WO2022004783A1 - Method for producing morphinan derivative - Google Patents

Abstract

This method for producing a morphinan derivative by means of a reduction reaction using formic acid or the like is represented by the following general formula (II).

Description

Method for producing morphinan derivative

The present invention relates to a method for producing a morphinan derivative having a buprenorphine skeleton.
The present application claims priority based on Japanese Patent Application No. 202-112310 filed in Japan on June 30, 2020, the contents of which are incorporated herein by reference.

Buprenorphine is a partial opioid agonist for opioid receptors and is a compound used for analgesia and treatment of opioid addiction. It was first launched by Reckitt & Colman as an analgesic, and high-dose tablets are approved by the US Food and Drug Administration (FDA) for the treatment of opioid addiction.

Buprenorphine has been pointed out to be dependent on long-term administration as a side effect, and has been designated as Schedule III drug in the Convention on Psychotropic Drugs of the International Convention, and is a second-class psychotropic drug under the Narcotics and Psychotropics Control Law. It has become.
Even now, drug discovery research aimed at creating new drugs aimed at reducing these side effects of buprenorphine is being actively conducted. For example, in Non-Patent Document 1, side chain derivatives having several buprenorphine skeletons are being actively conducted. Synthetic examples of are reported. In addition, Non-Patent Document 2 reports on BU08028, which is a side chain derivative of buprenorphine.

As described above, the conversion of side chain derivatives having a buprenorphine skeleton is an interesting subject of medical chemistry, and Non-Patent Document 3 describes drug design and synthesis of opioid ε receptor agonists in which the side chain site is converted to an amide. The law is mentioned.
The existence of several subtypes of opioid receptors is known, such as μ, δ, κ and ε. Morphine, which has a strong affinity for μ receptors, has long been used as an analgesic. However, opioid μ receptor agonists are known to cause adverse events such as dependence formation and respiratory depression via the μ receptor.
On the other hand, δ-receptor agonists also have analgesic effects, but are known not to be involved in the adverse events seen in morphine. Therefore, δ-receptor-selective agonists are expected as excellent analgesics.

For example, Patent Document 1 reports a compound represented by the following formula (A).

Since these derivatives have high δ receptor selectivity and analgesic action, they are expected to be applied to drugs such as analgesics.
Patent Document 1 discloses, in Reference Example 10, an example in which compound 70 is reduced with palladium / carbon under a hydrogen atmosphere and compound 71 having a buprenorphine skeleton is synthesized as an intermediate.

Further, Non-Patent Document 1 discloses an example of synthesis of a derivative having ε opioid receptor agonist activity. Among them, Scheme 4 discloses a synthesis example of a compound having a buprenorphine skeleton in which compounds 3C and 3G having a double bond in the molecule are reduced with palladium / carbon under a hydrogen atmosphere and converted into a single bond.

The intermediate having a buprenorphine skeleton disclosed in Patent Document 1 and Non-Patent Document 1 is useful as a production intermediate for obtaining a final target product.
However, in the conventional method, (i) it is necessary to use explosive hydrogen gas, (ii) it is necessary to carry out the reaction in a medium pressure hydrogen atmosphere, and a special reaction vessel such as an autoclave may be required. In that case, some facilities did not have a huge reaction vessel in industrial scale manufacturing, and it was sometimes difficult to carry out. Further, when the (iii) substrate has a cyclopropylmethyl group, there are problems such as the loss of the cyclopropylmethyl group or the opening of the cyclopropyl moiety as a side reaction, resulting in a by-product that is difficult to remove. was there.

International Publication No. 2013/035833 International Publication No. 2019/189479

An object of the present invention is to provide a method for producing an intermediate for producing a morphinan derivative having a buprenorphine skeleton.

Under such circumstances, as a result of diligent studies on the method for producing the intermediate, the present inventors have improved the problems (I) to (iii) by using formate or the like as a hydrogen source. , A manufacturing method applicable to industrial production was found, and the present invention was completed.
That is, one aspect of the present invention is
The following general formula (I),

