Preparation method of amino acid derivative

Abstract

The invention relates to a preparation method of amino acid derivatives. The purpose of the present invention is to provide a method for producing a (2S, 5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative, which can be carried out under mild reaction conditions that do not require extremely low-temperature equipment, is safer and cheaper, can easily control the quality of a target object, and has good operability on the production site. A method for producing a compound represented by general formula (2), which is characterized by reacting a compound represented by general formula (1) with a compound represented by general formula PG2NHOPG3 (wherein PG2 represents a protecting group for an amino group and PG3 represents a protecting group for a hydroxyl group). The present invention relates to a method for producing a hydroxylamine derivative represented by formula (1), in which a hydroxylamine derivative represented by formula (1) is reacted in a solvent in the presence of a base (in the formula, PG1 represents a protecting group for an amino group, LG represents a detachment group, and R represents a C1-8 hydrocarbon group which may have a substituent). ) # imgabs1 # (In the formula, each additional number is as defined above. ).

Description

[0001] This invention application is a divisional application of PCT patent application PCT / JP2019 / 037399, filed on September 24, 2019, and entitled “Method for preparing amino acid derivatives”. The application number of the parent application entering China is 201980061666.9. Technical Field

[0002] The present invention relates to a preparation method of (2S, 5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivatives and synthetic intermediates thereof or salts thereof. Background Art

[0003] β-lactam antibiotics such as penicillin antibiotics, cephem antibiotics, monobacterial antibiotics, and carbapenem antibiotics are widely used for the treatment and prevention of bacterial infections. However, the antibacterial activity of β-lactam antibiotics is reduced and inactivated by β-lactamase (an enzyme that hydrolyzes the β-lactam ring) produced by bacteria, and the treatment and prevention effects of β-lactam antibiotics on bacterial infections are often reduced, which is a problem.

[0004] Therefore, various β-lactamase inhibitors have been developed that can be used in combination with β-lactam antibiotics and can also exert their original antibacterial action against bacteria that are resistant to β-lactam antibiotics, and methods for producing the same.

[0005] (2S,5R)-5-(Protected oxyamino)-piperidine-2-carboxylic acid derivatives are known to be useful intermediates in the synthesis of β-lactamase inhibitors such as diazabicyclooctane derivatives.

[0006] As a method for producing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative, for example, the methods described in Patent Documents 1 and 2 are known.

[0007] Specifically, Patent Document 1 describes a method for preparing a (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid derivative by using (2S,5S)-5-hydroxypiperidine-2-carboxylic acid as a starting material, synthesizing N-trifluoroacetyl-5-hydroxypiperidine-2-carboxylic acid alkyl ester through esterification and N-trifluoroacetyl protection, then introducing a trifluoromethanesulfonyl group as a leaving group at the 5-hydroxyl group, and reacting with O-benzylhydroxylamine.

[0008] In addition, Patent Document 2 describes a method for preparing ethyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate by using ethyl (S)-1-(tert-butyloxycarbonyl)-5-oxopyrrolidine-2-carboxylate as a starting material to synthesize 2-ethyl (S)-1-tert-butyl-5-oxopiperidine-1,2-dicarboxylate, reducing the carbonyl group at the 5-position to synthesize 2-ethyl (2S,5S)-1-tert-butyloxycarbonyl-5-hydroxypiperidine-1,2-dicarboxylate, introducing a leaving group at the 5-position, reacting with N-(benzyloxy)-2-nitrobenzenesulfonamide, and then deprotecting the nitrobenzenesulfonyl group and the tert-butyloxycarbonyl group.

[0009] Prior art literature

[0010] Patent Literature

[0011] [Patent Document 1] WO2013 / 180197

[0012] [Patent document 2] US9120795. Summary of the invention

[0013] Problem that the invention aims to solve

[0014] However, the above-mentioned prior art related to the synthetic intermediates of β-lactamase inhibitors has the following various technical problems.

[0015] The preparation method of patent document 1 includes the raw materials used, the generated intermediate is very unstable and requires ultra-low temperature conditions, so it is necessary to use equipment that can be used under ultra-low temperature conditions to prepare. In addition, the generated intermediate is mostly oily, so it is difficult to use crystallization for purification, and it is not easy to obtain in the preparation site. Then, the N-protecting group of the generated intermediate is a high electron-withdrawing protecting group, so it is easy to cause isomerization at the 2nd position, and the quality control is difficult, so the quality of the target object is easily reduced. In addition, expensive solvents and leaving group introducing agents are required.

[0016] Therefore, a more inexpensive industrial production method is desired which can be carried out under mild reaction conditions without requiring extremely low temperature equipment, has good operability at the production site, is easy to control the quality of the target product, and is easy to manufacture.

[0017] The preparation method of Patent Document 2 requires expensive solvents and reagents, and the yield of the intermediate is not high. In addition, diethyl azodicarboxylate used as a reagent may generate a large amount of heat and react explosively due to self-reaction during heating and decomposition, which has the risk of causing the reaction to run away. Furthermore, the post-treatment and removal of the triphenylphosphine oxide compound as a by-product are difficult, so it is not easy to control the quality of the target product.

[0018] Therefore, an industrial production method that is cheaper, safer, and allows for easy quality control of the target product is desired.

[0019] As described above, in the method for preparing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative useful as a synthetic intermediate of a β-lactamase inhibitor, it is desired to have an industrial preparation method that can be carried out under mild reaction conditions that does not require extremely low-temperature equipment, is safer, has easy quality control of the target product, has good operability at the preparation site, and is cheaper.

[0020] Means used to solve problems

[0021] The present inventors conducted intensive research and found a method for preparing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative that can be carried out under mild reaction conditions that do not require extremely low temperature equipment, is safer, has easy quality control of the target product, has good operability at the preparation site, and is cheaper, thereby completing the present invention.

[0022] That is, the contents of the present invention are as follows.

[0023] [1] A method for preparing a compound represented by the general formula (2), characterized in that the compound represented by the general formula (1) and the compound represented by the general formula PG 2 NHOPG 3 (In the formula, PG 2 Indicates the protecting group of amino group, PG 3 represents a protecting group of a hydroxyl group. The hydroxylamine derivative shown in ) is reacted in the presence of a base in a solvent,

[0024] [Chemistry 1]

[0025]

[0026] (In the formula, PG 1 represents a protecting group of an amino group, LG represents a leaving group, and R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0027] [Chemistry 2]

[0028]

[0029] (In the formula, each symbol is as defined above.)

[0030] [2] A method for preparing a compound represented by the general formula (4) or a salt thereof, characterized in that the method comprises removing the PG of the compound represented by the general formula (2). 2 The step of obtaining a compound represented by the general formula (3) or a salt thereof; and removing the PG of the compound represented by the general formula (3) 1 Steps,

[0031] [Chemistry 3]

[0032]

[0033] (In the formula, PG 1 and PG 2 Each independently represents a protecting group of an amino group, PG 3 represents a protective group for a hydroxyl group, and R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0034] [Chemistry 4]

[0035]

[0036] (In the formula, each symbol is as defined above.)

[0037] [Chemistry 5]

[0038]

[0039] (In the formula, each symbol is as defined above.)

[0040] [3] A method for preparing a compound represented by the general formula (4) or a salt thereof, characterized in that the method comprises removing the PG of the compound represented by the general formula (2) 1 The step of obtaining a compound represented by the general formula (5) or a salt thereof; and removing the PG of the compound represented by the general formula (5) 2 The step of obtaining the compound represented by the general formula (4) is:

[0041] [Chemistry 6]

[0042]

[0043] (In the formula, PG 1 and PG 2 Each independently represents a protecting group of an amino group, PG 3 represents a protective group for a hydroxyl group, and R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0044] [Chemistry 7]

[0045]

[0046] (In the formula, each symbol is as defined above.)

[0047] [Chemistry 8]

[0048]

[0049] (In the formula, each symbol is as defined above.)

[0050] [4] A method for preparing a compound represented by the general formula (1), characterized in that it comprises the step of reacting a compound represented by the general formula (6) with an amino protecting agent to obtain a compound represented by the general formula (7) or a salt thereof;

[0051] The steps of reacting the compound represented by the general formula (7) with a lactonizing agent to obtain a compound represented by the general formula (8); reacting the compound represented by the general formula (8) with an esterifying agent to obtain a compound represented by the general formula (9); and reacting the compound represented by the general formula (9) with a leaving group introducing agent,

[0052] [Chemistry 9]

[0053]

[0054] [Chemistry 10]

[0055]

[0056] (In the formula, PG 1 represents a protecting group for an amino group. )

[0057] [Chemistry 11]

[0058]

[0059] (In the formula, each symbol is as defined above.)

[0060] [Chemistry 12]

[0061]

[0062] (wherein, R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent, PG 1 As defined above.)

[0063] [Chemistry 13]

[0064]

[0065] (In the formula, LG represents a leaving group, and the other symbols are as defined above.)

[0066] [5] A method for producing a compound represented by the general formula (1), characterized in that it comprises the steps of reacting a compound represented by the general formula (8) with an esterifying agent to obtain a compound represented by the general formula (9); and reacting the compound represented by the general formula (9) with a leaving group-introducing agent.

[0067] [Chemistry 14]

[0068]

[0069] (In the formula, PG 1 represents a protecting group for an amino group. )

[0070] [Chemistry 15]

[0071]

[0072] (wherein, R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent, PG 1 As defined above.)

[0073] [Chemistry 16]

[0074]

[0075] (In the formula, LG represents a leaving group, and the other symbols are as defined above.)

[0076] [6] A method for preparing a compound represented by the general formula (4) or a salt thereof, characterized in that the method comprises reacting a compound represented by the general formula (1) with a compound represented by the general formula PG 2 NHOPG 3 (In the formula, PG 2 Indicates the protecting group of amino group, PG 3 represents a protecting group for a hydroxyl group. ) is reacted in the presence of a base in a solvent to obtain a compound represented by the general formula (2); removing the PG 2 The step of obtaining a compound represented by the general formula (3) or a salt thereof; and removing the PG of the compound represented by the general formula (3) 1 Steps,

[0077] [Chemistry 17]

[0078]

[0079] (In the formula, PG 1 represents a protecting group of an amino group, LG represents a leaving group, and R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0080] [Chemistry 18]

[0081]

[0082] (In the formula, each symbol is as defined above.)

[0083] [Chemistry 19]

[0084]

[0085] (In the formula, each symbol is as defined above.)

[0086] [Chemistry 20]

[0087]

[0088] (In the formula, each symbol is as defined above.)

[0089] [7] A method for preparing a compound represented by the general formula (4) or a salt thereof, characterized in that the method comprises: reacting a compound represented by the general formula (1) with a compound represented by the general formula PG 2 NHOPG 3 (In the formula, PG 2 Indicates the protecting group of amino group, PG 3 represents a protecting group for a hydroxyl group. ) is reacted in the presence of a base in a solvent to obtain a compound represented by the general formula (2); removing the PG 1 The step of obtaining a compound represented by the general formula (5) or a salt thereof; and removing the PG of the compound represented by the general formula (5) 2 The step of obtaining the compound represented by the general formula (4) or a salt thereof,

[0090] [Chemistry 21]

[0091]

[0092] (In the formula, PG 1 represents a protecting group of an amino group, LG represents a leaving group, and R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0093] [Chemistry 22]

[0094]

[0095] (In the formula, each symbol is as defined above.)

[0096] [Chemistry 23]

[0097]

[0098] (In the formula, each symbol is as defined above.)

[0099] [Chemistry 24]

[0100]

[0101] (In the formula, each symbol is as defined above.)

[0102] [8] The method according to [1], [6] or [7], characterized in that PG 1 is a carbamate protecting group or an amide protecting group, wherein p - The value is below 1.00.

[0103] [9] The method according to any one of [1] and [6] to [8], wherein LG is a sulfonyloxy group.

[0104]

[10] The method according to any one of [1] and [6] to [9], characterized in that the compound represented by the general formula (1) is reacted with a compound represented by the general formula: PG 2 NHOPG 3 (In the formula, PG 2 Indicates the protecting group of amino group, PG 3 represents a protecting group for a hydroxyl group, and the other reference numerals are as defined above. The hydroxylamine derivative represented by ) is reacted at a temperature of 10°C to 70°C.

[0105]

[11] A compound represented by the following formula (1a), (1b), (2a), (2b), (3b), (5a) or (9b).

[0106] [Chemistry 25]

[0107]

[0108] (In the formula, Boc represents tert-butoxycarbonyl, Ac represents acetyl, Ns represents p-nitrobenzenesulfonyl, and Bn represents benzyl).

[0109] Effects of the Invention

[0110] According to the present invention, a method for preparing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative can be provided, which can be carried out under mild reaction conditions without requiring extremely low temperature equipment, is safer, facilitates quality control of the target product, has good operability at the preparation site, and is cheaper.

[0111] Specifically, regarding the preparation method of the present invention, as a compound with pipecolic acid as the basic structure, by using a compound that introduces a leaving group at the 5-position and an amine protecting group with low electron-withdrawing property at the 1-position, hydroxyamination can be performed while suppressing isomerization at the 2-position under mild conditions, so that a high-quality target product can be prepared. Furthermore, the preparation method of the present invention can reduce the polarity of the generated intermediate by protecting the amino group and esterifying the carboxyl group, and improve the solubility and crystallinity of the intermediate in an organic solvent. Thus, the purification efficiency of the generated intermediate is improved, and in addition, the operability at the preparation site can be improved. DETAILED DESCRIPTION

[0112] Hereinafter, the present invention will be described in detail.

[0113] [Terms used in this manual]

[0114] Hereinafter, each reference numeral and term in the general formula in the present invention will be described.

[0115] PG 1 and PG 2 Each independently represents a protecting group for an amino group.

[0116] The amino group-protecting group is not particularly limited as long as it is a group that protects the amino group, and examples thereof include known amino group-protecting groups, and preferably include carbamate-based protecting groups, amide-based protecting groups, and sulfonamide-based protecting groups.

[0117] Examples of the carbamate protecting group include aliphatic oxycarbonyl groups such as methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl and allyloxycarbonyl; and aromatic oxycarbonyl groups such as benzyloxycarbonyl, p-methyloxybenzylcarbonyl, p-nitrobenzyloxycarbonyl and 9-fluorenylmethyloxycarbonyl.

[0118] As the amide protecting group, for example, formyl, acetyl, pivaloyl, benzoyl, trichloroacetyl or trifluoroacetyl can be mentioned. Among them, as the amide protecting group with low electron-withdrawing property, hydrocarbon acyl groups such as acetyl, pivaloyl and benzoyl can be mentioned. In addition, as the amide protecting group with high electron-withdrawing property, halogen-substituted hydrocarbon acyl groups such as trichloroacetyl and trifluoroacetyl can be mentioned.

[0119] Examples of the sulfonamide protecting group include hydrocarbon sulfonamide protecting groups such as methanesulfonyl, benzenesulfonyl, p-toluenesulfonyl and triisopropylbenzenesulfonyl; and nitrobenzenesulfonamide protecting groups such as o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl and o-,p-dinitrobenzenesulfonyl.

[0120] PG 3 It represents a protecting group for a hydroxyl group.

[0121] Examples of the hydroxyl group-protecting group include known hydroxyl group-protecting groups, such as ether-based protecting groups, acetal-based protecting groups, silyl ether-based protecting groups, and acyl-based protecting groups.

