Method for producing cis-(-) flocinopiperidol

Abstract

To provide a method for producing cis-(-)-flocinopiperidol with surprisingly high selectivity.SOLUTION: The present invention provides a method in which: when using (+)-dibenzoyl-D-tartaric acid to optically divide (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone, an ether-based solvent is added to obtain (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate in extremely high yield, a slurry thereof is treated with a base, and a "three-dimensionally bulky reducing agent" is subsequently used.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a process for the preparation of various intermediates of alvocidib which are useful as pharmaceuticals. [Background technology]

[0002] Alvocidib (flavopiridol, chemical name: 2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]-4H-1-benzopyran-4-one) has the following structure:

[0003] [ka] Alvocidib is a synthetic flavone having the formula: Alvocidib is a potent and selective inhibitor of cyclin-dependent kinases (CDKs) and is an attractive cancer treatment currently in clinical development for hematological malignancies.

[0004] Known methods for producing cis-(-)-furosinopiperidol, which is an intermediate of alvocidib, are described, for example, in Patent Document 1 and Non-Patent Document 1. Also known methods for producing 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one, which is an intermediate in the production of cis-(-)-furosinopiperidol, are described, for example, in Non-Patent Document 2, Patent Document 2, and Patent Document 3.

[0005] Patent Document 1 and Non-Patent Document 1 describe a method for obtaining cis-(-)-furosinopiperidol from (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one.

[0006] Patent Document 2 and Non-Patent Document 2 describe a method for obtaining cis-(-)-furosinopiperidol from (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol.

[0007] Patent Document 3 describes a method for obtaining cis-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one from (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] WO 98 / 13344 [Patent Document 2] U.S. Pat. No. 4,900,727 [Patent Document 3] U.S. Pat. No. 5,849,733 [Non-patent literature]

[0009] [Non-Patent Document 1] KS Kim, et al., J. Med. Chem. 43, 4126(2000) [Non-Patent Document 2] R. Naik., et al., Tetrahedron 44, 2081(1988) Summary of the Invention [Means for solving the problem]

[0010] The present invention relates to a method for producing cis-(-)-furosinopiperidol suitable for industrial production. That is, the present invention provides a method for producing high-purity cis-(-)-furosinopiperidol safely, simply, and in high yield.

[0011] In more detail, as a result of intensive investigations, the present inventors have found that by reacting "(±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol (1)" with "sulfur trioxide complex (2)" in an appropriate solvent, "(±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (3)" (also referred to as "(±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one" in this specification) can be produced at around room temperature and in high yield. Furthermore, when (3) was subjected to dynamic kinetic optical resolution using (+)-dibenzoyl-D-tartaric acid (4), the addition of an ether solvent gave (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate (5) (also referred to as (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one in this specification) in extremely high yield. In addition, the free form (6) of (5) is usually unstable, but it was found that it can be handled stably by treating a slurry of (5) with a base, and that (6) can be reduced to cis-(-)-furosinopiperidol (I) with surprisingly high selectivity by using a sterically bulky reducing agent (7).

[0012] [ka]

[0013] That is, the present invention is as follows.

[0014] [Item 1] A method for producing a compound represented by formula (I), comprising the following step (d): [ka] A method for producing cis-(-)-furosinopiperidol or a salt thereof, or a solvate thereof, represented by the following formula: (d) Formula (6) [ka] or a salt thereof, or a solvate thereof, in a solvent. Formula (7) [ka] or a solvate thereof, wherein M is an alkali metal. By reacting with Formula (I) [ka] A process for producing cis-(-)-furosinopiperidol represented by the formula:

[0015] [Item 2] The method according to item 1, wherein M in the formula (7) used in the step (d) is lithium, sodium or potassium.

[0016] [Item 3] The method according to item 1 or 2, wherein M in the formula (7) used in the step (d) is lithium.

[0017] [Item 4] The method according to any one of items 1 to 3, wherein in the step (d), the product after the reduction reaction is extracted with an acidic aqueous solution and the pH of the extracted solution is increased to obtain the compound of formula (I) or a solvate thereof.

[0018] [Item 5] The method according to any one of items 1 to 4, wherein in the step (d), the product after the reduction reaction is extracted with an acidic aqueous solution, and the extracted solution is added dropwise to a basic aqueous solution to obtain the compound of formula (I) or a solvate thereof.

[0019] [Item 6] The method according to any one of Items 1 to 5, wherein in the step (d), the acidic aqueous solution has a pH of 6.0 to 6.5.

[0020] [Item 7] The method according to any one of Items 1 to 6, wherein in the step (d), the acidic aqueous solution has a pH of 6.0.

[0021] [Item 8] The method according to any one of Items 1 to 7, further comprising the following step (c) prior to the step (d): (c) Formula (5) [ka] or a solvate thereof is reacted with a base in a solvent, Formula (6) [ka] A process for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by the following formula:

[0022] [Item 9] The method according to any one of Items 1 to 8, wherein the base used in the step (c) is an organic base.

[0023] [Item 10] The method according to any one of Items 1 to 9, wherein the base used in the step (c) is a tertiary amine.

[0024] [Item 11] The method according to any one of items 1 to 10, wherein the solvent used in the step (c) is an ether solvent.

[0025] [Item 12] The method according to any one of items 1 to 11, wherein in the step (c), the product neutralized with a base is not isolated, and the step (d) is carried out in a solution state.

[0026] [Item 13] The method according to any one of items 1 to 12, further comprising the following step (b) before the step (c): (b) Formula (3) [ka] or a salt thereof, or a solvate thereof, in a reaction solvent. Formula (4) [ka] (+)-Dibenzoyl-D-tartaric acid or a salt thereof, or a solvate thereof, represented by the formula: By reacting with Formula (5) [ka] A process for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate represented by the following formula (1):

[0027] [Item 14] The method according to any one of items 1 to 13, wherein in the step (b), the reaction solvent is at least one selected from the group consisting of ester solvents, ether solvents, alcohol solvents, amide solvents, nitrile solvents, and aromatic solvents.

[0028] [Item 15] The method according to any one of items 1 to 14, wherein the reaction solvent used in the step (b) is an alcohol solvent.

[0029] [Item 16] The method according to any one of items 1 to 15, characterized in that in the step (b), (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3) or a salt thereof, or a solvate thereof is reacted with a compound represented by formula (4), and then a poor solvent is added to the reaction solution to precipitate a compound represented by formula (5) or a solvate thereof.

[0030] [Item 17] The method according to any one of items 1 to 16, wherein the poor solvent used in the step (b) is at least one poor solvent selected from the group consisting of ester solvents, ether solvents, alkane solvents, and aromatic solvents.

[0031] [Item 18] The method according to any one of Items 1 to 17, wherein the poor solvent used in the step (b) is an ether solvent.

[0032] [Item 19] The method according to any one of items 1 to 18, further comprising the following step (a) before the step (b): (a) Formula (1) [ka] or a salt thereof, or a solvate thereof, Formula (2) [ka] or a salt or solvate thereof, wherein Y is a 5- to 10-membered heteroaryl group, a tertiary amine, or an amide; and a dialkyl sulfoxide By reacting with Formula (3) [ka] A process for producing (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by the following formula:

[0033] [Item 20] The method according to any one of Items 1 to 19, wherein Y in the formula (2) used in the step (a) is pyridine.