(In the formula, R ¹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, and a cycloalkylalkyl group which may have a substituent (the number of carbon atoms in the cycloalkyl moiety is 3 to 3 to In 6, the number of carbon atoms of the alkylene moiety is 1 to 5), and the aralkyl group which may have a substituent (the number of carbon atoms of the aryl moiety is 6 to 10 and the number of carbon atoms of the alkylene moiety is 1). ~ 5;), a heteroarylalkyl group which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and is an alkylene moiety. The number of carbon atoms indicates 1 to 5), which represents a C _3-6 cycloalkyl group which may have a substituent or a C _6-10 aryl group which may have a substituent.
R ² and R ³ are a hydrogen atom, 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 portion is 6 to 10, and the alkylene group is used. The number of carbon atoms in the moiety indicates 1 to 5) or represents a hydroxy protective group.
R ⁴ , R ⁵ and R ⁶ are the same or different hydrogen atoms, C _1-10 alkyl groups which may have substituents, C _3-6 cycloalkyl groups which may have substituents, substitutions. _{Representing a C 6-10} aryl group which may have a group
R ⁴ and R ⁵ represents an C _3-6 saturated hydrocarbon ring which may have a substituent bonded, which may have a substituent bonded R ⁵ and R ⁶ are C _3- Represents a _{C 3-6 cycloalkene which may have a 6-} saturated hydrocarbon ring or substituents.
R ⁷ is 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, and a cycloalkyl which may have a substituent. Alkyl group (the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the number of carbon atoms in the alkylene moiety is 1 to 5), and the aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 1 to 5). 6 to 10, the number of carbon atoms of the alkylene moiety indicates 1 to 5), a heteroarylalkyl group which may have a substituent (heteroaryl is 1 to 4 selected from N, O and S). The heteroatom of the above is contained as a ring-constituting atom, and the number of carbon atoms of the alkylene moiety indicates 1 to 5), which may have a C _6-10 aryl group or a substituent. It represents a heteroaryl group (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety indicates 1 to 5).
R ⁸ is a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and a cycloalkyl alkyl group which may have a substituent ( The cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms), and an aralkyl group which may have a substituent (the aryl moiety has 6 to 10 carbon atoms). The number of carbon atoms in the alkylene moiety is 1 to 5), a heteroarylalkyl group which may have a substituent (heteroaryl is 1 to 4 heteroatoms selected from N, O and S). As a ring-constituting atom, the number of carbon atoms in the alkylene moiety is 1 to 5), an aryl group which may have a substituent or a heteroaryl group which may have a substituent (heteroaryl is It contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety indicates 1 to 5), representing an amino group. ) Is allowed to act in the presence of a palladium catalyst and formic acid or a salt thereof or a mixture of formic acid and trialkylamine, in a solvent or in the absence of a solvent, according to the following general formula (II).

