TW202003522A - Process for preparation of morphinan derivatives - Google Patents

Abstract

Process for the preparation of a compound represented by following general formula by a dealkylation reaction using a boron trifluoride complex (in the formula, R¹ is C_1-10 alkyl group or the like, R² is C_1-10 alkyl group or the like, R³ is hydrogen atom or the like, R⁴ is hydrogen atom or the like, R⁵ and R⁶ may be the same or different, and is hydrogen atom or the like, R⁷ and R⁸ may be the same or different, and is hydrogen atom or the like, R⁹ , R¹⁰ and R¹¹ may be the same or different, and is hydrogen atom, C_1-10 alkyl group or the like, R¹² is -C(=O)OR¹³ group, -C(=O)-R¹⁴ group, -C(=O)NR²⁰ R²¹ group or the like).

Description

Method for manufacturing morphinan derivatives

The invention relates to a method for manufacturing a morphinan derivative having a butylorphane skeleton. This application claims priority based on Japanese Patent Application No. 2018-68325, which has been filed in Japan on March 30, 2018, and the contents are invoked here.

Background technique Buprenorphine is an opioid partial agonist for opioid receptors, and is a compound used for analgesia and treatment of opioid addiction. As an analgesic, it was first marketed by Reckitt & Colman, and for the treatment of opioid addiction, it is a compound whose high dosage lozenges have been approved by the US Food and Drug Administration (FDA).

[Chemical Formula 1]

Derivatives using butylorphine as the lead compound are still interesting objects in the field of medicinal chemistry. For example, Non-Patent Document 1 reports the 7-position conversion of butylorphine. There are many others Discussions are ongoing. Among them, butylorphine in particular has attracted attention because the hydroxyl group at the 6-position of the skeleton is used as the introduction position of the 18F modified functional group used to create PET ligands. For example, Non-Patent Document 2 and Non-Patent Document 3 have reported on the synthesis and properties of PET ligand [18F] FBPN, etc. with an 18F ethyl group introduced at the 6-position of butylorphanine skeleton.

[Chemical Formula 2]

In addition, Non-Patent Document 4 also reports the synthesis of PET ligands with an 11C methyl group introduced at the 6-position of the butylorphanine skeleton in the same way. Furthermore, in Non-Patent Document 5, Srivastava et al. introduced an amine alkyl substituent at the 6-position of the butylorphanine skeleton, and then modified the amine group as a pedal, and reported the birth of the butylorphanine skeleton. Synthesis and application of chemical tools.

[Chemical Formula 3]

In addition, Kyle et al. disclosed in Patent Document 1 the synthesis of a derivative having a polyether functional group introduced at the 6-position of a butylorphanine skeleton for the purpose of a pain treatment drug. For the synthesis of these modified derivatives of butylorphine at the 6-position of the backbone, it is indispensable to prepare a compound (A) in which the 6-position hydroxyl group is unprotected and only the phenolic hydroxyl group is protected as a precursor.

[Chemical Formula 4]

In the above-mentioned patent documents and non-patent documents, there are many cases where the following method is adopted: after the intermediate product having 2 hydroxyl groups (6-position hydroxyl group, phenolic hydroxyl group) in the butylorphanine skeleton is prepared, and then selectively only Protect phenolic hydroxyl groups.

[Chemical Formula 5]

At this time, the reagent used to remove the methyl group of the tertiary alcohol must use LiAlH ₄ , boron tribromide and other reagents that require severe conditions and highly toxic and dangerous reagents, which are difficult to apply in industrial production. on.

It is known that there are several subtypes of opioid receptors such as μ, δ, κ and ε. Morphine, which shows a strong affinity for the μ receptor, has been used as an analgesic since ancient times. However, opioid μ receptor agonists are known to cause harmful phenomena such as addiction and respiratory depression via the μ receptor. On the other hand, it is known that although the delta receptor effector also has analgesic effects, it is not involved in the harmful phenomena that can be seen in morphine. Therefore, the delta receptor selective agonist is expected as an excellent analgesic.

For compounds having delta receptor selective agonist activity, for example, Patent Document 2 has reported compounds represented by the following formula (B).

[Chemical Formula 6]

In addition, Patent Document 3 reports a compound represented by the following formula (C).

[Chemical Formula 7]

Since these derivatives have high delta receptor selectivity and analgesic effects, they are expected to be applied to analgesics and other drugs.

In these reports, the intermediate product (j) with the butylorphine skeleton was set as the intermediate product for the final purpose. It can be said that (j) corresponds to the 6-position hydroxyl group which is unprotected and contains only phenol The compound of the aforementioned (A) in which the protective hydroxyl group is protected. The preparation method here is also as described in paragraph [0023] of Patent Document 2. The boron tribromide acts on (h) to remove the methyl groups of two hydroxyl groups at a time to form a dihydroxy compound (i). (J) is prepared by reprotecting only the phenolic hydroxyl group. That is, in order to obtain (j), two steps are required, that is, after the two methyl groups of (h) are completely removed at once, only the phenolic hydroxyl group is selectively reprotected.

[Chemical Formula 8]

Since the production of morphinan derivatives requires more stages of reaction than Patent Document 2, it becomes very important to produce each intermediate product in the shortest possible process and at a high yield, and it takes 2 to obtain (j) from (h) above. This step is obviously very economically disadvantageous. Therefore, this problem can be solved by developing a reaction path that can directly remove the methyl group of non-phenolic hydroxyl group from the two methoxy groups of (h) and directly obtain (j) in one step. It can be said to suggest a very useful methodology for these fields.

For such a selective demethylation reaction, for example, Non-Patent Document 4 reports a method represented by the following formula.

[Chemical Formula 9]

In addition, as far as the conventional technology is concerned, although the demethylation reaction from the alkoxy group using hydrochloric acid at a high temperature is known, as for the derivative having a butylorphanine skeleton, it also proceeds The ring-opening reaction of the basic skeleton makes it impossible to obtain the target compound. In this way, due to the extremely high reactivity of the reagents used in these reactions, and the presence of other functional groups in the compound, in addition to the demethylation reaction of the purpose, side reactions that damage the other functional groups will proceed and the purpose cannot be obtained. Compounds and other issues can be applied to the reaction of the compound is limited and lacks versatility. Therefore, in terms of the production method of the intermediate product (A) or (j) for the production of butylorphanine derivatives, it is hoped to develop a method that can be used under mild conditions with universality and high yield from bonding to tertiary carbon The alkoxy group is selectively dealkylated without damaging the alkyl group protecting the phenolic hydroxyl group, and requires only one step. Advanced technical literature Patent Literature

[Patent Literature 1] International Publication No. 2012/038813 [Patent Literature 2] International Publication No. 2013/035833 [Patent Document 3] International Publication No. 2014/136305 Non-patent literature

[Non-Patent Document 1] HELVETICA CHMICA ACTA Vol. 83, 3122-3130 [Non-Patent Document 2] J. Med. Chem, 57, 5464-5469. 2014 [Non-Patent Document 3] Molecules, 18, 7271-7278. 2013 [Non-Patent Document 4] Tetrahedron Letters, 28(35), 4015-18. 1987 [Non-Patent Document 5] Tetrahedron, 72(40), 6127-6135. 2016 [Non-Patent Document 6] Protective Groups in Organic Synthesis, 1991

Summary of the invention Problems to be solved by invention The object of the present invention is to provide an intermediate product manufacturing method for manufacturing a morphinan derivative having a butylorphanine skeleton. Means to solve the problem

Based on the above facts, the inventors of the present application have carefully discussed the aforementioned intermediate product manufacturing method, and found that the boron trifluoride complex can be selectively used from the bond to the tertiary carbon by using a boron trifluoride complex in a suitable solvent. The alkoxy group undergoes a dealkylation reaction without compromising the alkyl group protecting the phenolic hydroxyl group, and finally the present invention is completed. [1] That is, one aspect of the present invention relates to a method for producing a compound represented by the following general formula (II), which includes the step of reacting the following compound (I) with boron trifluoride complex in a solvent;

(式中，R¹ 、R³ ~R¹² 同後所示)； [化學式10]

