, thiophenecarbonyl group, nicotinyl group and isonicotinoyl group. Can be mentioned.
Examples of "silyl" herein include, but are not limited to, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl and tert-butyldiphenylsilyl. Preferably, silyl, which is used in the art as a protecting group for hydroxy, is used.

In the present specification, the example of "heteroaryl" is not limited to a monocyclic type such as a pyridyl group, a frill group, an imidazolyl group, a pyrimidinyl group, a pyrazinyl group or a thiazolyl group having 5 to 10 ring constituent atoms. Bicyclic heteroaryl groups such as a heteroaryl group, a quinolyl group and an indrill group can be mentioned.

As used herein, "alkenyl" includes straight-chain or branched-chain alkenyl, and examples thereof include, but are not limited to, straight-chain or branched-chain C _2-6 alkenyl. Examples of straight or branched C _2-6 alkenyl are, but are not limited to, vinyl, 1-propenyl, 2-propenyl (allyl), 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-. 2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-hexenyl, 2- Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 3-methyl-2-pentenyl, cinnamyl, and preferred examples include, but are not limited to, vinyl, 2-propenyl (allyl), 3-butenyl, Examples thereof include 4-pentenyl, 5-hexenyl and cinnamyl.
As used herein, examples of "heteroarylalkyl" are, but are not limited to, (pyridine-2-yl) methyl, (pyridine-3-yl) methyl, (pyridine-4-yl) methyl, and (furan-yl). 2-yl) methyl, (fran-3-yl) methyl, (imidazol-2-yl) methyl, (imidazol-4-yl) methyl, (imidazol-5-yl) methyl, (thiazole-2-yl) methyl , (Thiazole-4-yl) methyl, (thiazole-5-yl) methyl, 2- (pyridine-2-yl) ethyl, 2- (pyridine-3-yl) ethyl, 2- (pyrazol-1-yl) Ethyl, 2- (thiophen-2-yl) ethyl, or 2- (thiophen-3-yl) ethyl can be mentioned.
In the present specification, "1 to 4 heteroatoms selected from N, O and S and at least one carbon atom are contained as ring-constituting atoms, and at least one set of adjacent ring-constituting atoms has a double bond. Examples of "heterocycles having and further substituted with at least one oxo group" are, but are not limited to,
(A) pyridine 1-oxide, 1 to 4 substituents selected from the _{2-C 1-10} alkyl that is not _{C 1-10} alkyl and substituted substituted with 1 to 3 fluorine and methyl 1-oxide Pyridine 1-oxide, which may be substituted with a substituent of
(B) Pyridine-2 (1H) -on, 1-methylpyridine-2 (1H) -on, 1-ethylpyridine-2 (1H) -on, 6-methylpyridine-2 (1H) -on, 6- _{C 1-10} alkyl substituted with 1-3 fluorines such as ethylpyridine-2 (1H) -one or 6-trifluoromethylpyridine-2 (1H) -one and non-substituted C _1-10 alkyl Pyridine-2 (1H) -on, which may be substituted with 1 to 4 substituents selected from.
(C) Pyridine-4 (1H) -on, 1-methylpyridine-4 (1H) -on, 1-ethylpyridine-4 (1H) -on or 1- (fluoroethyl) pyridine-4 (1H) -on 1-3 fluorine substituted C _1-10 alkyl and substituted 1 is selected from C _1-10 alkyl not to four substituents may be substituted pyridine etc. -4 (IH )-on,
_{(D) C 1-10} alkyl substituted with 1 to 3 fluorines such as pyridazine-3 (2H) -one, 2-methylpyridazine-3 (2H) -one _{and C 1-10} alkyl not substituted. Pyridazine-3 (2H) -on, which may be substituted with 1 to 3 substituents selected from.
_{(E) C 1-10} alkyl substituted with 1 to 3 fluorines such as pyrazine-2 (1H) -one, 1-methylpyran-2 (1H) -one _{and C 1-10} alkyl not substituted. Pyrazine-2 (1H) -on (F) 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H which may be substituted with 1 to 3 substituents selected from - pyran-2-one, 1 selected from 5-methyl -2H- pyran-2-one _{C 1-10} alkyl that is not _{C 1-10} alkyl and substituted substituted with 1 to 3 fluorine, such as 4H-pyran-4-one, 2H-pyran-2-one (G) quinoline-2 (1H) -on, 6-methylquinolin-2 (1H)-which may be substituted with up to 3 substituents. one, quinoline-1-oxide, 4-methyl-quinoline-1-oxide 1 - is selected from one to three _{C 1-10} substituted by fluorine alkyl and _{C 1-10} alkyl which is unsubstituted, such as 3 Kinolin-2 (1H) -one, quinoline-1-oxide, which may be substituted with multiple substituents,
_{(H) C 1-10} alkyl substituted with 1-3 fluorines such as pyrimidine-4 (3H) -one, pyrimidine-2,4 (1H, 3H) -dione and non-substituted C _1-10 Pyrimidine-4 (3H) -one, pyrimidine-2,4 (1H, 3H) -dione, which may be substituted with 1 to 3 substituents selected from alkyl,
Can be mentioned.

As used herein, "may have a substituent" means "substituent or unsubstituted". The position and number of substituents are not particularly limited. The number of substituents may be preferably 1 to 5, more preferably 1 to 3, as long as it does not exceed the number of positions capable of having substituents, and is substituted with 2 or more substituents. If so, their substituents may be the same or different. Unless otherwise specified herein, examples of substituents are, but are not limited to, C _1-6 alkyl, halogenated C _1-6 alkyl (eg, fluoromethyl, difluoromethyl, trifluoromethyl). , C _1-6 alkoxy, halogenated C _1-6 alkoxy (eg, trifluoromethoxy, 2,2,2-trifluoroethoxy), halogen atom (eg, fluorine atom, chlorine atom), having substituents Amino; acyl (eg, acetyl, cyclopropylcarbonyl, benzoyl), C _2-6 alkoxy (eg, 2-propenyl), cyano, hydroxy, nitro, sulfonyl, aryl, heteroaryl may be mentioned. Examples of amino groups that may have the above-mentioned substituents include a linear or branched C _1-6 alkylamino group and N- (straight or branched C _1-6 alkylamino group) -N. _{-(C 1-6} alkylamino group of linear or branched chain) Amino group, acylamino group, amino group which may have a protecting group can be mentioned.
In the present specification, examples of "salt" include, but are not limited to, acid addition salts. Examples of acid addition salts include, but are not limited to, inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitrate, hydrobromic acid), organic carboxylic acids (eg, carbonic acid, acetic acid, citric acid, benzoic acid, malein). Acids, fumaric acid, tartaric acid, succinic acid, trifluoroacetic acid, tannic acid, butyric acid, decanoic acid, salicylic acid, lactic acid, oxalic acid, mandelic acid, malic acid), organic sulfonic acid (eg methanesulfonic acid, p-toluenesulfon) Acid, salt with benzenesulfonic acid) can be mentioned.
In the present specification, the example of "electron-withdrawing group" is not limited, but is limited.
-C (= O) -R ^b , -NO ₂ , Rx-SO _2- , -CN or Rx- (Rx'-) P (= O)-
(Here, R ^b , Rx and Rx'are the same or different, and have C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or 6 to 10 ring-constituting atoms. (Representing a heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms in addition to carbon atoms),
Can be mentioned.

The present invention is one aspect of the present invention.
i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
R ^a OOC-N = N-COOR ^a
(Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Including the step of reacting the compound represented by
A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, wherein R 1} is a hydrogen atom or a substituent not involved in the reaction. provide.
Here, R ¹ may be a hydrogen atom or a substituent that does not participate in the reactions of steps i) and ii) in the method provided by the present invention. Step i) and a substituent which does not participate in the reaction step ii), _- any that does not interfere with the production of "R ¹ -CH 2 substituents represented by the secondary amine of cyclic substituted with hydrogen atom" It can be a substituent, for example, a hydrogen atom, an alkyl which may have a substituent, an alkenyl which may have a substituent, a cycloalkyl which may have a substituent, and a substituent. Examples thereof include aryls which may be present and heteroaryls which may have a substituent. Preferably, R ¹ is a hydrogen atom, vinyl, alkyl, cyclopropyl, which may have a substituent, or phenyl, which may have a substituent, and more preferably, R ¹ is a hydrogen atom. is there.

In step i), a cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- ^{is bonded to a nitrogen atom, and a general formula: Ra} OOC-N = N-COOR ^a.
(Wherein, ^{R a} _{represents C 1-6} alkyl)
The dialkyl azodicarboxylate represented by is reacted.