(In the formula, R ¹ to R ⁸ indicate the same as above.) The present invention relates to a method for producing a compound represented by the above.
[2] Further, in the present invention, R ² may have a hydrogen atom or a substituent C _1-10 alkyl group, and R ³ may have a hydrogen atom or a substituent C _1-10 alkyl. The present invention relates to the production method according to the above [1], which is a group or a hydroxy protective group.
[3] The present invention also comprises the above [1] or [2], wherein ^{R 2} is a hydrogen atom or a methyl group, and R ³ _{is a C 1-10} alkyl group or a hydroxy protecting group which may have a substituent. The manufacturing method according to any one.
[4] The production method according to any one of the above [1] to [3], wherein ^{R 2} is a hydrogen atom or a methyl group, and R ^{3 is a methyl group or a silyl protecting group.}
[5] Further, in the present invention, R ⁷ has a hydrogen atom, a C _1-10 alkyl group which may have a substituent, and a cycloalkylalkyl group which may have a substituent (carbon atom of the cycloalkyl moiety). The number is 3 to 6, and the number of carbon atoms in the alkylene moiety is 1 to 5.), an aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 6 to 10, and the carbon in the alkylene moiety). The number of atoms indicates 1 to 5), an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a heteroarylalkyl group which may have a substituent (hetero). Aryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety is 1 to 5). Any one of the above [1] to [4]. The manufacturing method described in 1.
[6] Further, in the present invention, R ¹ may have a C _1-10 alkyl group having a substituent and a cycloalkyl alkyl group may have a substituent (the number of carbon atoms in the cycloalkyl moiety is 3). 6 to 6, the number of carbon atoms in the alkylene moiety is 1 to 5) or 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 is 1 to 5), the production method according to any one of the above [1] to [5], which is a substituent selected from.
[7] Further, in the present invention, R ¹ may have a C _1-10 alkyl group which may have a substituent or a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms of the cycloalkyl moiety is 3). 6; the production method according to any one of the above [1] to [6], which is a substituent according to any one of (1 to 5), the number of carbon atoms in the alkylene moiety is 1.
[8] Further, the present invention indicates a ^{cycloalkylalkyl group in which R 1} 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 moiety is 1 to 5). The production method according to any one of the above [1] to [7].
[9] The present invention relates to the production method according to the above [8], wherein the cycloalkylalkyl group which may have the substituent according to the above [8] is a cyclopropylmethyl group.
[10] The present invention also relates to the production method according to any one of the above [1] to [7], wherein ^{R 1} _{is a C 1-10} alkyl group which may have a substituent.
[11] The present invention also relates to the production method according to the above [10], wherein the _{C 1-10 alkyl group which may have the substituent according to the above [10] is a methyl group.}
[12] Further, the present invention relates to the production method according to any one of the above [1] to [11], wherein the palladium catalyst according to the above [1] is a palladium-supported catalyst.
[13] The present invention also relates to the production method according to the above [12], wherein the palladium-supporting catalyst according to the above [12] is selected from palladium / carbon, palladium / carbon hydroxide, palladium / alumina, and palladium / barium sulfate. Regarding
[14] The present invention also relates to the production method according to the above [13], wherein the palladium-supported catalyst according to the above [13] is selected from palladium / carbon and palladium / carbon hydroxide.
[15] In the present invention, the amount of the palladium-supported catalyst according to the above [12] to [14] is 5 to 100% by weight based on the compound of the general formula (I). The manufacturing method according to any one.
[16] In the present invention, the amount of the palladium-supported catalyst according to the above [12] to [14] is 10 to 60% by weight based on the compound of the general formula (I). The manufacturing method according to any one.
[17] Further, the present invention is the production method according to any one of the above [1] to [16], wherein the salt in the formic acid or the salt thereof according to the above [1] is a salt with ammonia, amines or an alkali metal. Regarding.
[18] The present invention also relates to the production method according to the above [17], wherein the salt in the formic acid or a salt thereof according to the above [17] is potassium formate.
[19] The present invention also relates to the production method according to any one of the above [1] to [16], wherein the trialkylamine in the mixture of formic acid and trialkylamine according to the above [1] is triethylamine.
[20] The present invention also relates to the production method according to the above [19], wherein the molar ratio of the mixture of formic acid and triethylamine according to the above [19] is 10: 1 to 1: 1.
[21] The present invention also relates to the production method according to the above [20], wherein the molar ratio of the mixture of formic acid and triethylamine according to the above [20] is 1: 1.
[22] Further, in the present invention, the solvent according to the above [1] is selected from an alcohol-based solvent, a ketone-based solvent, an ether-based solvent, an aprotonic polar solvent, a hydrocarbon-based solvent, an ester-based solvent, water, or a mixed solution thereof. The production method according to any one of the above [1] to [21].
[23] The present invention also relates to the production method according to the above [21], wherein the solvent according to the above [21] is selected from an alcohol solvent, an ether solvent, an ester solvent, water or a mixed solution thereof.
[24] Further, the present invention relates to the production method according to the above [23], wherein the solvent according to the above [23] is selected from an alcohol solvent, water or a mixed solution thereof.
[25] Further, the present invention relates to the production method according to the above [1] to [24], wherein the production method according to the above [1] to [24] is based on flow chemistry.
[26] In the present invention, the compound represented by the general formula (II) is a compound selected from the compounds represented by the following numbers 1 to 58 or a salt thereof. The manufacturing method according to any one.

FIG. 1 shows an example of a reaction device in flow chemistry. FIG. 2 shows an example in which reaction devices in flow chemistry are connected.

Next, the present invention will be described in more detail.
Of the morphinan derivatives represented by the above general formulas (I) and (II), homomorphs of the compounds, stereoisomers (geometric isomers, optical isomers), salts thereof, or solvates thereof. The following are preferable. It also contains stable isotopes such as deuterium and ^13C.

In the present specification, the _{C 1-10} alkyl group in the C _1-10 alkyl group which may have the substituents represented by ^{R 1} to R ⁸ includes a methyl group, an ethyl group, an n-propyl group and iso. -Clinical or branched alkyl groups such as propyl group, n-butyl group, iso-butyl group, tert-butyl group, pentyl group, hexyl group, heptyl group and octyl group are preferable, and C _{1-6 is preferable.} An alkyl group, more preferably a _C1-3 alkyl group, and even more preferably a methyl group. Further, these alkyl groups may be deuterated, and examples of the deuterated alkyl groups include methyl-d3, ethyl-1,1-d2, ethyl-d5 and the like.
Examples of the substituent include those described in paragraph [0048], preferably a halogen atom and more preferably a fluorine atom, and examples of the alkyl group substituted with the fluorine atom include a trifluoromethyl group and a pentafluoromethyl group. And so on.

R ^1, R ⁷ and the carbon atom number of good cycloalkylalkyl group (the cycloalkyl moiety may have a substituent group represented by R ⁸ is 3-6, carbon atoms in the alkylene moiety represents 1 to 5 _{Examples of the cycloalkylalkyl group in () include a methyl group substituted with a C 3-6} cycloalkyl group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group, an ethyl group and the like, and cyclopropylmethyl is preferable. Examples thereof include a group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclobutylethyl group and the like, but a cyclopropylmethyl group is more preferable. Further, the cycloalkylalkyl group may be dehydrogenated, and examples thereof include a (cyclopropyl-d5) methyl group and a cyclopropylmethyl-d2 group.