[0034] [Item 21] The method according to any one of items 1 to 20, wherein the reaction in step (a) is carried out at a temperature of -10°C or higher.

[0035] [Item 22] The method according to any one of items 1 to 21, wherein the reaction in step (a) is carried out at a temperature of 0°C to 30°C. [Item 23] The method comprises the following step (c), [ka] A method for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone, a salt thereof, or a solvate thereof, represented by the following formula: (c) Formula (5) [ka] or a solvate thereof is reacted with a base in a solvent, Formula (6) [ka] A process for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by the following formula:

[0036] [Item 24] The method according to Item 23, wherein the base used in step (c) is an organic base.

[0037] [Item 25] The method according to any one of Items 23 and 24, wherein the base used in step (c) is a tertiary amine.

[0038] [Item 26] The method according to any one of Items 23 to 25, wherein the solvent used in the step (c) is an ether solvent. [Item 27] ​​The method comprises the following step (b), [ka] A method for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate or a solvate thereof represented by the following formula: (b) Formula (3) [ka] or a salt thereof, or a solvate thereof, in a reaction solvent. Formula (4) [ka] (+)-Dibenzoyl-D-tartaric acid or a salt thereof, or a solvate thereof, represented by the formula: By reacting with Formula (5) [ka] A process for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate represented by the following formula (1):

[0039] [Item 28] The production method according to Item 27, wherein in the step (b), the reaction solvent is at least one reaction solvent selected from the group consisting of ester solvents, ether solvents, alcohol solvents, amide solvents, nitrile solvents, and aromatic solvents.

[0040] [Item 29] The method according to item 27 or 28, wherein the reaction solvent used in step (b) is an alcohol solvent.

[0041] [Item 30] The method according to any one of Items 27 to 29, characterized in that in the step (b), (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3) or a salt thereof, or a solvate thereof is reacted with a compound represented by formula (4), and then a poor solvent is added to the reaction solution to precipitate a compound represented by formula (5) or a solvate thereof.

[0042] [Item 31] The method according to any one of Items 27 to 30, wherein the poor solvent used in the step (b) is at least one poor solvent selected from ester solvents, ether solvents, alkane solvents, and aromatic solvents.

[0043] [Item 32] The method according to any one of Items 27 to 31, wherein the poor solvent used in the step (b) is an ether solvent.

[0044] [Item 33] The method comprises the following step (a): Formula (3) [ka] A method for producing (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone, a salt thereof, or a solvate thereof, represented by the following formula: (a) Formula (1) [ka] or a salt thereof, or a solvate thereof, Formula (2) [ka] or a salt or solvate thereof, wherein Y is a 5- to 10-membered heteroaryl group, a tertiary amine, or an amide; and a dialkyl sulfoxide By reacting with Formula (3) [ka] A process for producing (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by the following formula:

[0045] [Item 34] The method according to Item 33, wherein Y in the formula (2) used in the step (a) is pyridine.

[0046] [Item 35] The method according to any one of Items 33 and 34, wherein the reaction in step (a) is carried out at a temperature of -10°C or higher.

[0047] [Item 36] The method according to any one of Items 33 to 35, wherein the reaction in step (a) is carried out at a temperature of 0°C to 30°C.

[0048] It is contemplated that one or more of the above features may be provided in combinations other than those specifically described. Further embodiments and advantages of the present invention will be recognized by those skilled in the art upon reading and understanding the following detailed description, if necessary. Effect of the Invention

[0049] According to the manufacturing method of the present invention, cis-(-)-furosinopiperidol can be produced in high yield, with high selectivity, and with high purity, compared to known manufacturing methods, and has the advantages of being highly reproducible, safe, inexpensive, and simple.

[0050] The present invention provides an industrially suitable method for efficiently producing the target compound without the need for column chromatographic purification, because the selectivity of the reduction leading to cis-(-)-furosinopiperidol is significantly higher than that of the known production methods described in the prior art (step (d)).

[0051] Furthermore, the present invention provides advantages such as a higher yield of dynamic kinetic resolution and ease of operation since there is no need to isolate the free form after neutralization, as compared with known production methods described in the prior art (steps (b) and (c)).

[0052] In addition, in the reaction of the present invention, the oxidation of alcohol, which previously required an extremely low temperature of about -60°C, can be carried out at about room temperature, making the production easier (step (a)). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] The present invention will be described below while showing the best mode. Throughout this specification, the expression of the singular form should be understood to include the concept of the plural form, unless otherwise specified. Therefore, the singular article (for example, in the case of English, "a", "an", "the", etc.) should be understood to include the concept of the plural form, unless otherwise specified. In addition, it should be understood that the terms used in this specification are used in the sense commonly used in the field, unless otherwise specified. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In case of conflict, this specification (including definitions) will take precedence.

[0054] The terms used in this specification are explained below.

[0055] In the present invention, the term "solvate" refers to a complex formed by combining a compound with a solvent. Examples of the solvate include hydrates, methanol solvates, and ethanol solvates.

[0056] As used herein, "a certain compound, or a salt thereof, or a solvate thereof" means the compound, a salt of the compound, a solvate of the compound, or a solvate of a salt of the compound.

[0057] In this specification, the term "ester solvent" refers to a compound containing one or more ester bonds in the molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "ester solvent" include methyl formate, ethyl formate, propyl formate, isopropyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, and isobutyl acetate. Preferred are ethyl acetate and isopropyl acetate.

[0058] In this specification, the term "ether solvent" refers to a compound containing one or more ether bonds in the molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "ether solvent" include dimethyl ether, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 2-methyltetrahydrofuran, and cyclopentyl methyl ether. Preferably, methyl tertiary butyl ether is used.

[0059] In this specification, the term "alcohol-based solvent" refers to a compound that contains one or more hydroxyl groups in the molecule, is liquid at the reaction temperature, and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "alcohol-based solvent" include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, and tert-butyl alcohol. Methanol is preferable.

[0060] In this specification, the term "amide solvent" refers to a compound containing one or more amide bonds in the molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "amide solvent" include N,N-dimethylacetamide, N,N-dimethylformamide, and N-methyl-2-pyrrolidone.

[0061] In this specification, the term "nitrile solvent" refers to a compound containing one or more cyano groups in the molecule, which is liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "nitrile solvent" include acetonitrile and propionitrile.

[0062] In this specification, the term "alkane solvent" refers to a non-aromatic compound consisting only of carbon and hydrogen, which is liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of the "alkane solvent" include n-pentane, n-hexane, and n-heptane.

[0063] In this specification, the term "aromatic solvent" refers to a compound containing one or more benzene rings, which is liquid at reaction temperatures and has the property of dissolving or dispersing reaction substrates. Specific examples of the "aromatic solvent" include toluene, xylene, and mesitylene.

[0064] As used herein, "dialkyl sulfoxide" refers to 1-10 It is a sulfoxide having two alkyl groups, and specific examples thereof include dimethyl sulfoxide, dibutyl sulfoxide, and dodecyl methyl sulfoxide. Dimethyl sulfoxide is preferable.