Tertiary amines annular be used in step i), _- as long as they do not interfere with the production of "R ¹ -CH 2 annular substituent is substituted to the hydrogen atom represented by secondary amines", a wide range of structure Can be a compound having, and its nitrogen atom is represented by R ^1- CH _2- (in the formula, R ¹ is a phenyl which may have a hydrogen atom, vinyl, cyclopropyl or a substituent). A cyclic tertiary amine to which a substituent is attached and having a wide range of structures may be used in step i). ^{For example, R 1-} CH _2- (in the formula, R ¹ is a hydrogen atom, substituted with a nitrogen atom constituting a heterocycle of an aliphatic cyclic secondary amine such as pyrrolidine, piperazine, piperidine, azepan, or morpholin. A compound having a structure in which an alkyl, vinyl, cyclopropyl or a phenyl which may have a substituent (which may have a group) is bonded, or a compound containing the structure as a partial structure is provided in step i). May be used as a cyclic tertiary amine. Preferably, it is a cyclic tertiary amine having a morphinan skeleton, and the nitrogen atom constituting the amine may have R ^1- CH _2- (in the formula, R ¹ has a hydrogen atom and a substituent. A compound to which a substituent represented by (a good alkyl, vinyl, cyclopropyl or a phenyl which may have a substituent) is bonded, or a cyclic tertiary amine having a tropane skeleton, the amine thereof. ^{A substituent represented by R 1-} CH _2- (in the formula, R ¹ is a hydrogen atom, vinyl, cyclopropyl, or a phenyl which may have a substituent) is bonded to the nitrogen atom constituting the above. The compound may be used as a cyclic tertiary amine in step i).
Cyclic tertiary amines that can be used in step i) are optionally tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or optionally salts thereof (eg, acid addition salts). It can be a solvate, a hydrate or a polymorph.
In one embodiment, the cyclic tertiary amine that can be used in step i) is a free form.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following general formula (I):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
R ² and R ³ represent the same or different hydrogen atoms, hydroxy or C _1-6 alkoxy, or R ² and R ³ together represent = O or ethylenedioxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R ⁷ represents a hydrogen atom or hydroxy, or, ^{R 7,} together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - may be formed, ^{R 8} and R ⁹ is a hydrogen atom, or one of R ⁸ and R ⁹ is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, and a substituent. Represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent)
A morphinan derivative represented by or an optical isomer thereof may be used.

Preferred morphinan derivatives used in this embodiment include
In formula (I)
R ¹ represents a hydrogen atom;
A double line consisting of a solid line and a broken line represents a single bond or a double bond;
R ³ represents a hydrogen atom or C _{1-6 alkoxy;}
R ⁴ and ^{R 5} together represent an epoxy;
R ⁶ represents a hydroxy or hydrogen atom;
R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - may be formed, or ^{R 8} and ^{R 9} are both hydrogen atoms, ^{R 8} and A morphinan derivative representing an alkyl in which one of R ⁹ is a hydrogen atom and the other may be hydroxy-substituted, a carbamoyl which may have a substituent or an alkoxyalkyl which may have a substituent. Can be mentioned.
Another preferred morphinan derivative used in this embodiment is
In formula (I)
R ¹ represents a hydrogen atom;
A double line consisting of a solid line and a broken line represents a single bond or a double bond;
R ² and R ³ together represent = O;
R ⁴ and ^{R 5} together represent an epoxy;
R ⁶ represents hydroxy or methoxy;
Examples thereof include morphinan derivatives in which R ^{7 represents a hydrogen atom or hydroxy.}

Another preferred morphinan derivative used in this embodiment is any of the following hydromorphone or oxycodone compounds:

Can be mentioned.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following general formula (III):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
R ² and R ³ _{represent the same or different hydrogen atoms, hydroxy or C 1-6} alkoxy when the double bond consisting of a solid line and a broken line is a single bond, or ^{R 2} and R ³ are combined. = O or ethylenedioxy, where the double bond consisting of a solid line and a broken line is a double bond, R ³ does not exist and R ² represents a hydrogen atom or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group)
A morphinan derivative represented by or an optical isomer thereof may be used.

Preferred morphinan derivatives used in this embodiment include
In formula (III)
R ¹ represents a hydrogen atom;
A double line consisting of a solid line and a broken line represents a single bond or a double bond;
R ² and R ³ _{represent the same or different hydrogen atoms, hydroxy or C 1-6} alkoxy when the double bond consisting of a solid line and a broken line is a single bond, or ^{R 2} and R ³ are combined. = O or ethylenedioxy, where the double bond consisting of a solid line and a broken line is a double bond, R ³ is absent and R ² is a hydrogen atom or C _1-6 alkoxy;
R ⁴ and ^{R 5} together represent an epoxy;
Examples include morphinan derivatives in which R ⁶ represents hydroxy or C _{1-6 alkoxy.}
Another preferred morphinan derivative used in this embodiment is thebaine or oripavine, which
In formula (III)
R ¹ represents a hydrogen atom;
A double line consisting of a solid line and a broken line represents a double bond;
R ³ is absent and R ² represents methoxy;
R ⁴ and ^{R 5} together represent an epoxy;
R ⁶ is a morphinan derivative representing hydroxy or methoxy.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following formula (V):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
Both m and n represent 1 or 2.
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by or an optical isomer thereof may be used.

Preferred morphinan derivatives used in this embodiment include
In formula (V)
R ¹ represents a hydrogen atom;
Both m and n are 1 and a double line consisting of a solid line and a broken line represents a double bond, or both m and n are 2 and a double line consisting of a solid line and a broken line represents a single bond;
R ² represents C _1-6 alkoxy;
R ⁴ and ^{R 5} together represent an epoxy;
R ⁶ represents C _1-6 alkoxy or hydroxy, which may have a protecting group;
One of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, an alkoxyalkyl or a substituent optionally substituted. Examples thereof include morphinan derivatives representing alkanoyl which may have a group.
Another preferred morphinan derivative used in this embodiment is
In formula (V)
R ¹ represents a hydrogen atom;
Both m and n are 1 and a double line consisting of a solid line and a broken line represents a double bond, or both m and n are 2 and a double line consisting of a solid line and a broken line represents a single bond;
R ² represents methoxy;
R ⁴ and ^{R 5} together represent an epoxy;
R ⁶ represents methoxy or hydroxy;
One of R ^p and R ^q is a hydrogen atom, and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, or a morphinan representing an alkanoyl optionally having a substituent. Derivatives can be mentioned.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following formula (VII):

(In the formula, m and n both represent 1 or 2,
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by or an optical isomer thereof may be used.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following formula (IX):

(In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, have a phenyl which may have a substituent or substituents Is also a good benzyl)
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
R _aa represents a hydrogen atom or hydroxy and represents
R _bb is a hydrogen atom;
_{C 1-10} alkyl which may have a substituent;
_{C 3-6} cycloalkyl which may have a substituent;
_{C 6-10} aryl, which may have a substituent;
Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
Y represents CH ₂ , C = O or bond)
A morphinan derivative represented by or an optical isomer thereof may be used.

Preferred morphinan derivatives used in this embodiment include
In formula (IX)
R ¹ represents a hydrogen atom or cyclopropyl;
R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
R ⁶ represents hydroxy or methoxy;
R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
R _aa represents a hydrogen atom;
Y represents C = O or bond;
R _bb is a hydrogen atom, phenyl, morphinan derivatives represents benzyl or 6-oxo-1,6-dihydropyridin-2-yl.

Another preferred morphinan derivative used in this embodiment is
In formula (IX)
R ¹ represents a hydrogen atom;
R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
R ⁶ represents hydroxy or methoxy;
R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
R _aa represents a hydrogen atom or hydroxy;
Y represents the bond;
Examples thereof include morphinan derivatives in which R _{bb represents a hydrogen atom or benzyl.}

Another preferred morphinan derivative used in this embodiment is
In formula (IX)
R ¹ represents a hydrogen atom;
R ⁵ represents a phenoxy which may have a substituent;
R ⁶ represents methoxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents the bond;
Examples thereof include morphinan derivatives in which R _{bb represents benzyl.}

Another preferred morphinan derivative used in this embodiment is
In formula (IX)
R ¹ represents a hydrogen atom;
R ⁵ represents a hydrogen atom;
R ⁶ represents hydroxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents C = O;
R _bb is include morphinan derivative representing a 6-oxo-1,6-dihydropyridin-2-yl.

In one embodiment, as a cyclic tertiary amine that can be used in step i).
The following formula (XI):

(In the formula, R ^1a represents a hydrogen atom, vinyl, alkyl, cyclopropyl, which may have a substituent, or phenyl, which may have a substituent.
^R2a , ^R3a , ^R11a and ^R12a represent the same or different hydrogen atoms or alkoxycarbonyls.
^R4a and ^R5a are the same or different,
Hydrogen atom;
Hydroxy;
Alkanoyloxy which may have a substituent;
Alkyl which may have a substituent;
Alkoxycarbonyl;
Amino which may have protecting groups;
-OR ^10a (where R ^10a is an alkyl, aryl, silyl or heteroaryl that may have a substituent);
-NR'R'' (where R'and R'' are the same or different, alkyl, aryl, acyl, alkoxycarbonyl, heteroaryl or sulfonyl);
Cyano;
Aryl which may have a substituent (here, the number of carbon atoms of the aryl is 6 to 10); or a heteroaryl which may have a substituent (where, the ring-constituting atom of the heteroaryl) The number is 6 to 10, and in addition to the carbon atom, 1 to 4 heteroatoms selected from N, O, and S are included as ring-constituting atoms of the heteroaryl).
R ^4a and R ^5a together form an olefin that may have = O, ethylenedioxy or a substituent, or R ^4a and R ^5a are attached to have a substituent. Heterocycle (here, the heterocycle is a non-aromatic ring which may contain a double bond, the heterocyclic portion has 1 to 10 carbon atoms, and 1 to 4 selected from N, O and S. Heteroatoms may be included as ring-constituting atoms of the heterocycle).
A double line consisting of a solid line and a broken line represents a single bond or a double bond.
When the double line consisting of a solid line and a broken line is a single bond,
R ^6a and R ^7a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 6a} nor R ^7a represents hydroxy).
R ^8a and R ^9a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 8a} nor R ^9a represents hydroxy).
Or
R ^6a and R ^8a may be combined to form an epoxy (where R ^7a and R ^9a are hydrogen).
When the double line consisting of a solid line and a broken line is a double bond, R ^7a and R ^9a do not exist, and ^{both R 6a} and R ^8a represent hydrogen atoms).
A tropane derivative represented by is used.