The _{C 3-6} cycloalkyl group in the C _3-6 cycloalkyl group which may have the substituents represented by ^{R 1} , R ⁴ to R ⁸ includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group. And the like, preferably a cyclopropyl group.

The _{C 3-6} saturated hydrocarbon ring in the C _3-6 saturated hydrocarbon ring which may have a substituent formed by bonding ^{R 4} and R ⁵ or R ⁵ and R ⁶ is a cyclopropane ring. , Cyclobutane ring, cyclopentane ring, cyclohexane ring and the like.

The _{C 3-6} cycloalkene at the R ⁵ and optionally _{C 3-6} cycloalkene ^{R 6} is not a bond to a substituent, cyclopentene and cyclohexene.

Aralkyl groups may have substituents represented by R ¹ , R ² , R ³ , R ⁷ and R ⁸ (the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is Examples of the aralkyl group in 1 to 5) include a methyl group substituted with a phenyl group or a naphthyl group, an ethyl group and the like, and preferably a methyl group substituted with a phenyl group (benzyl group). ..

Heteroaryl alkyl group which may have a substituent represented by R ¹ , R ⁷ and R ⁸ (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms. , The number of carbon atoms in the alkylene moiety is 1 to 5), as the heteroarylalkyl group, a (pyridine-2-yl) methyl group having 5 to 10 ring-constituting atoms of the heteroaryl, (pyridine-3-3). Il) methyl group, (pyridine-4-yl) methyl group, 2- (pyridine-2-yl) ethyl group, (fran-2-yl) methyl group, (fran-3-yl) methyl group, (imidazole- 2-yl) Methyl group, (imidazole-4-yl) methyl group, (imidazole-5-yl) methyl group, (thiazol-2-yl) methyl group, (thiazol-4-yl) methyl group, (thiazol-) Monocyclic heteroarylalkyl groups such as 5-yl) methyl group, (thiophen-2-yl) methyl group, 2- (thiophen-2-yl) ethyl group or (1H-tetrazole-5-yl) methyl group, Examples thereof include a bicyclic heteroarylalkyl group such as a (quinolin-3-yl) methyl group and a (indole-3-yl) methyl group.

_{Examples of the} C 6-10 aryl group which may have a substituent represented by R ¹ , R ⁴ to R ⁸ include a phenyl group and a naphthyl group.

Pyridyl group of R ⁷ and R ⁸ ring constituting atoms of 5 to 10 as the heteroaryl group in heteroaryl group optionally having a substituent represented, furyl group, imidazolyl group, pyrimidinyl group, pyrazinyl group or thiazolyl Examples thereof include a monocyclic heteroaryl group such as a group, a bicyclic heteroaryl group such as a quinolyl group and an indrill group.

Examples of the hydroxy protective group represented by R ² and R ³ include generally known hydroxy protective groups (for example, the hydroxy protective group described in Non-Patent Document 2), such as a benzyl group, a 4-methoxybenzyl group or a trityl. Examples thereof include an aralkyl group which may have a substituent such as a group; an acyl group such as an acetyl group; a silyl group having a substituent such as a trimethylsilyl group or a tert-butyldimethylsilyl.

_{Substituents described herein include linear or branched C 1-6} alkyl groups such as methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl groups; fluoro. Methyl halide group such as methyl group, difluoromethyl group, trifluoromethyl group; C _{2-6 alkenyl group such as 2-propenyl group; C 3-8} cycloalkyl group such as cyclopropyl group and cyclohexyl group; phenyl group and the like C _6-10 aryl group; heteroaryl group such as pyridyl group, frill group, imidazolyl group; halogen atom such as fluorine atom, chlorine atom; C _1-6 alkylamino group, di-C _1-6 alkylamino group, Amino group which may have a substituent such as an acylamino group, an amino group which may have a protective group; an acyl group such as a formyl group, an acetyl group, a cyclopropylcarbonyl group and a benzoyl group; a hydroxy group and a guanidyl. Examples include a group or a cyano group.

Suitable morphinan derivatives (II) in the present embodiment include the following compounds Nos. 1 to 58.

Examples of the acid addition salt of the morphinan derivative (IV) include salts with mineral acids such as hydrochloric acid and sulfuric acid, and organic carboxylics such as formic acid, oxalic acid, acetic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid. Examples thereof include salts with acids, salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid.