[0122] Examples of the ether protecting groups include chain alkyl ether protecting groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, etc.; cyclic alkyl ether protecting groups such as cyclopentyl, cyclohexyl, etc.; and aromatic ether protecting groups such as benzyl, p-methyloxybenzyl, trityl, etc.

[0123] Examples of the acetal protecting group include chain acetal protecting groups such as methyloxymethyl, methyloxyethyl, ethyloxymethyl, and ethyloxyethyl; and cyclic acetal protecting groups such as tetrahydropyranyl.

[0124] Examples of the silyl ether protecting group include hydrocarbon silyl groups such as trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, triisopropylsilyl, and tert-butyldiphenylsilyl.

[0125] Examples of the acyl protecting group include hydrocarbon acyl groups such as acetyl, pivaloyl, and benzoyl; and halogen-substituted hydrocarbon acyl groups such as trichloroacetyl and trifluoroacetyl.

[0126] LG represents a leaving group.

[0127] Examples of the leaving group include known leaving groups such as a sulfonyloxy group and a halogen atom.

[0128] Examples of the sulfonyloxy group include alkylsulfonyloxy groups such as methanesulfonyloxy, trichloromethanesulfonyloxy and trifluoromethanesulfonyloxy; arylsulfonyloxy groups such as benzenesulfonyloxy and p-toluenesulfonyloxy; and nitrobenzenesulfonyloxy groups such as p-nitrobenzenesulfonyloxy and o-nitrobenzenesulfonyloxy.

[0129] Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

[0130] R represents a hydrocarbon group having 1 to 8 carbon atoms which may have a substituent.

[0131] As the hydrocarbon group having 1 to 8 carbon atoms, preferably, an aliphatic hydrocarbon group having 1 to 8 carbon atoms and an aromatic hydrocarbon group having 6 to 8 carbon atoms are mentioned.

[0132] Examples of the aliphatic hydrocarbon group having 1 to 8 carbon atoms include alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, and alkynyl groups having 2 to 8 carbon atoms, and these groups may be linear, branched, or cyclic.

[0133] Examples of the aromatic hydrocarbon group having 6 to 8 carbon atoms include a phenyl group, a benzyl group, a tolyl group, and a phenylethyl group.

[0134] Examples of the “substituent” in “optionally having a substituent” include an oxo group, a hydroxyl group, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkynyl group having 2 to 8 carbon atoms, an alkyloxy group having 1 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, an alkynyloxy group having 2 to 8 carbon atoms, an acyl group having 1 to 8 carbon atoms, an acyloxy group having 1 to 8 carbon atoms, and a halogen atom. These substituents may be substituted at any substitutable position with any substitutable number.

[0135] Examples of the alkyl group having 1 to 8 carbon atoms include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, and isomers thereof.

[0136] Examples of the alkenyl group having 2 to 8 carbon atoms include ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, and isomers thereof.

[0137] Examples of the alkynyl group having 2 to 8 carbon atoms include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, and isomers thereof.

[0138] Examples of the alkyloxy group having 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, and isomers thereof.

[0139] Examples of the alkenyloxy group having 2 to 8 carbon atoms include vinyloxy, propenyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, and isomers thereof.

[0140] Examples of the alkynyloxy group having 2 to 8 carbon atoms include ethynyloxy, propynyloxy, butynyloxy, pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, and isomers thereof.

[0141] Examples of the acyl group having 1 to 8 carbon atoms include formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, octanoyl, and isomers thereof.

[0142] Examples of the acyloxy group having 1 to 8 carbon atoms include formyloxy, acetyloxy, propionyloxy, butyryloxy, valeryloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, and isomers thereof.

[0143] Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

[0144] The formula weight of R may be a formula weight at which the bonded compound is substantially soluble in an organic solvent, and there is no particular lower limit, but the upper limit is usually 300 or less, preferably 250 or less, more preferably 200 or less, further preferably 150 or less, and particularly preferably 100 or less, from the viewpoint of operability such as solubility in a solvent. For example, the formula weight of a methyl group is 15, and the formula weight of a benzyl group is 91.

[0145] M represents a metal atom.

[0146] Examples of the "metal atom" include known metals, such as alkali metals, alkaline earth metals, and transition metals.

[0147] Examples of the alkali metal include lithium, sodium, potassium, rubidium, cesium, and francium.

[0148] Examples of the alkaline earth metal include beryllium, magnesium, calcium, strontium and barium.

[0149] Examples of the transition metal include titanium, zirconium, hafnium, vanadium, niobium, tantalum, bismuth, and antimony.

[0150] M is preferably an alkali metal or an alkaline earth metal, and from the viewpoint of raw material availability and cost, lithium, sodium, potassium, cesium, magnesium, calcium, or barium is more preferred, and sodium and potassium are particularly preferred.

[0151] [Preparation route of the present invention]

[0152] The preparation routes A and B of the present invention comprise the following steps.

[0153] Preparation Routes A and B

[0154] [Chemistry 26]

[0155]

[0156] That is, the preparation routes A and B are methods for preparing the compound represented by the general formula (4) from the compound represented by the general formula (1).

[0157] Preparation route A is a preparation route having step 1, step 2 and step 3, and preparation route B is a preparation route having step 1, step 4 and step 5.

[0158] In addition, the preparation route C of the present invention comprises the following steps.

[0159] Preparation Route C

[0160] [Chemistry 27]

[0161]

[0162] That is, Production Route C is a production route for producing the compound represented by the general formula (1) as a starting material of Step 1 from the compound represented by the above formula (6).

[0163] In addition, the preparation routes A and B of the present invention may further have a preparation route C, respectively.

[0164] The production routes A, B and C of the present invention are excellent in terms of obtaining high-purity intermediates because they are unlikely to cause isomerization of the substituent at the 2-position of the pipecolic acid skeleton by using a low electron-withdrawing protecting group as the protecting group for the amino group of the pipecolic acid skeleton.

[0165] In addition, in step 1 common to preparation routes A and B, a stable compound, i.e., a compound represented by the general formula (1), is used as a starting material, so the reaction can be carried out under mild conditions. In addition, even if the compound represented by the general formula (1) remains as an unreacted product, it can be easily removed. Thus, step 1 is a step suitable for industrial production and is a characteristic step of the present invention.

[0166] Furthermore, in the production route C, most of the compounds produced as intermediates are compounds with low polarity and high crystallinity, and operations such as extraction and recrystallization can be efficiently performed, so it is suitable for industrial production.

[0167] [Preparation method of the present invention]

[0168] In this specification, Preparation Methods 1 to 7 refer to the following preparation methods, respectively.

[0169] Preparation method 1: Preparation method having step 1

[0170] Preparation method 2: Preparation method having steps 2 and 3

[0171] Preparation method 3: Preparation method having steps 4 and 5

[0172] Preparation method 4: Preparation method having steps 6, 7, 8 and 9

[0173] Preparation method 5: Preparation method having steps 8 and 9

[0174] Preparation method 6: Preparation method having steps 1, 2 and 3

[0175] Preparation method 7: Preparation method having steps 1, 4 and 5

[0176] Hereinafter, the production method of the present invention will be described in detail.

[0177] <Preparation method 1>

[0178] [Chemistry 28]

[0179]

[0180] (In the formula, each symbol is as defined above.)

[0181] Preparation method 1 comprises reacting a compound represented by the general formula (1) with a compound represented by the general formula PG 2 NHOPG 3 A step of reacting the hydroxylamine derivative shown in the present invention in a solvent in the presence of a base to obtain a compound represented by the general formula (2) (step 1).

[0182] [Step 1]

[0183] (raw material)

[0184] The compound represented by the general formula (1) can be produced by any known method, and is preferably produced by the Production Method 4 or Production Method 5 described below.

[0185] In the general formula (1), the leaving group LG is not particularly limited as long as it reacts with the hydroxylamine derivative, but is preferably a sulfonyloxy group.

[0186] Examples of the sulfonyloxy group include alkylsulfonyloxy groups such as a methanesulfonyloxy group; halogenated alkylsulfonyloxy groups such as a trichloromethanesulfonyloxy group and a trifluoromethanesulfonyloxy group; arylsulfonyloxy groups such as a benzenesulfonyloxy group and a p-toluenesulfonyloxy group; and nitroarylsulfonyloxy groups such as a p-nitrobenzenesulfonyloxy group, an o-nitrobenzenesulfonyloxy group and an o,p-dinitrobenzenesulfonyloxy group.

[0187] Among them, arylsulfonyloxy and nitroarylsulfonyloxy are preferred. Furthermore, from the viewpoint of high leaving energy and leaving reaction under mild conditions, nitroarylsulfonyloxy is more preferred, from the viewpoint of cost, p-nitrobenzenesulfonyloxy and o-nitrobenzenesulfonyloxy are more preferred, and from the viewpoint of less generation of by-products, p-nitrobenzenesulfonyloxy is particularly preferred.

[0188] If the leaving energy of the leaving group LG is too low, the reaction may not proceed efficiently and a high temperature may be required. If it is too high, the reaction may become unstable under heat or alkaline conditions, resulting in an increase in the leaving product as a by-product and a decrease in quality and yield.

[0189] Here, "leaving energy" represents the level of reactivity, which is proportional to the level of stability of the conjugate acid of the leaving group LG after leaving. In addition, the level of stability of the conjugate acid can be estimated based on, for example, the value of the acid dissociation constant pKa, and the greater the value of pKa, the higher the stability.

[0190] The size of the leaving energy of the leaving group LG (the size of the pKa of the conjugate acid of the leaving group) is, as a lower limit, usually greater than -13, preferably greater than -10, more preferably greater than -6, from the viewpoint of suppressing by-products, and as an upper limit, from the viewpoint of reactivity, usually less than -1.5, preferably less than -2, more preferably less than -2.5.

[0191] For example, the pKa of methanesulfonic acid is -2.6, and the pKa of sulfuric acid is -3. Here, the pKa of trifluoromethanesulfonic acid is -14, which is not preferable as a leaving group LG.

[0192] In the general formulas (1) and (2), the amino protecting group PG is 1 The lower the electron-withdrawing property, the more isomerization is suppressed. Therefore, from the viewpoint of quality and purity, a protecting group of the amino group having a low electron-withdrawing property is preferred.

[0193] Here, "electron-withdrawing property" refers to the effect of reducing the electron density at a specific position of a molecule. The magnitude of electron-withdrawing property is known to be related to σ described in A survey of Hammett substituent constants and resonance and field parameters (Chem. Rev. 1991, 91, 165-195). p - (hereinafter sometimes referred to as substituent constant.) is proportional to the value.

[0194] As a PG 1 The magnitude of the electron-withdrawing property, the value of the substituent constant, as the upper limit, is usually 1.2 or less, from the viewpoint of suppressing isomerization, preferably 1.00 or less, more preferably 0.9 or less, particularly preferably 0.85 or less, as the lower limit, is usually -0.3 or more, preferably -0.2 or more, more preferably -0.1 or more, particularly preferably 0 or more.

[0195] For example, the substituent constant value of 1.06 for p-nitrobenzylsulfonyl and the substituent constant value of 1.09 for trifluoroacetyl are highly electron-withdrawing and thus are used as PG. 1 Not preferred.

[0196] PG as a protective group for amino groups with low electron-withdrawing properties 1 , preferably a carbamate protecting group and an amide protecting group with low electron-withdrawing property. Examples of the carbamate protecting group include aliphatic oxycarbonyl groups such as methyloxycarbonyl, ethyloxycarbonyl, tert-butyloxycarbonyl, and allyloxycarbonyl; aromatic oxycarbonyl groups such as benzyloxycarbonyl, p-methyloxybenzylcarbonyl, p-nitrobenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl; and examples of the amide protecting group with low electron-withdrawing property include hydrocarbon acyl groups such as acetyl, pivaloyl, and benzoyl.

[0197] Among them, PG 1 , more preferably tert-butyloxycarbonyl and acetyl.

[0198] The values ​​of the substituent constants were 0.64 for the tert-butoxycarbonyl group and 0.84 for the acetyl group.

[0199] In the general formula (2) and the above-mentioned hydroxylamine derivatives, the protecting group PG of the amino group is 2 From the viewpoint of the reactivity of the hydroxylamine derivative, a protecting group of the amino group having high electron-withdrawing property is preferred.

[0200] As a PG 2 The magnitude of the electron-withdrawing property, σ p - It can be greater than 1.

[0201] PG is a protective group for an amino group with high electron-withdrawing properties. 2 The protecting group may be a sulfonamide protecting group, and from the viewpoint of ease of deprotection, a nitrobenzenesulfonyl protecting group such as o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl and o-,p-dinitrobenzenesulfonyl is preferred.

[0202] In the general formula (2) and the above-mentioned hydroxylamine derivatives, the protective group PG for the hydroxyl group is 3 From the viewpoint of improving the reactivity of the hydroxylamine derivative, an ether protecting group is preferred, and from the viewpoint of ease of deprotection, an aromatic ether protecting group is more preferred, and benzyl and p-methoxybenzyl are particularly preferred.

[0203] The hydroxylamine derivative is not particularly limited as long as the reaction proceeds, but N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine is preferred from the viewpoints of reactivity, availability of raw materials, and cost. Among the hydroxylamine derivatives, compounds with free amino groups are thermally unstable and easily decomposed, and the purity may be reduced, so it is preferred to use substances with protected amino groups.

[0204] The hydroxylamine derivative may be a commercially available product or may be prepared by any known method and used. When the hydroxylamine derivative is prepared and used, a previously prepared substance may be added to the reaction system or may be prepared in the reaction system and used directly.

[0205] The amount of the hydroxylamine derivative used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (1), as a lower limit, from the viewpoint of productivity, and is generally 10 molar equivalent or less, preferably 3 molar equivalent or less, more preferably 2 molar equivalent or less, as an upper limit, from the viewpoint of operability, quality and cost.

[0206] Step 1 is preferably carried out in the presence of a base in a solvent.

[0207] The base is not particularly limited as long as the reaction proceeds, and examples thereof include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, and cyanides. The base used in step 1 may be used alone or in any combination and ratio.

[0208] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0209] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0210] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0211] Examples of the metal amide include lithium amide, sodium ethylamide, calcium diethylamide, lithium diisopropylamide, potassium benzylamide, sodium bis(trimethylsilyl)amide, indole lithium, sodium pyrrole, lithium pyrrole, potassium pyrrole, potassium pyrrolidine, diethyl pyrrole aluminum, ethyl dipyrrole aluminum, tripyrrole aluminum, lithium diisopropylamide, and sodium hexamethyldisilazide.

[0212] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0213] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0214] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0215] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0216] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0217] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0218] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0219] If the base used is too weak, the hydroxylamine derivative may not be activated and the reaction may not proceed. If the base is too strong, isomerization at the 2-position may occur, by-products may increase, and the purity may decrease. If the base is further strong, the ester part of the substrate may be hydrolyzed, and the purity may decrease.

[0220] Therefore, as the base, pyridines, carbonates, metal hydrides and metal alkoxides are preferred, carbonates are more preferred, and sodium carbonate, potassium carbonate and cesium carbonate are further preferred.

[0221] The amount of the base used is generally 0.1 molar equivalent or more relative to the compound represented by the general formula (1) as a lower limit, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more from the viewpoint of productivity, and generally 10 molar equivalent or less, preferably 3 molar equivalent or less, more preferably 2 molar equivalent or less, as an upper limit, from the viewpoint of operability, quality and cost.