(式中，R¹ 表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之環烷基烷基(環烷基部分之碳原子數為3~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之雜芳烷基(雜芳基包含選自N、O及S中之至少1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)、可具有取代基之C_3-6 環烷基、可具有取代基之C_2-6 烯基、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)； R² 表示可具有取代基之C_1-10 烷基、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之雜芳烷基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)或可具有取代基之C_2-6 烯基； R³ 表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之環烷基烷基(環烷基部分之碳原子數為3~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之雜芳烷基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)、可具有取代基之C_2-6 烯基、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)； R⁴ 表示氫原子、可具有取代基之C_1-10 烷基、-OR²² 基(R²² 表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之芳基或可具有取代基之C_1-6 烷醯基)、鹵素原子、氰基、胺甲醯基、可具有取代基之醯基、硝基及可具有取代基之胺基； R⁵ 及R⁶ 相同或互異，表示氫原子、氟原子或羥基； R⁷ 及R⁸ 相同或互異，表示氫原子、氟原子或羥基，或者，R⁷ 及R⁸ 與其所鍵結之碳共同表示羰基)； R⁹ 、R¹⁰ 、R¹¹ 相同或互異，表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_3-6 環烷基、可具有取代基之環烷基烷基(環烷基部分之碳原子數為3~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之雜芳烷基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)，或者，R⁹ 與R¹⁰ 鍵結而表示可具有取代基之C_3-6 飽和烴環，R⁹ 及R¹⁰ 中任一者與R¹¹ 鍵結而表示可具有取代基之C_3-6 飽和烴環或可具有取代基之C_3-6 環烯烴； R¹² 表示-C(=O)OR¹³ 基(R¹³ 表示氫原子、可具有取代基之C_1-10 烷基或羧基保護基)、-C(=O)-R¹⁴ 基(R¹⁴ 表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5))、-OR¹⁵ 基(R¹⁵ 表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_3-6 環烷基、可具有取代基之芳基、可具有取代基之雜芳基或羥基保護基)、-NR¹⁶ R¹⁷ 基(R¹⁶ 與R¹⁷ 可相同或互異，表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_3-6 環烷基、可具有取代基之C_6-10 芳基、可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5))、或胺基保護基、-C(OR¹⁵ )R¹⁸ R¹⁹ 基(R¹⁸ 與R¹⁹ 可相同或互異，表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_3-6 環烷基、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基)、或-C(NR¹⁶ R¹⁷ )R¹⁸ R¹⁹ 基(R¹⁶ 、R¹⁷ 、R¹⁸ 、R¹⁹ 同前所示)、-C(=O)NR²⁰ R²¹ 基(R²⁰ 與R²¹ 相同或互異，表示氫原子、可具有取代基之C_1-10 烷基、可具有取代基之C_3-6 環烷基、可具有取代基之環烷基烷基(環烷基部分之碳原子數為3~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之雜芳烷基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)、可具有取代基之C_2-6 烯基、可具有取代基之芳烯基(芳基部分之碳原子數為6~10，烯基部分之碳原子數表示2~6)、可具有取代基之雜芳烯基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，烯基部分之碳原子數表示2~6)、可具有取代基之環烷基烯基(環烷基部分之碳原子數為3~6，烯基部分之碳原子數表示2~6)、可具有取代基之C_4-6 環烯基、可具有取代基之環烯基烷基(環烯基部分之碳原子數為4~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之環烯基烯基(環烯基部分之碳原子數為4~6，烯基部分之碳原子數表示2~6)、可具有取代基之芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)；或者，R²⁰ 與R²¹ 鍵結而表示可具有取代基且4~8員環之環狀胺基，或，R²⁰ 及R²¹ 中任一者可與R⁹ 、R¹⁰ 及R¹¹ 中任一者共同形成可具有取代基之內醯胺環)。 [2]本發明之另一態樣有關前述[1]之製造方法，其中R¹ 為選自下列之取代基：可具有取代基之C_1-10 烷基、可具有取代基之環烷基烷基(環烷基部分之碳原子數為3~6，伸烷基部分之碳原子數表示1~5)、可具有取代基之芳烷基(芳基部分之碳原子數為6~10，伸烷基部分之碳原子數表示1~5)、可具有取代基之C_2-6 烯基、可具有取代基之C_6-10 芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)。 [3]本發明之另一態樣有關前述[1]或[2]之製造方法，其中R⁴ 為氫原子或鹵素原子。 [4]本發明之另一態樣有關前述[1]至[3]中任一項之製造方法，其中R⁵ 及R⁶ 為氫原子。 [5]本發明之另一態樣有關前述[1]至[4]中任一項之製造方法，其中R⁷ 及R⁸ 為氫原子。 [6]本發明之另一態樣有關前述[1]至[5]中任一項之製造方法，其中R⁹ 為氫原子、可具有取代基之C_1-10 烷基、可具有取代基之環烷基、可具有取代基之芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)。 [7]本發明之另一態樣有關前述[1]至[6]中任一項之製造方法，其中R¹⁰ 為氫原子、可具有取代基之C_1-10 烷基、可具有取代基之環烷基、可具有取代基之芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)。 [8]本發明之另一態樣有關前述[1]至[7]中任一項之製造方法，其中R¹¹ 為氫原子、可具有取代基之C_1-10 烷基、可具有取代基之環烷基、可具有取代基之芳基或可具有取代基之雜芳基(雜芳基包含選自N、O及S中之1~4個雜原子作為環構成原子，伸烷基部分之碳原子數表示1~5)。 [9]本發明之另一態樣有關前述[1]至[8]中任一項之製造方法，其中R¹² 為-C(=O)OR¹³ 基、-C(=O)-R¹⁴ 基、-OR¹⁵ 基、-NR¹⁶ R¹⁷ 基、-C(OH)R¹⁸ R¹⁹ 基、-C(NR¹⁶ R¹⁷ )R¹⁸ R¹⁹ 基或-C(=O)NR²⁰ R²¹ 基(R¹³ ~R²⁰ 及R²¹ 同前所示)。 [10]本發明之另一態樣有關前述[1]至[9]中任一項之製造方法，其中R³ 為可具有取代基之C_1-10 烷基。 [11]本發明之另一態樣有關前述[1]至[10]中任一項之製造方法，其中R² 為可具有取代基之C_1-10 烷基。 [12]本發明之另一態樣有關前述[1]至[11]中任一項之製造方法，其中前述通式(II)所示化合物係選自下列編號1~48所示化合物之化合物或其鹽。 [化學式12]

[化學式13]

[化學式14]

[化學式15]

[化學式16]

[化學式17]

[化學式18]

[化學式19]

[化學式20]

[化學式21]

[13]本發明之另一態樣有關前述[1]至[12]中任一項之製造方法，其中前述通式(I)所載化合物為酸加成鹽之形態。 [14]本發明之另一態樣有關前述[13]之製造方法，其中如前述[13]之酸加成鹽選自礦酸類、有機羧酸類或磺酸類。 [15]本發明之另一態樣有關前述[13]或[14]之製造方法，其中如前述[13]或[14]之酸加成鹽選自鹽酸、硫酸、甲酸、草酸、乙酸、檸檬酸、三氯乙酸、三氟乙酸、順丁烯二酸、反丁烯二酸、甲磺酸、苯磺酸、對甲苯磺酸、均三甲苯磺酸或萘磺酸。 [16]本發明之另一態樣有關前述[1]至[15]中任一項之製造方法，其中如前述[1]之三氟化硼錯合物選自三氟化硼-醚錯合物、三氟化硼-水錯合物、三氟化硼-醇錯合物、三氟化硼-胺錯合物、三氟化硼-酚錯合物、三氟化硼-硫化物錯合物、三氟化硼-亞碸錯合物、三氟化硼-羧酸錯合物或三氟化硼-磷酸錯合物等。 [17]本發明之另一態樣有關前述[16]之製造方法，其中如前述[16]之三氟化硼錯合物選自三氟化硼-醚錯合物、三氟化硼-醇錯合物或三氟化硼-羧酸錯合物。 [18]本發明之另一態樣有關前述[1]至[17]中任一項之製造方法，其使用相對於前述化合物(I)為1~50重量倍之三氟化硼錯合物。 [19]本發明之另一態樣有關前述[1]至[18]中任一項之製造方法，其中前述溶劑選自羧酸類、羧酸酯類、醇類、烴類、鹵烷類、腈類、醚類、酮類、醯胺類、亞碸類、脲類或碳酸酯類。 [20]本發明之另一態樣有關前述[19]之製造方法，其中前述溶劑選自羧酸類、烴類、腈類或醚類。 [21]本發明之另一態樣有關前述[19]或[20]之製造方法，其中前述溶劑選自乙酸、乙腈、甲苯或二甲苯。 [22]本發明之另一態樣有關前述[1]至[21]中任一項之製造方法，其使前述化合物(I)與三氟化硼錯合物於溶劑中反應時之反應溫度為20~150℃之範圍。 [23]本發明之另一態樣有關前述通式(I)所示化合物之酸加成鹽。 發明效果[Chemical Formula 11]

(In the formula, R ¹ and R ³ ~R ^{12 are the} same as shown later); [Chemical formula 10]