Preferred tropan derivatives used in this embodiment include
In formula (XI)
R ^1a represents a hydrogen atom;
R ^2a and R ^3a are the same or different and represent hydrogen atoms or alkoxycarbonyls;
R ^4a represents alkyl, hydroxy, alkanoyloxy or −OR ^10a which may have a substituent (where R ^10a is a methyl substituted with phenyl) and R ^5a represents a hydrogen atom or R ^4a. And R ^5a together represent = O;
R ^6a , R ^7a , R ^8a and R ^9a represent a hydrogen atom, or R ^6a and R ^8a together form an epoxy, and R ^7a and R ^9a represent a hydrogen atom, a tropane derivative or its optical isomers. The body is mentioned.

General formula that can be used in step i): ^Ra OOC-N = N-COOR ^a
(Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
Examples of the dialkyl azodicarboxylate represented by the above include dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditert-butyl and dibenzyl, and diisopropyl azodicarboxylate is preferable.
The dialkyl azodicarboxylates that can be used in step i) are, if desired, their tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or, if desired, salts, solvates, hydrates or polymorphs thereof. It can be a form.

Examples of the solvent that can be used in step i) include hydrocarbons such as toluene, amides such as DMF, nitriles such as acetonitrile, ethers such as THF, and alkyl halides such as 1,2-dichloroethane. Acetonitrile or toluene is preferred.
The amount of the solvent is not particularly limited, to a nitrogen atom R ¹ -CH 2 _- with respect to the annular substituent is attached represented by tertiary amines 1 g, 10 mL is preferred.
The amount of dialkyl azodicarboxylate is a nitrogen atom R ¹ -CH 2 _- with respect to the tertiary amine 1 mol of cyclic substituents are bonded, represented by may be a 1 mole to 10 moles, Preferably, it can be 2 to 3 mol.
The reaction temperature may be 30 ° C. to 150 ° C., preferably 40 ° C. to 100 ° C.
The reaction time may be 2 hours to 36 hours, preferably 3 hours to 18 hours.

The cyclic tertiary amine that can be used in step i) can be obtained by purchasing it as a commercial product, or can be prepared by a person skilled in the art by a known method. For example, the morphinan derivative represented by the formulas (I), (III), (V), (VII) and (IX) or an optical isomer thereof is referred to the method described in WO2013 / 0358333, WO2016 / 148232 and the like. Can be appropriately prepared by those skilled in the art.

Step i) The result of performing, in one embodiment, the nitrogen atom R ¹ -CH 2 _- ring the substituent is bond represented by tertiary amines R ¹ -CH 2 _- is represented by substituted The group (in the formula, R ¹ is a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent) is
The following general formula:
R ^a OOC-NH-N (COOR ^a ) -CHR ^1-
(Wherein, ^{R a} _{represents C 1-6} alkyl)
An aminal intermediate substituted with a substituent represented by is produced.

In step ii), the reaction product obtained in step i) is subjected to the following general formula:
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
The compound represented by is reacted.
In one embodiment, EWG ¹ and EWG ² are the same or different, -C (= O) -R ^b , -NO ₂ , Rx-SO _2- , -CN or Rx- (Rx'-) P ( = O) -Can be
Here, R ^b , Rx and Rx'are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon. Represents a heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms in addition to atoms.
In this embodiment, EWG ¹ and EWG ² can both be -C (= O) -R ^b , but R ^b may be different. Similarly, EWG ¹ and EWG ² can both be Rx-SO _2- or Rx- (Rx'-) P (= O)-but may differ in Rx and / or Rx'.
Further, in one embodiment, ^{either EWG 1} or EWG ² has -C (= O) -R ^b.
(Here, R ^b is the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and N other than the carbon atom. , Representing a heteroaryl containing 1 to 4 heteroatoms selected from O and S as ring-constituting atoms), and the other may be -NO ₂ or -CN.
The reaction of step ii) includes a step of decomposing the aminal intermediate produced as a result of performing step i) to produce a dealkylated cyclic secondary amine.

The present inventors have focused on improving the purity of the target product by focusing on the fact that the aldehyde (for example, formaldehyde) produced by the decomposition of the aminal intermediate complicates the reaction system and reduces the purity of the target product. .. As a result, the weak acid EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
In using the compound represented by allowed to proceed decomposition of aminal intermediate, at the same time by-produced aldehyde (e.g., formaldehyde) and ^EWG 1 _-CH ² -EWG 2
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
It has been found that the desired product can be obtained with high purity by a simple and mild operation by capturing and removing the compound represented by.
^EWG 1 _-CH ² -EWG 2 that can be used in these steps ii)
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
In the examples of the compounds represented by include, but are not limited _{to, NO 2 -CH 2 -COOC 2 H} 5, CN-CH 2 -COOCH 3 and 1,3-diketo compounds.
Examples of 1,3-diketopiperazine are not limited, but the following general formula:
R ^c- C (= O) -CH _2- C (= O) -R ^d
(In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
Examples thereof include 1,3-diketopiperazine represented by, and specific examples thereof include, but are not limited to.

Examples thereof include compounds having a structure represented by, and dimedone or meldrum's acid is preferable.
^EWG 1 _-CH ² -EWG 2 that can be used in step ii)
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
The compounds represented by can be tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or salts, solvates, hydrates or polymorphs thereof, if desired.
In one embodiment, the dialkyl azodicarboxylate used in step i), using diisopropyl azodicarboxylate, ^EWG 1 _-CH ² -EWG 2 used in step ii)
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Dimedone is used as the compound represented by.
In one embodiment, the dialkyl azodicarboxylate used in step i), using diisopropyl azodicarboxylate, ^EWG 1 _-CH ² -EWG 2 used in step ii)
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Meldrum's acid is used as the compound represented by.
In one embodiment, ^EWG 1 _-CH ² -EWG 2 it used in step ii)
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
When the compound represented by is dimedone, R ⁷ of the compound represented by the general formula (I) is not hydroxy.
As a result of performing step ii), the aldehyde produced as a by-product is EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
It can react with the compound represented by to give rise to a reaction product and be removed from the reaction system. Examples of such reaction products are, but are not limited to,
EWG ^1- C (= CHR ¹ ) -EWG ² (In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing group, and R ¹ may have a hydrogen atom or a substituent. A good alkyl, vinyl, cyclopropyl or phenyl which may have a substituent)
Examples thereof include compounds represented by.
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
The compound represented by is the following general formula:
R ^c- C (= O) -CH _2- C (= O) -R ^d
(In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
In the case of the 1,3-diketo compound represented by, examples of the reaction product of the by-produced aldehyde and the 1,3-diketo compound are not limited, but the following general formula:
R ^c- C (= O) -C (= CHR ¹ ) -C (= O) -R ^d
(In the formula, R ¹ is a hydrogen atom, an alkyl, vinyl, cyclopropyl, which may have a substituent, or a phenyl, which may have a substituent, and R ^c and R ^d are the same or different. The number of ring-constituting atoms is 6 to 10, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or 1 to selected from N, O, and S in addition to carbon atoms. Represents a heteroaryl containing four heteroatoms as ring-constituting atoms, or R ^c and R ^d may together have a substituent or an alkylene dioxy or an alkylene having a substituent. Represents)
Examples thereof include compounds represented by.

Solvents that can be used in step ii) include, but are not limited to, hydrocarbons such as toluene, amides such as DMF, ethers such as THF, nitriles such as acetonitrile, hydrogen halides such as chloroform, DMSO, N-. Examples thereof include aprotic polar solvents such as methylpyrrolidone, alcohols such as methanol, water and acetic acid, and hydrocarbons such as toluene, nitriles such as acetonitrile, and ethers such as THF are preferable. The solvent used in step i) and step ii) may be the same (for example, acetonitrile).
In step ii), it is possible to add a solvent for decomposing the intermediate such as methanol, but it is not always necessary to add the solvent.
EWG ^1- CH _2- ^{EWG 2}
(In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
Step ii) proceeds only with the compound represented by (for example, 1,3-diketopiperazine).
The amount of the solvent used is not particularly limited, but 1 mL to 100 mL, preferably 3 mL to 10 mL is preferable with respect to 1 g of the cyclic tertiary amine in which the substituent represented by ^{R 1-} CH _{2- is bonded to the nitrogen atom.} ..
The amount of the dialkyl azodicarboxylate to be used can be 1 mol to 20 mol with respect to 1 mol of the cyclic tertiary amine in which the substituent represented by ^{R 1-} CH _{2- is bonded to the nitrogen atom.} Preferably, it can be 1 mol to 5 mol.
The reaction temperature may be 30 ° C. to 150 ° C., preferably 40 ° C. to 100 ° C.
The reaction time may be 2 hours to 36 hours, preferably 3 hours to 18 hours.
The amount of ^EWG 1 _-CH ² -EWG 2 used in step ii) comprises the steps i) 1 ~ 100 equivalents relative to the amount of the tertiary amine of the annular used in, preferably 1 to 5 equivalents, more preferably It can be 2-4 equivalents.