[0222] The solvent is not particularly limited as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used.

[0223] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0224] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms can be preferably used, and more preferably methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof can be used.

[0225] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0226] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0227] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0228] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0229] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0230] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0231] As the hydrocarbon solvent, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.

[0232] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0233] As the solvent, from the viewpoint of reactivity, amides, ether solvents and hydrocarbons are preferred, amides are more preferred, and from the viewpoint of cost and availability of raw materials, N,N-dimethylformamide and N,N-dimethylacetamide are further preferred.

[0234] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0235] The amount of the solvent used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more, relative to 1 kg of the compound represented by the general formula (1), as the lower limit, and is usually 30 L or less, preferably 20 L or less, and more preferably 10 L or less, as the upper limit, from the viewpoints of operability, productivity and cost.

[0236] (Reaction Conditions)

[0237] The reaction temperature may vary depending on the base and solvent used, but the lower limit is usually 0°C or higher, preferably 10°C or higher, more preferably 15°C or higher, further preferably 20°C or higher, and particularly preferably 25°C or higher, from the viewpoint of productivity, and the upper limit is usually 100°C or lower, preferably 70°C or lower, more preferably 65°C or lower, further preferably 60°C or lower, and particularly preferably 55°C or lower, from the viewpoint of quality and cost.

[0238] If the reaction temperature is too low, the reaction proceeds slowly and productivity may decrease. If it is too high, the leaving form and the 2-isomer increase and the quality of the obtained compound may decrease.

[0239] The reaction time may vary depending on the base and solvent used, but is usually 1 to 120 hours, preferably 12 to 72 hours, from the viewpoint of productivity.

[0240] The pressure during the reaction is usually normal pressure.

[0241] When the compound represented by the general formula (1) is reacted with a hydroxylamine derivative in the presence of a base, the supply order of these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at one time or in multiple times. For example, the compound represented by the general formula (1), the hydroxylamine derivative, and any one or more components of the base are supplied together with a solvent in a reactor and used as a base liquid (compression liquid), and the remaining components are supplied as a supply liquid under reaction conditions, thereby allowing the reaction to proceed. From the viewpoint of being able to react while controlling the temperature and pH of the reaction liquid, the supply order thereof is preferably: a supply method in which the compound represented by the general formula (1), the hydroxylamine derivative, and a solvent are supplied together in a reactor and used as a base liquid, and a base is added under reaction conditions for reaction. When an excess of base exists in the reaction system, over-reactants may be generated. The base may be present in the reaction system from the beginning or may be supplied midway. In addition, the base may be supplied at one time or in multiple times.

[0242] (Post-processing)

[0243] The reaction solution can be directly supplied to the next step, and is usually supplied in the form of an organic layer after neutralization, liquid separation, filtration, etc. In addition, the product can be supplied after being separated from the organic layer by separation means such as concentration and crystallization, or the product can be supplied after being further purified by purification means such as recrystallization and column chromatography.

[0244] The reaction of step 1 can stably obtain the compound represented by general formula (2) without passing through an unstable intermediate. In particular, from the viewpoint that isomerization at the 2-position can be suppressed by using a protective group with low electron-withdrawing property and deprotection of the amino group is easy, the compound represented by the following formula (2a) is particularly preferred. It should be noted that this compound is a novel compound.

[0245] [Chemistry 29]

[0246]

[0247] (In the formula, Boc represents tert-butyloxycarbonyl, Ns represents p-nitrobenzenesulfonyl, Bn represents benzyl, and Me represents methyl.)

[0248] The compound represented by the general formula (2) may form a solvate such as a hydrate or an organic solvate. The form thereof may vary depending on the starting materials and solvent used, and is not particularly limited as long as the target reaction is not inhibited.

[0249] In the present invention, unless otherwise specified, "a compound represented by the general formula (2)" means both the compound represented by the general formula (2) and a solvate thereof.

[0250] <Preparation method 2>

[0251] [Chemistry 30]

[0252]

[0253] (In the formula, each symbol is as defined above.)

[0254] Preparation method 2 is characterized in that it has

[0255] The compound represented by the general formula (2) and PG 2 A step of reacting with a deprotecting agent to obtain a compound represented by the general formula (3) or a salt thereof (step 2); and

[0256] The compound represented by the general formula (3) or a salt thereof is reacted with PG 1 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof (step 3).

[0257] [Step 2]

[0258] Step 2 is to react the compound represented by the general formula (2) with PG 2 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (3) or a salt thereof.

[0259] (raw material)

[0260] As a PG 2 Deprotecting agent, as long as it can remove the amino protecting group PG 2 That is, the deprotection agent is not particularly limited, and can be carried out using a known deprotecting agent such as an acid, a base, an oxidizing agent, a reducing agent, a metal catalyst, a secondary amine, a thiol compound, a fluoride salt, or the like.

[0261] PG 2 In the case of a nitrobenzenesulfonyl-based protecting group, it is preferred to use a thiol compound to deprotect the amino group.

[0262] The thiol compound is not particularly limited as long as it can deprotect an amino group protected by a nitrobenzenesulfonamide-based protecting group, and examples thereof include alkylthiols, arylthiols, and mercaptocarboxylic acids.

[0263] Examples of the alkyl mercaptan include ethanethiol, 1-propanethiol, 2-propanethiol, 1-butanethiol, 2-butanethiol, 1-pentanethiol, octanethiol, decanethiol, dodecanethiol, and pentadecanethiol.

[0264] Examples of the aryl mercaptan include thiophenol, methylbenzenethiol, dimethylbenzenethiol, ethylbenzenethiol, diethylbenzenethiol, and naphthanethiol.

[0265] Examples of the mercaptocarboxylic acid include thioglycolic acid, 2-mercaptopropionic acid, 3-mercaptopropionic acid, 3-mercaptobutane acid, 2-mercaptoisobutyric acid, 3-mercaptoisobutyric acid, 3-mercapto-3-methylbutyric acid, 2-mercaptovaleric acid, 3-mercaptoisovaleric acid, 4-mercaptovaleric acid, and 3-phenyl-3-mercaptopropionic acid.

[0266] As the thiol compound, from the viewpoint of the availability of raw materials and cost, mercaptocarboxylic acid is preferred, and thioglycolic acid is more preferred.

[0267] PG 2 The amount of deprotecting agent used is sufficient to remove PG 2 The amount is not particularly limited, but is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (2), as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0268] Step 2 is preferably carried out in the presence of a base in a solvent.

[0269] As the base, there are no particular limitations as long as the reaction proceeds, and examples include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, and cyanides, etc. The base used in step 2 may be used alone or in any combination and ratio.

[0270] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0271] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0272] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0273] Examples of the metal amide include lithium amide, sodium ethylamide, calcium diethylamide, lithium diisopropylamide, potassium benzylamide, sodium bis(trimethylsilyl)amide, indole lithium, sodium pyrrole, lithium pyrrole, potassium pyrrole, potassium pyrrolidine, diethyl pyrrole aluminum, ethyl dipyrrole aluminum, tripyrrole aluminum, lithium diisopropylamide, and sodium hexamethyldisilazide.

[0274] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0275] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0276] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0277] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0278] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0279] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0280] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0281] Among these bases, from the viewpoint of the strength of basicity, tertiary amines, pyridines, carbonates, metal hydrides, metal alkoxides, and metal hydroxides are preferred, carbonates are more preferred, and potassium carbonate and cesium carbonate are further preferred.

[0282] If the alkalinity of the base is too weak, the thiol compound is not sufficiently activated and the reaction may proceed slowly. If the alkalinity is too strong, the carboxylate at the 2-position may be deesterified and the purity and yield of the reaction product may be reduced.

[0283] The amount of the base used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (2), as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0284] The solvent is not particularly limited as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used.

[0285] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0286] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms are preferred, and examples thereof include methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof.

[0287] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0288] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0289] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0290] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0291] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0292] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0293] As the hydrocarbon solvent, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.

[0294] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0295] As the solvent, from the viewpoint of the purity of the reaction product, an alcohol represented by the general formula ROH (R is as defined above) is preferred. From the viewpoint of suppressing impurities due to transesterification, an alcohol having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms, which has the same carbon number as R of the compound represented by the general formula (2), is more preferred. From the viewpoint of cost and availability of raw materials, an alcohol having an aliphatic hydrocarbon group having 1 to 3 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol is further preferred.

[0296] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0297] The amount of the solvent used is usually 1 L or more, preferably 2 L or more, more preferably 3 L or more, relative to 1 kg of the compound represented by the general formula (2), as a lower limit, from the viewpoint of operability, and is usually 30 L or less, preferably 20 L or less, more preferably 15 L or less, as an upper limit, from the viewpoint of operability, productivity and cost.

[0298] (Reaction Conditions)

[0299] The reaction temperature can be adjusted according to the PG used. 2 The lower limit is usually 0°C or higher, preferably 5°C or higher, more preferably 10°C or higher, from the viewpoint of productivity, and the upper limit is usually 60°C or lower, preferably 50°C or lower, more preferably 40°C or lower, from the viewpoint of purity of the reaction product and cost.

[0300] The reaction time can be adjusted according to the PG used. 2 The time varies depending on the deprotecting agent, base, solvent and the like, but is usually 0.5 to 48 hours, preferably 1 to 24 hours, from the viewpoint of productivity.

[0301] The pressure during the reaction is usually normal pressure.

[0302] The compound represented by the general formula (2) and PG 2 During the deprotection reaction, the order of supplying these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by the general formula (2) and PG are supplied to the reaction system in a reactor. 2 The reaction can be carried out by adding one or more of the deprotecting agents together with the solvent as a base liquid, and supplying the remaining components as a supply liquid under the reaction conditions. The base may be present in the reaction system from the beginning or supplied during the reaction, and may be supplied all at once or in multiple times.

[0303] (Post-processing)

[0304] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after the reaction product is separated by separation means such as concentration and crystallization. In addition, the product can also be further purified by known purification means such as recrystallization and column chromatography and then supplied to the next step.

[0305] The compound represented by general formula (3) is usually in the form of a free amine, but its form is not particularly limited as long as the reaction proceeds, and may form a salt or a solvate such as a hydrate or an organic solvate. The form of the compound represented by general formula (3) can be appropriately selected according to the raw materials and solvents used.

[0306] In the present invention, unless otherwise specified, "a compound represented by the general formula (3)" means both the compound represented by the general formula (3) and a solvate thereof, and "a salt of a compound represented by the general formula (3)" means both a salt of the compound represented by the general formula (3) and a solvate of the salt thereof.

[0307] When the compound represented by the general formula (3) is obtained in the form of a free amine, it can be converted into a salt or a hydrate or a solvate such as an organic solvate according to the desired method according to the conventional method. When the compound represented by the general formula (3) is obtained in the form of a salt or a hydrate or a solvate such as an organic solvate, it can be converted into a free amine according to the desired method according to the conventional method.

[0308] Examples of the salt of the compound represented by the general formula (3) include inorganic acid salts and organic acid salts.

[0309] Examples of the inorganic acid salt include hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, and polyphosphates.

[0310] Examples of the organic acid salt include carboxylates such as acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, glucuronate, and gluconate; and sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, and trifluoromethanesulfonate.

[0311] The salt of the compound represented by the general formula (3) is preferably an inorganic acid salt, and more preferably a hydrochloride because of good crystallinity and easy industrial availability.

[0312] [Step 3]

[0313] Step 3 is to react the compound represented by the general formula (3) or its salt with PG 1 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof.

[0314] When obtaining a salt of the compound represented by the general formula (4), for example, the amino group of the compound represented by the general formula (3) can be protected by a protective group PG 1 Removal and salt formation, removal of PG 1 Afterwards, a salt may be formed.

[0315] Simultaneous PG 1 When the removal and salt formation are carried out, for example, by reacting the compound represented by the general formula (3) with PG 1 The deprotecting agent reacts to remove PG 1 , a salt of the compound represented by the general formula (4) can be obtained. 1 After forming a salt, for example, the compound represented by the general formula (3) is reacted with PG 1After the free amine form of the compound represented by the general formula (4) is obtained by reacting with a deprotecting agent, the free amine form is reacted with a salt-forming acid to obtain a salt of the compound represented by the general formula (4).

[0316] (raw material)

[0317] As a PG 1 Deprotecting agent, as long as it can remove PG 1 There are no particular limitations on the deprotecting agent, and known deprotecting agents such as acids, bases, oxidizing agents, reducing agents, metal catalysts, secondary amines, thiol compounds, and fluoride salts can be used.

[0318] For example, PG 1 When it is tert-butyloxycarbonyl or acetyl, as PG 1 Deprotection agent, acid can be used to remove PG 1 .

[0319] As the acid, at least one acid selected from inorganic acids and organic acids can be used.

[0320] As the inorganic acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid and the like can be used.

[0321] As the organic acid, for example, carboxylic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzoic acid, citric acid, glucuronic acid, and gluconic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxyethanesulfonic acid, and trifluoromethanesulfonic acid can be used.

[0322] As the acid, from the viewpoint of raw material availability and cost, trifluoroacetic acid, p-toluenesulfonic acid, and hydrochloric acid are preferred, and hydrochloric acid is more preferred.

[0323] PG 1 The amount of deprotecting agent used is sufficient to remove PG 1 The amount is not particularly limited, but is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (3) or its salt, as a lower limit, from the viewpoint of productivity, and generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0324] Step 3 is preferably carried out in a solvent.

[0325] As a solvent, there is no particular limitation as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used. From the viewpoint of the purity of the reaction product, the organic solvent is preferably an alcohol represented by the general formula ROH (R is defined as above). From the viewpoint of suppressing impurities based on transesterification, an alcohol having an aliphatic hydrocarbon group with 1 to 8 carbon atoms or an aromatic hydrocarbon group with 6 to 8 carbon atoms, which has the same carbon number as R of the compound represented by the general formula (2), is more preferably used. From the viewpoint of cost and availability of raw materials, alcohols having an aliphatic hydrocarbon group with 1 to 3 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol are further preferred.

[0326] Regarding the amount of solvent used, relative to 1 kg of the compound represented by the general formula (3) or its salt, the lower limit is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more from the viewpoint of operability, and the upper limit is usually 30 L or less, preferably 20 L or less, and more preferably 15 L or less from the viewpoint of operability, productivity and cost.

[0327] (Reaction Conditions)

[0328] The reaction temperature can be adjusted according to the PG used. 1 The lower limit is usually 20°C or higher, preferably 25°C or higher, more preferably 30°C or higher, from the viewpoint of productivity, and the upper limit is usually 80°C or lower, preferably 70°C or lower, more preferably 60°C or lower, from the viewpoint of purity of the reaction product and cost.

[0329] The reaction time can be adjusted according to the PG used. 1 The time varies depending on the deprotecting agent, solvent, etc., but is usually 0.5 to 24 hours, preferably 1 to 12 hours, from the viewpoint of productivity.

[0330] The pressure during the reaction is usually normal pressure.

[0331] The compound represented by the general formula (3) or a salt thereof is reacted with PG 1 During the deprotection reaction, the order of supplying these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by the general formula (3) and PG are supplied to the reaction system in a reactor. 1 One or more deprotecting agents are added together with a solvent as a base liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby allowing the reaction to proceed. 1 When removing the protecting agent, the acid may be present in the reaction system from the beginning or supplied during the reaction. Furthermore, the acid may be supplied all at once or in multiple portions.