[0065] In this specification, the term "5- to 10-membered heteroaryl group" refers to a group containing 1 to 4 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and includes a monocyclic 5- to 7-membered aromatic heterocyclic group (a "5- to 7-membered heteroaryl group") and a bicyclic 8- to 10-membered aromatic heterocyclic group (a "8- to 10-membered heteroaryl group").

[0066] The "5- to 10-membered heteroaryl group" is preferably a monocyclic 5- to 7-membered aromatic heterocyclic group ("5- to 7-membered heteroaryl group"), more preferably a 5- or 6-membered monocyclic aromatic heterocyclic group ("5- to 6-membered heteroaryl group"), and most preferably a 6-membered monocyclic aromatic heterocyclic group ("6-membered heteroaryl group").

[0067] Specific examples of the "5- to 10-membered heteroaryl group" include a pyridyl group, a pyridazinyl group, an imidazolyl group, a pyrimidinyl group, a pyrazolyl group, an oxazolyl group, an isoxazolyl group, a pyrazinyl group, a triazinyl group, a triazolyl group, a tetrazolyl group, an indolyl group, an indazolyl group, a quinolyl group, an isoquinolyl group, a benzimidazolyl group, a quinoxalyl group, a naphthyridinyl group, a pyrrolo[3,2-c]pyridinyl group, a pyrido[3,2-d]pyridinyl group, a pyrido[3,2-d]pyrimidinyl group, an imidazolo[4,5-c]pyridyl group, and a 2-oxo-1,2-dihydro-1,7-naphthyridinyl group.

[0068] The "5- to 10-membered heteroaryl group" is preferably a pyridyl group, a pyrimidinyl group, an imidazolyl group, or a pyridazinyl group, more preferably a pyridyl group, a pyrimidinyl group, or an imidazolyl group, further preferably a pyridyl group or a pyrimidinyl group, and most preferably a pyridyl group.

[0069] As used herein, the term "amide" refers to a compound containing one or more amide bonds in the molecule, and is preferably N,N-dimethylacetamide, N,N-dimethylformamide, or N-methyl-2-pyrrolidone, and more preferably N,N-dimethylformamide.

[0070] As used herein, the term "base" includes both inorganic bases and organic bases.

[0071] Specific examples of the "inorganic base" include, but are not limited to, ammonia, lithium hydroxide, sodium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or a mixture thereof. Preferably, lithium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate is used. More preferably, sodium carbonate, potassium carbonate, or cesium carbonate is used. Most preferably, potassium carbonate or cesium carbonate is used.

[0072] Specific examples of the "organic base" include triethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, N,N-dimethylaniline, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, 1,4-diazabicyclo[2.2.2]octane, N-methylmorpholine, diazabicycloundecene, methylamine, diisopropylamine, pyrimidine, or pyridine. More preferably, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, or pyridine. Even more preferably, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, or pyridine. Most preferably, triethylamine is used.

[0073] Specific examples of the "tertiary amine" include triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, and N-methylmorpholine. More preferably, triethylamine is used.

[0074] Specific examples of "acidic aqueous solutions" include, but are not limited to, aqueous solutions of acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glutamic acid, glucorenic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, potassium hydrogen sulfate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, etc. Preferred examples include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, potassium hydrogen sulfate, potassium dihydrogen phosphate, and sodium dihydrogen phosphate.

[0075] Specific examples of the "basic aqueous solution" include, but are not limited to, ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, or mixtures thereof. Preferably, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or cesium carbonate is used.

[0076] As used herein, examples of acids that form "salts" include, but are not limited to, acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid, formic acid, fumaric acid, furoic acid, gluconic acid, glutamic acid, glucorenic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0077] The method for producing the compound of formula (I) according to the present invention, or a salt thereof or a solvate thereof as necessary, is described below. (±)1-Methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol (1) can be produced by the method described in Patent Document 2 or Patent Document 3, a method similar thereto, or a suitable combination of synthetic methods well known to those skilled in the art.

[0078] The compounds obtained in each step can be used in the next reaction either as a reaction solution or as a mixture, or can be isolated from the reaction mixture in a conventional manner and easily purified by a separation means such as recrystallization, distillation, or chromatography.

[0079] In the following reactions, each symbol of the compound has the same meaning as defined above unless otherwise specified.

[0080] The production methods of the compounds of the present invention will be described below with reference to examples, but the present invention is not limited to these.

[0081] These production methods can be appropriately improved based on the knowledge of those skilled in organic synthetic chemistry. In the production methods described below, the compounds used as raw materials may be used in the form of salts thereof, so long as they do not interfere with the reaction.

[0082] In the following production methods, even if the use of a protective group is not specifically indicated, if any functional group other than the reactive site changes under the reaction conditions or if it is not suitable for post-reaction treatment, the target compound can be obtained by protecting the functional group other than the reactive site as necessary and deprotecting it after the reaction or after a series of reactions. The protective groups used in these processes are described in the literature (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3 rd Ed., John Wiley and Sons, Inc., New York (1999) The introduction and removal of the protecting group can be carried out by a method commonly used in organic synthesis chemistry (for example, the methods described in the above-mentioned documents) or a method similar thereto.

[0083] The starting materials and intermediates in the following production methods are commercially available or can be obtained by synthesis from known compounds according to known methods or methods described in known publications. These starting materials and intermediates may be used in the form of salts or solvates, provided that they do not interfere with the reaction.

[0084] Manufacturing method [ka]

[0085] As described below, in the method of the present invention, the step (d) of reducing the cyclic ketone substituted at the α-position in a cis-selective manner is one of the most important features, but the steps (a), (b) and (c) are also important features of the present invention. The steps (a), (b), (c) and (d) will be described below with reference to preferred embodiments, but the present invention is not limited thereto.

[0086] Process (a) [ka]

[0087] (In the formula, Y is a 5- to 10-membered heteroaryl group, a tertiary amine, or an amide.)

[0088] The (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol represented by formula (1) can be a commercially available product or can be produced by the method described in various documents. For example, it can be produced by the method described in Patent Document 2.

[0089] The sulfur trioxide complex represented by formula (2) can be commercially available or can be prepared by methods described in various literature, for example, DC Akwaboah, et al., Org. It can be produced by the method described in Lett. 19, 1180 (2017).

[0090] This process involves reacting (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol represented by formula (1) with a sulfur trioxide complex represented by formula (2) and a dialkyl sulfoxide in a solvent or without a solvent to obtain (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3).

[0091] The dialkyl sulfoxide used in this step includes dimethyl sulfoxide, dibutyl sulfoxide, and dodecyl methyl sulfoxide. Dimethyl sulfoxide is preferable. The solvent used in this step includes dichloromethane, but a dialkyl sulfoxide may be used as the solvent.

[0092] The amount of the compound represented by formula (2) used is usually 0.8 to 10 equivalents, preferably 2.5 to 3.5 equivalents, relative to 1 equivalent of the compound represented by formula (1).

[0093] The amount of dialkyl sulfoxide used is usually 0.8 to 10 equivalents, preferably 6 to 7 equivalents, relative to 1 equivalent of the compound represented by formula (1).

[0094] The reaction time is usually about 1 to 12 hours, and preferably 2 to 4 hours.

[0095] The reaction temperature is usually from -10°C to 50°C, and preferably from 10°C to 30°C.