After performing step ii), a cyclic secondary amine or a salt thereof in which the substituent represented by ^{R 1-} CH _2- ^{is substituted with a hydrogen atom is produced as a target product (in the formula, R 1).} Is a hydrogen atom, an alkyl, vinyl, cyclopropyl, which may have a substituent, or a phenyl, which may have a substituent).
The cyclic secondary amine in which the substituent represented by ^{R 1-} CH _2- is substituted with a hydrogen atom, which is produced as a target product by the production method provided by the present invention, is, if desired, a tautomer thereof. , Racemic, enantiomers, diastereomers or mixtures thereof, or optionally salts (eg, acid addition salts), solvates (eg, hydrates) or polymorphs thereof.
In one embodiment, be produced as the desired product by the process of the present invention provides, R 1 ^-CH 2 _- secondary amines annular substituent is substituted to the hydrogen atom represented by the free form Is.
In one embodiment, in the production method provided by the present invention, after performing step ii), the obtained reaction solution or reaction solvent is distilled off, and the obtained reaction residue is dissolved in a water-insoluble organic solvent. it the step of washing with a basic solution, treating the separated organic layer with an acid, R ¹ -CH 2 as the desired product _- the substituent represented by the secondary annular substituted with a hydrogen atom Amine (for example, having a morphinan skeleton and having ^{a cyclic secondary amine in which the substituent represented by R 1-} CH _2- is substituted with a hydrogen atom, a tropane skeleton, represented by R ^1- CH _2- It may further include the step of forming an acid addition salt of a cyclic secondary amine) in which the substituent is substituted with a hydrogen atom.
In one embodiment, in the production method provided by the present invention, after performing step ii), the obtained reaction solution or reaction solvent is distilled off, and the obtained reaction residue is dissolved in a water-insoluble organic solvent. it a basic step of treating with acid without washing with a solution, the desired product as R ¹ -CH 2 _- ring substituent is substituted with a hydrogen atom represented by secondary amines (e.g., a morphinan It has a skeleton and has ^{a cyclic secondary amine in which the substituent represented by R 1-} CH _2- is substituted with a hydrogen atom, and a tropane skeleton, and the substituent represented by ^{R 1-} CH _2- It may further include the step of forming an acid addition salt of a cyclic secondary amine) substituted with a hydrogen atom.
In one embodiment, in the production method provided by the present invention, after performing step ii), the obtained reaction solution or reaction solvent is distilled off, and the obtained reaction residue is dissolved in a water-insoluble organic solvent. , The step of washing it with a basic solution, the step of treating the separated organic layer with an acid, the step of making the liquid of the acid-treated solution neutral or basic, and from this solution, R ^{1 as the target product.} -CH 2 _- ring substituent is substituted with a hydrogen atom represented by secondary amines (e.g., having a morphinan skeleton, R 1 ^-CH 2 _- substituent represented by is substituted with hydrogen atom annular secondary amine having a tropane skeleton, R 1 ^-CH 2 _- further comprise the step of extracting the secondary amine) cyclic substituents represented by is substituted with hydrogen atom in an organic solvent But it may be.
In one embodiment, in the production method provided by the present invention, after performing step ii), the obtained reaction solution or reaction solvent is distilled off, and the obtained reaction residue is dissolved in a water-insoluble organic solvent. , A cyclic secondary amine in which the substituent represented by ^{R 1-} CH _2- is substituted with a hydrogen atom in the aqueous layer in an acidic aqueous solution (for example, it has a morphinan skeleton and is represented by ^{R 1-} CH _2-. that secondary amines of the cyclic substituents is substituted with a hydrogen atom, a tropane skeleton, R 1 ^-CH 2 _- secondary amine) cyclic substituents represented by is substituted with hydrogen atom After the extraction, the organic layer may be separated, and then the aqueous layer may be made basic and extracted again into the organic layer.
The basic solution that can be used in the production method provided by the present invention can be appropriately selected by those skilled in the art, and examples thereof include, but are not limited to, sodium hydroxide aqueous solution and aqueous ammonia.

As a result of performing step ii) according to the "cyclic tertiary amine in which the substituent represented by ^{R 1-} CH _2- is bonded to the nitrogen atom" used in step i) ^{, "R 1-} CH _2-" A cyclic secondary amine in which the substituent represented by − is substituted with a hydrogen atom or a salt thereof ”is produced (in the formula, R ¹ is a hydrogen atom, an alkyl which may have a substituent, Vinyl, cyclopropyl or phenyl which may have a substituent).
Can be used in the manufacturing method of the present invention provides _- (In the table below, referred to as starting material) "to a nitrogen atom R ¹ -CH 2 tertiary amines cyclic substituents represented by binds" and it Non-limiting of the correspondingly produced "cyclic secondary amine in which the substituent represented by R ^1- CH _2- is substituted with a hydrogen atom or a salt thereof" (referred to as a product in the table below). Examples are described in Examples 1 to 18 in the table below.

In one embodiment, after the reaction of step ii), the reaction product is concentrated, dissolved in a solvent (eg, ethyl acetate) and added with a hydrochloric acid / ethyl acetate solution to precipitate the desired product as a hydrochloride. The target product may be separated from reagents such as dialkyl azodicarboxylate and 1,3-diketo compounds. Since the salt of the target product can be easily isolated, the production method provided by the present invention can be useful as an industrially applicable production method.
Further, in one embodiment, by using the production method provided by the present invention, the desired product can be obtained in a simple and mild method in good yield.
Also, in one embodiment, the production methods provided by the present invention can be used for highly toxic reagents (eg, cyanogen bromide), expensive reagents (eg, palladium complexes) and / or for harsh conditions or handling. It is not necessary to use reagents that require caution (for example, zirconium complexes). Therefore, the manufacturing method provided by the present invention may be useful as an industrially applicable manufacturing method.
Further, in one embodiment, the target product can be obtained at low cost by using the production method of the present invention.
Moreover, in one embodiment, the production method of the present invention can be applied to the dealkylation of N-alkylated cyclic amine compounds having various structures.

By carrying out the production method of the present invention is to provide, it is represented by _{- -} a "nitrogen atom to R ¹ -CH 2 ring substituents are bonded, represented by tertiary amine""R ¹ -CH 2 A cyclic secondary amine or a salt thereof in which the substituent is substituted with a hydrogen atom is produced (in the formula, R ¹ is a hydrogen atom or a substituent not involved in the reaction, specifically R ¹ is A hydrogen atom, an alkyl, vinyl, cyclopropyl, which may have a substituent, or a phenyl, which may have a substituent).
Accordingly, in one aspect, the present invention comprises the steps i) and step ii), R ¹ -CH 2 the nitrogen atom _- by dealkylation method of a tertiary amine annular substituent is attached represented ( ^{A method for converting R 1-} CH _2- to a hydrogen atom) is provided. The dealkylation method provided by the present invention can be carried out in the same manner as the above-mentioned production method provided by the present invention.
The present invention also provides, in one aspect, a compound produced by the production method provided by the present invention. The compounds produced by the production methods provided by the present invention may be useful as drug substances or intermediates in their synthesis.
The compounds produced by the production methods provided by the present invention are optionally tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or optionally salts and solvates thereof (eg, water). It can be a Japanese product) or a polymorph.
In one embodiment, the compound produced by the production method provided by the present invention may be a salt (eg, an acid addition salt) or a free form.
Examples of such compounds provided by the present invention are not limited, but the following general formula (VI):

(In the formula, R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
R ⁶ represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
Both m and n represent 1 or 2.
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
Examples thereof include morphinan derivatives represented by, or optical isomers thereof, or salts thereof.
As a preferable example of the above, the following general formula (VIII):

(In the formula, m and n both represent 1 or 2,
When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
A morphinan derivative represented by, an optical isomer thereof, or a salt thereof,
Can be mentioned.
Further, as another example of the compound provided by the present invention, the following general formula (X):

(Wherein, R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents Represents (which is a benzyl that may have)
R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
R _aa represents a hydrogen atom or hydroxy and represents
R _bb is a hydrogen atom;
_{C 1-10} alkyl which may have a substituent;
_{C 3-6} cycloalkyl which may have a substituent;
_{C 6-10} aryl, which may have a substituent;
Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
Y represents CH ₂ , C = O or bond)
Examples thereof include morphinan derivatives represented by, or optical isomers thereof, or salts thereof.
As a preferable example of the above, in the general formula (X),
R ⁵ represents phenoxy;
R ⁶ represents methoxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents the bond;
R _bb represents a benzyl, a morphinan derivative or an optical isomer thereof or a salt thereof; and R ⁵ represents a hydrogen atom;
R ⁶ represents hydroxy;
R _y and R _z both represent a hydrogen atom;
R _aa represents a hydrogen atom;
Y represents C = O;
R _bb is 6-oxo-1,6-representative dihydropyridine-2-yl include morphinan derivative or an optical isomer or a salt thereof.

The name of the compound in the examples is described in ChemDraw ver. The structural formula drawn using No. 14 was converted into an English name by the naming algorithm installed in the software, and then translated into Japanese.
Hereinafter, the present invention will be further described with reference to Examples, but the present invention is not limited thereto.