In such a substituent, as a more preferable combination of substituents, R ¹ is a C _1-10 alkyl group and a cycloalkyl alkyl group (the number of carbon atoms in the cycloalkyl moiety is 3 to 6, and the number of carbon atoms in the alkylene moiety is 3 to 6). represents 1 to 5.), preferably the number of carbon atoms of a cycloalkyl group (the cycloalkyl moiety with 3-6 carbon atoms in the alkylene moiety represents 1 to 5.) and hydrogen atoms as R ² Alternatively, a methyl group, R ³ is a hydrogen atom, a C _1-10 alkyl group, a hydroxy protective group, preferably a C _1-10 alkyl group, a hydroxy protective group and R ⁴ to R ⁶ are the same or different hydrogen atoms, C. _1-10 alkyl group, preferably a hydrogen atom, as R ⁷ is a hydrogen atom, which may have a substituent C _1-10 alkyl group which may have a substituent cycloalkylalkyl group (cycloalkyl The moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms), and an aralkyl group which may have a substituent (the aryl moiety has 6 to 10 carbon atoms). The number of carbon atoms in the alkylene moiety is 1 to 5), an aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a heteroaryl which may have a substituent. alkyl group (the heteroaryl include N, 1 to 4 hetero atoms selected from O and S as a ring-constituting atom, the carbon atoms in the alkylene moiety 1-5.) and have a substituent as R ⁸ Examples thereof include an aralkyl group which may be used (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms).

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

The production of a morphinan derivative having a buprenorfin skeleton represented by the general formula (II) is carried out by using a compound of the general formula (I) in a solvent or in the presence of a palladium catalyst and formic acid or a salt thereof or a mixture of formic acid and trialkylamine. It can be done by acting in the absence.

(In the formula, R ¹ to R ⁸ indicate the same as above.)

As the palladium catalyst used in this reaction, a palladium-supported catalyst can be used. The palladium-supported catalyst means a catalyst in which palladium is supported on a carrier.
Examples of the palladium-supported catalyst include palladium / carbon, palladium / carbon hydroxide / carbon, palladium / alumina, palladium / barium sulfate and the like, and preferably palladium / carbon or palladium / carbon hydroxide.
The amount of the palladium catalyst used in this reaction can be 5 to 100% by weight, preferably 10 to 60% by weight, based on the compound of the general formula (I).

As the formate used in this reaction, metal salts such as lithium formate, potassium formate, sodium formate, cesium formate, ammonium formate and the like can be used, and potassium formate is preferable.

Examples of the trialkylamine used in this reaction include trimethylamine, triethylamine, tripropylamine, N-methylmorpholine, N-methylpiperidine and the like, and triethylamine is preferable.
The amount of the trialkylamine used can be in the range of 10: 1 to 1: 1 with respect to formic acid, preferably 5: 1 and more preferably 1: 1.

The solvent used in this reaction includes alcohol solvents such as metanol, etanol, 2,2,2-trifluoroethanol, 1-propanol and 2-propanol, and ketones such as acetone. System solvents, nitrile solvents such as acetonitrile, ether solvents such as tetrahydrofuran, aprotonic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide, hydrocarbon solvents such as benzene, toluene and xylene, ethyl acetate and the like. Examples thereof include an ester solvent and water, preferably an alcohol solvent, an ether solvent, an ester solvent, water or a mixed solution thereof, and more preferably an alcohol solvent or a mixed solvent with water thereof. Ethanol is mentioned as a preferable alcohol solvent. The mixing ratio of the alcohol solvent and water is arbitrary, but it can be used in the range of alcohol / water = 50/1 to 1/1.
It is also possible to carry out the reaction under solvent-free conditions. When a solvent is used, the amount of the solvent used is not particularly limited, but is preferably in the range of 1 to 10 times by weight with respect to compound (I).
The reaction temperature is 0 ° C. to 120 ° C., preferably room temperature to 100 ° C., more preferably 40 ° C. to 90 ° C., still more preferably 50 ° C. to 70 ° C., and the reaction time is 5 minutes to 300 hours. It is preferably completed in 1 to 20 hours.

The present invention can be carried out using the batch method or flow chemistry. The batch method is a method in which a raw material is put into a reaction vessel each time in the production of a compound, a reaction is carried out, and after the reaction is completed, the reaction product is isolated and produced to obtain a reaction product each time. It can be done based on the conditions.
On the other hand, in the method using flow chemistry, a generally known method can be used. For example, a starting material or the like is continuously charged from one end of a reaction device such as a column, and a product is continuously obtained from the other end. be able to. In the present invention, (a) a step of filling the reaction apparatus with a catalyst, (b) a step of dissolving compound (I) and formic acid or a salt thereof or a mixture of formic acid and trialkylamine in a solvent to prepare a solution. The target compound (II) is obtained by (c) sending the solution to a reaction apparatus filled with a palladium catalyst at a specific temperature, and (d) recovering the solution and distilling off the solvent if necessary. be able to.
Examples of the reaction device that can be used for flow chemistry include commercially available ones, and for example, reaction devices such as cartridges, columns, and microreactors can be used.
Further, the solution of (b) can be sent to the reaction apparatus by using a liquid feeding pump or the like. The liquid feeding rate in this case can be appropriately adjusted depending on the concentration of the solution, and can be set, for example, in the range of 0.1 mL / min to 200 mL / min, preferably 0.3 mL / min to 150 mL / min.
When the flow chemistry is used, the reaction temperature is 0 ° C. to 120 ° C., preferably room temperature to 100 ° C., more preferably 40 ° C. to 90 ° C., and further preferably 50 ° C. to 70 ° C. The reaction time depends on the amount of the raw material and the size of the reaction device such as a cartridge, but is from several seconds to 10 hours, preferably from several seconds to 5 hours.
The flow chemistry of the present invention is shown, for example, as shown in FIG. Further, when the reaction amount is large, it is also possible to carry out the reaction by connecting the reaction devices as shown in FIG. 2, for example.