(In the formula, R ¹ represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms of the cycloalkyl portion is 3 to 6, and the alkylene portion The number of carbon atoms represents 1 to 5), the aralkyl group which may have a substituent (the number of carbon atoms of the aryl portion is 6 to 10, and the number of carbon atoms of the alkylene portion represents 1 to 5), which may have a substituent Heteroaralkyl (heteroaryl contains at least 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5), C which may have a substituent _3-6 cycloalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _6-10 aryl, or optionally substituted heteroaryl (heteroaryl includes selected from N, O and 1 to 4 heteroatoms in S are used as ring constituent atoms, and the number of carbon atoms in the alkylene extension means 1 to 5); R ² represents a C _1-10 alkyl group which may have a substituent, and an aralkyl which may have a substituent Group (the number of carbon atoms in the aryl part is 6~10, and the number of carbon atoms in the alkylene part represents 1~5), heteroaralkyl which may have a substituent (heteroaryl includes selected from N, O and S 1 to 4 heteroatoms are used as ring constituent atoms, the number of carbon atoms in the alkylene moiety represents 1 to 5) or C _2-6 alkenyl which may have a substituent; R ³ represents a hydrogen atom, C which may have a substituent _1-10 alkyl groups, cycloalkylalkyl groups which may have substituents (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), aromatic groups which may have substituents Alkyl groups (the number of carbon atoms in the aryl group is 6-10, and the number of carbon atoms in the alkylene group represents 1~5), heteroaralkyl groups that may have substituents (heteroaryl groups include selected from N, O, and S Among them, 1 to 4 heteroatoms are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), C _2-6 alkenyl which may have a substituent, C _6-10 aryl which may have a substituent Or a heteroaryl group which may have a substituent (the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5); R ⁴ Represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, -OR ²² group (R ²² represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, an aryl group which may have a substituent, or may have a substitution C _1-6 alkyl amide group), halogen atom, cyano group, amine methyl amide group, optionally substituted acetyl group, nitro group and optionally substituted amine group; R ⁵ and R ^{6 are the} same or different , Represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁷ and R ^{8 are the} same or different from each other, represent a hydrogen atom, a fluorine atom or a hydroxyl group, or R ⁷ and R ⁸ together with the carbon to which they are bonded represent a carbonyl group); R ⁹ , R ¹⁰ and R ^{11 are the} same or different from each other, and represent a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C _3-6 cycloalkyl group that may have a substituent, and a cycloalkyl alkyl group that may have a substituent ( The number of carbon atoms in the cycloalkyl moiety is 3~6, and the number of carbon atoms in the alkylene moiety indicates 1~5), aralkyl group (aryl moiety) which may have a substituent The number of carbon atoms is 6~10, and the number of carbon atoms in the alkylene portion represents 1~5), heteroaralkyl groups which may have substituents (heteroaryl groups include 1~4 selected from N, O and S Heteroatoms as ring-forming atoms, the number of carbon atoms in the alkylene moiety represents 1 to 5), a C _6-10 aryl group which may have a substituent, or a heteroaryl group which may have a substituent (the heteroaryl group includes a member selected from N 1 to 4 heteroatoms in O, S are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), or R ⁹ and R ^{10 are} bonded to represent C _{3- which} may have a substituent ₆ saturated hydrocarbon ring, any one of R ⁹ and R ¹⁰ is bonded to R ¹¹ to represent a C _3-6 saturated hydrocarbon ring which may have a substituent or a C _3-6 cycloalkene which may have a substituent; R ¹² represents- C(=O)OR ¹³ group (R ¹³ represents a hydrogen atom, a C _1-10 alkyl group or a carboxyl protecting group which may have a substituent), -C(=O)-R ¹⁴ group (R ¹⁴ represents a hydrogen atom, may C _1-10 alkyl group with substituents, C _6-10 aryl group with substituents or heteroaryl group with substituents (heteroaryl groups include 1 to 4 hetero groups selected from N, O and S Atoms are ring-constituting atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5)), -OR ¹⁵ groups (R ¹⁵ represents a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C group that may have a substituent _3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or hydroxy protecting group), -NR ¹⁶ R ¹⁷ group (R ¹⁶ and R ¹⁷ may be the same or different from each other, indicating 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 (heteroaryl Contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5)), or an amine protecting group, -C(OR ¹⁵ )R ¹⁸ R ¹⁹ group (R ¹⁸ and R ¹⁹ may be the same or different from each other, and represent a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C _3-6 cycloalkyl group that may have a substituent, a C that may have a substituent _6-10 aryl or heteroaryl which may have a substituent), or -C (NR ¹⁶ R ¹⁷ ) R ¹⁸ R ¹⁹ group (R ¹⁶ , R ¹⁷ , R ¹⁸ , R ^{19 are the} same as shown above), -C (=O)NR ²⁰ R ²¹ group (R ²⁰ is the same as or different from R ²¹ and represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, may Cycloalkylalkyl groups with substituents (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), aralkyl groups that may have substituents (the aryl portion The number of carbon atoms is 6~10, and the number of carbon atoms in the alkylene moiety represents 1~5), heteroaralkyl groups which may have substituents (heteroaryl groups include 1 to 4 hetero groups selected from N, O and S Atoms as rings constitute atoms, alkylene The number of carbon atoms in the base portion represents 1 to 5), C _2-6 alkenyl group which may have a substituent, aralkenyl group which may have a substituent (the carbon number of the aryl portion is 6 to 10, the carbon of the alkenyl portion The number of atoms represents 2 to 6), a heteroarylalkenyl group which may have a substituent (the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkenyl part represents 2~6), cycloalkylalkenyl which may have a substituent (the number of carbon atoms in the cycloalkyl portion is 3-6, and the number of carbon atoms in the alkenyl portion represents 2-6), C _4- which may have a substituent ₆ cycloalkenyl, cycloalkenyl alkyl which may have a substituent (the number of carbon atoms in the cycloalkenyl part is 4 to 6, and the number of carbon atoms in the alkylene part represents 1 to 5), cycloalkene which may have a substituent Alkenyl (the number of carbon atoms in the cycloalkenyl part is 4 to 6, and the number of carbon atoms in the alkenyl part represents 2 to 6), aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl Contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5); or, R ²⁰ and R ^{21 are} bonded to indicate that they may have a substituent In addition, a cyclic amine group having 4 to 8 member rings, or any one of R ²⁰ and R ²¹ may be combined with any one of R ⁹ , R ¹⁰ and R ¹¹ to form an internal amide ring which may have a substituent). [2] Another aspect of the present invention relates to the manufacturing method of the aforementioned [1], wherein R ¹ is a substituent selected from the group consisting of a C _1-10 alkyl group which may have a substituent, and a cycloalkyl group which may have a substituent Alkyl groups (the number of carbon atoms in the cycloalkyl part is 3~6, and the number of carbon atoms in the alkylene part represents 1~5), aralkyl groups which may have substituents (the number of carbon atoms in the aryl part is 6~10) , The number of carbon atoms in the alkylene moiety represents 1 to 5), a C _2-6 alkenyl group that may have a substituent, a C _6-10 aryl group that may have a substituent, or a heteroaryl group that may have a substituent (heteroaryl) The group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5). [3] Another aspect of the present invention relates to the manufacturing method of the aforementioned [1] or [2], wherein R ⁴ is a hydrogen atom or a halogen atom. [4] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [3], wherein R ⁵ and R ⁶ are hydrogen atoms. [5] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [4], wherein R ⁷ and R ⁸ are hydrogen atoms. [6] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [5], wherein R ⁹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, alkylene moiety The number of carbon atoms represents 1~5). [7] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [6], wherein R ¹⁰ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, alkylene moiety The number of carbon atoms represents 1~5). [8] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [7], wherein R ¹¹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, which may have a substituent Cycloalkyl, aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, alkylene moiety The number of carbon atoms represents 1~5). [9] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [8], wherein R ¹² is -C(=O)OR ¹³ group, -C(=O)-R ¹⁴ Group, -OR ¹⁵ group, -NR ¹⁶ R ¹⁷ group, -C(OH)R ¹⁸ R ¹⁹ group, -C(NR ¹⁶ R ¹⁷ )R ¹⁸ R ¹⁹ group or -C(=O)NR ²⁰ R ²¹ group (R ¹³ ~R ²⁰ and R ^{21 are the} same as before). [10] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [9], wherein R ³ is a C _1-10 alkyl group which may have a substituent. [11] Another aspect of the present invention relates to the production method of any one of the aforementioned [1] to [10], wherein R ² is a C _1-10 alkyl group which may have a substituent. [12] Another aspect of the present invention relates to the production method of any one of the aforementioned [1] to [11], wherein the compound represented by the general formula (II) is a compound selected from the following compounds represented by Nos. 1 to 48 Or its salt. [Chemical Formula 12]

[Chemical Formula 13]

[Chemical Formula 14]

[Chemical Formula 15]

[Chemical Formula 16]

[Chemical Formula 17]

[Chemical Formula 18]

[Chemical Formula 19]

[Chemical Formula 20]

[Chemical Formula 21]

[13] Another aspect of the present invention relates to the production method of any one of the aforementioned [1] to [12], wherein the compound contained in the aforementioned general formula (I) is in the form of an acid addition salt. [14] Another aspect of the present invention relates to the manufacturing method of the aforementioned [13], wherein the acid addition salt as described in the aforementioned [13] is selected from mineral acids, organic carboxylic acids or sulfonic acids. [15] Another aspect of the present invention relates to the manufacturing method of the aforementioned [13] or [14], wherein the acid addition salt as described in the aforementioned [13] or [14] is selected from hydrochloric acid, sulfuric acid, formic acid, oxalic acid, acetic acid, Citric acid, trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid. [16] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [15], wherein the boron trifluoride complex as described in the aforementioned [1] is selected from boron trifluoride-ether complex Compound, boron trifluoride-water complex, boron trifluoride-alcohol complex, boron trifluoride-amine complex, boron trifluoride-phenol complex, boron trifluoride-sulfide Complex, boron trifluoride-sulfonate complex, boron trifluoride-carboxylic acid complex or boron trifluoride-phosphate complex, etc. [17] Another aspect of the present invention relates to the manufacturing method of the aforementioned [16], wherein the boron trifluoride complex of the aforementioned [16] is selected from boron trifluoride-ether complex, boron trifluoride- Alcohol complex or boron trifluoride-carboxylic acid complex. [18] Another aspect of the present invention relates to the manufacturing method of any one of the aforementioned [1] to [17], which uses a boron trifluoride complex of 1 to 50 times the weight of the compound (I) . [19] Another aspect of the present invention relates to the production method of any one of the aforementioned [1] to [18], wherein the aforementioned solvent is selected from carboxylic acids, carboxylic acid esters, alcohols, hydrocarbons, haloalkanes, Nitriles, ethers, ketones, amides, sulfonamides, ureas or carbonates. [20] Another aspect of the present invention relates to the manufacturing method of the aforementioned [19], wherein the aforementioned solvent is selected from carboxylic acids, hydrocarbons, nitriles or ethers. [21] Another aspect of the present invention relates to the manufacturing method of the aforementioned [19] or [20], wherein the aforementioned solvent is selected from acetic acid, acetonitrile, toluene or xylene. [22] Another aspect of the present invention relates to the production method of any one of the aforementioned [1] to [21], which is a reaction temperature when the aforementioned compound (I) and boron trifluoride complex are reacted in a solvent It is in the range of 20~150℃. [23] Another aspect of the present invention relates to an acid addition salt of the compound represented by the aforementioned general formula (I). Invention effect

The present invention uses boron trifluoride complex and utilizes selective dealkylation reaction from morphinan derivative (I) to produce compound (II), which requires 2 steps, 1 In this step, the target compound can be obtained in high yield and shows a high degree of versatility, and it can be widely used in the production of morphinan derivatives.