[0332] PG of the compound represented by general formula (3) 1 When the protecting group is a tert-butyloxycarbonyl group, isobutylene and carbon dioxide are produced as by-product gases during deprotection. Therefore, in order to control the amount of these gases produced while conducting the reaction, it is preferred to supply an acid together with a solvent in a reactor as a base liquid, and supply a compound represented by the general formula (3) and a solvent as a supply liquid under the reaction conditions to conduct the reaction.

[0333] (Post-processing)

[0334] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after the reaction product is separated by separation means such as concentration and crystallization. In addition, the product can also be further purified by known purification means such as recrystallization and column chromatography and then supplied to the next step.

[0335] The form of the compound represented by general formula (4) is not particularly limited as long as the reaction proceeds, and may be a free amine, or may form a salt, hydrate, or solvate such as an organic solvate. The form of the compound represented by general formula (4) may be appropriately selected according to the raw materials and solvents used.

[0336] When the compound represented by the general formula (4) is obtained in the form of a free amine, it can be converted into a salt or a hydrate or a solvate such as an organic solvate according to the desired method according to the conventional method. When the compound represented by the general formula (4) is obtained in the form of a salt or a hydrate or a solvate such as an organic solvate, it can be converted into a free amine according to the desired method according to the conventional method.

[0337] In the present invention, unless otherwise specified, "a compound represented by the general formula (4)" means both the compound represented by the general formula (4) and a solvate thereof, and "a salt of a compound represented by the general formula (4)" means both a salt of the compound represented by the general formula (4) and a solvate of the salt thereof.

[0338] In the present invention, the compound represented by the general formula (4) is preferably in the form of a salt.

[0339] Examples of the salt of the compound represented by the general formula (4) include inorganic acid salts and organic acid salts.

[0340] Examples of the inorganic acid salt include hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, and polyphosphates.

[0341] Examples of the organic acid salt include carboxylates such as acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, glucuronate, and gluconate; and sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, and trifluoromethanesulfonate.

[0342] The salt of the compound represented by the general formula (4) is preferably an inorganic acid salt, and more preferably a hydrochloride because of its good crystallinity and easy industrial availability.

[0343] When the compound represented by the general formula (4) is converted into a salt, an acid that forms a salt may be used.

[0344] The acid is not particularly limited as long as it forms a salt, and at least one acid selected from inorganic acids and organic acids can be used.

[0345] As the inorganic acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, polyphosphoric acid and the like can be used.

[0346] As the organic acid, for example, carboxylic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzoic acid, citric acid, glucuronic acid, and gluconic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxyethanesulfonic acid, and trifluoromethanesulfonic acid can be used.

[0347] As the acid, from the viewpoint of the availability of raw materials and cost, hydrochloric acid, sulfuric acid, trifluoroacetic acid, and p-toluenesulfonic acid are preferred, and hydrochloric acid is more preferred.

[0348] The amount of the acid used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (4), as a lower limit, from the viewpoint of productivity, and generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0349] When the compound represented by the general formula (4) is reacted with an acid, the order in which these compounds are supplied can be appropriately selected. In addition, these compounds can be supplied to the reaction system at one time or in multiple times. For example, in a reactor, one or more of the compound represented by the general formula (4) and the acid are added together with a solvent and used as a bottom liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby reacting.

[0350] In step 3, the protecting group PG of the amino group of the compound represented by the general formula (5) is more preferably 2 The removal of and salt formation occur simultaneously.

[0351] <Preparation method 3>

[0352] [Chemistry 31]

[0353]

[0354] (In the formula, each symbol is as defined above.)

[0355] Preparation method 3 is characterized by having

[0356] The compound represented by the general formula (2) and PG 1 A step of reacting with a deprotecting agent to obtain a compound represented by the general formula (5) or a salt thereof (step 4); and

[0357] The compound represented by the general formula (5) or a salt thereof is reacted with PG 2 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof (step 5).

[0358] [Step 4]

[0359] Step 4 is to react the compound represented by the general formula (2) with PG 1 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (5) or a salt thereof.

[0360] (raw material)

[0361] As a PG 1 Deprotection agent, the same PG as in step 3 can be used 1 Deprotecting agent.

[0362] PG 1 The amount of deprotecting agent used is sufficient to remove PG 1 The amount is not particularly limited, but is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 3 molar equivalents or more, as a lower limit, from the viewpoint of productivity, relative to the compound represented by the general formula (2); and generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, productivity and cost.

[0363] Step 4 can be carried out in a solvent.

[0364] As a solvent, there is no particular limitation as long as the reaction proceeds, and an organic solvent can be used. From the viewpoint of the purity of the reaction product, the organic solvent is preferably an alcohol represented by the general formula ROH (R is defined as above). From the viewpoint of suppressing impurities based on transesterification, an alcohol having an aliphatic hydrocarbon group with 1 to 8 carbon atoms or an aromatic hydrocarbon group with 6 to 8 carbon atoms, which has the same carbon number as R of the compound represented by the general formula (2), is more preferably used. From the viewpoint of cost and availability of raw materials, alcohols having an aliphatic hydrocarbon group with 1 to 3 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol are further preferred.

[0365] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0366] The amount of the solvent used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more, relative to 1 kg of the compound represented by the general formula (2), as a lower limit, and is usually 30 L or less, preferably 20 L or less, and more preferably 15 L or less, as an upper limit, from the viewpoints of operability, productivity and cost.

[0367] (Reaction Conditions)

[0368] The reaction temperature can be adjusted according to the PG used. 1 The lower limit is usually 20°C or higher, preferably 25°C or higher, more preferably 30°C or higher, from the viewpoint of productivity, and the upper limit is usually 80°C or lower, preferably 70°C or lower, more preferably 60°C or lower, from the viewpoint of purity of the reaction product and cost.

[0369] The reaction time can be adjusted according to the PG used. 1 The reaction time varies depending on the deprotecting agent, solvent, etc., but is usually 0.5 to 24 hours, preferably 1 to 12 hours, from the viewpoint of productivity.

[0370] The pressure during the reaction is usually normal pressure.

[0371] The compound represented by the general formula (2) and PG 1 During the deprotection reaction, the order of supplying these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by the general formula (2) and PG are supplied to the reaction system in a reactor. 1 One or more deprotecting agents are added together with a solvent as a base liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby allowing the reaction to proceed. 1When removing the protecting agent, the acid may be present in the reaction system from the beginning or supplied during the reaction, or may be supplied all at once or in multiple portions.

[0372] PG of the compound represented by general formula (2) 1 When the protecting group is a tert-butyloxycarbonyl group, isobutylene and carbon dioxide are produced as by-product gases during deprotection. Therefore, in order to control the amount of these gases produced while conducting the reaction, it is preferred to supply an acid together with a solvent in a reactor as a base liquid, and supply a compound represented by the general formula (2) and a solvent as a supply liquid under the reaction conditions to conduct the reaction.

[0373] (Post-processing)

[0374] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after the reaction product is separated by separation means such as concentration and crystallization. In addition, the product can also be further purified by known purification means such as recrystallization and column chromatography and then supplied to the next step.

[0375] Among the compounds represented by the general formula (5), the compound represented by the following formula (5a) is a novel compound. Since the compound has high crystallinity, it can be easily separated from the reaction by-products without complicated purification such as chromatography, and is therefore suitable for industrial production.

[0376] [Chemistry 32]

[0377]

[0378] (In the formula, Ns represents p-nitrobenzenesulfonyl, Bn represents benzyl, and Me represents methyl.)

[0379] The compound represented by general formula (5) is usually in the form of a free amine, but is not particularly limited in form as long as the reaction proceeds, and may form a salt. The form of the compound represented by general formula (5) can be appropriately selected according to the raw materials and solvents used.

[0380] When the compound represented by the general formula (5) is obtained in the form of a free amine, it can be converted into a salt or a hydrate or a solvate such as an organic solvate according to the desired method according to the conventional method. When the compound represented by the general formula (5) is obtained in the form of a salt or a hydrate or a solvate such as an organic solvate, it can be converted into a free amine according to the desired method according to the conventional method.

[0381] In the present invention, unless otherwise specified, "a compound represented by the general formula (5)" means both the compound represented by the general formula (5) and a solvate thereof, and "a salt of a compound represented by the general formula (5)" means both a salt of the compound represented by the general formula (5) and a solvate of the salt thereof.

[0382] Examples of the salt of the compound represented by the general formula (5) include inorganic acid salts and organic acid salts.

[0383] Examples of the inorganic acid salt include hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, and polyphosphates.

[0384] Examples of the organic acid salt include carboxylates such as acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, glucuronate, and gluconate; and sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, and trifluoromethanesulfonate.

[0385] The salt of the compound represented by the general formula (5) is preferably an inorganic acid salt, and more preferably a hydrochloride from the viewpoint of good crystallinity and easy industrial availability.

[0386] [Step 5]

[0387] Step 5 is to react the compound represented by the general formula (5) or its salt with PG 2 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof.

[0388] When obtaining a salt of the compound represented by the general formula (4), the protecting group PG of the amino group of the compound represented by the general formula (5) can be simultaneously carried out. 2 Removal and salt formation, removal of PG 2 Afterwards, a salt may be formed.

[0389] Simultaneous PG 2 When the removal and salt formation are carried out, for example, by reacting the compound represented by the general formula (5) with PG 2 The deprotecting agent reacts to remove PG 2 , a salt of the compound represented by the general formula (4) can be obtained. 2 After forming a salt, for example, the compound represented by the general formula (5) is reacted with PG 2 After the deprotecting agent is reacted to obtain a free amine form of the compound represented by the general formula (4), the free amine form is reacted with a salt-forming acid to obtain a salt of the compound represented by the general formula (4).

[0390] (raw material)

[0391] As a PG 2 Deprotection agent, the same PG as in step 2 can be used 2 Deprotecting agent.

[0392] PG 2The amount of the deprotecting agent used is usually 1 molar equivalent or more, preferably 1.5 molar equivalent or more, more preferably 2 molar equivalent or more, relative to the compound represented by the general formula (5) or its salt, as a lower limit, and is usually 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, from the viewpoint of reactivity, as an upper limit.

[0393] Step 5 is preferably carried out in the presence of a base in a solvent.

[0394] The base is not particularly limited as long as the reaction proceeds, and examples thereof include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, cyanides, etc. The base used in step 5 may be used alone or in any combination and ratio.

[0395] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0396] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0397] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0398] Examples of the metal amide include lithium amide, sodium ethylamide, calcium diethylamide, lithium diisopropylamide, potassium benzylamide, sodium bis(trimethylsilyl)amide, indole lithium, sodium pyrrole, lithium pyrrole, potassium pyrrole, potassium pyrrolidine, diethyl pyrrole aluminum, ethyl dipyrrole aluminum, tripyrrole aluminum, lithium diisopropylamide, and sodium hexamethyldisilazide.

[0399] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0400] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0401] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0402] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0403] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0404] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0405] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0406] Among these bases, from the viewpoint of basicity strength, tertiary amines, pyridines, carbonates, metal hydrides, metal hydrides, metal alkoxides, and hydroxides are preferred, carbonates are more preferred, and potassium carbonate and cesium carbonate are further preferred.

[0407] If the alkalinity of the base is too weak, the thiol compound is not sufficiently activated and the reaction may proceed slowly. If the alkalinity is too strong, the carboxylate at the 2-position may be deesterified and the purity and yield of the reaction product may be reduced.

[0408] The amount of the base used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (5) or its salt, as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0409] The solvent is not particularly limited as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used.

[0410] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0411] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms are preferred, and examples thereof include methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof.

[0412] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0413] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0414] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0415] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0416] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0417] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0418] As the hydrocarbon solvent, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.

[0419] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0420] As the solvent, from the viewpoint of the purity of the reaction product, an alcohol represented by the general formula ROH (R is as defined above) is preferred. From the viewpoint of suppressing impurities due to transesterification, an alcohol having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms, which has the same carbon number as R of the compound represented by the general formula (2), is more preferred. From the viewpoint of cost and availability of raw materials, an alcohol having an aliphatic hydrocarbon group having 1 to 3 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol is further preferred.

[0421] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0422] The amount of the solvent used is usually 1 L or more, preferably 2 L or more, and more preferably 3 L or more, relative to 1 kg of the compound represented by the general formula (5) or its salt, as a lower limit, from the viewpoint of operability, and is usually 30 L or less, preferably 20 L or less, and more preferably 15 L or less, as an upper limit, from the viewpoint of operability, productivity and cost.

[0423] (Reaction Conditions)

[0424] The reaction temperature can be adjusted according to the PG used. 2 The lower limit is usually 0°C or higher, preferably 5°C or higher, more preferably 10°C or higher, from the viewpoint of productivity, and the upper limit is usually 60°C or lower, preferably 50°C or lower, more preferably 45°C or lower, from the viewpoint of purity of the reaction product and cost.

[0425] The reaction time can be adjusted according to the PG used. 2 The reaction time varies depending on the deprotecting agent, base, solvent and the like, but is usually 0.5 to 48 hours, preferably 1 to 24 hours, from the viewpoint of productivity.

[0426] The pressure during the reaction is usually normal pressure.

[0427] The compound represented by the general formula (5) or a salt thereof is reacted with PG 2 During the deprotection reaction, the order of supplying these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by the general formula (5) and PG are supplied to the reaction system in a reactor. 2 The reaction can be carried out by adding one or more of the deprotecting agents together with the solvent as a base liquid, and supplying the remaining components as a supply liquid under the reaction conditions. The base may be present in the reaction system from the beginning or supplied during the reaction, and may be supplied all at once or in multiple times.

[0428] (Post-processing)

[0429] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after the reaction product is separated by separation means such as concentration and crystallization. In addition, the product can also be further purified by known purification means such as recrystallization and column chromatography and then supplied to the next step.

[0430] The form of the compound represented by general formula (4) is not particularly limited as long as the reaction proceeds, and may be a free amine, or may form a salt, hydrate, or solvate such as an organic solvate. The form of the compound represented by general formula (4) may be appropriately selected according to the raw materials and solvents used.

[0431] When the compound represented by the general formula (4) is obtained in the form of a free amine, it can be converted into a salt or a hydrate or a solvate such as an organic solvate according to the desired method according to the conventional method. When the compound represented by the general formula (4) is obtained in the form of a salt or a hydrate or a solvate such as an organic solvate, it can be converted into a free amine according to the desired method according to the conventional method.

[0432] In the present invention, unless otherwise specified, "a compound represented by the general formula (4)" means both the compound represented by the general formula (4) and a solvate thereof, and "a salt of a compound represented by the general formula (4)" means both a salt of the compound represented by the general formula (4) and a solvate of the salt thereof.

[0433] The form of the compound represented by the general formula (4) is preferably the same salt as in the above step 3.

[0434] Examples of the salt of the compound represented by the general formula (4) include inorganic acid salts and organic acid salts.

[0435] Examples of the inorganic acid salt include hydrochlorides, hydrobromides, hydroiodides, sulfates, phosphates, nitrates, and polyphosphates.

[0436] Examples of the organic acid salt include carboxylates such as acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, glucuronate, and gluconate; and sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxyethanesulfonate, and trifluoromethanesulfonate.

[0437] The salt of the compound represented by the general formula (4) is preferably an inorganic acid salt, and more preferably a hydrochloride because of its good crystallinity and easy industrial availability.

[0438] When the compound represented by the general formula (4) is converted into a salt, the method described in the above step 3 can be used. When the compound represented by the general formula (4) is converted into a salt, an acid that forms a salt may be used.