Next, the present invention will be described in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto. The compound of the example was named ChemDraw ver. By Cambridgesoft. The structural formula drawn using No. 15 was converted into an English name by the naming algorithm installed in the software, and then translated into Japanese.

(4R, 4aS, 6S, 7R, 7aR, 12bS) -N-benzyl-3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,5,6,7a- Production of Octahydro-4a, 7-Etano-4,12-methanobenzoflo [3,2-e] isoquinoline-6-carboxamide

To a 100 L reactor, (4R, 4aR, 7R, 7aR, 12bS, 14S) -7-benzyl-3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,7, 7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinoline-14-carboxamide (2.84 kg, 1 eq), ethanol (29 L) and water (29 L) were added. Potassium formate (9.77 kg, 20 eq) and 10% palladium / carbon (1.45 kg) were added to the resulting solution and stirred at 75-80 ° C. for 8 hours.
The reaction mixture was cooled to room temperature and then filtered through a Celite pad to remove insoluble matter. The pad was washed with ethanol, the filtrate and the washing liquid were combined, and ethanol was concentrated under reduced pressure. The remaining aqueous layer was extracted with ethyl acetate (10 L × 3 times). The combined organic layers were washed with water (10 L × 2 times), dried over anhydrous sodium sulfate, filtered off, and concentrated under reduced pressure to give the title compound crude (2.81 kg).
The obtained crude product was crystallized from a 3: 1 mixed solution of n-heptane and ethyl acetate to give the title compound (2.62 kg, 92% yield, 98.03% purity) as a white solid.

The proton NMR of the obtained compound was in agreement with the value of compound 70 (Reference Example 10) described in Patent Document 1.

The potassium formate of Example 1 was changed to formic acid / triethylamine, and the following experiment was carried out in the same manner. To a 1000 L reactor, (4R, 4aR, 7R, 7aR, 12bS, 14S) -7-benzyl-3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,7, 7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinoline-14-carboxamide (9.00 kg, 1 equivalent), ethanol (202.5 L), tetrahydrofuran (67.5 L) and Water (54.0 L) was added. Formic acid (16.5 kg, 20 eq) and triethylamine (36.8 kg, 20 eq) were added to the obtained solution, and the mixture was stirred at room temperature for 30 minutes to prepare a transparent solution. 10% Palladium / carbon (3.64 kg) was added to the reaction mixture, and the mixture was stirred at 60-70 ° C. for 2 hours.
The reaction mixture was cooled to room temperature and then filtered through a Celite pad to remove insoluble matter. The pad was washed with ethanol, the filtrate and the washing liquid were combined, and concentrated to 60 L under reduced pressure. Water (45 L) was added to the remaining aqueous layer, and the mixture was extracted with ethyl acetate (45 L × 3 times). The combined organic layer was washed with 8% aqueous sodium hydrogen carbonate solution (90 L) and water (82 L), and the organic layer was concentrated to 10 L. Ethyl acetate (27 L) was added and stirred at 60-70 ° C. for 30 minutes, and then n-heptane (81 L) was added at the same temperature. The resulting mixture was stirred at 60-70 ° C for 30 minutes, then cooled to 10-20 ° C and stirred for 6 hours. The solid in the mixture was filtered off and dried to give the title compound crude (7.95 kg, 88% yield, 98.10% purity) as a white solid.

The proton NMR of the obtained compound was in agreement with the value of compound 70 (Reference Example 10) described in Patent Document 1.