[0096] Process (b) [ka]

[0097] The (+)-dibenzoyl-D-tartaric acid represented by formula (4) is a commercially available product.

[0098] This step is a step of obtaining only (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate (a compound having a specific stereochemistry related to (+)-dibenzoyl-D-tartaric acid) represented by formula (5) by dynamic kinetic resolution of the racemic compound related to (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3) produced in the above-mentioned production step (a) using (+)-dibenzoyl-D-tartaric acid represented by formula (4) in a reaction solvent. In this specification, the solvent used in the chemical reaction of this step (b) is referred to as the "reaction solvent". As the reaction solvent, any solvent may be used as long as it contributes to the progress of the reaction of step (b).

[0099] The reaction solvent may be, for example, at least one solvent selected from ester solvents, ether solvents, alcohol solvents, amide solvents, nitrile solvents, and aromatic solvents. The reaction solvent used in this reaction is preferably an alcohol solvent. More preferably, methanol is used.

[0100] In addition, in this reaction, it is preferable to react (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (3) or a salt thereof, or a solvate thereof with a compound represented by formula (4), and then add a poor solvent to the reaction solution to precipitate a compound represented by formula (5) or a solvate thereof. A "poor solvent" is a solvent in which the solubility of the target product in the reaction solvent is lower in a mixture of the reaction solvent and the poor solvent when the poor solvent is added to the reaction solution than the solubility of the target product in the reaction solvent, and a person skilled in the art can appropriately select a poor solvent appropriate for the reaction solvent to be used by referring to the description in this specification and known techniques. Examples of poor solvents include at least one poor solvent selected from ester solvents, ether solvents, alkane solvents, and aromatic solvents. Examples of poor solvents include ether solvents. Examples of methyl-tertiary butyl ether are more preferable.

[0101] The amount of the compound represented by formula (4) used is usually 0.8 to 10 equivalents, preferably 1 to 1.5 equivalents, relative to 1 equivalent of the compound represented by formula (3).

[0102] The reaction time is usually about 10 minutes to 10 hours, and preferably 30 minutes to 2 hours.

[0103] The reaction temperature is usually from -10°C to 100°C, and preferably from 40°C to 60°C.

[0104] Process (c) [ka]

[0105] This step is a step of treating (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone (+)-dibenzoyl-D-tartrate salt represented by formula (5) obtained in the above step (b) with a base. This base treatment removes tartaric acid, and (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (6) is produced in the system.

[0106] The base used in this step is preferably an organic base. More preferably, it is a tertiary amine. Even more preferably, it is triethylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, or N-methylmorpholine. Most preferably, it is triethylamine.

[0107] The solvent used in this reaction may be an ester solvent, an ether solvent, an alcohol solvent, an amide solvent, a nitrile solvent, or an aromatic solvent. More preferably, an ether solvent may be used. Even more preferably, 1,2-dimethoxyethane and / or tetrahydrofuran may be used.

[0108] This reaction is preferably characterized in that it is carried out consecutively to step (d), in which case step (d) is carried out without isolating the compound represented by formula (6).

[0109] The amount of the base used is usually 1 to 10 equivalents, preferably 3 to 5 equivalents, relative to 1 equivalent of the compound represented by formula (5).

[0110] The reaction time is usually about 10 minutes to 10 hours, and preferably 20 minutes to 1 hour.

[0111] The reaction temperature is usually from -10°C to 50°C, and preferably from 10°C to 25°C.

[0112] Process (d) [ka]

[0113] This step is a step in which (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)-3-piperidinone represented by formula (6) obtained in the step (c) is reduced in a solvent using triisobutylborohydride salt represented by formula (7) to obtain cis-(-)-furosinopiperidol represented by formula (I).

[0114] The amount of the triisobutylborohydride salt represented by formula (7) used is usually 1 to 10 equivalents, preferably 1.5 to 3 equivalents, relative to 1 equivalent of the compound represented by formula (6). Preferred examples of the triisobutylborohydride salt include sodium triisobutylborohydride, potassium triisobutylborohydride, and lithium triisobutylborohydride. More preferred examples include lithium triisobutylborohydride. That is, preferred examples of the alkali metal M according to formula (7) include lithium, sodium, and potassium, more preferred examples include lithium.

[0115] The solvent used in this reaction is preferably an ether solvent or an aromatic solvent. An ether solvent is preferable. More preferably, 1,2-dimethoxyethane and / or tetrahydrofuran is preferable. The reaction time is usually about 10 minutes to 10 hours, and preferably 1 hour to 3 hours.

[0116] The reaction temperature is usually from -10°C to 50°C, and preferably from -5°C to 15°C.

[0117] The post-treatment of this reaction is preferably characterized in that the product after the reduction reaction is extracted with an acidic aqueous solution, and the pH of the extracted solution is increased (for example, the extracted solution is dropped into a basic aqueous solution) to obtain the compound represented by formula (I). The pH of the acidic aqueous solution is preferably 5.5 to 6.5, and more preferably 6.0 to 6.4. As the basic aqueous solution, preferred are an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution, an aqueous potassium carbonate solution, an aqueous cesium carbonate solution, and an aqueous sodium hydrogen carbonate solution. Preferred are an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, and an aqueous potassium hydroxide solution. More preferred are an aqueous 3 to 20% potassium hydroxide solution. Most preferred are an aqueous 5 to 10% potassium hydroxide solution.

[0118] According to the production method (d) of the present invention, cis-(-)-furosinopiperidol can be produced cheaply, safely, with high purity and in high yield. In addition, by carrying out steps (a), (b) and (c) on a starting material, each intermediate can be produced cheaply, safely and simply.

[0119] The compound of formula (1) is a known substance and can be easily synthesized according to the method described in the known literature. By carrying out step (a) using this compound in dimethyl sulfoxide in the presence of a sulfur trioxide pyridine complex, the compound of formula (3) can be produced in high yield, high purity, inexpensively, safely and simply. While the commonly used Swern oxidation requires an extremely low temperature of -60°C, this reaction can be carried out at around room temperature, which is extremely useful for production.

[0120] By carrying out step (b) of forming a salt from the compound of formula (3) and the compound of formula (4) in methanol, followed by the addition of methyl tertiary butyl ether (MTBE), crystals of the compound of formula (5) can be produced in high yield, high purity, inexpensively, safely and simply. In the method described in the known literature, the second crystal is obtained from the filtrate after crystallization, but in this reaction, only the first crystal is obtained, making it possible to produce the compound in a higher yield. The operation is simpler and more useful for production.

[0121] By carrying out step (c) using the compound of formula (5) and triethylamine as a base in a mixed solvent of 1,2-dimethoxyethane (DME) and tetrahydrofuran (THF), an ether solution of formula (6) can be produced in high yield, high purity, inexpensively, safely and stably. The compound of formula (6) easily racemises, but this reaction can produce the compound of formula (6) with high optical purity without racemisation.

[0122] By carrying out step (d) in an ethereal solvent using an ether solution of the compound of formula (6) and lithium triisobutylborohydride, cis-(-)-furosinopiperidol can be produced in high yield, high selectivity, and high purity. In known methods, such as Non-Patent Document 1, the cis / trans selectivity of cis-(-)-furosinopiperidol is about 7 / 3, but this reaction shows a surprising selectivity of 99.8 / 0.2. In addition, this makes purification easy and does not require purification by silica gel column chromatography, making it extremely useful in production.