[0439] The acid is not particularly limited as long as it forms a salt, and at least one acid selected from inorganic acids and organic acids can be used.

[0440] As the inorganic acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid and the like can be used.

[0441] As the organic acid, for example, carboxylic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzoic acid, citric acid, glucuronic acid, and gluconic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxyethanesulfonic acid, and trifluoromethanesulfonic acid can be used.

[0442] As the acid, from the viewpoint of availability of raw materials and cost, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, and sulfuric acid are preferred, and hydrochloric acid is more preferred.

[0443] The amount of the acid used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (4), as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 15 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0444] When the compound represented by the general formula (4) is reacted with an acid, the order in which these compounds are supplied can be appropriately selected. In addition, these compounds can be supplied to the reaction system at one time or in multiple times. For example, in a reactor, one or more of the compound represented by the general formula (4) and the acid are added together with a solvent and used as a bottom liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby reacting.

[0445] (Post-processing)

[0446] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after the reaction product is separated by separation means such as concentration and crystallization. In addition, the product can also be further purified by known purification means such as recrystallization and column chromatography and then supplied to the next step.

[0447] <Preparation method 4>

[0448] [Chemistry 33]

[0449]

[0450] (In the formula, each symbol is as defined above.)

[0451] Preparation method 4 is the same as the above-mentioned preparation route C, which is a preparation route for preparing the compound represented by general formula (1) from the compound represented by formula (6).

[0452] Preparation method 4 is characterized in that it has

[0453] The compound represented by formula (6) is reacted with PG 1 A step of reacting with a protecting agent to obtain a compound represented by the general formula (7) (step 6);

[0454] A step of reacting the compound represented by the general formula (7) with a lactonization agent to obtain a compound represented by the general formula (8) (step 7);

[0455] a step of reacting the compound represented by the general formula (8) with an esterifying agent to obtain a compound represented by the general formula (9) (step 8); and

[0456] A step of reacting the compound represented by the above general formula (9) with a leaving group-introducing agent to obtain the compound represented by the general formula (1) (step 9).

[0457] In the preparation method 4, most of the compounds produced as intermediates are compounds with low polarity and high crystallinity, and operations such as extraction and recrystallization can be efficiently performed, so it is suitable for industrial production.

[0458] [Step 6]

[0459] Step 6 is to react the compound represented by formula (6) with PG 1 A step of reacting with a protecting agent to obtain a compound represented by the general formula (7).

[0460] (raw material)

[0461] The compound represented by formula (6) (cis-5-hydroxypiperidinic acid) can be produced by a known method, for example, the method described in International Publication No. 2014 / 098188, International Publication No. 2014 / 129459, International Publication No. 2015 / 098774, and the like.

[0462] The form of the compound of formula (6) is not particularly limited as long as the reaction proceeds, but is preferably a free form.

[0463] In the present invention, unless otherwise specified, "the compound represented by formula (6)" means both the compound represented by general formula (6) and its solvate, and "the salt of the compound represented by general formula (6)" means both the salt of the compound represented by general formula (6) and its solvate.

[0464] Here, the protecting group PG of the amino group in the general formula (7) is 1 , particularly preferably a carbamate protective group, an amide protective group with low electron-withdrawing property, or a sulfonamide protective group with low electron-withdrawing property, 1 Protective agent, preferably as the respective corresponding PG 1 The protecting agent is a carbamate protecting agent such as a tert-butyloxycarbonylating agent, or an amide protecting agent such as an acetylating agent. These are not particularly limited as long as the reaction proceeds, and known ones can be used.

[0465] Examples of the tert-butyloxycarbonylating agent include di-tert-butyl dicarbonate, N-tert-butylcarbonylimidazole, tert-butylphenyl carbonate, tert-butyl carbamate, and N-tert-butyloxycarbonylimidazole. From the viewpoint of cost and availability of raw materials, di-tert-butyl dicarbonate is preferred.

[0466] Examples of the acetylating agent include acetic anhydride, acetyl chloride, and acetyl bromide. From the viewpoint of cost and availability of raw materials, acetic anhydride is preferred.

[0467] Among these protecting agents, a tert-butyloxycarbonylating agent and an acetylating agent are more preferred because they can introduce a protecting group with low electron-withdrawing property.

[0468] PG 1The amount of the protecting agent used is not particularly limited as long as the reaction proceeds. The lower limit is usually 0.1 molar equivalent or more, preferably 1 molar equivalent or more, and more preferably 1.02 molar equivalent or more, relative to the compound represented by formula (6), from the viewpoint of productivity, and the upper limit is usually 10 molar equivalents or less, preferably 3 molar equivalents or less, and more preferably 2 molar equivalents or less, from the viewpoint of operability, purity of the reaction product and cost.

[0469] Step 6 is preferably carried out in the presence of a base in a solvent.

[0470] The base is not particularly limited as long as the reaction proceeds, and examples thereof include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, and cyanides, etc. The base used in step 6 may be used alone or in any combination and ratio.

[0471] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0472] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0473] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0474] Examples of the metal amide include lithium amide, sodium ethylamide, calcium diethylamide, lithium diisopropylamide, potassium benzylamide, sodium bis(trimethylsilyl)amide, indole lithium, sodium pyrrole, lithium pyrrole, potassium pyrrole, potassium pyrrolidine, diethyl pyrrole aluminum, ethyl dipyrrole aluminum, tripyrrole aluminum, lithium diisopropylamide, and sodium hexamethyldisilazide.

[0475] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0476] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0477] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0478] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0479] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0480] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0481] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0482] Among these bases, tertiary amines, pyridines and carbonates are preferred from the viewpoint of basicity, triethylamine, pyridine and potassium carbonate are more preferred, and triethylamine is further preferred from the viewpoint of reactivity. If the basicity of the base used is too strong, an over-reactant may be generated.

[0483] The amount of the base used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by formula (6), as a lower limit, from the viewpoint of productivity, and is generally 15 molar equivalent or less, preferably 10 molar equivalent or less, more preferably 5 molar equivalent or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0484] The base used in step 6 may be used alone or in any combination and ratio.

[0485] The solvent is not particularly limited as long as the reaction proceeds, and an aqueous solvent such as water or an organic solvent can be used. From the viewpoint of operability and cost, water or a mixed solvent of water and an organic solvent is preferred, and water is more preferred.

[0486] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0487] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms are preferred, and examples thereof include methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof.

[0488] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0489] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether, tert-butyl methyl ether and cyclopentyl methyl ether; and cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0490] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0491] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0492] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0493] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0494] As the hydrocarbon solvent, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane; and aromatic hydrocarbons such as toluene and xylene can be used.

[0495] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0496] The above-mentioned organic solvents may be used alone or in combination of two or more at any ratio.

[0497] As the solvent, water is preferred from the viewpoints of cost and handling properties.

[0498] The amount of the solvent used is, relative to 1 kg of the compound represented by formula (6), generally 1 L or more, preferably 2 L or more, and more preferably 3 L or more, as the lower limit, from the viewpoint of operability, and generally 30 L or less, preferably 20 L or less, and more preferably 10 L or less, as the upper limit, from the viewpoint of operability, productivity and cost.

[0499] When a mixed solvent of water and an organic solvent is used as the solvent of step 6, the mixing ratio of the organic solvent relative to water is, as a lower limit, usually 0.1 times by mass or more, preferably 0.2 times by mass or more, and more preferably 0.3 times by mass or more, and as an upper limit, usually 20 times by mass or less, preferably 15 times by mass or less, and more preferably 10 times by mass or less.

[0500] From the viewpoint of reactivity, the pH of the reaction solution is usually 5 to 14, more preferably 7 to 12, and even more preferably 8 to 11. If the pH of the reaction solution is too low, the reaction may not proceed smoothly, and if it is too high, the over-reactant increases, and the purity and yield of the reaction product may decrease. Here, the pH of the reaction solution refers to the pH of the layer containing water when water is used as the solvent, and refers to the pH of the water layer when the same volume of water as the reaction solution is added when an organic solvent is used.

[0501] (Reaction Conditions)

[0502] The reaction temperature can be adjusted according to the PG used. 1 The lower limit is usually 5°C or higher, preferably 10°C or higher, more preferably 15°C or higher, from the viewpoint of productivity, and the upper limit is usually 50°C or lower, preferably 45°C or lower, more preferably 40°C or lower, from the viewpoint of purity of the reaction product and cost.

[0503] The reaction time can be adjusted according to the PG used. 1 The reaction time varies depending on the protecting agent, base, solvent, etc., but is usually 0.1 to 24 hours, preferably 0.5 to 12 hours, from the viewpoint of productivity.

[0504] The pressure during the reaction is usually normal pressure.

[0505] The compound represented by formula (6) is reacted with PG 1 When the protective agent is reacted, the order of supplying these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by formula (6) or PG 1 The reaction can be carried out by adding one or more protective agents together with a solvent as a base liquid and supplying the remaining components as a supply liquid under the reaction conditions. The base may be present in the reaction system from the beginning or supplied during the process, and may be supplied all at once or in multiple times.

[0506] (Post-processing)

[0507] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after separating the reaction product by separation means such as concentration and crystallization. In addition, the product can also be further refined by known purification means such as recrystallization and column chromatography and then supplied to the next step. Among them, from the viewpoint of productivity, it is preferred that the reaction solution is directly supplied to the next step.

[0508] The compound represented by the general formula (7) may form a salt, a hydrate, or a solvate such as an organic solvate. The form thereof may vary depending on the starting materials and solvent used, and is not particularly limited as long as the target reaction is not inhibited.

[0509] In the present invention, unless otherwise specified, "a compound represented by the general formula (7)" means both the compound represented by the general formula (7) and a solvate thereof, and "a salt of a compound represented by the general formula (7)" means both a salt of the compound represented by the general formula (7) and a solvate of the salt thereof.

[0510] Among the compounds represented by the general formula (7), the compound represented by the following formula (7a) has high crystallinity and can be easily separated from reaction by-products without complicated purification such as chromatography, and is therefore suitable for industrial production.

[0511] [Chemistry 34]

[0512]

[0513] [Step 7]

[0514] Step 7 is a step of reacting the compound represented by the general formula (7) obtained in Step 6 with a lactonization agent to obtain a compound represented by the general formula (8).

[0515] (raw material)

[0516] As the lactonization agent, at least one compound selected from the group consisting of an acylating agent, an alkoxycarbonylating agent, and a sulfonylating agent can be used.

[0517] As the acylating agent, for example, an acid anhydride acylating agent such as formic acid-acetic anhydride, acetic anhydride, and trifluoroacetic anhydride; and an acid halide such as acetyl chloride, chloroacetyl chloride, dichloroacetyl chloride, trichloroacetyl chloride, propionyl chloride, benzoyl chloride, 4-chlorobenzoyl chloride, acetyl bromide, propionyl bromide, and benzoyl bromide can be used.

[0518] As the alkoxycarbonylating agent, for example, an acid anhydride alkoxycarbonylating agent such as di-tert-butyl dicarbonate; or a halogenated alkoxycarbonylating agent such as benzyloxycarbonyl chloride, allyloxycarbonyl chloride, benzyloxycarbonyl bromide, or allyloxycarbonyl bromide can be used.

[0519] As the sulfonylating agent, for example, a halogenated sulfonylating agent such as methanesulfonyl chloride, p-toluenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, methanesulfonyl bromide, p-toluenesulfonyl bromide, or 2-nitrobenzenesulfonyl bromide can be used.

[0520] As the lactonization agent, from the viewpoint of reactivity, an acylating agent is preferred, an acid anhydride acylating agent is more preferred, and acetic anhydride is further preferred.

[0521] The amount of the lactonizing agent used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (7), as a lower limit from the viewpoint of productivity, and is generally 10 molar equivalents or less, preferably 3 molar equivalents or less, more preferably 2 molar equivalents or less, as an upper limit from the viewpoint of operability, purity of the reaction product and cost.

[0522] Step 7 can be carried out in the presence of a base in a solvent.

[0523] The base is not particularly limited as long as the reaction proceeds, and examples thereof include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, cyanides, etc. The base used in step 7 may be used alone or in any combination and ratio.

[0524] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0525] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0526] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0527] Examples of the metal amide include lithium diisopropylamide and sodium hexamethyldisilazide.

[0528] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0529] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0530] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0531] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0532] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0533] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0534] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0535] Among these bases, tertiary amines, pyridines and carbonates are preferred from the viewpoint of basicity strength, triethylamine, pyridine and potassium carbonate are more preferred, and triethylamine is further preferred from the viewpoint of reactivity.

[0536] The amount of the base used is usually 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (7), as a lower limit, from the viewpoint of productivity, and is usually 10 molar equivalents or less, preferably 3 molar equivalents or less, more preferably 2 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0537] The solvent is not particularly limited as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used.

[0538] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0539] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms are preferred, and examples thereof include methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof.

[0540] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0541] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0542] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0543] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0544] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0545] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0546] As the hydrocarbon solvent, for example, an aliphatic hydrocarbon solvent such as hexane, cyclohexane, heptane, cycloheptane, or the like; or an aromatic hydrocarbon solvent such as toluene, xylene, or the like can be used.

[0547] As the basic organic solvent, for example, a pyridine-based solvent such as pyridine, 2-picoline, 3-picoline, 4-picoline, or 2,6-lutidine can be used.

[0548] As the solvent, from the viewpoint of cost and handling properties, an ester solvent is preferred, and ethyl acetate is more preferred.

[0549] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0550] The amount of the solvent used is, relative to 1 kg of the compound represented by the general formula (7), generally 1 L or more, preferably 2 L or more, and more preferably 3 L or more as the lower limit, from the viewpoint of operability, and generally 30 L or less, preferably 20 L or less, and more preferably 10 L or less, as the upper limit, from the viewpoint of operability, productivity and cost.

[0551] (Reaction time)

[0552] The reaction temperature may vary depending on the lactonization agent, base, solvent, etc. used, but is usually 0° C. or higher, preferably 5° C. or higher, more preferably 10° C. or higher, as a lower limit, from the viewpoint of productivity, and is usually 50° C. or lower, preferably 45° C. or lower, more preferably 40° C. or lower, as an upper limit, from the viewpoint of the purity of the reaction product and cost.

[0553] The reaction time may vary depending on the lactonization agent, base, solvent, etc. used, but is usually 0.5 to 48 hours, preferably 1 to 24 hours, from the viewpoint of productivity.

[0554] The pressure during the reaction is usually normal pressure.

[0555] When the compound represented by the general formula (7) is reacted with the lactonizing agent, the supply order of these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at one time or in multiple times. For example, in a reactor, any one or more of the compound represented by the general formula (7) or the lactonizing agent is added together with a solvent and used as a base liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby allowing the reaction to proceed. The base can be present in the reaction system from the beginning or supplied midway, and can be supplied at one time or in multiple times.

[0556] (Post-processing)

[0557] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after separating the reaction product by separation means such as concentration and crystallization. In addition, the product can also be further refined by known purification means such as recrystallization and column chromatography and then supplied to the next step. Among them, from the viewpoint of productivity, it is preferred that the reaction solution is directly supplied to the next step.

[0558] The compound represented by the general formula (8) may form a solvate such as a hydrate or an organic solvate. The form thereof may vary depending on the starting materials and solvent used, and is not particularly limited as long as the target reaction is not inhibited.