(式中，R¹ ~R¹² 同前所示，L表示鹵素原子(例如溴原子、碘原子)、甲磺醯氧基或對甲苯磺醯氧基等脫離基)。[Chemical Formula 22]

(In the formula, R ¹ to R ^{12 are} as described above, and L represents a halogen atom (for example, bromine atom, iodine atom), mesyloxy group, p-toluenesulfonyloxy group, or other leaving group).

The form for carrying out the invention will be explained in more detail as follows. Among the morphinan derivatives represented by the above general formulas (I) and (II), tautomers, stereoisomers of the compounds or pharmaceutically acceptable salts thereof or solvates thereof, preferably Those can be listed as follows. In addition, stable isotopes such as deuterium and ¹³ C are also included. ^{R 1 ~ R 4, R 9} ~ R 11 and R ¹³ group shown may have a substituent of C _1-10 alkyl, C _1-10 alkyl may be cited methyl, ethyl, n-propyl, isopropyl, Straight-chain or branched-chain alkyl groups such as alkyl, n-butyl, isobutyl, tertiary butyl, pentyl, hexyl, heptyl or octyl, and preferably C _1-6 alkyl, more preferably such as C _1-3 alkyl, more preferably methyl. In addition, such alkyl groups may be deuterated. Examples of deuterated alkyl groups include methyl-d3, ethyl-1,1-d2, and ethyl-d5. The substituent in the aforementioned alkyl group may be as described in paragraph [0054], but is preferably exemplified by a hydroxyl group or a halogen atom (more preferably a fluorine atom), for example, 2-fluoroethyl, 3-fluoropropyl, 4- Fluorobutyl, 2-hydroxyethyl or trifluoromethyl.

_Among the C _3-6 cycloalkyl groups which may have substituents represented by R ¹ , R ⁹ to R ¹¹ , R ¹⁵ to R ²⁰ and R ²¹ , C _3-6 cycloalkyl groups may be exemplified by cyclopropyl and cyclobutyl , Cyclopentyl or cyclohexyl, etc., and preferably such as cyclopropyl.

R ¹ , R ³ , R ⁹ to R ¹¹ , R ²⁰ and R ²¹ may have a substituted cycloalkylalkyl group (the number of carbon atoms of the cycloalkyl portion is 3 to 6, the carbon atoms of the alkylene portion The numbers represent 1 to 5). The cycloalkylalkyl group may include methyl and ethyl groups substituted with C _3-6 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl groups, and the Examples thereof include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl or cyclobutylethyl, and more preferred examples include cyclopropylmethyl. In addition, the cycloalkylalkyl group may be deuterated, and examples thereof include (cyclopropyl-d5)methyl or cyclopropylmethyl-d2 groups.

^In the cycloalkylalkenyl group which may have a substituent represented by R ²⁰ and R ²¹ (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkenyl portion represents 2 to 6), the cycloalkylalkenyl group Examples thereof include 2-propenyl or 3-methyl-2-butenyl substituted with C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

^In the cycloalkenyl alkyl group which may have a substituent represented by R ²⁰ and R ²¹ (the number of carbon atoms in the cycloalkenyl portion is 4 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), the cycloalkenyl alkyl group Examples of the group include methyl or ethyl substituted with cyclopentenyl or cyclohexenyl.

Among the optionally substituted cycloalkenylalkenyl groups represented by R ²⁰ and R ²¹ (the number of carbon atoms in the cycloalkenyl portion is 4 to 6, and the number of carbon atoms in the alkenyl portion represents 2 to 6), the cycloalkenyl alkenyl group Examples include 2-propenyl or 3-methyl-2-butenyl substituted with cyclopentenyl or cyclohexenyl.

R ¹ ~R ³ , R ⁹ ~R ¹¹ , R ²⁰ and R ²¹ may be substituted aralkyl groups (the number of carbon atoms in the aryl part is 6~10, and the number of carbon atoms in the alkylene part indicates 1 In ~5), the aralkyl group can be exemplified by methyl or ethyl substituted with phenyl or naphthyl, etc., and preferably exemplified by methyl substituted with phenyl.

The arylalkenyl group which may have a substituent represented by R ²⁰ and R ²¹ (the carbon number of the aryl part is 6-10, and the carbon number of the alkenyl part represents 2-6), the arylalkenyl group may be exemplified by benzene 2-propenyl or 3-methyl-2-butenyl substituted with alkyl or naphthyl.

R ¹ to R ³ , R ⁹ to R ¹¹ , R ²⁰ and R ²¹ may have a heteroaralkyl group which may have a substituent (the heteroaryl group contains 1 to 4 hetero atoms selected from N, O and S as a ring Constituent atoms, the number of carbon atoms in the alkylene extending portion is 1~5), heteroaralkyl groups can be exemplified by: the ring of heteroaryl group constitutes (pyridin-2-yl)methyl group having 5-10 atoms, ( Pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 2-(pyridin-2-yl)ethyl, (furan-2-yl)methyl, (furan-3-yl)methyl , (Imidazol-2-yl)methyl, (imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl, (thiazol-4-yl)methyl , (Thiazol-5-yl)methyl, (thiophen-2-yl)methyl, 2-(thiophen-2-yl)ethyl or (1H-tetrazol-5-yl)methyl and other monocyclic heteroarane Groups; and bicyclic heteroaralkyl groups such as (quinolin-3-yl)methyl or (indol-3-yl)methyl.

The heteroarylalkenyl group which may have a substituent represented by R ²⁰ and R ²¹ (the heteroaryl group contains 1 to 4 hetero atoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkenyl part represents 2 In ~6), the heteroarylalkenyl group includes 2-propenyl or 3-methyl-2-butenyl substituted with pyridyl, furyl, imidazolyl, or thiazolyl.

_Among the C _4-6 cycloalkenyl groups which may have a substituent represented by R ²⁰ and R ²¹ , the C _4-6 cycloalkenyl group is preferably cyclopentenyl or cyclohexenyl.

_Among the C _2-6 alkenyl groups which may have a substituent represented by R ¹ to R ³ , R ²⁰ and R ²¹ , the C _2-6 alkenyl group may be exemplified by 2-propenyl or 3-methyl-2-butenyl Etc., and preferably such as 2-propenyl.

In the C _3-6 saturated hydrocarbon ring which may be substituted by R ⁹ and R ¹⁰ , or any of R ⁹ and R ¹⁰ bonded to R ¹¹ , the C _3-6 saturated hydrocarbon ring may be exemplified by cyclopropane Ring, cyclobutane ring, cyclopentane ring or cyclohexane ring, etc.

R ²⁰ or R ²¹ and any one of R ⁹ , R ¹⁰ and R ¹¹ may form an internal amide ring which may have a substituent, and the internal amide ring may be exemplified by δ-lactam or γ-lactam .

R ⁹ and R ¹⁰ and any one of R ¹¹ may be bonded to form the cyclic olefin having _3-6 substituents of the group C, C _3-6 cyclic olefins such as cyclopentene, may be cited cyclohexene or the like.

_Among the C _6-10 aryl groups which may have a substituent represented by R ¹ , R ³ , R ⁹ to R ¹¹ , R ¹⁴ to R ²⁰ and R ²¹ , the C _6-10 aryl group may be phenyl or naphthyl, etc. .

基或噻唑基等單環雜芳基；以及喹啉基或吲哚基等二環雜芳基。Among the heteroaryl groups which may have substituents represented by R ¹ , R ³ , R ⁹ to R ¹¹ , R ¹⁴ to R ²⁰ and R ²¹ , the heteroaryl group (heteroaryl group includes 1 selected from N, O and S ~4 heteroatoms as ring constituent atoms) can be exemplified by pyridyl, furanyl, imidazolyl, pyrimidinyl, pyridine with 5 to 10 ring constituent atoms

Monocyclic heteroaryl groups such as alkyl or thiazolyl; and bicyclic heteroaryl groups such as quinolinyl or indolyl.

基或

啉基等環狀胺基。Among the cyclic amine groups having 4 to 8 member rings formed by bonding R ²⁰ and R ²¹ , the cyclic amine groups having 4 to 8 member rings can be exemplified by acryl, pyrrolidyl, piper

Base or

Cyclic amine groups such as porphyrinyl.

Among the acyl groups which may have a substituent shown by R ⁴ and R ²² , the acyl group may be exemplified by acetyl, propyl, or benzoyl.

The halogen atom represented by R ⁴ may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom, more preferably a fluorine atom.