[0123] The order of adding the reagents is not limited to the above. EXAMPLES

[0124] The present invention will be described in more detail below with reference to the following Reference Examples and Examples, but the present invention is not limited thereto. The compounds were identified by elemental analysis, mass spectrometry, high performance liquid chromatography mass spectrometry (LCMS), NMR spectrometry, high performance liquid chromatography (HPLC), etc.

[0125] The measurement conditions for high performance liquid chromatography (HPLC) are as follows, and the retention time is indicated as Rt (min). The measurement conditions used for each measured value are also indicated. In the following, the HPLC purity (area%) is calculated by comparing the peak areas using one of the measurement conditions below.

[0126] Method A Column: Kinetex 1.7um C18 100A (100×2.1mm) Eluent: Solution A: 0.01 mol / l disodium hydrogen phosphate aqueous solution, Solution B: acetonitrile Gradient conditions:

[0127] [Table 1] Flow rate: 1.2mL / min Column temperature: 40℃ Wavelength: 230nm

[0128] The Rt of 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol measured by Method A is shown in the table below.

[0129] [Table 2]

[0130] Method B Column: Kinetex 1.7um C18 100A (100×2.1mm) Eluent: Solution A: 0.05% trifluoroacetic acid aqueous solution, Solution B: acetonitrile (0.05% trifluoroacetic acid Gradient conditions:

[0131] [Table 3] Flow rate: 0.3mL / min Column temperature: 40℃ Wavelength: 220nm

[0132] The Rt values ​​of 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one, (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one and cis-(-)-furosinopiperidol measured by method B are shown in the table below.

[0133] [Table 4]

[0134] Method C Column: Chiralpak AD 5um (250×4.6mm) Eluent: heptane / 2-propanol / triethylamine: 80 / 20 / 0.02 Flow rate: 0.5mL / min Column temperature: 40℃ Wavelength: 235nm

[0135] The Rt values ​​of 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one, (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one and cis-(-)-furosinopiperidol measured by Method C are shown in the table below.

[0136] [Table 5]

[0137] In order to simplify the description of the specification, the following abbreviations may be used in the examples and tables therein. MTBE: Methyl tertiary butyl ether DME: 1,2-dimethoxyethane; THF: tetrahydrofuran; DBU: 1,8-diazabicyclo[5.4.0]-7-undecene, DMF: N,N-dimethylformamide MEK: Methyl ethyl ketone DMSО: Dimethyl sulfoxide CDCl3: Deuterated chloroform MeOH: Methanol min:minutes The symbols used in NMR are δ for chemical shift, s for singlet, d for doublet, t for triplet, q for quartet, m for multiplet, and J for spin coupling constant.

[0138] The present invention will now be described in more detail with reference to examples and reference examples, but the technical scope of the present invention is not limited to these examples. In addition, the compounds may be modified within the scope of the present invention. The compound names shown in the following examples and reference examples do not necessarily conform to the IUPAC nomenclature.

[0139] Example 1: Method for the preparation of (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one

[0140] [ka]

[0141] Under a nitrogen atmosphere, sulfur trioxide pyridine complex (52.6 g) was dissolved in dimethyl sulfoxide (172 g) at 30° C. and cooled to 15° C. In a separate vessel, under a nitrogen atmosphere, (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol hydrochloride (35 g) was suspended in dimethyl sulfoxide (55.9 g), and diisopropylethylamine (56.9 g) was added dropwise while maintaining the temperature at 20° C., followed by DBU (16.77 g) at 20° C. The dimethyl sulfoxide solution of the sulfur trioxide pyridine complex was added dropwise to this suspension while maintaining the internal temperature at 20°C, and the resulting solution was stirred at 20°C for 2 hours. Chilled toluene (210g) was added dropwise at 20°C, and the resulting solution was cooled to 10°C. Water (245g) was added dropwise at 10°C, and the temperature was raised to 25°C. After separation, the lower aqueous layer was extracted twice with toluene (105g), and after combining with the upper separated layer, the organic layer was washed twice with saturated saline (140g), saturated aqueous ammonium chloride (70g), and water (35g). Toluene (105g) was added and concentrated to an amount of 96g. MTBE (280g) was added and concentrated to an amount of 98g. MTBE (280g) was added and concentrated to an amount of 95g. MTBE (280g) was added and concentrated to an amount of 91g. The residue was heated to 55°C, acetonitrile (10.5g) was added, and heptane (65g) was added dropwise at 55°C. After cooling to 30°C, a small amount of 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one was added and stirred at 30°C. After heating again to 55°C, the mixture was filtered, and the filtrate was cooled to 30°C. A small amount of 1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one was added again and cooled to 0°C. Heptane (65g) was added, and the precipitate was collected by filtration. The precipitate was washed with a mixed solvent of MTBE and heptane, and then dried to obtain (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (18.5g, yield: 60%, HPLC area%: 95.3 area%). 1 H-NMR (400 MHz, CDCl3) δ:1.90-1.97 (m, 1H), 2.33 (s, 1H), 2.38 (s, 3H), 2.45-2.52 (m, 1H), 2.81 (d,J = 16.0 Hz, 1H), 2.89 (d,J = 11.6 Hz, 1H),3.44 (d,J = 15.6 Hz, 1H), 3.73 (s, 6H), 3.78 (s, 3H), 3.87 (dd,J = 11.8, 7.4 Hz, 1H),6.12 (s, 2H)

[0142] The production method of Example 1 is superior in terms of industrialization, since the reaction can be carried out at around room temperature, as compared with the methods of Patent Documents 2 and 3 and Non-Patent Document 2. It is also superior to Patent Document 3 in that purification by silica gel column chromatography is not required.

[0143] Example 2: Method for preparing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate

[0144] [ka]

[0145] Under a nitrogen atmosphere, (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (500 g) and (+)-dibenzoyl-D-tartaric acid (352.7 g) were dissolved in methanol (1750 g) at room temperature, and the temperature was raised to 50°C. A solution of (+)-dibenzoyl-D-tartaric acid (352.7 g) in methanol (500 g) was added dropwise at 50°C over 30 minutes, and the mixture was kept warm for 1 hour and stirred. MTBE (2250 g) was added dropwise at 50°C, and after the dropwise addition, the mixture was heated to 55°C, and the mixture was kept warm for 5 hours and stirred. The mixture was cooled to 20°C, and the mixture was kept warm overnight and stirred. The precipitate was collected by filtration, washed twice with a mixture of methanol (500 g) and MTBE (500 g), washed twice with MTBE (1000 g), and then dried to obtain (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate (901.2 g, yield: 79%, HPLC purity: 41.84 area%, HPLC area% of (+)-dibenzoyl-D-tartaric acid: 57.64 area%). 1H-NMR (400MHz,DMSО-d6)δ:1.80-1.85(m,1H),2.18-2.28(m,1H),2.46(s,3H) ,2.71-2.79(m,1H),3.05-3.09(m,1H),3.15-3.19(m,1H),3.43-3.48(m, 1H),3.70(s,6H),3.76(s,3H),3.83(dd,J=12.0Hz,6.8Hz,1H),5.79(s,2H),6.22(s ,2H),7.56(dd,J=7.8,7.8Hz,4H),7.70(dd,J=7.4Hz,7.4Hz,2H),7.98(d,J=7.6Hz)

[0146] The production method of Example 2 is superior in terms of reproducibility compared to Patent Document 1 and Non-Patent Document 1. In addition, a yield of 79% can be achieved in one crystallization, making it superior in terms of operability. Compared to Patent Document 2 and Non-Patent Document 2, the method is superior in terms of yield, since no unnecessary enantiomers are produced. It is also superior in terms of operability, since there is no need to remove unnecessary enantiomers.