Example 1 (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-7,4a-Etano-4,12 -Manufacture of metanobenzoflo [3,2-e] isoquinoline-14-carboxamide hydrochloride

(4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-3-methyl-1,2,3,4,7,7a-hexahydro-7,4a-etano-4, 12-Metanobenzoflo [3,2-e] isoquinolin-14-carboxamide (10.0 g, 21.2 mmol) was dissolved in acetonitrile (200 mL) and diisopropylazodicarboxylate (8.6 g, 42.4 mmol) was added. Then, the mixture was stirred at 60-65 ° C. for 22 hours in a nitrogen atmosphere.
After confirming the disappearance of the raw materials and the formation of the aminal intermediate by LCMS, dimedone (8.91 g, 63.6 mmol) and methanol (4 mL) were added to the reaction mixture, and the mixture was stirred at 60 to 65 ° C. for 3 hours.
After confirming the disappearance of the aminal intermediate by LCMS, the reaction solution was cooled to 25 ° C. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (100 mL) and cooled to 0 to 5 ° C.
The obtained solution was washed with a 4% aqueous sodium hydroxide solution (50 mL), and the aqueous layer was extracted with ethyl acetate (100 mLx2). The collected organic layer was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After removing unnecessary substances, the mixture was concentrated under reduced pressure to obtain a foam-like substance.
The obtained foam material was dissolved in ethyl acetate (30 mL), and an ethyl acetate solution of hydrogen chloride (4M, 30 mL) and tert-butyl methyl ether (100 mL) were added with vigorous stirring at 0 to 5 ° C. The obtained suspension was stirred at 25 ° C. for 30 minutes, and the obtained powder was collected by filtration and washed with tert-butyl methyl ether (50 mL). The powder was dried under reduced pressure to give the title compound (11 g, quant) as a pale yellow powder. Purity 88.7%
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ10.99 (d, 1H, J = 11.4 Hz), 8.87-8.93 (m, 1H), 8.36-8.39 (t, 1H, J = 5.8Hz), 7.21-7.33 (m, 5H), 6.72 (d, 1H, J = 8.2Hz), 6.61 (d, 1H, J = 8.2Hz) ), 5.73 (d, 1H, J = 8.8Hz), 5.48 (d, 1H, J = 8.8Hz), 4.64 (s, 1H), 4.30-4.38 (m) , 1H), 4.14-4.18 (m, 2H), 3.70 (s, 3H), 3.45 (s, 3H), 3.30 (d, 1H, J = 19.4Hz), 3.07-3.17 (m, 2H), 2.85-2.92 (m, 2H), 2.01 (d, 2H, J = 6.2Hz), 1.42 (dd, 1H, J) = 16.7 and 10.0 Hz), 1.10-1.21 (m, 2H).

Example 2 (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-7,4a-Etano-4,12 -Production of Metanobenzoflo [3,2-e] Isoquinoline-14-Carboxamide Free Form (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-1,2 , 3,4,7,7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinoline-14-carboxamide hydrochloride (2.0 g, 4.0 mmol) in 1N sodium hydroxide It was dissolved in aqueous solution (60 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried and then concentrated to give the title compound (1.6 g, 91%) as a pale yellow amorphous solid.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ7.22-7.33 (m, 5H), 6.63 (d, 1H, J = 8.1 Hz), 6.54 (d, 1H, J = 8. 1Hz), 6.41 (br s, 1H), 5.92 (d, 1H, J = 8.8Hz), 5.55 (d, 1H, J = 8.8Hz), 4.52 (s, 1H) ), 4.43 (d, 2H, J = 5.6Hz), 3.81 (s, 3H), 3.59 (s, 3H), 3.51 (d, 1H, J = 4.6Hz), 2.84-3.07 (m, 2H), 2.66-2.70 (m, 1H), 1.65-2.03 (m, 4H), 1.23-1.26 (m, 2H) ).

Example 3 (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-7,4a-Etano-4,12 -Metalnobenzoflo [3,2-e] Isoquinoline-14-carboxamide hydrochloride production (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-3-methyl-1,2, 3,4,7,7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinolin-14-carboxamide (100 g, 212 mmol) was dissolved in acetonitrile (2 L) and diisopropylazodi After adding carboxylate (85.6 g, 424 mmol), the mixture was stirred at 60-65 ° C. for 22 hours under a nitrogen atmosphere.
After confirming the disappearance of the raw materials and the formation of the aminal intermediate by LCMS, dimedone (89.1 g, 636 mmol) and methanol (50 mL) were added to the reaction mixture, and the mixture was stirred at 60 to 65 ° C. for 3 hours.
After confirming the disappearance of the aminal intermediate by LCMS, the reaction solution was cooled to 25 ° C. The reaction solution was concentrated under reduced pressure, and the obtained residue was diluted with ethyl acetate (800 mL) and cooled to 0 to 5 ° C.
The obtained solution was washed with a 4% aqueous sodium hydroxide solution (90 mL), and the aqueous layer was extracted with ethyl acetate (400 mLx3). The collected organic layer was washed with saturated brine (400 mL) and dried over anhydrous sodium sulfate. After removing unnecessary substances, the mixture was concentrated under reduced pressure to obtain a foam-like substance.
The obtained foam material was dissolved in ethyl acetate (500 mL), and an ethyl acetate solution of hydrogen chloride (10%, 130 mL) and tert-butyl methyl ether (300 mL) were added with vigorous stirring at 0 to 5 ° C. The obtained suspension was stirred at 25 ° C. for 30 minutes, and the obtained powder was collected by filtration and washed with tert-butyl methyl ether (300 mL). The powder was dried under reduced pressure to give the title compound (101 g, 97%) as a pale yellow powder. Purity 86.1%
The NMR spectrum of the obtained compound was consistent with that of Example 1.

Example 4 (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-1,2,3,4,7,7a-hexahydro-7,4a-Etano-4,12 -Production of methanobenzoflo [3,2-e] isoquinoline-14-carboxamide hydrochloride (4R, 4aR, 7R, 7aR, 12bS, 14S) -N-benzyl-7,9-dimethoxy-3-methyl-1,2, 3,4,7,7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinolin-14-carboxamide (1.0 g, 2.12 mmol) was dissolved in acetonitrile (5 mL). , Diisopropylazodicarboxylate (0.43 g, 2.47 mmol) was added, and the mixture was stirred at 60-65 ° C. for 22 hours and in a nitrogen atmosphere for 16 hours.
After cooling the reaction solution, the disappearance of the raw material was confirmed by LCMS, divided into two, and meldrum's acid (458 mg, 3.18 mmol) and methanol (0.25 mL) were added to one (starting material 500 mg, equivalent to 1.06 mmol) at the same temperature. Was heated and stirred for 3 hours.
After confirming the completion of the reaction by LCMS, the reaction solution was cooled to room temperature and concentrated under reduced pressure.
The obtained residue was adjusted to pH 8-9 with a 10% aqueous sodium hydroxide solution, and the aqueous layer was extracted with ethyl acetate (5 mLx2). The collected organic layer was washed with saturated brine, dried over anhydrous sodium sulfate to remove unnecessary substances, and then concentrated under reduced pressure.
The obtained foam-like substance was dissolved in ethyl acetate, and then a solution of hydrogen chloride in ethyl acetate and tert-butyl methyl ether were added with vigorous stirring. The obtained suspension was stirred at 25 to 30 ° C. for 30 minutes, and the obtained powder was collected by filtration and washed with tert-butyl methyl ether (300 mL). The powder was dried under reduced pressure to give the title compound (380 mg, 76.8%) as a pale yellow powder. Purity 71.4%
The NMR spectrum of the obtained compound was consistent with that of Example 1.

Example 5 Demethylation reaction from tropane derivative General procedure (1R, 3r, 5S) -8-azabicyclo [3.2.1] Octane-3-yl 1H-indol-3-carboxylate Production of Hydrochloride (nor-tropisetron hydrochloride: (3-endo) -8-azabicyclo [3.2.1] octane-3-yl 1H-indole-3-carboxylate hydrochloride)

Add acetonitrile (9.0 mL) to a 25 mL flask and add (1R, 3r, 5S) -8-methyl-8-azabicyclo [3.2.1] octane-3-yl 1H-indole-3-carboxylate (Tropisetron). : (3-endo) -8-methyl-8-azabicyclo [3.2.1] octane-3-yl 1H-indole-3-carboxylate) (0.3 g, 1.06 mmol, 1 equivalent) is added and stirred. did. Diisopropyl azodicarboxylate (DIAD) (0.43 g, 2.12 mmol, 2 eq) was added to the obtained mixture, and the reaction solution was heated and stirred at 60 to 70 ° C. for 12 hours. When the reaction was confirmed by HPLC, the disappearance of the raw material was observed.
Add 1,3-diketo compound (4,5,4-trifluoro-1- (thiophen-2-yl) butane-1,3-dione) (0.71 g, 3.18 mmol, 3 equivalents) to the reaction solution. The mixture was added at warm temperature and heated and stirred for two and a half hours. When the reaction was confirmed by HPLC, the disappearance of the aminal intermediate was observed.
The reaction solution was cooled to room temperature, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate (6.0 mL, 2.0 v / w) to obtain a yellow solution. The obtained solution was washed with water (1.5 mL, 5.0 v / w) and the aqueous layer was separated.
A 4N hydrogen chloride / ethyl acetate solution (1.0 mL, 3.0 v / w) was added to the organic layer with stirring.
The obtained solution is concentrated under reduced pressure to distill off excess hydrogen chloride, and then the residue is diluted with ethyl acetate (1.0 mL, 3.0 v / w) and stirred at room temperature for 1 hour to form a powdery substance. Was obtained.
The obtained suspension was collected by filtration, washed with ethyl acetate (0.5 mL, 2.0 v / w), and dried to obtain nor-tropisetron hydrochloride as a light brown powder.
The HPLC purity was 99.0%.
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ12.10 (s, 1H), 9.34 (br s, 1H), 9.22 (br s, 1H), 8.10-8.08 (m) , 2H), 7.52 (dd, 1H, J = 1.6 and 6.0Hz), 7.17-7.24 (m, 2H), 5.16 (t, 1H, J = 4.8Hz) , 3.99 (s, 1H), 2.05-2.46 (m, 2H), 2.25-2.89 (m, 4H).