The amine protecting groups represented by R ¹⁶ , R ¹⁷ , R ²⁰ and R ²¹ can be exemplified by general conventional materials (for example, the amine protecting group described in Non-Patent Document 6), and examples thereof include acetyl group and trifluoroacetyl group , Tertiary butoxycarbonyl, tertiary pentoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzylcarbonyl, p-nitrobenzyloxycarbonyl, p-benzene Azobenzyloxycarbonyl, p-methoxyphenylazobenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxy Carbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, p-biphenylisopropyloxycarbonyl, diisopropylmethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 9-茀methoxymethoxycarbonyl, benzyl Or p-methoxybenzyl and so on.

The carboxyl protecting group represented by R ¹³ may be a general conventional substance (for example, the carboxyl protecting group described in Non-Patent Document 6), and may be exemplified by methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl C _1-6 alkyl group, tertiary butyl, pentyl, hexyl or heptyl; vinyl, allyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexene C _1-6 alkenyl such as alkyl or 1-heptenyl; aralkyl having 7 to 11 carbons such as benzyl; aryl having 6 to 14 carbons such as phenyl or naphthyl can be hydrolyzed and contacted Removal and removal under isothermal conditions; Acetoxy C _1-6 alkyl such as acetoxymethyl or trimethylacetoxymethyl; methoxycarbonyloxymethyl or 1-ethoxy carbonyloxy ethyl and the like C _1-6 alkoxycarbonyl-C _1-6 alkyl; methoxymethyl and the like C _1-6 alkoxy C _1-6 alkyl; phthalazin lactones lactone group; Di-C _1-6 alkylamino C _1-6 alkyl such as 1-dimethylaminoethyl; and (5-methyl-2-oxo-1,3-diazol-4-yl ) Methyl, etc., and preferably such as C _1-6 alkyl, C _1-6 alkenyl and C _7-11 aralkyl, more preferably such as: methyl, ethyl, n-propyl, isopropyl , C _1-4 alkyl such as n-butyl and isobutyl (except tertiary butyl); C _3-5 alkenyl such as allyl, 1-propenyl and 1-butenyl; and, benzyl, More preferably, it is methyl or ethyl.

The hydroxy-protecting group represented by R ¹⁵ can be a general conventional substance (for example, the hydroxy-protecting group described in Non-Patent Document 6), and examples thereof include benzyl, 4-methoxybenzyl, trityl, etc. which may have a substituent. Aralkyl; acetyl groups such as acetyl; silane groups with substituents such as trimethylsilyl or tertiary butyldimethylsilyl.

The substituents described in this specification can be exemplified by straight-chain or branched C _1-6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl or tertiary butyl groups; fluoromethyl, Halogenated methyl such as difluoromethyl or trifluoromethyl; linear or branched C _1-8 alkoxy such as methoxy, ethoxy, propoxy or isopropoxy; 2-propenyl etc. C _2-6 alkenyl; C _3-8 cycloalkyl such as cyclopropyl or cyclohexyl; C _6-14 aryl such as phenyl; heteroaryl such as pyridyl, furyl or imidazolyl; fluorine atom or chlorine atom Etc. halogen atoms; C _1-6 alkylamine groups, di C _1-6 alkylamine groups or amide groups such as amine groups which may have substituents; amine groups which may have protective groups; methyl acetyl and acetyl Acyl groups such as alkyl, cyclopropylcarbonyl or benzoyl; hydroxyl; guanidino; nitro; cyano, etc.

Among these substituents, the preferred combination of substituents is as follows: R ¹ can be exemplified by a C _1-10 alkyl group which may have a substituent, a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the number of carbon atoms in the alkylene extension means 1 to 5) and its deuterated compounds and C _2-6 acetyl groups which may have substituents; R ² may be exemplified by C _1-10 alkyl groups which may have substituents ; R ³ may be exemplified by a C _1-10 alkyl group which may have a substituent; R ⁴ to R ⁸ may be exemplified by a hydrogen atom; R ⁹ to R ¹¹ may be the same or different from each other, and may be exemplified by a hydrogen atom and may have a substituent The C _1-10 alkyl group is more preferably a hydrogen atom; R ¹² may be exemplified by -C(=O)OR ¹³ group, -C(=O)-R ¹⁴ group, -OR ¹⁵ group, and -C(OR ¹⁵ ) R ¹⁸ R ¹⁹ group, -NR ¹⁶ R ¹⁷ group or -C(=O)NR ²⁰ R ²¹ group, more preferably such as -C(=O)OR ¹³ group, -C(=O)-R ¹⁴ Group, -C(OR ¹⁵ )R ¹⁸ R ¹⁹ group or -C(=O)NR ²⁰ R ²¹ group; R ¹³ , R ¹⁴ , R ¹⁸ , R ¹⁹ and R ²⁰ can be exemplified by hydrogen atom, which may have a substituent C _1-10 alkyl group; R ²¹ can be exemplified by a hydrogen atom, a C _1-10 alkyl group which may have a substituent, an aralkyl group which may have a substituent (the carbon number of the aryl part is 6 to 10 and extends The number of carbon atoms in the alkyl portion represents 1 to 5) and an aryl group which may have a substituent, and may be more specifically exemplified by benzyl amide amino group, amide phenyl group, hydrazide group, -C(OH)Me(tert -Bu), -C(OH)Me ₂ , -C(=O)OEt, -C(OH)MePr, phenethylamide, -CH ₂ OBn, -CH ₂ OH, or -C(OH)MeCF ₃ .

Among these substituents, the more ideal combination of substituents is as follows: R ¹ can be exemplified by hydrogen atom, methyl, cyclopropylmethyl, cyclobutylmethyl and its deuterium compounds and allyl groups; R ² and R ³ can be exemplified Such as methyl; R ⁴ ~R ⁸ can be exemplified by hydrogen atom; R ⁹ ~R ^{11 are the} same or different from each other, can be exemplified by hydrogen atom and C _1-10 alkyl group, more preferably by hydrogen atom; R ¹² can be exemplified by Benzylamide, -C(OH)Me(tert-Bu), -C(OH)Me ₂ , -CH ₂ OH or -C(OH)MeCF _3, etc.

The compound represented by the general formula (I) can be produced by a generally known method, for example, a method described in Patent Document 2, Non-Patent Document 1, or Non-Patent Document 6.

、三氟化硼(氮原子可經取代)

啉及三氟化硼氨等)、三氟化硼-酚錯合物(例如三氟化硼酚、三氟化硼(可具有取代基之)酚等)、三氟化硼-硫化物錯合物(例如三氟化硼二乙硫及三氟化硼二甲硫等)、三氟化硼-亞碸錯合物(例如三氟化硼二甲亞碸錯合物等)、三氟化硼-羧酸錯合物(例如三氟化硼甲酸、三氟化硼乙酸、三氟化硼苯甲酸及三氟化硼酞酸單酯錯合物等)或三氟化硼-磷酸錯合物(例如三氟化硼磷酸等)等；且宜舉如三氟化硼-醚錯合物、三氟化硼-醇錯合物或三氟化硼-羧酸錯合物，較宜舉如三氟化硼二甲醚、三氟化硼二乙醚、三氟化硼二異丙醚、三氟化硼二正丁醚、三氟化硼甲醇、三氟化硼乙醇、三氟化硼丙醇、三氟化硼異丙醇或三氟化硼乙酸，更宜舉如三氟化硼二乙醚。The boron trifluoride complex used in this embodiment can be a commercially available product or a product prepared by a generally known method. Examples of the boron trifluoride complex used in this embodiment include: boron trifluoride-ether complex (for example, boron trifluoride dimethyl ether, boron trifluoride diethyl ether, and boron trifluoride diisopropyl Ether, boron trifluoride di-n-butyl ether, boron trifluoride tertiary butyl methyl ether and boron trifluoride tetrahydrofuran, etc.), boron trifluoride-water complex (such as boron trifluoride monohydrate and trifluoride Boron dihydrate, etc.), boron trifluoride-alcohol complex (e.g. boron trifluoride methanol, boron trifluoride ethanol, boron trifluoride propanol, boron trifluoride isopropanol, boron trifluoride butyl butyl fluoride Alcohol, boron trifluoride isobutanol, boron trifluoride ethylene glycol and boron trifluoride 2-aminoethanol, etc.), boron trifluoride-amine complex (e.g. boron trifluoride dimethylamine, trifluoride Boron fluoride triethylamine, boron trifluoride diisopropylamine, boron trifluoride diisopropylethylamine, boron trifluoride diethylamine, boron trifluoride trimethylamine, boron trifluoride diisopropylethyl Amine, boron trifluoride tributylamine, boron trifluoride (may have substituents) pyridine, boron trifluoride aniline, boron trifluoride N-methylaniline, boron trifluoride N,N-dimethyl Aniline, boron trifluoride diazabicycloundecene, boron trifluoride benzimidazole, boron trifluoride imidazole, boron trifluoride (nitrogen atom can be substituted) pyrrolidine, boron trifluoride (nitrogen atom can Substituted) piperidine, boron trifluoride (nitrogen atom can be substituted) piper

, Boron trifluoride (nitrogen atom can be substituted)

Porphyrin and boron trifluoride ammonia, etc.), boron trifluoride-phenol complex (such as boron trifluoride phenol, boron trifluoride (which may have a substituent) phenol, etc.), boron trifluoride-sulfide complex Compounds (such as boron trifluoride diethyl sulfide and boron trifluoride dimethyl sulfide, etc.), boron trifluoride-sulfonate complex (such as boron trifluoride dimethylsulfide complex, etc.), trifluoro Boron trifluoride-carboxylic acid complex (such as boron trifluoride formic acid, boron trifluoride acetic acid, boron trifluoride benzoic acid, and boron trifluoride phthalate monoester complex, etc.) or boron trifluoride-phosphate triphosphate Compound (for example, boron trifluoride phosphoric acid, etc.), etc.; and, for example, boron trifluoride-ether complex, boron trifluoride-alcohol complex or boron trifluoride-carboxylic acid complex, preferably Examples include boron trifluoride dimethyl ether, boron trifluoride diethyl ether, boron trifluoride diisopropyl ether, boron trifluoride di-n-butyl ether, boron trifluoride methanol, boron trifluoride ethanol, trifluoride Boron propanol, boron trifluoride isopropanol or boron trifluoride acetic acid, more preferably boron trifluoride diethyl ether.