[0147] Example 3: Base treatment of (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate salt

[0148] [ka]

[0149] (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate (400 g) was dried in a reaction vessel at 50° C. for 8 hours under reduced pressure, and then cooled to 5° C. DME (2000 g) and THF (2000 g) were added, and triethylamine (253.9 g) was added dropwise at an internal temperature of 5° C. The temperature was raised to 18° C., and the mixture was kept warm and stirred for 30 minutes. The precipitate was removed by filtration and washed twice with THF (240 g), and the filtrate and washings were combined (4461 g, yield: 100%, HPLC purity: 97.55 area%, optical purity: 99.36% ee). This solution was used in the next step without purification.

[0150] The base treatment of Example 3 is superior to Patent Document 1 or 2 and Non-Patent Document 1 or 2 in that it is not necessary to isolate a relatively unstable product. Furthermore, it is also superior in that racemization can be suppressed by using triethylamine. It is superior to Patent Document 2 and Non-Patent Document 2 in that racemization can be suppressed.

[0151] Example 4: Method for producing cis-(-)-furosinopiperidol

[0152] [ka]

[0153] Under a nitrogen atmosphere, a THF solution of lithium triisobutylborohydride (1210.6 g) was cooled to 0°C. The solution obtained in Example 3 (4461.0 g) was added dropwise at an internal temperature of 0°C, and the mixture was kept at 0°C for 2 hours while stirring. This solution was added dropwise to a 15% aqueous potassium hydroxide solution (1875 g) cooled to 5°C at 10°C or less. After the dropwise addition, the temperature was raised to 15°C, and 30% aqueous hydrogen peroxide solution (426.7 g) was added dropwise at an internal temperature of 30°C or less. After stirring at 20°C for 30 minutes, 24% aqueous sodium hydrogen sulfite solution (413.55 g) was added dropwise at 20°C, and the mixture was stirred for 1 hour. The peroxide was checked with potassium iodide starch test paper, and toluene (1752 g) was added. After stirring for 10 minutes, the aqueous layer was removed, and the organic layer (7403 g) was concentrated under reduced pressure to 2802 g. Toluene (1752 g) was added again, and the mixture was concentrated under reduced pressure to 958 g, and toluene (1456 g) was added. At 20° C., 5% potassium dihydrogen phosphate aqueous solution (525.7 g) was added, and concentrated hydrochloric acid (56 g) was added to adjust the pH to 6.37. A part of the lower layer after separation (37.2 g) was dropped into 7% potassium hydroxide aqueous solution (876 g) at 20° C., and cis-(-)-furosinopiperidol (0.88 g) was added. The remaining lower layer after separation (710.1 g) was dropped at 20° C., and the mixture was kept warm and stirred at 20° C. for 2 hours. The precipitate was collected by filtration, washed twice with water (200 g), and then dried to obtain cis-(-)-furosinopiperidol (156.4 g, yield: 88.6%, HPLC purity: 99.91 area%, optical purity: 99.3% ee). 1H-NMR (400 MHz, CDCl3) δ:1.37-1.42(m,1H),1.65(s,3H),2.04(ddd,J=11.6,11.6,2.7Hz,1H),2.12-2.15(m,1H),2.31(s,3H) ,2.83-2.94(m,1H),2.96-3.02(m,2H),3.34-3.39(m,1H),3.81(s,9H),3.84-3.85(m,1H),6.17(s,2H)

[0154] The production method of Example 4 is superior in yield and cis selectivity compared to Patent Document 1 and Non-Patent Document 1. Furthermore, it is also superior in operability because the reaction temperature is 0°C and does not require a cryogenic temperature, and purification can be performed without using column chromatography. It is superior in reduction reaction yield compared to Patent Document 2 or 3 and Non-Patent Document 2.

[0155] By using the production methods of Examples 1 to 4 according to the present invention, cis-(-)-furosinopiperidol can be industrially produced with high efficiency, high selectivity and high purity.

[0156] For comparison with the production method of the present invention, (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one was produced by Swern oxidation (Reference Example 1). In addition, (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate was produced by optical resolution (Reference Example 2).

[0157] Reference Example 1: Method for producing (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one hydrochloride

[0158] [ka]

[0159] Under a nitrogen atmosphere, oxalyl chloride (13.8 g) was dissolved in methylene chloride (150 g) and cooled to -78°C. A solution of dimethyl sulfoxide (18.95 g) in methylene chloride (100 g) was added dropwise to this solution at -70°C over 30 minutes. The mixture was stirred at -70°C for 15 minutes. A solution of (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-ol (25 g) in methylene chloride (75 g) was added dropwise to this solution at -70°C over 25 minutes. The mixture was stirred at -78°C for 1 hour. Triethylamine (40.9 g) was added dropwise at -78°C over 30 minutes and the mixture was stirred for 30 minutes. The mixture was heated to -20°C, and saturated aqueous sodium bicarbonate (250 g) was added dropwise over 30 minutes. Water (250 g) was added, and the mixture was extracted twice with toluene (250 ml). The organic layers were combined, saturated saline (100 ml) was added, and the organic layers were separated, then dried over sodium sulfate. After filtration, the mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (100 g), and the insoluble matter was filtered off. 4N hydrochloric acid / ethyl acetate (30 ml) was added dropwise to the filtrate, and the mixture was stirred at room temperature. The precipitate was collected by filtration, washed with ethyl acetate, and then dried to obtain crude (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (26.5 g). The obtained solid (20 g) was suspended in 2-propanol (200 g), heated to 75° C., and stirred for 1 hour. The mixture was cooled to 20° C. and stirred for 30 minutes. The precipitate was collected by filtration, washed twice with 2-propanol (50 ml), and dried to obtain (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one hydrochloride (17.9 g, yield: 70%). 1 H-NMR (400MHz, CDCl3) δ:1.90-1.97(m,1H),2.33(s,1H),2.38(s,3H),2.45-2.52(m,1H),2.81(d,J=16.0Hz,1H),2.89(d,J=11 .6Hz,1H),3.44(d,J=15.6Hz,1H),3.73(s,6H),3.78(s,3H),3.87(dd,J=11.8Hz,7.4Hz,1H),6.12(s,2H)

[0160] The production method of Reference Example 1 is a method similar to Patent Document 2 or 3, or Non-Patent Document 2, and requires extremely low temperatures during the reaction, which makes the process complicated and causes major problems in mass synthesis, such as limited production facilities. On the other hand, the production method of Example 1 does not require extremely low temperatures, and mass synthesis can be performed inexpensively and easily in ordinary production facilities.