Examples using the 1,3-diketopiperazine compounds shown in the table below were also carried out in the same manner as the above general operation method to obtain nor-tropisetron hydrochloride.

An example in which the following compound was used instead of the 1,3-diketo compound was also carried out in the same manner as the above general operation method to obtain nor-tropisetron hydrochloride.

The present invention provides an industrially applicable method for producing a high-purity N-dealkylated cyclic secondary amine compound by a simple and mild operation. The morphinan derivative and the tropane derivative that can be produced by using the production method provided by the present invention may be useful in the production of a pharmaceutical product or a pharmaceutical product.

This application is based on Japanese Patent Application No. 2019-239380 (Filing date: December 27, 2019) and Japanese Patent Application No. 2020-05805 (Filing date: March 19, 2020). All are included herein.

Claims (92)

1. i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
   R ^a OOC-N = N-COOR ^a
   (Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
   The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
   EWG ^1- CH _2- ^{EWG 2}
   (In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
   Including the step of reacting the compound represented by
   A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, wherein R 1} is a hydrogen atom or a substituent not involved in the reaction.
2. EWG ¹ and EWG ² are the same or different and represent -C (= O) -R ^b , -NO ₂ , Rx-SO _2- , -CN or Rx- (Rx'-) P (= O)-. ,
   Here, R ^b , Rx and Rx'are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon. The method according to claim 1, wherein the heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms in addition to atoms.
3. EWG ¹ or EWG ² is -C (= O) -R ^b ,
   Here, R ^b is C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or has 6 to 10 ring-constituting atoms, and is selected from N, O, and S in addition to carbon atoms. The method according to claim 1 or 2, wherein the heteroaryl contains 1 to 4 heteroatoms as ring-constituting atoms.
4. i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
   R ^a OOC-N = N-COOR ^a
   (Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
   The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
   EWG ^1- CH _2- ^{EWG 2}
   (In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
   Including the step of reacting the compound represented by
   A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, and R 1} is a hydrogen atom or a substituent not involved in the reaction.
   Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
   NO ₂ -CH ₂ -COOC ₂ H ₅ or _CN-CH 2 -COOCH method _3.
5. i) A cyclic tertiary amine in which a substituent represented by ^{R 1-} CH _2- is bonded to a nitrogen atom, and the following general formula:
   R ^a OOC-N = N-COOR ^a
   (Wherein, ^{R a} represents a _{C 1-6} alkyl optionally having substituent)
   The step of reacting the dialkyl azodicarboxylate represented by ii) and the reaction product obtained in the above step i) have the following general formula:
   EWG ^1- CH _2- ^{EWG 2}
   (In the formula, EWG ¹ and EWG ² represent the same or different electron-withdrawing groups)
   Including the step of reacting the compound represented by
   A method for producing a cyclic secondary amine in which the substituent represented by R ^1- CH _2- ^{is substituted with a hydrogen atom, and R 1} is a hydrogen atom or a substituent not involved in the reaction.
   Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
   R ^c- C (= O) -CH _2- C (= O) -R ^d
   (In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
   A method that is a 1,3-diketopiperazine represented by.
6. Compounds represented by EWG ¹ -CH ^₂ -EWG ₂ is,
   R ^c- C (= O) -CH _2- C (= O) -R ^d
   (In the formula, R ^c and R ^d are the same or different, C _1-6 alkyl, C _1-6 alkoxy, C _6-10 aryl, or the number of ring-constituting atoms is 6 to 10, and carbon atoms. addition to N, or one to four heteroatoms selected from O and S represents a heteroaryl comprising a ring-constituting atom, alkyl also R ^c and R ^d are substituted together Represents an alkylene that may have a rangeoxy or a substituent)
   It is a 1,3-diketo compound represented by
   1,3-Diketopiperazine
   

   

   
   

   

   
   

   

   
   

   

   
   

   

   
   

   

   
   

   

   
   

   

   
   The method according to any one of claims 1, 2 and 5, which is a compound having a structure represented by.
7. The method according to claim 6, wherein the 1,3-diketo compound is dimedone or meldrum's acid.
8. The method according to any one of claims 1 to 7, wherein R ¹ is a hydrogen atom, an alkyl, vinyl, cyclopropyl, which may have a substituent, or a phenyl, which may have a substituent. ..
9. The method according to any one of claims 1 to 8, wherein R ¹ is an alkyl, vinyl, cyclopropyl or phenyl which may have a hydrogen atom and a substituent.
10. The method according to any one of claims 1 to 9, wherein the aldehyde produced as a by-product is removed by the above-mentioned 1,3-diketopiperazine as a result of performing step ii).
11. Step ii) is performed in the presence of a solvent selected from hydrocarbons, amides, nitriles, ethers, hydrogen halides, aprotic polar solvents, alcohols, water and acetic acid, claim 1. The method according to any one of 10 to 10.
12. The method according to any one of claims 1 to 11, wherein step i) and step ii) are performed in the presence of the same solvent.
13. The method according to any one of claims 1 to 12, wherein step ii) is performed at a temperature of 30 ° C to 150 ° C.
14. The method according to any one of claims 1 to 13, wherein step ii) is performed at a temperature of 40 ° C to 100 ° C.
15. The method according to any one of claims 1 to 14, wherein the dialkyl azodicarboxylate is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, ditert-butyl azodicarboxylate or dibenzyl azodicarboxylate. ..
16. Further, the reaction solution or the reaction solvent obtained in step ii) was distilled off, the obtained reaction residue was dissolved in an organic solvent insoluble in water, and then treated with a neutral or basic solution and separated. Claims 1 to 15 include a step of treating the organic layer with an acid and ^{isolating a cyclic secondary amine in which the substituent represented by R 1-} CH _2- is substituted with a hydrogen atom as an acid addition salt. The method according to any one of the above.
17. Further, the reaction solution or reaction solvent obtained in step ii) was distilled off, and the reaction residue obtained was dissolved in an organic solvent insoluble in water, and then treated with an acid instead of being treated with a basic solution. The invention according to any one of claims 1 to 15, which comprises a step of isolating a cyclic secondary amine in which the substituent represented by ^{R 1-} CH _{2- is substituted with a hydrogen atom as an acid addition salt.} Method.
18. Further, the reaction solution or reaction solvent obtained in step ii) is distilled off, and the reaction residue obtained is dissolved in an organic solvent insoluble in water, and then the aqueous layer is represented by R ^1- CH _{2- with an acidic aqueous solution.} Any of claims 1 to 15, which comprises a step of extracting a cyclic secondary amine in which the substituent is substituted with a hydrogen atom, separating the organic layer, and then extracting the aqueous layer into the organic layer again as basic. The method according to item 1.
19. The cyclic tertiary amine is represented by the following general formula (I):
    

    

    
    (In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
    A double line consisting of a solid line and a broken line represents a single bond or a double bond.
    R ² and R ³ represent the same or different hydrogen atoms, hydroxy or C _1-6 alkoxy, or R ² and R ³ together represent = O or ethylenedioxy.
    R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
    R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
    R ⁷ represents a hydrogen atom or hydroxy, or, ^{R 7,} together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - may be formed, ^{R 8} and R ⁹ is a hydrogen atom, or one of R ⁸ and R ⁹ is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, and a substituent. Represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent)
    A morphinan derivative represented by or an optical isomer thereof.
    The cyclic secondary amine is the following general formula (II):
    

    

    
    (In the formula, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are the same as above)
    The method according to any one of claims 1 to 18, which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof.
20. 19. The method of claim 19, wherein R ^{1 represents a hydrogen atom or phenyl.}
21. R ² and ^{R 3} are the same or different, a hydrogen atom, or a hydroxy or _{C 1-6} alkoxy, ^{R 2} and ^{R 3} together represent ethylenedioxy, in claim 19 or claim 20 The method described.
22. The method according to any one of claims 19 to 21, wherein both R ⁴ and R ^{5 represent a hydrogen atom.}
23. R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of claims 19 to 21, which represents (may be benzyl).
24. The method according to any one of claims 19 to 21, wherein R ⁴ and R ^{5 together represent an epoxy.}
25. The method according to any one of claims 19 to 24, wherein R ⁶ represents C _{1-6 alkoxy.}
26. The method according to any one of claims 19 to 25, wherein R ^{7 represents a hydrogen atom.}
27. R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, ^{R 8} and ^{R 9} are both hydrogen, according to claim 19-25 The method according to any one item.
28. R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, a one hydrogen atom of ^{R 8} and ^{R 9,} the other is substituted with hydroxy 19-25, which represent an alkyl which may be, a carbamoyl which may have a substituent, an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent. The method according to any one item.
29. R ⁷ together with ^{R 2, -CR 8 = CR 9} - or -CHR ⁸ -CHR ⁹ - to form, one of ^{R 8} and ^{R 9} is a hydrogen atom, the other substituents The method according to any one of claims 19 to 25, which represents carbamoyl which may be possessed.
30. The cyclic tertiary amine is the following general formula (III):
    