The ideal morphinan derivative (II) of this embodiment can be exemplified by the following compound numbers 1 to 48.

[化學式24]

[化學式25]

[化學式26]

[化學式27]

[化學式28]

[化學式29]

[化學式30]

[化學式31]

[化學式32]

[Chemical Formula 23]

[Chemical Formula 24]

[Chemical Formula 25]

[Chemical Formula 26]

[Chemical Formula 27]

[Chemical Formula 28]

[Chemical Formula 29]

[Chemical Formula 30]

[Chemical Formula 31]

[Chemical Formula 32]

The morphinan derivative (I) as a raw material can use not only a free base but also an acid addition salt. Especially when the salt-free base of the morphinan derivative (I) is foamy amorphous, the volume becomes large and it is often difficult to handle on an industrial scale. Relatively speaking, the morphinan derivative (I) becomes a powdery substance when it is a salt, so it is easier to dispose than a foamy substance and is easy to apply to industrial-scale manufacturing. Examples of acid addition salts include salts with mineral acids such as hydrochloric acid or sulfuric acid; organic carboxylates with formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid, or maleic acid, etc. Salts of acids, etc.; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid or camphorsulfonic acid.

The production of a morphinan derivative having a butylorphanine skeleton represented by the general formula (II) can be carried out by causing a boron trifluoride complex to act on the compound represented by the general formula (I).

[Chemical Formula 33]

Examples of solvents used in this reaction include solvents such as carboxylic acids, carboxylic acid esters, alcohols, hydrocarbons, haloalkanes, nitriles, ethers, ketones, amides, sulfonates, and carbonates. Examples include: carboxylic acids such as formic acid or acetic acid; carboxylic acid esters such as ethyl acetate; alcohols such as methanol, ethanol or propanol; aromatic hydrocarbons such as benzene, toluene or xylene; methylene chloride, chloroform or tetrachloride Halogenated hydrocarbons such as carbon; nitriles such as acetonitrile or propionitrile; ethers such as diethyl ether, tertiary butyl methyl ether, tetrahydrofuran or dioxane; ketones such as acetone or methyl ethyl ketone; dimethylformamide or dimethylacetamide Amides such as amines; sulfides such as dimethyl sulfoxide; carbonates such as diethyl carbonate and 1,3-dioxan-2-one; N,N'-dimethyl propyl urea, etc. Urea; water or their mixed solvents; and preferably such as carboxylic acids, carboxylic acid esters, alcohols, hydrocarbons, haloalkanes, nitriles, ethers, ketones, amides, sulfonamides, Urea or carbonates are more preferably carboxylic acids, hydrocarbons, nitriles or ethers, more preferably acetic acid, acetonitrile, xylene and toluene, particularly preferably acetic acid or acetonitrile. The amount of solvent used is not particularly limited, but it is preferably in the range of 1 to 200 times the weight (preferably 1 to 100, more preferably 1 to 50, and more preferably 1 to 20 times the weight) relative to compound (I). The reaction temperature can be appropriately set according to the solvent used. For example, it can be carried out at a temperature between 20°C and 150°C (preferably 40°C to 120°C, more preferably 50°C to 100°C, more preferably 50 to 90°C). The reaction temperature is completed within 5 minutes to 300 hours (preferably 1 hour to 20 hours). The boron trifluoride complex can be used from 1.0 to 50 times the weight of the compound (I), and preferably from 1 to 30 times, and more preferably from 1 to 10 times. Examples

Next, reference examples, examples, and test examples are given to explain the present invention in more detail, but the present invention is not limited thereto. In addition, the naming of the compound of the example and the compound of the reference example used ChemDraw ver.15 manufactured by Cambridge Soft Co., Ltd., and the structural formula described by the software was converted into English names according to the naming rules built in the software, and then translated into Japanese.

[Example 1] (4R, 4aR, 7R, 7aR, 12bS)-N-benzyl-3-(cyclopropylmethyl)-7-hydroxy-9-methoxy-1,2,3,4,7,7a-hexa Manufacture of hydrogen-4a,7-ethyl bridge-4,12-methyl bridge benzofuro[3,2-e]isoquinoline-14-methylamide

[Chemical Formula 34]

For a 100L three-necked flask, make the raw material (4R, 4aR, 7R, 7aR, 12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2, 3,4,7,7a-hexahydro-4a,7-ethyl bridge-4,12-methyl bridge benzofuro[3,2-e]isoquinoline-14-methylamide (4.2kg) was dissolved in Acetonitrile (42L). Boron trifluoride diethyl ether complex (17.1 kg) was added to the resulting solution at room temperature. The mixture was stirred at 65°C to 68°C for 5 hours and then the reaction was confirmed by HPLC, and the raw material had disappeared. The reaction solution was cooled to 0°C to 15°C, 4 equivalents of sodium hydroxide aqueous solution (120L) were slowly added, and finally the pH was adjusted to 10-12. The reaction solution was extracted twice with ethyl acetate (30 L), and the collected organic layer was washed twice with saturated brine (20 L). After the organic layer was dried over anhydrous sodium sulfate (5 kg), the insoluble matter was filtered and the filtrate was concentrated under reduced pressure to obtain a yellow crystalline solid. The resulting solid was stirred and washed in a mixed solvent of n-heptane and ethyl acetate (1:1, 1.2 L) and water (1.8 L) and pulverized. The crystalline solid was collected by filtration and dried, and the title compound (2.85 kg, 70%) was obtained as a yellow crystalline solid. (HPLC purity 98.9%) After separating the organic layer of the filtrate, it was concentrated to about 600 mL to obtain a suspension. The produced solid was filtered and dried to obtain the second crystal (100 g) of the title compound. (HPLC purity 95.6%) The NMR spectrum of the obtained compound is consistent with the data of Patent Document 2.

[Example 2] The solvent of Example 1 was changed to acetic acid, and the following experiment was carried out similarly. For a 100L three-necked flask, make the raw material (4R, 4aR, 7R, 7aR, 12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-1,2, 3,4,7,7a-Hexahydro-4a,7-ethyl bridge-4,12-methyl bridge benzofuro[3,2-e]isoquinoline-14-carboxamide (7.4kg) was dissolved in Acetic acid (45kg). Boron trifluoride diethyl ether complex (20.5 kg) was added to the resulting solution at room temperature. The mixture was stirred at 90°C for 8 hours, and the reaction was confirmed by HPLC. Although 2.4% of the raw material remained, the heating was stopped. After concentrating the reaction solution and distilling off acetic acid, the residue was dissolved in dichloromethane (80 kg). Move half of the solution to a 100L flask, add 4 equivalents of sodium hydroxide aqueous solution (about 5kg) and adjust the pH to 11-12. The organic layer was separated and dried over anhydrous sodium sulfate (10 kg). The same applies to the remaining half. After filtering to select insoluble materials, the filtrate was concentrated under reduced pressure, and the resulting residue was stirred at room temperature in n-hexane and ethyl acetate (1; 1,20 kg) for 3 hours to obtain a suspension. The obtained solid was collected by filtration and washed with n-hexane, and then dried under reduced pressure to obtain the title compound (2.5 kg) as an ivory crystalline solid. (HPLC purity 97.5%) The NMR spectrum of the obtained compound is consistent with the data of Patent Document 2.

[Example 3] (4R, 4aR, 7R, 7aR, 12bS)-N-benzyl-3-(cyclopropylmethyl)-7-hydroxy-9-methoxy-1,2,3,4,7,7a-hexa Production of hydrogen-4a,7-ethyl bridge-4,12-methyl bridge benzofuro[3,2-e]isoquinoline-14-carboxamide (Experimental example of using p-toluenesulfonate as starting material )

[Chemical Formula 35]

Add acetonitrile (47.6kg) and (4R, 4aR, 7R, 7aR, 12bS)-N-benzyl-3-(cyclopropylmethyl)-7,9-dimethoxy-1 to a 100L reaction vessel ,2,3,4,7,7a-hexahydro-4a,7-ethyl bridge-4,12-methyl bridge benzofuro[3,2-e]isoquinoline-14-methylamide p-toluenesulfonate Acid salt 1 p-toluenesulfonic acid adduct (6.02 kg). Boron trifluoride diethyl ether complex (24.5 kg) was added to the resulting solution at room temperature, and the reaction mixture was stirred at 65-68°C for 6 hours. HPLC analysis confirmed that the raw material had disappeared. The reaction solution was cooled to 0-15°C, and 4 equivalents of sodium hydroxide aqueous solution (180.6 kg, 89.1 equivalent) was slowly added under ice cooling to adjust the pH to 10-12. The reaction mixture was extracted twice with ethyl acetate (38 kg), and the collected organic layer was washed twice with saturated brine (28.7 kg). The organic layer was concentrated under reduced pressure to obtain a yellow solid. This was stirred and washed in a mixture of n-heptane (8.18 kg) and ethyl acetate (5.41 kg) and water (8.43 kg), and the solid was filtered to obtain the title compound (3.1 kg, as a gray crystalline solid). 88%). The NMR spectrum of the obtained compound is consistent with the data of Patent Document 2.