[0161] Reference Example 2: Method for producing (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate

[0162] [ka]

[0163] Under a nitrogen atmosphere, (±)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (15 g) and (+)-dibenzoyl-D-tartaric acid (21.2 g) were dissolved in methanol (68.2 g) at 65 ° C. and stirred at 65 ° C. for 1 hour. This was cooled to 0 ° C. over 6 hours and stirred at 0 ° C. overnight. The precipitate was collected by filtration, washed twice with cold methanol (30 g), and dried to obtain the first crystals of (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate (20.2 g, yield: 59%). The filtrate and washings (133.5 g) were concentrated under reduced pressure to 33.3 g and heated to 65 ° C. After cooling to 55° C., (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate (7 mg) was added, stirred for 1 hour, cooled to 0° C. over 6 hours, and stirred overnight at 0° C. The precipitate was collected by filtration, washed twice with cold methanol (9.6 g), and dried to obtain the second crystal of (R)-1-methyl-4-(2,4,6-trimethoxyphenyl)piperidin-3-one (+)-dibenzoyl-D-tartrate (4.2 g, yield: 12%). 1H-NMR (400 MHz,DMSO-d6) δ:1.80-1.85(m,1H),2.18-2.28(m,1H),2.46(s,3H),2.71-2.79(m,1H),3 .05-3.09(m,1H),3.15-3.19(m,1H),3.43-3.48(m,1H),3.70(s,6H),3.76 (s,3H),3.83(dd,J=12.0Hz,6.8Hz,1H),5.79,(s,2H),6.22(s,2H),7.56(dd,J=7.8Hz,7.8Hz,4H),7.70(dd,J=7.4Hz,7.4Hz,2H),7.98(d,J=7.6Hz)

[0164] The method of Reference Example 2 is similar to that of Patent Document 1 or Non-Patent Document 1, and involves concentrating the filtrate of the first crystals and then extracting the second crystals, which makes the process complicated and time-consuming, and is not suitable for mass synthesis. The yield is also lower than that of Example 2. On the other hand, the method of Example 2 can achieve a 79% yield with only one crystallization, making it an excellent method that can be industrialized at low cost and easily.

[0165] In the following Reference Examples 3 to 7, it was confirmed that alvocidib could be efficiently produced from cis-(-)-furosinopiperidol produced according to the present invention.

[0166] Reference Example 3: Method for producing cis-(-)-acetofurosinopiperidol

[0167] [ka]

[0168] Acetic anhydride (80g) was cooled to 6°C under a nitrogen atmosphere, and cis-(-)-furosinopiperidol (100g) was added over 30 minutes while maintaining the internal temperature at 25°C or less. The mixture was kept warm at 13-18°C for 4 hours, and cooled to 14°C. Boron trifluoride acetate complex (200g) was added dropwise over 30 minutes while maintaining the internal temperature at 45°C or less. The mixture was heated to 55°C and kept warm for 5 hours. The mixture was cooled to 25°C, water (184g) was added dropwise at 35°C, and the dropping funnel was washed with water (90g). The mixture was kept warm at 35°C for 3 hours, 30% sodium hydroxide water (900g) was added dropwise at 40-55°C, the mixture was heated to 60°C, kept warm for 1 hour, and cooled to 20°C. This solution was added to butanol (1111g). Concentrated hydrochloric acid (138 g) was added dropwise at 30° C. or less, and the pH was adjusted to 11.2 with concentrated hydrochloric acid (37.7 g). The aqueous layer was extracted with butanol (270 g). The organic layer was washed with water (300 g) and separated, and then the organic layer was washed with hydrochloric acid (a mixture of concentrated hydrochloric acid: 5.5 g and water: 200 g) and separated. It was further washed with water (200 g) and separated. The organic layer was concentrated under reduced pressure to 222 g, and diisopropyl ether (220 g) was added to the residue and the temperature was raised to 65° C. After keeping at 65° C. for 1 hour, it was cooled to 0° C. and kept at that temperature for 1 hour. The precipitate was collected by filtration, washed twice with diisopropyl ether (73 g), and dried to obtain cis-(-)-acetofurosinopiperidol (123 g, yield: 92%). 1 H-NMR (400 MHz,DMSO-d6) δ:1.22(d,J=11.6Hz,1H),1.90(dd,J=11.0Hz,11.0Hz,1),2.03(d,J=9.6Hz,1H),2.17(s,3H ),2.47(s,3H),2.78-2.87(m,3H),3.08-3.13(m,3H),3.71(s,1H),3.82(s,3H),3.83(s,3H)

[0169] Reference Example 4: Method for producing cis-(-)-flavodimethoxol hydrochloride

[0170] [ka]

[0171] Under a nitrogen atmosphere, potassium tert-butoxide (80.3 g) was dissolved in DMF (373 g). and dissolved. The mixture was cooled to 5°C, and cis-(-)-acetofurosinopiperidol (75g) was added while maintaining the temperature at 12°C or less. The mixture was kept at 25°C for 1 hour and 30 minutes, and 2-chlorobenzoic acid ethyl (116g) was added over 30 minutes while maintaining the internal temperature at 25°C. The mixture was heated to 30°C and kept at that temperature for 6 hours. The mixture was cooled to 16°C, and concentrated hydrochloric acid (458g) was added dropwise at 50°C or less. The mixture was washed with water (19g), and this was also added. The mixture was kept at 50°C for 6 hours and 30 minutes, stirred, and cooled to 25°C. Water (773g) was added, and 30% sodium hydroxide solution (614g) was added dropwise. The pH was adjusted to 11.1 with 30% sodium hydroxide solution (69g), and butanol (243g) was added, and the mixture was separated. The aqueous layer was extracted with butanol (243g), and the organic layer was combined. The mixture was concentrated under reduced pressure at 65°C (distillate amount: 603g) and cooled to 25°C. Methanol (269g) was added to the residue and kept warm for 30 minutes, filtered, the filter cake was washed with methanol (30g), and combined with the filtrate. Concentrated hydrochloric acid (32g) was added dropwise to the filtrate and kept warm for 40 minutes at 25°C. cis-(-)-flavodimethoxol hydrochloride (1.1g) was added, and after stirring at 25°C for 30 minutes, diisopropyl ether (544g) was added dropwise over 45 minutes. The mixture was kept warm at 20°C for 1 hour. The precipitate was collected by filtration and washed with a mixture of diisopropyl ether (163g) and methanol (89g). The mixture was washed twice with diisopropyl ether (163g) to obtain crude cis-(-)-flavodimethoxol hydrochloride (102.6g, yield: 92%). Under a nitrogen atmosphere, crude cis-(-)-flavodimethoxol hydrochloride (90 g) was dissolved in a mixture of 2-propanol (113 g) and water (216 g) at 40°C and incubated for 30 minutes. The solution was cooled to 30°C, cis-(-)-flavodimethoxol hydrochloride (0.9 g) was added, and incubated for 1 hour. The solution was cooled to 5°C over 3 hours and incubated at 5°C for 2 hours. The precipitate was washed with 2-propanol (70 g) and dried to obtain cis-(-)-flavodimethoxol hydrochloride (76.2 g, yield: 87%). 1H-NMR (400 MHz,DMSО-d6) δ:1.83(d,J=13.2Hz,1H),2.71(s,3H),3.09-3.21(m,4H),3.29-3.33(m, 1H),3.44(d,J=11.2Hz,1H),3.92(d,J=3.2Hz,3H),3.95(d,J=2.8Hz,3H), 3.99(s,1H),5.46-5.48(m,1H),6.34(d,J=2.8Hz,1H),6.71(d,J=3.2Hz, 1H),7.54-7.62(m,2H),7.67-7.69(m,1H),7.80-7.82(m,1H),9.49(s,1H)