    

    
    (In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
    A double line consisting of a solid line and a broken line represents a single bond or a double bond.
    R ² and R ³ _{represent the same or different hydrogen atoms, hydroxy or C 1-6} alkoxy when the double bond consisting of a solid line and a broken line is a single bond, or ^{R 2} and R ³ are combined. = O or ethylenedioxy, where the double bond consisting of a solid line and a broken line is a double bond, R ³ does not exist and R ² represents a hydrogen atom or C _1-6 alkoxy.
    R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
    R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group)
    A morphinan derivative represented by or an optical isomer thereof.
    The cyclic secondary amine is represented by the following general formula (IV):
    

    

    
    (In the formula, R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are the same as above)
    The method according to any one of claims 1 to 18, which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof.
31. The method of claim 30, wherein R ^{1 represents a hydrogen atom or phenyl.}
32. 30 or 31, wherein the double line consisting of a solid line and a broken line is a single bond, and R ² and R ³ represent the same or different hydrogen atom, hydroxy or C _{1-6 alkoxy.} The method described.
33. The method according to claim 30 or 31, wherein the double line consisting of a solid line and a broken line is a single bond, and R ² and R ^{3 together represent O or ethylenedioxy.}
34. The method of claim 30 or 31, wherein the double line consisting of a solid line and a broken line is a double bond, R ³ does not exist, and R ² represents a hydrogen atom or C _{1-6 alkoxy.} ..
35. The method according to any one of claims 30 to 34, wherein R ⁴ and R ^{5 both represent a hydrogen atom.}
36. R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of claims 30 to 34, which represents (may be benzyl).
37. The method according to any one of claims 30 to 34, wherein R ⁴ and R ^{5 together represent an epoxy.}
38. The cyclic tertiary amine is represented by the following formula (V):
    

    

    
    (In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
    R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
    R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
    R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
    R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
    Both m and n represent 1 or 2.
    When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
    When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
    A morphinan derivative represented by or an optical isomer thereof.
    The cyclic secondary amine is represented by the following formula (VI):
    

    

    
    (In the equation, R ² , R ⁴ , R ⁵ , R ⁶ , R ^p , R ^q , m, n, and the double line consisting of a solid line and a broken line are the same as above)
    The method according to any one of claims 1 to 18, which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof.
39. 38. The method of claim 38, wherein R ^{1 represents a hydrogen atom or phenyl.}
40. 38. The method of claim 39, wherein R ² represents a hydrogen atom or C _{1-6 alkoxy.}
41. The method according to any one of claims 38 to 40, wherein R ⁴ and R ^{5 both represent a hydrogen atom.}
42. R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The method according to any one of claims 38 to 40, which represents (may be benzyl).
43. The method according to any one of claims 38 to 40, wherein R ⁴ and R ^{5 together represent an epoxy.}
44. The method according to any one of claims 38 to 43, wherein R ⁶ represents hydrogen or C _{1-6 alkoxy.}
45. The method according to any one of claims 38 to 44, wherein R ^p and R ^{q both represent a hydrogen atom.}
46. One of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, an alkoxyalkyl optionally comprising a substituent, or The method according to any one of claims 38 to 44, which represents an alkanoyl which may have a substituent.
47. Any of claims 38 to 44, wherein R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other represents a carbamoyl which may have a substituent. The method according to item 1.
48. The method according to any one of claims 38 to 47, wherein the double line consisting of a solid line and a broken line represents a single bond.
49. The method according to any one of claims 38 to 47, wherein the double line consisting of a solid line and a broken line represents a double bond.
50. The method according to any one of claims 1 to 49, wherein R ^{1 is hydrogen.}
51. The cyclic tertiary amine is represented by the following formula (VII):
    

    

    
    (In the formula, m and n both represent 1 or 2,
    When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
    When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
    A morphinan derivative represented by or an optical isomer thereof.
    The cyclic secondary amine is represented by the following formula (VIII):
    

    

    
    (In the formula, m and n both represent 1 or 2,
    When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
    When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
    38. The method of claim 38, which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof.
52. The cyclic tertiary amine is represented by the following formula (IX):
    

    

    
    (In the formula, R ¹ represents a phenyl that may have a hydrogen atom, vinyl, cyclopropyl or a substituent.
    R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, have a phenyl which may have a substituent or substituents Is also a good benzyl)
    R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
    R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
    R _aa represents a hydrogen atom or hydroxy and represents
    R _bb is a hydrogen atom;
    _{C 1-10} alkyl which may have a substituent;
    _{C 3-6} cycloalkyl which may have a substituent;
    _{C 6-10} aryl, which may have a substituent;
    Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
    Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
    Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
    Y represents CH ₂ , C = O or bond)
    A morphinan derivative represented by or an optical isomer thereof.
    The cyclic secondary amine is represented by the following formula (X):
    

    

    
    (In the equation, R ⁵ , R ⁶ , R _y , R _z , R _aa , R _bb and Y are the same as above)
    The method according to any one of claims 1 to 18, which is a morphinan derivative represented by the above, an optical isomer thereof, or a salt thereof.
53. 52. The method of claim 52, wherein R ¹ represents a hydrogen atom, vinyl, cyclopropyl or phenyl.
54. 52. The method of claim 53, wherein R ^{1 represents a hydrogen atom or cyclopropyl.}
55. The method according to any one of claims 52 to 54, wherein R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent.
56. The method according to any one of claims 52 to 55, wherein R ^{6 represents hydroxy or methoxy.}
57. The method according to any one of claims 52 to 56, wherein R _y and R _z both represent a hydrogen atom, or R _y and R _{z together represent = O.}
58. The method according to any one of claims 52 to 57, wherein R _{aa represents a hydrogen atom.}
59. The method according to any one of claims 52 to 58, wherein Y represents C = O or a bond.
60. The method according to any one of claims 52 to 59, wherein R _bb represents a hydrogen atom, phenyl, benzyl or 6-oxo-1,6-dihydropyridine-2-yl.
61. R ^1- CH _2- is R ^1a- CH _2- , and the cyclic tertiary amine is the following general formula (XI) :.
    

    

    
    (In the formula, R ^1a represents a hydrogen atom, vinyl, alkyl, cyclopropyl, which may have a substituent, or phenyl, which may have a substituent.
    R ^2a , R ^3a , R ^11a and R ^12a represent the same or different hydrogen atom or alkoxycarbonyl, and R ^4a and R ^5a are the same or different.
    Hydrogen atom;
    Hydroxy;
    Alkanoyloxy which may have a substituent;
    Alkyl which may have a substituent;
    Alkoxycarbonyl;
    Amino which may have protecting groups;
    -OR ^10a (where R ^10a is an alkyl, aryl, silyl or heteroaryl optionally having a substituent);
    -NR'R'' (where R'and R'' are the same or different, alkyl, aryl, acyl, alkoxycarbonyl, heteroaryl or sulfonyl);
    Cyano;
    Aryl which may have a substituent (here, the number of carbon atoms of the aryl is 6 to 10); or a heteroaryl which may have a substituent (where, the ring-constituting atom of the heteroaryl) The number is 6 to 10, and in addition to the carbon atom, 1 to 4 heteroatoms selected from N, O, and S are included as ring-constituting atoms of the heteroaryl).
    R ^4a and R ^5a together form an olefin that may have = O, ethylenedioxy or a substituent, or R ^4a and R ^5a are attached to have a substituent. Heterocycle (here, the heterocycle is a non-aromatic ring which may contain a double bond, the heterocyclic portion has 1 to 10 carbon atoms, and 1 to 4 selected from N, O and S. Heteroatoms may be included as ring-constituting atoms of the heterocycle).
    A double line consisting of a solid line and a broken line represents a single bond or a double bond.
    When the double line consisting of a solid line and a broken line is a single bond,
    R ^6a and R ^7a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 6a} nor R ^7a represents hydroxy).
    R ^8a and R ^9a represent the same or different hydrogen atom or hydroxy (however, ^{neither R 8a} nor R ^9a represents hydroxy).
    Or
    R ^6a and R ^8a may be combined to form an epoxy (where R ^7a and R ^9a are hydrogen).
    If the double line consisting of a solid line and a broken line is a double bond,
    R ^7a and R ^9a do not exist, and ^{both R 6a} and R ^8a represent hydrogen atoms)
    It is a tropane derivative represented by, or an optical isomer thereof.
    The cyclic secondary amine is represented by the following formula (XII):
    

    