The production of Example 2 was carried out using flow chemistry as follows.
To a 1000 L reactor, (4R, 4aR, 7R, 7aR, 12bS, 14S) -7-benzyl-3- (cyclopropylmethyl) -7-hydroxy-9-methoxy-1,2,3,4,7, 7a-Hexahydro-7,4a-Etano-4,12-methanobenzoflo [3,2-e] isoquinolin-14-carboxamide (9.0 kg, 1 eq), ethanol (202 L), tetrahydrofuran (67 L), water (54 L) , Formic acid (16.65 kg, 20 eq) and triethylamine (36.54 kg, 20 eq) were added and stirred at room temperature for 30 minutes to give a clear solution. Each of the 19 fixed bed reactors was filled with 10% palladium / carbon (0.18 kg, total 3.42 kg). After that, the mixed solution was sent to each stationary phase reactor heated to 70-80 ° C. at a flow rate of 126 mL / min for 3 hours each. Each reaction solution was combined and concentrated to 60 L. Water (45 L) was added to the remaining aqueous layer, and the mixture was extracted with ethyl acetate (45 L × 2 times). The combined organic layer was washed with 8% aqueous sodium hydrogen carbonate solution (90 L) and water (90 L), and the organic layer was concentrated to 10 L. Ethyl acetate (27 L) was added and stirred at 60-70 ° C. for 30 minutes, and then n-heptane (81 L) was added at the same temperature. The resulting mixture was stirred at 65-70 ° C for 30 minutes, then cooled to 10-20 ° C and stirred for 6 hours. The solid in the mixture was filtered off and dried to give the title compound crude (8.08 kg, 90% yield, 99.55% purity) as a white solid.

The proton NMR of the obtained compound was in agreement with the value of compound 70 (Reference Example 10) described in Patent Document 1.

Claims (26)

1. 

   (In the formula, R ¹ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, and a cycloalkylalkyl group which may have a substituent (the number of carbon atoms in the cycloalkyl moiety is 3 to 3 to In 6, the number of carbon atoms of the alkylene moiety is 1 to 5), and the aralkyl group which may have a substituent (the number of carbon atoms of the aryl moiety is 6 to 10 and the number of carbon atoms of the alkylene moiety is 1). ~ 5;), a heteroarylalkyl group which may have a substituent (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and is an alkylene moiety. The number of carbon atoms indicates 1 to 5), which represents a C _3-6 cycloalkyl group which may have a substituent or a C _6-10 aryl group which may have a substituent.
   R ² and R ³ are a hydrogen atom, 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 portion is 6 to 10, and the alkylene group is used. The number of carbon atoms in the moiety indicates 1 to 5) or represents a hydroxy protective group.
   R ⁴ , R ⁵ and R ⁶ are the same or different hydrogen atoms, C _1-10 alkyl groups which may have substituents, C _3-6 cycloalkyl groups which may have substituents, substitutions. _{Representing a C 6-10} aryl group which may have a group
   R ⁴ and R ⁵ represents an C _3-6 saturated hydrocarbon ring which may have a substituent bonded, which may have a substituent bonded R ⁵ and R ⁶ are C _3- Represents a _{C 3-6 cycloalkene which may have a 6-} saturated hydrocarbon ring or substituents.
   R ⁷ is 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, and a cycloalkyl which may have a substituent. Alkyl group (the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the number of carbon atoms in the alkylene moiety is 1 to 5), and the aralkyl group which may have a substituent (the number of carbon atoms in the aryl moiety is 1 to 5). 6 to 10, the number of carbon atoms of the alkylene moiety indicates 1 to 5), a heteroarylalkyl group which may have a substituent (heteroaryl is 1 to 4 selected from N, O and S). The heteroatom of the above is contained as a ring-constituting atom, and the number of carbon atoms of the alkylene moiety indicates 1 to 5), which may have a C _6-10 aryl group or a substituent. It represents a heteroaryl group (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety indicates 1 to 5).
   R ⁸ is a C _1-10 alkyl group which may have a substituent, a C _3-6 cycloalkyl group which may have a substituent, and a cycloalkyl alkyl group which may have a substituent ( The cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms), and an aralkyl group which may have a substituent (the aryl moiety has 6 to 10 carbon atoms). The number of carbon atoms in the alkylene moiety is 1 to 5), a heteroarylalkyl group which may have a substituent (heteroaryl is 1 to 4 heteroatoms selected from N, O and S). As a ring-constituting atom, the number of carbon atoms in the alkylene moiety is 1 to 5), an aryl group which may have a substituent or a heteroaryl group which may have a substituent (heteroaryl is It contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety indicates 1 to 5), representing an amino group. ) Is allowed to act in the presence of a palladium catalyst and formic acid or a salt thereof or a mixture of formic acid and trialkylamine, in a solvent or in the absence of a solvent, according to the following general formula (II).
   