[0172] Reference Example 5: Manufacturing method of rough アルボシジブフリーbody

[0173]

change

[0174] Under a nitrogen atmosphere, cis-(-)-flavodimethoxol hydrochloride (40 g) was dissolved in chlorobenzene (354 g) and heated to 75°C. Boron tribromide (177 g) was added dropwise over 4 hours while maintaining the internal temperature at 75°C. The dropping funnel was washed with chlorobenzene (4 g) and added. The temperature was raised to 80°C and kept for 6 hours. The mixture was cooled to room temperature and stirred overnight. The temperature was raised to 100°C, kept warm for 2 hours and 30 minutes, and stirred. The mixture was cooled to 20°C, and a mixture of water (40 g) and methanol (63 g) was added dropwise over 3 hours while maintaining the internal temperature at 25°C. The mixture was kept warm at 25°C for 15 minutes and stirred, after which methanol (63 g) was added dropwise while maintaining the internal temperature at 25°C, and stirred at 25°C overnight. The internal temperature was raised to 72-79°C, and the mixture was concentrated by atmospheric distillation (distilled volume: 79g). A mixture of water (18g), methanol (527g) and chlorobenzene (239g) was added dropwise, while the mixture was concentrated by atmospheric distillation (distilled volume: 799g). The mixture was cooled to 50°C, and 26.5% aqueous sodium hydroxide solution (25g) was added dropwise. The internal temperature was raised to 72-79°C, and a mixture of water (6g), methanol (176g) and chlorobenzene (80g) was added dropwise, while the mixture was concentrated by atmospheric distillation (distilled volume: 263g). After cooling to 40°C, the mixture was again heated to 72°C, and the mixture was concentrated at atmospheric pressure. The mixture was cooled to 50°C, and methanol (112g) and chlorobenzene (127g) were added, and 26.5% aqueous sodium hydroxide solution (14g) was added dropwise. The mixture was kept at 50°C for 1 hour, water (160g) was added dropwise, and then cooled to 20°C. The mixture was kept at 20°C for 1 hour, and the precipitate was collected by filtration and washed with a mixture of water (140g) and methanol (48g). The precipitate was suspended in water (140g) and methanol (48g), and the washing liquid was added and kept warm. The crystals were collected by filtration, washed with a mixture of water (140g) and methanol (48g), washed four times with water (200g), and then dried to obtain a crude free form of alvocidib (29.7g, yield: 86.1%). 1H-NMR (400 MHz,MeОH-d4) δ:1.59(d,J=11.6Hz,1H),2.75(s,3H),2.97(ddd,J=12.4Hz,12.4Hz,2.9Hz,1H),3.0 4-3.14(m,2H),3.30-3.32(m,1H),3.41(d,J=12.0Hz,1H),3.57-3.61(m,1H),4.17(s, 1H),6.03(s,1H),6.30(s,1H),7.49(ddd,J=7.4Hz,7.4Hz,1.6Hz,1H),7.54(ddd,J=7 .6Hz,7.6Hz,1.7Hz,1H),7.60(dd,J=8.4Hz,1.2Hz,1H),7.68(dd,J=7.4Hz,1.8Hz,1H)

[0175] Reference Example 6: Method for producing alvocidib hydrochloride ethanol solvate [ka]

[0176] Under a nitrogen atmosphere, the crude alvocidib free form (20 g) was dissolved in ethanol (228 g) and heated to 35°C. Concentrated hydrochloric acid (10.4 g) was added dropwise while maintaining the internal temperature at 35°C, and the dropping funnel was washed with ethanol (4.6 g). The temperature was raised to 74°C, hot filtration was performed, and the filter paper was washed with ethanol (23 g). The filtrate and washings were combined and concentrated under normal pressure. (Distilled amount 190 g) The mixture was cooled to 25°C and kept warm overnight. The mixture was cooled to -10°C and kept warm for 2 hours. The precipitate was collected by filtration, washed with cold ethanol (94 g), and dried to obtain alvocidib hydrochloride ethanol solvate (22.4 g, yield: 93%). 1H-NMR (400 MHz,MeОH-d4) δ:1.17(t,J=7.2Hz,3H),1.83-1.91(m,1H),2.86(s,3H),3.09-3.21(m,2H),3.32-3.35(m,1H ),3.45(ddd,J=12.6Hz,2.4Hz,2.4Hz,1H),3.50-3.53(m,1H),3.60(q,J=7.1Hz,2H),3.69-3.7 4(m,1H),4.26(s,1H),6.34(s,1H),6.48(s,1H),7.52(ddd,J=7.3Hz,7.3Hz,1.3Hz,1H),7.58( ddd,J=7.6Hz,7.6Hz,1.9Hz,1H),7.62(dd,J=7.8Hz,1.4Hz,1H),7.76(dd,J=7.6Hz,1.6Hz,1H)

[0177] Reference Example 7: Method for producing alvocidib hydrochloride

[0178] [ka] Under a nitrogen atmosphere, alvocidib hydrochloride ethanol solvate (20 g) was dissolved in methyl ethyl ketone (297 g), heated to 80° C., and kept at 80° C. for 4 hours. The mixture was cooled to 22° C. and kept at 80° C. for 1 hour. The precipitate was collected by filtration, washed with methyl ethyl ketone (69 g), and dried to obtain alvocidib hydrochloride (17.7 g, yield: 98%, HPLC purity: 99.6 area%, optical purity: >99.9% ee). 1 H-NMR (400 MHz,MeОH-d4) δ:1.83-1.91(m,1H),2.85(s,3H),3.10-3.22(m,2H),3.34(s,1H),3.42-3. 46(m,1H),3.49-3.53(m,1H),3.69-3.73(m,1H),4.26(s,1H),6.34(s,1H),6 .48(s,1H),7.52(ddd,J=7.4Hz,7.4Hz,1.5Hz,1H),7.58(ddd,J=7.8Hz,7.8Hz,2.0Hz,1H),7.63(dd,J=7.8Hz,1.4Hz,1H),7.75(dd,J=7.4Hz,1.4Hz,1H)

[0179] As described above, the present invention has been illustrated using preferred embodiments of the present invention, but it is understood that the scope of the present invention should be interpreted only by the claims. This application claims priority to Japanese Patent Application No. 2019-79299 (filed April 18, 2019), the contents of which are incorporated herein by reference in their entirety. It is understood that the patents, patent applications and other documents cited in this specification should be incorporated herein by reference in their entirety as if the contents themselves were specifically set forth in this specification. [Industrial Applicability]

[0180] By using the production method of the present invention, cis-(-)-furosinopiperidol, an intermediate of alvocidib, which is useful as a pharmaceutical, can be produced safely and inexpensively in high yield, with high selectivity and high purity.

Claims

[Claim 1] The invention described in the specification.

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