The preferred embodiments of the present invention have been described above, but the present invention is not limited by these embodiments. Additions, omissions, substitutions, and other changes to the structure can be made without departing from the scope of the invention. The present invention is not limited by the foregoing description, but only by the scope of the appended patent application.

(no)

Claims (23)

A method for manufacturing a compound represented by the following general formula (II), comprising the step of reacting the following compound (I) with boron trifluoride complex in a solvent; [Chemical Formula 2]

(In the formula, R ¹ and R ³ ~R ^{12 are the} same as shown later); [Chemical Formula 1]

(In the formula, R ¹ represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms of the cycloalkyl portion is 3 to 6, and the alkylene portion The number of carbon atoms represents 1 to 5), the aralkyl group which may have a substituent (the number of carbon atoms of the aryl portion is 6 to 10, and the number of carbon atoms of the alkylene portion represents 1 to 5), which may have a substituent Heteroaralkyl (heteroaryl contains at least 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5), C which may have a substituent _3-6 cycloalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _6-10 aryl, or optionally substituted heteroaryl (heteroaryl includes selected from N, O and 1 to 4 heteroatoms in S are used as ring constituent atoms, and the number of carbon atoms in the alkylene extension means 1 to 5); R ² represents a C _1-10 alkyl group which may have a substituent, and an aralkyl which may have a substituent Group (the number of carbon atoms in the aryl part is 6~10, and the number of carbon atoms in the alkylene part represents 1~5), heteroaralkyl which may have a substituent (heteroaryl includes selected from N, O and S 1 to 4 heteroatoms are used as ring constituent atoms, the number of carbon atoms in the alkylene moiety represents 1 to 5) or C _2-6 alkenyl which may have a substituent; R ³ represents a hydrogen atom, C which may have a substituent _1-10 alkyl groups, cycloalkylalkyl groups which may have substituents (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), aromatic groups which may have substituents Alkyl groups (the number of carbon atoms in the aryl group is 6-10, and the number of carbon atoms in the alkylene group represents 1~5), heteroaralkyl groups that may have substituents (heteroaryl groups include selected from N, O, and S Among them, 1 to 4 heteroatoms are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), C _2-6 alkenyl which may have a substituent, C _6-10 aryl which may have a substituent Or a heteroaryl group which may have a substituent (the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5); R ⁴ Represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, -OR ²² group (R ²² represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, an aryl group which may have a substituent, or may have a substitution C _1-6 alkyl amide group), halogen atom, cyano group, amine methyl amide group, optionally substituted acetyl group, nitro group and optionally substituted amine group; R ⁵ and R ^{6 are the} same or different , Represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁷ and R ^{8 are the} same or different from each other, represent a hydrogen atom, a fluorine atom or a hydroxyl group, or R ⁷ and R ⁸ together with the carbon to which they are bonded represent a carbonyl group); R ⁹ , R ¹⁰ and R ^{11 are the} same or different from each other, and represent a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C _3-6 cycloalkyl group that may have a substituent, and a cycloalkyl alkyl group that may have a substituent ( The number of carbon atoms in the cycloalkyl moiety is 3~6, and the number of carbon atoms in the alkylene moiety indicates 1~5), aralkyl group (aryl moiety) which may have a substituent The number of carbon atoms is 6~10, and the number of carbon atoms in the alkylene portion represents 1~5), heteroaralkyl groups which may have substituents (heteroaryl groups include 1~4 selected from N, O and S Heteroatoms as ring-forming atoms, the number of carbon atoms in the alkylene moiety represents 1 to 5), a C _6-10 aryl group which may have a substituent, or a heteroaryl group which may have a substituent (the heteroaryl group includes a member selected from N 1 to 4 heteroatoms in O, S are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), or R ⁹ and R ^{10 are} bonded to represent C _{3- which} may have a substituent ₆ saturated hydrocarbon ring, any one of R ⁹ and R ¹⁰ is bonded to R ¹¹ to represent a C _3-6 saturated hydrocarbon ring which may have a substituent or a C _3-6 cycloalkene which may have a substituent; R ¹² represents- C(=O)OR ¹³ group (R ¹³ represents a hydrogen atom, a C _1-10 alkyl group or a carboxyl protecting group which may have a substituent), -C(=O)-R ¹⁴ group (R ¹⁴ represents a hydrogen atom, may C _1-10 alkyl group with substituents, C _6-10 aryl group with substituents or heteroaryl group with substituents (heteroaryl groups include 1 to 4 hetero groups selected from N, O and S Atoms are ring-constituting atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5)), -OR ¹⁵ groups (R ¹⁵ represents a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C group that may have a substituent _3-6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or hydroxy protecting group), -NR ¹⁶ R ¹⁷ group (R ¹⁶ and R ¹⁷ may be the same or different from each other, indicating 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 (heteroaryl Contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5)), or an amine protecting group, -C(OR ¹⁵ )R ¹⁸ R ¹⁹ group (R ¹⁸ and R ¹⁹ may be the same or different from each other, and represent a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C _3-6 cycloalkyl group that may have a substituent, a C that may have a substituent _6-10 aryl or heteroaryl which may have a substituent), or -C (NR ¹⁶ R ¹⁷ ) R ¹⁸ R ¹⁹ group (R ¹⁶ , R ¹⁷ , R ¹⁸ , R ^{19 are the} same as shown above), -C (=O)NR ²⁰ R ²¹ group (R ²⁰ is the same as or different from R ²¹ and represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, may Cycloalkylalkyl groups with substituents (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), aralkyl groups that may have substituents (the aryl portion The number of carbon atoms is 6~10, and the number of carbon atoms in the alkylene moiety represents 1~5), heteroaralkyl groups which may have substituents (heteroaryl groups include 1 to 4 hetero groups selected from N, O and S Atoms as rings constitute atoms, alkylene The number of carbon atoms in the base portion represents 1 to 5), C _2-6 alkenyl group which may have a substituent, aralkenyl group which may have a substituent (the carbon number of the aryl portion is 6 to 10, the carbon of the alkenyl portion The number of atoms represents 2 to 6), a heteroarylalkenyl group which may have a substituent (the heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkenyl part represents 2~6), cycloalkylalkenyl which may have a substituent (the number of carbon atoms in the cycloalkyl portion is 3-6, and the number of carbon atoms in the alkenyl portion represents 2-6), C _4- which may have a substituent ₆ cycloalkenyl, cycloalkenyl alkyl which may have a substituent (the number of carbon atoms in the cycloalkenyl part is 4 to 6, and the number of carbon atoms in the alkylene part represents 1 to 5), cycloalkene which may have a substituent Alkenyl (the number of carbon atoms in the cycloalkenyl part is 4 to 6, and the number of carbon atoms in the alkenyl part represents 2 to 6), aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl Contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5); or, R ²⁰ and R ^{21 are} bonded to indicate that they may have a substituent In addition, a cyclic amine group having 4 to 8 member rings, or any one of R ²⁰ and R ²¹ may be combined with any one of R ⁹ , R ¹⁰ and R ¹¹ to form an internal amide ring which may have a substituent). The manufacturing method according to claim 1, wherein R ¹ is a substituent selected from the group consisting of C _1-10 alkyl which may have a substituent, and cycloalkylalkyl which may have a substituent (the number of carbon atoms in the cycloalkyl portion It is 3~6, and the number of carbon atoms in the alkylene moiety represents 1~5), and the aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 6~10, and the number of carbon atoms in the alkylene moiety represents 1 ~5), optionally substituted C _2-6 alkenyl, optionally substituted C _6-10 aryl, or optionally substituted heteroaryl (heteroaryl includes those selected from N, O, and S 1 to 4 heteroatoms are used as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5). The manufacturing method according to claim 1, wherein R ⁴ is a hydrogen atom or a halogen atom. The manufacturing method according to claim 1, wherein R ⁵ and R ⁶ are hydrogen atoms. The manufacturing method according to claim 1, wherein R ⁷ and R ⁸ are hydrogen atoms. The manufacturing method according to claim 1, wherein R ⁹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a hetero group which may have a substituent Aryl (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5). The manufacturing method according to claim 1, wherein R ¹⁰ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a hetero group which may have a substituent Aryl (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5). The manufacturing method according to claim 1, wherein R ¹¹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl group which may have a substituent, an aryl group which may have a substituent, or a hetero group which may have a substituent Aryl (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5). As in the manufacturing method of claim 1, wherein R ¹² is -C(=O)OR ¹³ group, -C(=O)-R ¹⁴ group, -OR ¹⁵ group, -NR ¹⁶ R ¹⁷ group, -C(OH) R ¹⁸ R ¹⁹ group, -C(NR ¹⁶ R ¹⁷ )R ¹⁸ R ¹⁹ group or -C(=O)NR ²⁰ R ²¹ group (R ¹³ ~R ²⁰ and R ^{21 are the} same as above). The manufacturing method according to claim 1, wherein R ³ is a C _1-10 alkyl group which may have a substituent. The manufacturing method according to claim 1, wherein R ² is a C _1-10 alkyl group which may have a substituent. The manufacturing method according to claim 1, wherein the compound represented by the aforementioned general formula (II) is a compound selected from the compounds represented by the following numbers 1 to 48 or a salt thereof. [Chemical Formula 3]