[0559] In the present invention, unless otherwise specified, "a compound represented by the general formula (8)" means both the compound represented by the general formula (8) and a solvate thereof.

[0560] It should be noted that among the compounds represented by general formula (8), the compounds represented by formula (8a) and formula (8b) have high crystallinity and can be easily separated from reaction by-products without complicated purification such as chromatography, and are therefore suitable for industrial production. The compound represented by formula (8b) is a novel compound.

[0561] [Chemistry 35]

[0562]

[0563] (In the formula, Boc represents tert-butyloxycarbonyl, and Ac represents acetyl).

[0564] [Step 8]

[0565] Step 8 is a step of reacting the compound represented by the general formula (8) obtained in Step 7 with an esterifying agent to obtain a compound represented by the general formula (9).

[0566] (raw material)

[0567] As the esterification agent, a metal alkoxide represented by the general formula ROM (R is as defined above) or an alcohol represented by the general formula ROH (R is as defined above) can be used.

[0568] The metal alkoxide is not particularly limited as long as the reaction proceeds, but preferably a metal alkoxide in which R is an aliphatic hydrocarbon group having 1 to 3 carbon atoms and M is an alkali metal or an alkaline earth metal, and examples thereof include lithium methoxide, lithium ethoxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, magnesium dimethanol, magnesium diethoxide, calcium dimethanol, calcium diethoxide, cesium dimethanol, and cesium diethoxide. More preferably, a metal alkoxide in which R is an aliphatic hydrocarbon group having 1 to 2 carbon atoms and M is an alkali metal, and from the viewpoint of cost and availability of raw materials, sodium methoxide and sodium ethoxide are used.

[0569] The alcohol is not particularly limited as long as it is an alcohol represented by the general formula ROH, and the reaction proceeds. Preferably, it is an alcohol having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms, and for example, methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomers thereof can be used. More preferred are alcohols having a hydrocarbon group having 1 to 3 carbon atoms, such as methanol, ethanol, 1-propanol, 2-propanol, and benzyl alcohol, and methanol and benzyl alcohol are particularly preferred.

[0570] When the esterification is carried out using an alcohol compound, the reaction is preferably carried out in the presence of an acid.

[0571] The acid is not particularly limited as long as the reaction proceeds, and an inorganic acid or an organic acid can be used.

[0572] Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, phosphoric acid, and polyphosphoric acid.

[0573] Examples of the organic acid include carboxylic acids such as acetic acid, trifluoroacetic acid, trichloroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzoic acid, citric acid, glucuronic acid, and gluconic acid; and sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and hydroxyethanesulfonic acid.

[0574] As the acid, sulfuric acid and p-toluenesulfonic acid are preferred from the viewpoint of reactivity.

[0575] The amount of the esterifying agent used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (8), as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 10 molar equivalents or less, more preferably 5 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0576] Step 8 is preferably carried out in a solvent.

[0577] The solvent is not particularly limited as long as the reaction proceeds, but preferably an alcohol represented by the general formula ROH (R is as defined above) is used, more preferably an alcohol having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms, and further preferably an alcohol having an aliphatic hydrocarbon group having 1 to 3 carbon atoms such as methanol, ethanol, propanol, etc.

[0578] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0579] The amount of the solvent used is, relative to 1 kg of the compound represented by the general formula (8), generally 1 L or more, preferably 2 L or more, and more preferably 3 L or more as the lower limit, from the viewpoint of operability, and generally 30 L or less, preferably 25 L or less, and more preferably 20 L or less, as the upper limit, from the viewpoint of operability, productivity and cost.

[0580] (Reaction Conditions)

[0581] The reaction temperature may vary depending on the esterification agent, solvent, etc. used, but the lower limit is usually 0°C or higher, preferably 1°C or higher, more preferably 2°C or higher from the viewpoint of productivity, and the upper limit is usually 30°C or lower, preferably 20°C or lower, more preferably 10°C or lower from the viewpoint of the purity of the reaction product and cost.

[0582] The reaction time may vary depending on the esterification agent, solvent, etc. used, but is usually 0.1 to 24 hours, preferably 0.5 to 12 hours, from the viewpoint of productivity.

[0583] The pressure during the reaction is usually atmospheric pressure, but may be pressurized.

[0584] When the compound represented by the general formula (8) is reacted with the esterifying agent, the supply order of these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at once or in multiple times. For example, the compound represented by the general formula (8) or any one or more of the esterifying agents are added together with a solvent in a reactor as a base liquid, and the remaining components are supplied as a supply liquid under the reaction conditions, thereby allowing the reaction to proceed.

[0585] (Post-processing)

[0586] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after separating the reaction product by separation means such as concentration and crystallization. In addition, the product can also be further refined by known purification means such as recrystallization and column chromatography and then supplied to the next step. Among them, from the viewpoint of productivity, it is preferred that the reaction solution is directly supplied to the next step.

[0587] The compound represented by the general formula (9) may form a solvate such as a hydrate or an organic solvate. The form thereof may vary depending on the starting materials and solvent used, and is not particularly limited as long as the target reaction is not inhibited.

[0588] In the present invention, unless otherwise specified, "a compound represented by the general formula (9)" means both the compound represented by the general formula (9) and a solvate thereof.

[0589] Among the compounds represented by general formula (9), the compound represented by formula (9b) is a novel compound. Since the compound has high crystallinity, it can be easily separated from the reaction by-products without complicated purification such as chromatography, and is therefore suitable for industrial production.

[0590] [Chemistry 36]

[0591]

[0592] (In the formula, Ac represents acetyl group and Me represents methyl group).

[0593] [Step 9]

[0594] Step 9 is a step of reacting the compound represented by the general formula (9) obtained in step 8 with a leaving group-introducing agent to obtain a compound represented by the general formula (1).

[0595] (raw material)

[0596] The leaving group-introducing agent is not particularly limited as long as it can introduce a leaving group LG into the compound represented by the general formula (9), and a known leaving group-introducing agent can be used.

[0597] Here, as the leaving group LG in the general formula (1), a sulfonyloxy group is particularly preferred, and therefore as the leaving group-introducing agent, a sulfonyloxylating agent that can introduce such a leaving group LG into the compound represented by the general formula (9) is preferred.

[0598] Examples of the sulfonyl oxylating agent include nitrobenzenesulfonylating agents, toluenesulfonylating agents, methanesulfonylating agents, trifluoromethanesulfonylating agents, etc. From the viewpoint of the reactivity of the leaving group introduced, a nitrobenzenesulfonylating agent is preferred.

[0599] The nitrobenzenesulfonylating agent is not particularly limited as long as it can protect the amino group with a nitrobenzenesulfonyl group, but a nitrobenzenesulfonyl halide is preferred.

[0600] Examples of the nitrobenzenesulfonyl halide include nitrobenzenesulfonyl fluoride such as o-nitrobenzenesulfonyl fluoride, p-nitrobenzenesulfonyl fluoride, 2,4-dinitrobenzenesulfonyl fluoride, 2,3-dinitrobenzenesulfonyl fluoride, 2,5-dinitrobenzenesulfonyl fluoride, and 2,6-dinitrobenzenesulfonyl fluoride; and o-nitrobenzenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, 2,4-dinitrobenzenesulfonyl chloride, 2,3-dinitrobenzenesulfonyl chloride, 2,5-dinitrobenzenesulfonyl chloride, and 2,6-dinitrobenzenesulfonyl chloride. Nitrobenzenesulfonyl chlorides such as o-nitrobenzenesulfonyl bromide, p-nitrobenzenesulfonyl bromide, 2,4-dinitrobenzenesulfonyl bromide, 2,3-dinitrobenzenesulfonyl bromide, 2,5-dinitrobenzenesulfonyl bromide, 2,6-dinitrobenzenesulfonyl bromide and the like; Nitrobenzenesulfonyl iodide such as o-nitrobenzenesulfonyl iodide, p-nitrobenzenesulfonyl iodide, 2,4-dinitrobenzenesulfonyl iodide, 2,3-dinitrobenzenesulfonyl iodide, 2,5-dinitrobenzenesulfonyl iodide, 2,6-dinitrobenzenesulfonyl iodide and the like.

[0601] Among them, from the viewpoint of cost and availability of raw materials, nitrobenzenesulfonyl chloride is preferred, and p-nitrobenzenesulfonyl chloride and o-nitrobenzenesulfonyl chloride are particularly preferred.

[0602] Examples of the tosylating agent include p-toluenesulfonyl chloride and p-toluenesulfonic anhydride. From the viewpoint of cost and availability of raw materials, p-toluenesulfonyl chloride is preferred.

[0603] Examples of the methanylating agent include methanesulfonyl chloride and methanesulfonic anhydride. From the viewpoint of cost and availability of raw materials, methanesulfonyl chloride is preferred.

[0604] Examples of the trifluoromethanesulfonylating agent include trifluoromethanesulfonyl fluoride, trifluoromethanesulfonyl chloride and trifluoromethanesulfonic anhydride. From the viewpoint of cost and availability of raw materials, trifluoromethanesulfonic anhydride is preferred.

[0605] The amount of the leaving group introducing agent used is generally 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (9), as a lower limit, from the viewpoint of productivity, and is generally 20 molar equivalents or less, preferably 10 molar equivalents or less, more preferably 5 molar equivalents or less, as an upper limit, from the viewpoint of operability, purity of the reaction product and cost.

[0606] Step 9 is preferably carried out in the presence of a base in a solvent.

[0607] The base is not particularly limited as long as the reaction proceeds, and examples thereof include tertiary amines, pyridines, organic strong bases, metal amides, alkyl metal compounds, metal hydrides, metal alkoxides, carbonates, phosphates, metal hydroxides, cyanides, etc. The base used in step 9 may be used alone or in any combination and ratio.

[0608] Examples of the tertiary amines include triethylamine, diisopropylethylamine, N-methylmorpholine, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane.

[0609] Examples of the pyridines include pyridine, 4-dimethylaminopyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, and 2,6-lutidine.

[0610] Examples of the organic strong base include 1,8-diazabicyclo[5.4.0]undec-7-ene and tetramethylguanidine.

[0611] Examples of the metal amide include lithium amide, sodium ethylamide, calcium diethylamide, lithium diisopropylamide, potassium benzylamide, sodium bis(trimethylsilyl)amide, indole lithium, sodium pyrrole, lithium pyrrole, potassium pyrrole, potassium pyrrolidine, diethyl pyrrole aluminum, ethyl dipyrrole aluminum, tripyrrole aluminum, lithium diisopropylamide, and sodium hexamethyldisilazide.

[0612] Examples of the alkyl metal compound include n-butyllithium, sec-butyllithium, tert-butyllithium, and isopropylmagnesium bromide.

[0613] Examples of the metal hydride include lithium hydride, sodium hydride, potassium hydride, magnesium hydride, calcium hydride, and cesium hydride.

[0614] Examples of the metal alkoxide include lithium methoxide, lithium ethoxide, lithium propoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium propoxide, and potassium tert-butoxide.

[0615] Examples of the carbonate include sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and cesium hydrogen carbonate.

[0616] Examples of the phosphate include sodium phosphate, sodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and potassium dihydrogen phosphate.

[0617] Examples of the metal hydroxide include lithium hydroxide, sodium hydroxide, potassium hydroxide, and calcium hydroxide.

[0618] Examples of the cyanide include sodium cyanide and potassium cyanide.

[0619] Among these bases, from the viewpoint of basicity strength, tertiary amines and pyridines are preferred, and triethylamine is more preferred.

[0620] The amount of the base used is usually 0.1 molar equivalent or more, preferably 1 molar equivalent or more, more preferably 1.02 molar equivalent or more, relative to the compound represented by the general formula (9), as a lower limit, from the viewpoint of productivity, and is usually 30 molar equivalents or less, preferably 20 molar equivalents or less, more preferably 10 molar equivalents or less, as an upper limit.

[0621] The solvent is not particularly limited as long as the reaction proceeds, and an organic solvent or an aqueous solvent can be used. From the viewpoint of reactivity, an organic solvent is preferably used.

[0622] As the organic solvent, for example, at least one solvent selected from the group consisting of alcohol solvents, ester solvents, ether solvents, ketone solvents, nitrile solvents, amide solvents, sulfoxide solvents, hydrocarbon solvents, and basic organic solvents can be used.

[0623] Examples of the alcohol solvent include alcohols represented by the general formula ROH (R is as defined above). Alcohols having an aliphatic hydrocarbon group having 1 to 8 carbon atoms or an aromatic hydrocarbon group having 6 to 8 carbon atoms are preferred, and examples thereof include methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, benzyl alcohol, phenylethyl alcohol, or isomeric alcohols thereof.

[0624] As the ester solvent, for example, acetate such as ethyl acetate, propyl acetate, and butyl acetate can be used.

[0625] As the ether solvent, for example, chain ethers such as diethyl ether, di-n-butyl ether, diisopropyl ether, di-n-butyl ether and tert-butyl methyl ether; and cyclic ethers such as cyclopentyl methyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and dioxane can be used.

[0626] As the ketone solvent, for example, aliphatic ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone can be used.

[0627] As the nitrile solvent, for example, aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, valeronitrile, and isovaleronitrile; and aromatic nitriles such as benzonitrile can be used.

[0628] As the amide solvent, for example, aprotic amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone can be used.

[0629] As the sulfoxide solvent, for example, an aprotic sulfoxide such as dimethyl sulfoxide can be used.

[0630] As the hydrocarbon solvent, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, and cycloheptane, and aromatic hydrocarbons such as toluene and xylene can be used.

[0631] As the basic organic solvent, for example, pyridine, 2-methylpyridine, 3-methylpyridine, 4-methylpyridine, 2,6-lutidine or the like can be used.

[0632] The solvent is preferably an ester solvent, and more preferably ethyl acetate.

[0633] As the solvent, the above-mentioned organic solvents may be used alone or in combination of two or more kinds at any ratio.

[0634] The amount of the solvent used is, relative to 1 kg of the compound represented by the general formula (9), generally 1 L or more, preferably 2 L or more, and more preferably 3 L or more as the lower limit, from the viewpoint of operability, and generally 30 L or less, preferably 20 L or less, and more preferably 15 L or less, as the upper limit, from the viewpoint of operability, productivity and cost.

[0635] (Reaction Conditions)

[0636] The reaction temperature may vary depending on the leaving group introducing agent, base, solvent, etc. used, but is usually 0°C or higher, preferably 5°C or higher, more preferably 10°C or higher from the viewpoint of productivity as the lower limit, and is usually 50°C or lower, preferably 40°C or lower, more preferably 30°C or lower from the viewpoint of the purity of the reaction product and cost as the upper limit.

[0637] The reaction time may vary depending on the leaving group-introducing agent, base, solvent, etc. used, but is usually 0.5 to 24 hours, preferably 1 to 12 hours.

[0638] The pressure during the reaction is usually normal pressure.

[0639] When the compound represented by the general formula (9) is reacted with a leaving group introducing agent, the supply order of these compounds can be appropriately selected. In addition, these compounds can be supplied to the reaction system at one time or in multiple times. For example, by adding one or more of the compound represented by the general formula (9) or the leaving group introducing agent together with a solvent in a reactor and using it as a bottom liquid, supplying the remaining components as a supply liquid under the reaction conditions, the reaction can be carried out. The base can be present in the reaction system from the beginning, or it can be supplied midway. In addition, it can be supplied at one time or in multiple times.