    
    (In the formula, R ^2a , R ^3a , R ^4a , R ^5a , R ^6a , R ^7a , R ^8a , R ^9a , R ^11a , R ^12a and the double line consisting of the solid line and the broken line are the same as above)
    The method according to any one of claims 1 to 18, which is a tropane derivative represented by the above, an optical isomer thereof, or a salt thereof.
62. The method of claim 61, wherein R ^{1a is a hydrogen atom or phenyl.}
63. The method of claim 61 or 62, wherein one of R ^2a and R ^{3a represents a hydrogen atom and the other represents an alkoxycarbonyl.}
64. R ^4a and R ^5a are the same or different,
    Hydrogen atom;
    Hydroxy;
    Alkanoyloxy which may have a substituent;
    Alkyl which may have a substituent;
    Alkoxycarbonyl;
    Amino which may have protecting groups;
    -OR ^10a (where R ^10a is alkyl, aryl, silyl or heteroaryl);
    -NR'R'' (where R'and R'' are the same or different, alkyl, aryl, acyl, alkoxycarbonyl, heteroaryl or sulfonyl);
    Cyano;
    Aryl which may have a substituent (here, the number of carbon atoms of the aryl is 6 to 10); or a heteroaryl which may have a substituent (where, the ring-constituting atom of the heteroaryl) The number is 6 to 10, and any one of claims 61 to 63, which represents 1 to 4 heteroatoms selected from N, O, and S in addition to carbon atoms as ring-constituting atoms of heteroaryl). The method described in the section.
65. ^{The method of any one of claims 61-63,} wherein R 4a and R ^5a together form an olefin that may have = O, ethylenedioxy or a substituent.
66. A ^{heterocycle in which R4a} and ^R5a are bonded and may have a substituent (here, the heterocycle is a non-aromatic ring which may contain a double bond, and the number of carbon atoms in the heterocyclic portion is 1. The method according to any one of claims 61 to 63, wherein 1 to 4 heteroatoms selected from N, O and S are formed as ring-constituting atoms of a heterocycle.
67. The double line consisting of a solid line and a broken line is a single bond,
    R ^6a and R ^7a represent a hydrogen atom.
    The method according to any one of claims 61 to 66, wherein R ^8a and R ^{9a represent a hydrogen atom.}
68. One of claims 61 to 66, wherein the double line consisting of a solid line and a broken line is a single bond, R ^6a and R ^8a together form an epoxy, and R ^7a and R ^{8a represent hydrogen.} The method described in the section.
69. The invention according to any one of claims 61 to 68, wherein the double line consisting of the solid line and the broken line is a double bond, R ^7a and R ^9a do not exist, and ^{both R 6a} and R ^{8a represent a hydrogen atom.} the method of.
70. The method according to any one of claims 61 to 69, wherein R ^{1a is hydrogen.}
71. The method according to any one of claims 61 to 70, wherein R ^11a and R ^{12a are hydrogen atoms.}
72. The method of claim 61, wherein the cyclic tertiary amine is atropine, scopolamine or cocaine.
73. The following general formula (VI):
    

    

    
    (In the formula, R ² represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
    R ⁴ and ^{R 5} are either both represent hydrogen atom, ^{R 4} is a hydrogen atom, ^{R 5} is -OR ^{5 '(wherein,} R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, a substituent or it represents a is benzyl which may be have a phenyl or substituted group optionally), or R ⁴ and R ⁵ represents an epoxy together,
    R ⁶ represents a hydrogen atom, hydroxy or C _1-6 alkoxy.
    R ^p and R ^q are both hydrogen atoms, or one of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, and a carbomoyl may have a substituent. , Which represents an alkoxyalkyl which may have a substituent, or an alkanoyl which may have a substituent.
    Both m and n represent 1 or 2.
    When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
    When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
    A morphinan derivative represented by, an optical isomer thereof, or a salt thereof.
74. R ² represents hydrogen atom or C _1-6 alkoxy, morphinan derivatives or optical isomers thereof, or salts thereof according to claim 73.
75. The morphinan derivative according to claim 73 or claim 74, an optical isomer thereof, or a salt thereof, wherein R ⁴ and R ^{5 both represent a hydrogen atom.}
76. R ⁴ is a hydrogen atom, R ⁵ is -OR 5 ^'(wherein, R ^5' is a hydrogen atom, have methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents The morphinan derivative according to claim 73 or claim 74, an optical isomer thereof, or a salt thereof, which represents (may be benzyl).
77. The morphinan derivative according to claim 73 or claim 74, an optical isomer thereof, or a salt thereof, wherein R ⁴ and R ^{5 together represent an epoxy.}
78. The morphinan derivative according to any one of claims 73 to 77, an optical isomer thereof, or a salt thereof, wherein R ⁶ represents a hydrogen atom or C _{1-6 alkoxy.}
79. The morphinan derivative according to any one of claims 73 to 78, an optical isomer thereof, or a salt thereof, wherein R ^p and R ^{q both represent a hydrogen atom.}
80. One of R ^p and R ^q is a hydrogen atom and the other is an alkyl optionally substituted with a hydroxy, a carbamoyl optionally having a substituent, an alkoxyalkyl optionally comprising a substituent, or The morphinan derivative according to any one of claims 73 to 78, an optical isomer thereof, or a salt thereof, which represents an alkanoyl which may have a substituent.
81. The following general formula (VIII):
    

    

    
    (In the formula, m and n both represent 1 or 2,
    When both m and n are 1, a double line consisting of a solid line and a broken line represents a double bond.
    When both m and n are 2, a double line consisting of a solid line and a broken line represents a single bond)
    A morphinan derivative represented by, an optical isomer thereof, or a salt thereof.
82. The following general formula (X):
    

    

    
    (Wherein, R ⁵ is a hydrogen atom or R ⁵ -OR 5 ^'(wherein, R ^5' is a hydrogen atom, methyl, trifluoromethanesulfonyl, phenyl which may have a substituent or substituents Represents (which is a benzyl that may have)
    R ⁶ represents a hydrogen atom, a hydroxy or C _1-6 alkoxy which may have a protecting group.
    R _y and R _z represent the same or different hydrogen atoms, hydroxy, or R _y and R _z together represent = O.
    R _aa represents a hydrogen atom or hydroxy and represents
    R _bb is a hydrogen atom;
    _{C 1-10} alkyl which may have a substituent;
    _{C 3-6} cycloalkyl which may have a substituent;
    _{C 6-10} aryl, which may have a substituent;
    Heteroaryl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl is 6 to 10, and 1 to 4 heteroatoms selected from N, O and S in addition to the carbon atom As a ring-constituting atom of heteroaryl);
    Aralkyl which may have a substituent (where, the aryl moiety of the aralkyl has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms);
    Heteroarylalkyl which may have a substituent (here, the number of ring-constituting atoms of the heteroaryl portion of the heteroarylalkyl is 6 to 10, and is selected from N, O and S in addition to the carbon atom 1 It contains up to 4 heteroatoms as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms); or 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom. As a ring-constituting atom, and at least one set of adjacent ring-constituting atoms represents a heteroatom having a double bond and further substituted with at least one oxo group.
    Y represents CH ₂ , C = O or bond)
    A morphinan derivative represented by, an optical isomer thereof, or a salt thereof.
83. R ⁵ is a hydrogen atom, a hydroxy or substituted represents also good phenoxy, morphinan derivatives or optical isomers thereof, or salts thereof according to claim 82.
84. The morphinan derivative according to claim 82 or claim 83, an optical isomer thereof, or a salt thereof, wherein R ^{6 represents hydroxy or methoxy.}
85. The morphinan derivative or an optical isomer thereof according to any one of claims 82 to 84, wherein R _y and R _z both represent a hydrogen atom, or R _y and R _{z together represent = O.} Those salts.
86. The morphinan derivative according to any one of claims 82 to 85, an optical isomer thereof, or a salt thereof, wherein R _{aa represents a hydrogen atom.}
87. The morphinan derivative according to any one of claims 82 to 86, an optical isomer thereof, or a salt thereof, wherein Y represents C = O or a bond.
88. R _bb is a hydrogen atom, phenyl, benzyl or 6-oxo-1,6-dihydropyridin-2 represents a yl, morphinan derivatives or their optical isomers or their according to any one of claims 82-87 salt.
89. R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
    R ⁶ represents hydroxy or methoxy;
    R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
    R _aa represents a hydrogen atom;
    Y represents C = O or bond;
    The morphinan derivative according to claim 82 or an optical isomer thereof or a salt thereof, wherein R _bb represents a hydrogen atom, phenyl, benzyl or 6-oxo-1,6-dihydropyridine-2-yl.
90. R ⁵ represents a phenoxy which may have a hydrogen atom, a hydroxy or a substituent;
    R ⁶ represents hydroxy or methoxy;
    R _y and R _z both represent a hydrogen atom, or R _y and R _z together represent = O;
    R _aa represents a hydrogen atom or hydroxy;
    Y represents the bond;
    The morphinan derivative according to claim 82, an optical isomer thereof, or a salt thereof, wherein R _{bb represents a hydrogen atom or benzyl.}
91. R ⁵ represents a phenoxy which may have a substituent;
    R ⁶ represents methoxy;
    R _y and R _z both represent a hydrogen atom;
    R _aa represents a hydrogen atom;
    Y represents the bond;
    The morphinan derivative according to claim 82, an optical isomer thereof, or a salt thereof, wherein R _{bb represents benzyl.}
92. R ⁵ represents a hydrogen atom;
    R ⁶ represents hydroxy;
    R _y and R _z both represent a hydrogen atom;
    R _aa represents a hydrogen atom;
    Y represents C = O;
    R _bb is 6-oxo-1,6-representative dihydropyridine-2-yl, morphinan derivatives or optical isomers thereof, or salts thereof according to claim 82.