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

[Chemical Formula 7]

[Chemical Formula 8]

[Chemical Formula 9]

[Chemical Formula 10]

[Chemical Formula 11]

[Chemical Formula 12]

The manufacturing method according to claim 1, wherein the compound of the general formula (I) is in the form of an acid addition salt. The manufacturing method according to claim 13, wherein the acid addition salt according to claim 13 is selected from mineral acids, organic carboxylic acids or sulfonic acids. The manufacturing method according to claim 14, wherein the acid addition salt is selected from hydrochloric acid, sulfuric acid, formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, maleic acid, fumaric acid, methanesulfonic acid Acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid or naphthalenesulfonic acid. The manufacturing method according to claim 1, wherein the boron trifluoride complex according to claim 1 is selected from boron trifluoride-ether complex, boron trifluoride-water complex, boron trifluoride-alcohol complex Compound, boron trifluoride-amine complex, boron trifluoride-phenol complex, boron trifluoride-sulfide complex, boron trifluoride-sulfonate complex, boron trifluoride- Carboxylic acid complex or boron trifluoride-phosphate complex, etc. The manufacturing method according to claim 16, wherein the boron trifluoride complex according to claim 16 is selected from boron trifluoride-ether complex, boron trifluoride-alcohol complex or boron trifluoride-carboxylic acid Complex. According to the manufacturing method of claim 1, boron trifluoride complex compound is used in an amount of 1 to 50 times by weight relative to the aforementioned compound (I). The manufacturing method according to claim 1, wherein the aforementioned solvent is selected from carboxylic acids, carboxylic acid esters, alcohols, hydrocarbons, haloalkanes, nitriles, ethers, ketones, amides, sulfonamides, ureas Or carbonates. The manufacturing method according to claim 19, wherein the aforementioned solvent is selected from carboxylic acids, hydrocarbons, nitriles or ethers. The manufacturing method according to claim 19, wherein the aforementioned solvent is selected from acetic acid, acetonitrile, toluene or xylene. The manufacturing method according to any one of claims 1 to 21, wherein the reaction temperature when the compound (I) and boron trifluoride complex is reacted in a solvent is in the range of 20 to 150°C. An acid addition salt of a compound represented by the following formula; [Chemical Formula 13]

(In the formula, R ¹ represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms of the cycloalkyl portion is 3 to 6, and the alkylene portion The number of carbon atoms represents 1 to 5), the aralkyl group which may have a substituent (the number of carbon atoms of the aryl portion is 6 to 10, and the number of carbon atoms of the alkylene portion represents 1 to 5), which may have a substituent Heteroaralkyl (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), C ₃ which may have a substituent _-6 cycloalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _6-10 aryl, or optionally substituted heteroaryl (heteroaryl includes selected from N, O, and S Among them, 1 to 4 heteroatoms are used as ring constituent atoms, and the number of carbon atoms in the alkylene extension means 1 to 5); R ² represents a C _1-10 alkyl group which may have a substituent, and an aralkyl group which may have a substituent (The number of carbon atoms in the aryl moiety is 6 to 10, and the number of carbon atoms in the alkylene moiety represents 1 to 5). Heteroaralkyl groups which may have a substituent (heteroaryl groups include those selected from N, O and S 1 to 4 heteroatoms are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5) or C _2-6 alkenyl which may have a substituent; R ³ represents a hydrogen atom and C ₁ which may have a substituent _-10 alkyl, optionally substituted cycloalkylalkyl (the number of carbon atoms in the cycloalkyl portion is 3 to 6, and the number of carbon atoms in the alkylene portion represents 1 to 5), aralkyl which may have a substituent Group (the number of carbon atoms in the aryl part is 6~10, and the number of carbon atoms in the alkylene part represents 1~5), heteroaralkyl which may have a substituent (heteroaryl includes selected from N, O and S One to four heteroatoms are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5), C _2-6 alkenyl which may have a substituent, C _6-10 aryl which may have a substituent, or Heteroaryl group which may have a substituent (heteroaryl group contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion represents 1 to 5); R ⁴ represents Hydrogen atom, optionally substituted C _1-10 alkyl group, -OR ²² group (R ²² represents a hydrogen atom, optionally substituted C _1-10 alkyl group, optionally substituted aryl group or optionally substituted group C _1-6 alkyl amide group), halogen atom, cyano group, amine methyl amide group, optionally substituted acetyl group, nitro group and optionally substituted amine group; R ⁵ and R ^{6 are the} same or different from each other, Represents a hydrogen atom, a fluorine atom or a hydroxyl group; R ⁷ and R ^{8 are the} same or different from each other, represent a hydrogen atom, a fluorine atom or a hydroxyl group, or R ⁷ and R ⁸ together with the carbon to which they are bonded represent a carbonyl group); R ⁹ and R ¹⁰ , R ^{11 is the} same or different from each other, represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, a cycloalkyl alkyl group which may have a substituent (ring The number of carbon atoms in the alkyl part is 3~6, and the number of carbon atoms in the alkylene part indicates 1~5), aralkyl which may have a substituent (carbon in the aryl part) The number of atoms is 6~10, and the number of carbon atoms in the alkylene portion represents 1~5), heteroaralkyl groups which may have substituents (heteroaryl groups contain 1 to 4 heteroatoms selected from N, O and S As a ring constituent atom, the number of carbon atoms in the alkylene moiety represents 1 to 5), a C _6-10 aryl group which may have a substituent, or a heteroaryl group which may have a substituent (the heteroaryl group includes a group selected from N, O, and 1 to 4 heteroatoms in S are used as ring-forming atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5); or, R ⁹ and R ^{10 are} bonded to represent a C _3-6 saturated hydrocarbon which may have a substituent Ring, any one of R ⁹ and R ¹⁰ is bonded to R ¹¹ to represent a C _3-6 saturated hydrocarbon ring which may have a substituent or a C _3-6 cycloalkene which may have a substituent; R ¹² represents -C(= O) OR ¹³ group (R ¹³ represents a hydrogen atom, a C _1-10 alkyl group or a carboxyl protecting group which may have a substituent), -C(=O)-R ¹⁴ group (R ¹⁴ represents a hydrogen atom, which may have a substituent C _1-10 alkyl, C _6-10 aryl which may have a substituent, or heteroaryl which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as rings Constituent atoms, the number of carbon atoms in the alkylene moiety represents 1 to 5)), -OR ¹⁵ group (R ¹⁵ represents a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a C _3-6 which may have a substituent) Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or hydroxy protecting group), -NR ¹⁶ R ¹⁷ group (R ¹⁶ and R ¹⁷ may be the same or different from each other, indicating a hydrogen atom, may have C _1-10 alkyl group for substituents, C _3-6 cycloalkyl group for substituents, C _6-10 aryl group for substituents, heteroaryl group for substituents (heteroaryl groups include 1 to 4 heteroatoms in N, O and S are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5)), or amine protecting group, -C(OR ¹⁵ )R ¹⁸ R ¹⁹ group (R ¹⁸ and R ¹⁹ may be the same or different from each other, and represent a hydrogen atom, a C _1-10 alkyl group that may have a substituent, a C _3-6 cycloalkyl group that may have a substituent, a C _6-10 that may have a substituent Aryl or heteroaryl which may have a substituent), or -C (NR ¹⁶ R ¹⁷ ) R ¹⁸ R ¹⁹ group (R ¹⁶ , R ¹⁷ , R ¹⁸ , R ^{19 are the} same as shown above), -C (=O )NR ²⁰ R ²¹ group (R ²⁰ and R ²¹ may be the same or different from each other, indicating a hydrogen atom, a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, may have a substitution Cycloalkylalkyl group (the number of carbon atoms in the cycloalkyl portion is 3~6, the number of carbon atoms in the alkylene portion represents 1~5), the aralkyl group which may have a substituent (carbon atoms in the aryl portion The number is from 6 to 10, and the number of carbon atoms in the alkylene portion represents 1 to 5), and heteroarylalkyl group which may have a substituent (heteroaryl group includes 1 to 4 heteroatoms selected from N, O, and S As ring constituent atoms, alkylene The number of carbon atoms in the part represents 1 to 5), C _2-6 alkenyl which may have a substituent, aryl alkenyl which may have a substituent (the number of carbon atoms in the aryl part is 6 to 10, and the carbon atoms in the alkenyl part The number represents 2 to 6), a heteroarylalkenyl group which may have a substituent (the heteroaryl group includes 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkenyl portion represents 2 ~6), cycloalkylalkenyl which may have a substituent (the number of carbon atoms in the cycloalkyl part is 3-6, and the number of carbon atoms in the alkenyl part represents 2-6), C _4-6 which may have a substituent Cycloalkenyl, optionally substituted cycloalkenylalkyl (cycloalkenyl moiety has 4 to 6 carbon atoms, alkylene moiety has 1 to 5 carbon atoms), and optionally substituted cycloalkenyl Alkenyl (the number of carbon atoms in the cycloalkenyl moiety is 4-6, and the number of carbon atoms in the alkenyl moiety represents 2-6), aryl which may have a substituent or heteroaryl which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S are used as ring constituent atoms, and the number of carbon atoms in the alkylene moiety represents 1 to 5); or, R ²⁰ and R ^{21 are} bonded to indicate that they may have a substituent and A cyclic amine group of 4-8 member rings, or any one of R ²⁰ and R ²¹ may together with any one of R ⁹ , R ¹⁰ and R ¹¹ form an internal amide ring which may have a substituent).