[0640] (Post-processing)

[0641] The reaction solution can be directly supplied to the next step, or it can be supplied to the next step after being subjected to treatments such as neutralization, liquid separation, filtration, etc., or it can be supplied to the next step after separating the reaction product by separation means such as concentration and crystallization. In addition, the product can also be further refined by known purification means such as recrystallization and column chromatography and then supplied to the next step. Among them, from the viewpoint of productivity, it is preferred that the reaction solution is directly supplied to the next step.

[0642] The compound represented by the general formula (1) may form a solvate such as a hydrate or an organic solvate. The form thereof may vary depending on the starting materials and solvent used, and is not particularly limited as long as the target reaction is not inhibited.

[0643] In the present invention, unless otherwise specified, "a compound represented by the general formula (1)" means both the compound represented by the general formula (1) and a solvate thereof.

[0644] Among the compounds represented by the general formula (1), the compound represented by the following formula (1a) is a novel compound. Since this compound has high crystallinity, it can be easily separated from reaction by-products without complicated purification such as chromatography, and is therefore suitable for industrial production.

[0645] [Chemistry 37]

[0646]

[0647] (In the formula, Boc represents tert-butyloxycarbonyl, Ns represents p-nitrobenzenesulfonyl, and Me represents methyl.)

[0648] <Preparation method 5>

[0649] [Chemistry 38]

[0650]

[0651] (In the formula, each symbol is as defined above.)

[0652] Preparation method 5 is characterized in that it has

[0653] a step of reacting the compound represented by the general formula (8) with an esterifying agent to obtain the compound represented by the general formula (9) (step 8); and

[0654] A step of reacting the compound represented by the general formula (9) with a leaving group-introducing agent to obtain the compound represented by the general formula (1) (step 9).

[0655] Step 8 and Step 9 of Production Method 5 are as described in the above section <Production Method 4>.

[0656] In the production method 5, most of the compounds produced as intermediates are compounds with low polarity and high crystallinity, and operations such as extraction and recrystallization can be efficiently performed, so it is suitable for industrial production.

[0657] <Preparation method 6>

[0658] [Chemistry 39]

[0659]

[0660] (In the formula, each symbol is as defined above.)

[0661] Preparation method 6 is characterized in that it has

[0662] The compound represented by the general formula (1) and the compound represented by the general formula PG 2 NHOPG 3 A step of reacting a hydroxylamine derivative shown in the presence of a base in a solvent to obtain a compound represented by the general formula (2) (step 1);

[0663] The compound represented by the general formula (2) obtained in step 1 is reacted with PG 2 A step of reacting with a deprotecting agent to obtain a compound represented by the general formula (3) or a salt thereof (step 2); and

[0664] The compound represented by the general formula (3) obtained in step 2 or its salt is reacted with PG 1 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof (step 3).

[0665] That is, Production Method 6 has Production Route A of the present invention.

[0666] Steps 1 to 3 of Production Method 6 are as described in the above-mentioned <Production Method 1> and <Production Method 2>.

[0667] In addition, the preparation method 6 may further include the following steps.

[0668] [Chemistry 40]

[0669]

[0670] (In the formula, each symbol is as defined above.)

[0671] Steps 6 to 9 of Production Method 6 are as described in the above section <Production Method 4>.

[0672] Preparation method 6 can obtain a high-purity intermediate, can react under mild conditions, and can easily remove unreacted products, and is therefore suitable for industrial preparation.

[0673] <Preparation method 7>

[0674] [Chemistry 41]

[0675]

[0676] (In the formula, each symbol is as defined above.)

[0677] Preparation method 7 is characterized in that it has

[0678] The compound represented by the general formula (1) and the compound represented by the general formula PG 2 NHOPG 3 A step of reacting a hydroxylamine derivative shown in the presence of a base in a solvent to obtain a compound represented by the general formula (2) (step 1);

[0679] The compound represented by the general formula (2) obtained in step 1 is reacted with PG 1 A step of reacting with a deprotecting agent to obtain a compound represented by the general formula (5) or a salt thereof (step 4); and

[0680] The compound represented by the general formula (5) obtained in step 4 or a salt thereof is reacted with PG 2 A step of reacting a deprotecting agent to obtain a compound represented by the general formula (4) or a salt thereof (step 5).

[0681] That is, Production Method 7 has Production Route B of the present invention.

[0682] Step 1, step 4 and step 5 of Production Method 7 are as described in the above-mentioned <Production Method 1> and <Production Method 3>.

[0683] In addition, the preparation method 7 may further include the following steps.

[0684] [Chemistry 42]

[0685]

[0686] (In the formula, each symbol is as defined above.)

[0687] Steps 6 to 9 of Production Method 7 are as described in the above section <Production Method 4>.

[0688] Preparation method 7 can obtain a high-purity intermediate, can react under mild conditions, and can easily remove unreacted products, so it is suitable for industrial preparation.

[0689] Example

[0690] Hereinafter, the present invention will be described in further detail with reference to Examples, but the present invention is not limited to these Examples.

[0691] In the following examples, the ratio of the 2-isomer of the obtained compound was measured under the following HPLC analysis conditions.

[0692] (HPLC analysis conditions)

[0693] [Table 1]

[0694]

[0695] Example 1: Step 6 → Step 7 → Step 8 → Step 9

[0696] [Step 6]

[0697] Preparation of (2S,5S)-1-(tert-butyloxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid

[0698] [Chemistry 43]

[0699]

[0700] (2S,5S)-5-hydroxypiperidine-2-carboxylic acid (hereinafter referred to as compound (6a)) as a raw material was synthesized according to the method described in International Publication No. WO2015 / 099126.

[0701] In a separable flask, 100.0 g (0.689 mol) of compound (6a) was dissolved in 500 g of water. 195.5 g (0.897 mol) of di-tert-butyl dicarbonate and 146.4 g (1.448 mol) of triethylamine were added to the resulting solution at 30°C. After stirring at 25°C for 1 hour, 146.4 g (1.448 mol) of triethylamine was added again, and the mixture was further stirred at 25°C for 6 hours.

[0702] After adding 200 mL of toluene to the obtained reaction solution and stirring, the organic layer was removed. The obtained aqueous layer was cooled to 5°C, 35 wt% hydrochloric acid was added, the pH was adjusted to 2.0, and then extracted with ethyl acetate (500 mL×2, 300 mL×1 time). The recovered organic layers were combined, washed with 100 mL of water, and the solvent was distilled off to adjust the liquid volume to 600 mL. 400 mL of n-heptane was added to the obtained residue, and seed crystals of (2S,5S)-1-(tert-butyloxycarbonyl)-5-hydroxypiperidine-2-carboxylic acid (hereinafter referred to as compound (7a)) prepared separately were seeded, and after aging, crystals precipitated. 1000 mL of n-heptane was further added, and after cooling to -5°C and aging, the obtained crystals were filtered to obtain 156.9 g (yield 92.9%) of white powder of the target compound (7a).

[0703] 1H-NMR (400MHz, CDCl3) δ1.24-1.33(1H,m),1.43-1.47(9H,m),1.66-1.76(1H,m),1.99(1H,d,J=10 .8Hz),2.28-2.30(1H,m),2.65-2.81(1H,m),3.63(1H,m),4.09-4.15(1H,m),4.688-4.84(1H,m).

[0704] [Step 7 → Step 8]

[0705] Preparation of (2S,5S)-1-(tert-butyloxycarbonyl)-5-hydroxy-piperidine-2-carboxylic acid methyl ester

[0706] [Chemistry 44]

[0707]

[0708] Under nitrogen atmosphere, 11.0 g (0.0448 mol) of the compound (7a) obtained in the above [Step 6] was dissolved in 33 mL of tetrahydrofuran in a separable flask. 5.44 g (0.0539 mol) of triethylamine and 5.04 g (0.0494 mol) of acetic anhydride were added to the resulting solution at 20°C, and the mixture was reacted at 20°C for 6 hours.

[0709] 33 mL of methanol was added to the obtained reaction solution, and after cooling to 5°C, 20.6 mL (0.103 mol) of a 5 mol / L sodium methoxide methanol solution was added, and the mixture was reacted at 5°C for 1 hour. 3.77 g (0.063 mol) of acetic acid and 33 mL of water were added to the obtained reaction solution, and methanol and tetrahydrofuran were distilled off. The residue was extracted with 66 mL of ethyl acetate. The obtained organic layer was washed with 22 mL of a 5 wt% sodium bicarbonate aqueous solution, and the solvent was distilled off to obtain 12.6 g (10.4 g in terms of pure amount) of a crude product of (2S,5S)-1-(tert-butyloxycarbonyl)-5-hydroxy-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (9a)) as a colorless oil (yield 89.1%).

[0710] 1 H-NMR (400MHz, CDCl3) δ1.17-1.28(1H,m),1.44-1.47(9H,m),1.68-1.78(1H,m),1.96-2.00(1H,m),2.2 7-2.30(1H,m),2.63-2.79(1H,m),3.62-3.64(1H,m),3.74(3H,s),4.09-4.21(1H,m),4.67-4.85(1H,m).

[0711] [Step 9]

[0712] Preparation of (2S,5S)-1-(tert-butyloxycarbonyl)-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester

[0713] [Chemistry 45]

[0714]

[0715] Under nitrogen atmosphere, ethyl acetate was added to 12.6 g (10.4 g, 0.0400 mol in pure amount) of the crude product of compound (9a) obtained in the above [Step 7 → Step 8] in a separable flask to adjust the liquid volume to 83.2 mL. 14.5 g (0.144 mol) of triethylamine and 15.9 g (0.0720 mol) of p-nitrobenzenesulfonyl chloride were added to the resulting solution at 15°C, and the mixture was stirred at 15°C for 4 hours.

[0716] After adding 41 mL of water to the obtained reaction solution and stirring, the aqueous layer was discarded. Subsequently, 31 mL of water and 2.44 g of acetic acid were added and stirred, and the aqueous layer was discarded. The organic layer was further washed with 30.9 mL of a 5 wt% sodium bicarbonate aqueous solution and 10 mL of water. The obtained organic layer was concentrated, and after adjusting the liquid volume to 32 mL, 21 mL of n-heptane was added at 45°C, and seed crystals of (2S,5S)-1-(tert-butyloxycarbonyl)-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester prepared separately were seeded, and 62 mL of n-heptane was further added to precipitate crystals. After cooling to 5°C and aging, the obtained crystals were filtered to obtain 16.1 g (yield 90.6%) of a light yellow powder of (2S,5S)-1-(tert-butyloxycarbonyl)-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (1a)).

[0717] 1 H-NMR (400MHz, CDCl3) δ1.41-1.48(10H,m),1.69-1.75(1H,m),1.97-2.12(1H,m),2.27-2.33(1H,m),2.78-2.99(1H, m),3.73-3.74(3H,m),4.06-4.20(1H,m),4.49-4.58(1H,m),4.64-4.84(1H,m),8.12-8.14(2H,m),8.41-8.43(2H,m).

[0718] Example 2

[0719] [Step 7]

[0720] Preparation of (1S,4S)-5-(tert-butyloxycarbonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3-one

[0721] [Chemistry 46]

[0722]

[0723] Under a nitrogen atmosphere, 3.00 g (0.0122 mol) of the compound (7a) obtained in [Step 6] of Example 1 was dissolved in 12 mL of ethyl acetate in a separable flask. 1.48 g (0.0147 mol) of triethylamine and 1.37 g (0.0134 mol) of acetic anhydride were added to the resulting solution at 20°C, and the mixture was reacted at 20°C for 6 hours.

[0724] The obtained reaction solution was washed with 9 mL of water and 9 mL of a 5 wt% sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain 2.65 g (yield 95.4%) of the target compound (1S, 4S)-5-(tert-butyloxycarbonyl)-2-oxa-5-azabicyclo[2.2.2]octane-3-one (hereinafter referred to as compound (8a)) as a white powder.

[0725] 1 H-NMR (400MHz, CDCl3) δ1.47(9H,s), 1.81-1.84(1H,m), 1.97-2.22(3H,m), 3.44-3.47(1H,m), 3.63(1H,d,J=11.6Hz), 4.60-4.83(2H,m).

[0726] Example 3: Step 1 → Step 2 → Step 3

[0727] [Step 1]

[0728] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0729] [Chemistry 47]

[0730]

[0731] Under nitrogen atmosphere, in a separable flask, 20 g (0.0450 mol) of compound (1a) obtained in [Step 9] of Example 1 was dissolved in 80 mL of N,N-dimethylformamide (hereinafter referred to as DMF). 14.98 g (0.0486 mol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 6.71 g (0.0486 mol) of potassium carbonate were added to the resulting solution, and stirred at 35°C for 30 hours until the reaction conversion rate reached 99% or more. The ratio of the 2-isomers in the resulting reaction solution was (2S, 5R): (2R, 5R) = 99.2: 0.8 (HPLC).

[0732] To the obtained reaction solution, 100 mL of toluene and 64.5 mL of water were added, and the pH was adjusted to 4.8 with acetic acid. After separation, the aqueous layer was extracted again with 40 mL of toluene. The organic layers were combined, 80 mL of water was added, potassium carbonate was added until the pH of the aqueous layer reached 9 or above, and the aqueous layer was discarded. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off to obtain 30.96 g (21.55 g in terms of pure amount) of a crude product of compound (2a) in the form of a light yellow oil (yield 87.0%).

[0733] 1 H-NMR(400MHz,DMSO-d6)δ1.32(9H,s),1.48-1.57(1H,m),1.73-1.76(2H,m),2.03-2.10(1H,m),3.19(1H,m),3.65-3.71(4H ,m),3.89(1H,d,J=12.0Hz),4.48-4.51(1H,m),5.01-5.07(2H,m),7.40-7.45(5H,m),8.12-8.15(2H,m),8.42-8.46(2H,m).

[0734] [Step 2]

[0735] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester

[0736] [Chemistry 48]

[0737]

[0738] Under nitrogen atmosphere, 31.9 g (21.4 g, 0.0390 mol in pure amount) of the crude product of compound (2a) obtained by the same method as in [Step 1] was dissolved in 128 mL of methanol in a separable flask. 14.3 g (0.156 mol) of thioglycolic acid and 43.0 g (0.312 mol) of potassium carbonate were added to the resulting solution at 25°C, and the mixture was stirred at 25°C for 18 hours, and then the solvent was distilled off.

[0739] To the residue was added 228 mL of water, 128 mL of toluene, and 102 mL of ethyl acetate. Acetic acid was further added to neutralize until pH 6 was reached, and the aqueous layer was discarded. 70 mL of water was added to the organic layer, and potassium carbonate was added until pH 9 was reached, and the aqueous layer was discarded. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off to obtain 20.8 g (13.2 g in pure amount) of a crude product of (2S,5R)-1-(tert-butyloxycarbonyl)-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (3a)) as a pale yellow oil (yield 92.8%).

[0740] 1 H-NMR(400MHz, CDCl3)δ1.46-1.59(10H,m),1.67-1.70(1H,m),1.88-2.04(2H,m),3.05-3.21(2H,m), 3.74(3H,s),4.18(1H,d,J=12.4Hz),4.68-4.76(2H,m),4.91(1H,br),5.46(1H,br)7.29-7.36(5H,m).