   

   (In the formula, R ¹ to R ⁸ indicate the same as above.) A method for producing a compound represented by the above.
2. Claimed ^{that R 2} _{is a C 1-10} alkyl group which may have a hydrogen atom or a substituent, and R ³ is a C _1-10 alkyl group or a hydroxy protective group which may have a hydrogen atom or a substituent. Item 1. The manufacturing method according to Item 1.
3. The production method according to any one of claims 1 or 2, wherein R ² is a hydrogen atom or a methyl group, and R ³ _{is a C 1-10} alkyl group or a hydroxy protecting group which may have a substituent.
4. The production method according to any one of claims 1 to 3, wherein R ² is a hydrogen atom or a methyl group, and R ^{3 is a methyl group or a silyl protecting group.}
5. R ⁷ is a hydrogen atom, a C _1-10 alkyl group which may have a substituent, and a cycloalkylalkyl group which may have a substituent (the cycloalkyl moiety has 3 to 6 carbon atoms and is alkylene. The number of carbon atoms in the moiety indicates 1 to 5), the 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 indicates 1 to 5). ), An aryl group which may have a substituent, a heteroaryl group which may have a substituent, or a heteroarylalkyl group which may have a substituent (heteroaryl is from N, O and S). The production method according to any one of claims 1 to 4, wherein 1 to 4 selected heteroatoms are contained as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety is 1 to 5).
6. C _1-10 alkyl group in which R ¹ may have a substituent, cycloalkylalkyl group in which a substituent may be present (the number of carbon atoms in the cycloalkyl moiety is 3 to 6, and the carbon in the alkylene moiety). The number of atoms indicates 1 to 5) or 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 indicates 1 to 5). The production method according to any one of claims 1 to 5, which is a substituent selected from.
7. R ¹ may have a substituent C _1-10 alkyl group or a cycloalkyl alkyl group which may have a substituent (the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the carbon in the alkylene moiety). The production method according to any one of claims 1 to 6, which is a substituent according to any one of (1 to 5).
8. Claims 1 to 1 to which R ¹ is a cycloalkylalkyl group which may have a substituent (the number of carbon atoms of the cycloalkyl moiety is 3 to 6 and the number of carbon atoms of the alkylene moiety is 1 to 5). The manufacturing method according to any one of 7.
9. The production method according to claim 8, wherein the cycloalkylalkyl group which may have the substituent according to claim 8 is a cyclopropylmethyl group.
10. The production method according to any one of claims 1 to 7, wherein R ¹ _{is a C 1-10} alkyl group which may have a substituent.
11. The production method according to claim 10 _{, wherein the C 1-10} alkyl group which may have the substituent according to claim 10 is a methyl group.
12. The production method according to any one of claims 1 to 11, wherein the palladium catalyst according to claim 1 is a palladium-supported catalyst.
13. The production method according to claim 12, wherein the palladium-supporting catalyst according to claim 12 is selected from palladium / carbon, palladium / carbon hydroxide, palladium / alumina, and palladium / barium sulfate.
14. The production method according to claim 13, wherein the palladium-supporting catalyst according to claim 13 is selected from palladium / carbon and palladium / carbon hydroxide.
15. The production method according to any one of claims 12 to 14, wherein the amount of the palladium-supported catalyst used according to claims 12 to 14 is 5 to 100 mol% with respect to the compound of the general formula (I).
16. The production method according to any one of claims 12 to 14, wherein the amount of the palladium-supported catalyst used according to claims 12 to 14 is 10 to 60 mol% with respect to the compound of the general formula (I).
17. The production method according to any one of claims 1 to 16, wherein the salt of formic acid or a salt thereof according to claim 1 is a salt with ammonia, amines or an alkali metal.
18. The production method according to claim 15, wherein the salt in the formic acid or a salt thereof according to claim 17 is potassium formate.
19. The production method according to any one of claims 1 to 16, wherein the trialkylamine in the mixture of formic acid and trialkylamine according to claim 1 is triethylamine.
20. The production method according to claim 19, wherein the molar ratio of the mixture of formic acid and triethylamine according to claim 19 is 10: 1 to 1: 1.
21. The production method according to claim 20, wherein the molar ratio of the mixture of formic acid and triethylamine according to claim 20 is 1: 1.
22. Any of claims 1 to 21, wherein the solvent according to claim 1 is selected from an alcohol solvent, a ketone solvent, an ether solvent, an aprotonic polar solvent, a hydrocarbon solvent, an ester solvent, water, or a mixed solution thereof. The manufacturing method described in item 1.
23. The production method according to claim 21, wherein the solvent according to claim 21 is selected from an alcohol solvent, an ether solvent, an ester solvent, water, or a mixed solution thereof.
24. The production method according to claim 23, wherein the solvent according to claim 23 is selected from an alcohol solvent, water, or a mixed solution thereof.
25. The manufacturing method according to claims 1 to 24, wherein the manufacturing method according to claims 1 to 24 is based on flow chemistry.
26. The production method according to any one of claims 1 to 25, wherein the compound represented by the general formula (II) is a compound selected from the compounds represented by the following numbers 1 to 58 or a salt thereof.
    

    

    

    

    

    

    

    

    

    

    

    

    

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