[0741] [Step 3]

[0742] Preparation method of (2S, 5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester dihydrochloride

[0743] [Chemistry 49]

[0744]

[0745] Under nitrogen atmosphere, 9.38 g (7.01 g, 0.0192 mol in pure amount) of the crude product of compound (3a) obtained in the above [Step 2] was dissolved in 15.2 g of methanol in a separable flask. The resulting solution was added dropwise to 28.8 mL of a 2 mol / L hydrochloric acid methanol solution adjusted to 45°C, and stirred at 45°C for 4 hours.

[0746] The obtained reaction solution was cooled to -5°C and filtered, and the obtained solid was dried to obtain 6.17 g (yield 95.2%) of white powdery (2S,5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester dihydrochloride (hereinafter referred to as compound (4aS)).

[0747] 1 H-NMR(400MHz,D2O)δ1.67-1.89(2H,m),2.12-2.15(1H,m),2.43-2.47(1H,m),3.05(1H,t,J=12.0H z),3.50-3.56(1H,m),3.71-3.75(1H,m),3.81(3H,s),4.04-4.08(1H,m),4.90(2H,s),7.43(5H,s).

[0748] Example 4: Step 1 → Step 4 → Step 5

[0749] [Step 1 → Step 4]

[0750] Preparation method of (2S, 5R)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0751] [Chemistry 50]

[0752]

[0753] In a test tube under nitrogen atmosphere, 2.16 g (4.86 mmol) of compound (1a) was dissolved in 10 mL of DMF, 1.65 g (5.35 mmol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 0.74 g (5.35 mmol) of potassium carbonate were added to the resulting solution, and the mixture was stirred at 65°C for 24 hours.

[0754] The obtained reaction solution was subjected to solvent extraction and washed with water, then dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off. A 0.5 mol / L methanol solution of hydrochloric acid was added to the obtained residue, and the mixture was stirred at 65°C for 17 hours.

[0755] The obtained reaction solution was concentrated, and ethyl acetate and 5 wt% sodium bicarbonate aqueous solution were added to the residue, and the aqueous layer was discarded after separation and extraction. The obtained organic layer was concentrated to obtain 1.45 g (yield 88.7%) of yellow oily (2S,5R)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (5a)).

[0756] 1H-NMR(400MHz, CDCl3)δ1.26-1.51(2H,m),1.95-2.04(2H,m),2.52(1H,dd),3.14(1H,dd,),3.51(1H, m),3.71-3.73(4H,m),5.01-5.17(2H,brs),7.26-7.41(5H,m),8.08-8.13(2H,m),8.32-8.37(2H,m).

[0757] [Step 5]

[0758] Preparation method of (2S, 5R)-5-(N-benzyloxyamino)-piperidine-2-carboxylic acid methyl ester dihydrochloride

[0759] [Chemistry 51]

[0760]

[0761] In a test tube under nitrogen atmosphere, 4.2 g (9.35 mmol) of compound (5a) obtained by the same method as in [Step 1 → Step 4] was dissolved in 42 mL of methanol. To the resulting solution were added 3.4 g (37.42 mmol) of thioglycolic acid and 9.9 g (74.8 mmol) of potassium carbonate at 25°C, and the mixture was stirred at 25°C for 19 hours.

[0762] Water and ethyl acetate were added to the obtained reaction solution, and after separation and extraction, the aqueous layer was discarded. The obtained organic layer was washed with a 5 wt% sodium bicarbonate aqueous solution. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off to obtain 1.27 g of residue. 48 ml of 0.5 mol / L hydrochloric acid methanol solution was added to the obtained residue, and stirred at 60°C for 19 hours. The obtained reaction solution was concentrated to obtain 1.27 g (yield 78%) of light red crystals of (2S,5R)-5-(N-benzyloxyamino)-piperidine-2-carboxylic acid methyl ester dihydrochloride (hereinafter referred to as compound (4aS)).

[0763] 1 H-NMR(400MHz,D2O)δ1.67-1.89(2H,m),2.13(1H,m),2.45(1H,m),3.05(1H,t,J=12.0Hz),

[0764] 3.53(1H,m),3.73(1H,m),3,81(3H,s),4.06(1H,m),4.90(2H,s),7.43(5H,m).

[0765] Example 5: Step 8 → Step 9

[0766] [Step 8]

[0767] Preparation method of (2S, 5S)-1-acetyl-5-hydroxy-piperidine-2-carboxylic acid methyl ester

[0768] [Chemistry 52]

[0769]

[0770] Under nitrogen atmosphere, 10.0 g (59.17 mmol) of (1S,4S)-5-acetyl-2-oxa-5-azabicyclo[2.2.2]octan-3-one synthesized according to the method described in International Publication No. WO2015 / 099126 was dissolved in 30 mL of methanol in a test tube. 5.6 g (29.6 mmol) of p-toluenesulfonic acid monohydrate was added to the obtained solution at room temperature, and the temperature was raised to 60°C, and stirred at 60°C for 1.5 hours.

[0771] The obtained reaction solution was concentrated to obtain 14.3 g of a colorless transparent oily residue containing (2S,5S)-1-acetyl-5-hydroxy-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (9b)).

[0772] 1 H-NMR (400MHz, CDCl3) δ1.28-1.32(2H,m),1.61-1.70(1H,m),1.96-2.00(1H,m),2. 20(3H,S),3.02(1H,dd),3.61-3.69(1H,m),3.73(3H,s),3.90(1H,dd),5.25(1H,d).

[0773] [Step 9]

[0774] Preparation method of (2S, 5S)-1-acetyl-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester

[0775] [Chemistry 53]

[0776]

[0777] In a test tube under a nitrogen atmosphere, 11.9 g (59.17 mmol) of the oily residue containing the compound (9b) obtained in the above [Step 8] was dissolved in 83 mL of ethyl acetate. 30 g (295.85 mmol) of triethylamine and 14.3 g (65.09 mmol) of p-nitrobenzenesulfonyl chloride were added to the resulting solution at 30°C, and the mixture was heated and stirred at 40°C for 16 hours.

[0778] The obtained reaction solution was washed with water, 10% acetic acid aqueous solution, and 5% by weight sodium bicarbonate water in sequence, and the organic layer was concentrated. The obtained residue was purified by silica gel column using a mixed solvent of ethyl acetate / n-heptane = 2 / 8 (volume ratio) to obtain 6.68 g of (2S,5S)-1-acetyl-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (1b)) as a colorless oil (continuous yield from step 8: 29.2%).

[0779] Example 6: Step 1 → Step 2 → Step 3

[0780] [Step 1]

[0781] Preparation method of (2S, 5R)-1-acetyl-5-(N-benzyloxy-p-nitrobenzenesulfonylamino]-piperidine-2-carboxylic acid methyl ester

[0782] [Chemistry 54]

[0783]

[0784] In a test tube under a nitrogen atmosphere, 1.1 g (2.85 mmol) of the compound (1b) obtained in [Step 9] of Example 5 was dissolved in 10 mL of DMF. 0.95 g (3.08 mmol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 0.43 g (3.08 mmol) of potassium carbonate were added to the resulting solution, and the mixture was stirred at 65°C for 7 hours.

[0785] After adding 50 mL of toluene to the obtained reaction solution, the organic layer was washed with 10% acetic acid aqueous solution and 5% by weight sodium bicarbonate aqueous solution in sequence. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off. The obtained residue was purified by silica gel column using a mixed solvent of ethyl acetate / n-heptane = 1:1 (volume ratio) to obtain 1.34 g (1.02 g in pure amount) of crude product of (2S,5R)-1-acetyl-5-(N-benzyloxy-p-nitrobenzenesulfonylamino]-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (2b)) as a pale yellow oil (yield 73.0%).

[0786] (2S,5R): (2R,5R)=91.2:8.8 (HPLC).

[0787] [Step 2]

[0788] Preparation method of (2S, 5R)-1-acetyl-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester

[0789] [Chemistry 55]

[0790]

[0791] In a test tube under a nitrogen atmosphere, 1.0 g (2.08 mmol) of the compound (2b) obtained in the above [Step 1] was dissolved in 20 mL of methanol. To the resulting solution were added 0.77 g (8.32 mmol) of thioglycolic acid and 2.3 g (16.64 mmol) of potassium carbonate at 25°C, and the mixture was stirred at 25°C for 13 hours, and then the solvent was distilled off.

[0792] Water and ethyl acetate were added to the obtained residue, and the aqueous layer was discarded. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off to obtain 0.37 g (0.31 g in terms of pure amount) of a crude product of (2S,5R)-1-acetyl-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (3b)) as a pale yellow oil (yield 43.8%).

[0793] 1 H-NMR (400MHz, CDCl3) δ1.63-1.66(2H,m),1.77-1.82(1H,m),1.98-2.02(1H,m),2.16(1H,S) ,3.21(1H,m),3.33(1H,dd),4.01(1H,dd),4.67-4.74(2H,m),5.33(1H,m),7.27-7.36(5H,m).

[0794] [Step 3]

[0795] Preparation method of (2S, 5R)-5-(benzyloxyamino)-piperidine-2-carboxylic acid methyl ester dihydrochloride

[0796] [Chemistry 56]

[0797]

[0798] Under a nitrogen atmosphere, 5 mL of a mixed solvent of 2 mol / L hydrochloric acid methanol solution was added to 0.15 g (pure amount) (0.44 mmol) of the crude product of compound (3b) obtained in the above [Step 2] in a test tube, and the mixture was stirred at 70°C for 5 hours.

[0799] The obtained reaction product was cooled to room temperature and concentrated, and 10 mL of ethyl acetate was added to the obtained concentrate to obtain 0.1 g (yield 68.2%) of compound (4aS).

[0800] (2S,5R): (2R,5R)=98.4:1.6(HPLC)

[0801] 1H-NMR(400MHz,D2O)δ1.67-1.89(2H,m),2.13(1H,m),2.45(1H,m),3.05(1H,t,J=12.0Hz),3.53

[0802] (1H,m),3.73(1H,m),3,81(3H,s),4.06(1H,m),4.90(2H,s),7.43(5H,m).

[0803] Example 7

[0804] [Step 1]

[0805] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0806] [Chemistry 57]

[0807]

[0808] In [Step 1] of Example 3, the reaction was carried out under the same conditions as in Example 3 except that the amount of the compound and the solvent used in the reaction was changed to 1 / 20, the reaction temperature was changed to 25° C., and the stirring time was changed to 37 hours for the reaction so that the reaction conversion rate reached 99% or more. As a result, the ratio of the 2-isomers in the obtained reaction solution was (2S, 5R): (2R, 5R) = 99.3: 0.7 (HPLC).

[0809] Example 8

[0810] [Step 1]

[0811] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0812] In [Step 1] of Example 3, the reaction was carried out under the same conditions as in Example 3 except that the amount of the compound and the solvent used in the reaction was changed to 1 / 20, the reaction temperature was changed to 45°C, and the stirring time was changed to 23 hours for the reaction so that the reaction conversion rate reached 99% or more. As a result, the ratio of the 2-isomers in the obtained reaction solution was (2S, 5R): (2R, 5R) = 98.5: 1.5 (HPLC).

[0813] Example 9

[0814] [Step 1]

[0815] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0816] In [Step 1] of Example 3, the reaction was carried out under the same conditions as in Example 3 except that the amount of the compound and the solvent used in the reaction was changed to 1 / 20, the reaction temperature was changed to 55° C., and the stirring time was changed to 6 hours for the reaction so that the reaction conversion rate reached 99% or more. As a result, the ratio of the 2-isomers in the obtained reaction solution was (2S, 5R): (2R, 5R) = 98.3: 1.7 (HPLC).

[0817] Example 10

[0818] [Step 1]

[0819] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0820] In [Step 1] of Example 3, the reaction was carried out under the same conditions as in Example 3 except that the amount of the compound and the solvent used in the reaction was changed to 1 / 20, the reaction temperature was changed to 65° C., and the stirring time was changed to 5 hours for the reaction so that the reaction conversion rate reached 99% or more. As a result, the ratio of the 2-isomers in the obtained reaction solution was (2S, 5R): (2R, 5R) = 96.3: 3.7 (HPLC).

[0821] Example 11: Step 9 → Step 1

[0822] [Step 9]

[0823] Preparation method of (2S,5S)-1-(tert-butyloxycarbonyl)-5-toluenesulfonyloxy-piperidine-2-carboxylic acid methyl ester

[0824] [Chemistry 58]

[0825]

[0826] In a test tube under nitrogen atmosphere, 1.0 g (3.86 mmol) of compound (9a) obtained by the same method as [Step 7 → Step 8] of Example 1 was dissolved in 20 mL of toluene. 0.94 g (7.72 mmol) of N,N-dimethylaminopyridine and 0.96 g (5.02 mmol) of tosyl chloride were added to the resulting solution at 25°C, and then heated and stirred at 45°C for 2 hours. Then, 0.47 g (3.86 mmol) of N,N-dimethylaminopyridine was added at 45°C, and stirred for 1.5 hours. 0.3 g (1.93 mmol) of N,N-dimethylaminopyridine was further added at 45°C, and the mixture was stirred for 16 hours, and then cooled to room temperature.

[0827] The obtained reaction solution was subjected to liquid extraction with ethyl acetate, and the aqueous layer was discarded. The organic layer was washed with 10 wt% aqueous acetic acid solution and 5% sodium bicarbonate water in sequence, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated, and the precipitated crystals were filtered out and dried to obtain 0.53 g (yield 34.5%) of white powder (2S,5S)-1-(tert-butyloxycarbonyl)-5-toluenesulfonyloxy-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (1a-1)).

[0828] 1 H-NMR (400MHz, CDCl3) δ1.42-1.51(10H,m),1.65-1.72(1H,m),1.93-2.08(1H,m),2.25-2.28(1H,m),2.45(3H,s),2.7 4-2.92(1H,dd),3.72(3H,s),3.99-4.17(1H,m),4.34(1H,m),4.62-4.82(m,1H),7.34-7.36(2H,m),7.78-7.80(2H,m).

[0829] [Step 1]

[0830] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0831] [Chemistry 59]

[0832]

[0833] The reaction was carried out in the same manner as in Example 3 except that the compound (1c) obtained in the above [Step 9] was used instead of the compound (1a). After the reaction, the obtained reaction solution was analyzed by NMR, and it was confirmed that the compound (2a) was the main product.

[0834] 1H-NMR(400MHz,DMSO-d6)δ1.32(9H,s),1.53(1H,m),1.73(2H,m),2.06(1H,m),

[0835] 3.19(1H,m),3.67(4H,m),3.89(1H,d,J=12.0Hz),4.50(1H,m),5.04(2H,m),7.41(5H,m),8.13(2H,m),8.44(2H,m).

[0836] Example 12

[0837] [Step 1]

[0838] Preparation method of (2S, 5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-benzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0839] [Chemistry 60]

[0840]

[0841] In a test tube under nitrogen atmosphere, 300 mg (0.68 mmol) of compound (1a) obtained by the same method as [Step 9] of Example 1 was dissolved in 5 mL of DMF. 213 mg (0.81 mmol) of N-(benzyloxy)-benzenesulfonamide and 111.9 mg (0.81 mmol) of potassium carbonate were added to the obtained solution, and the mixture was stirred at 65°C for 26 hours. The reaction solution was analyzed by thin layer chromatography (hereinafter referred to as TLC) (hexane:ethyl acetate (volume ratio) = 2:1), and the main product was confirmed to be (2S,5R)-1-(tert-butyloxycarbonyl)-5-(N-benzyloxy-benzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester (hereinafter referred to as compound (2c)). The obtained reaction solution was extracted and washed with toluene, and the organic layer was washed with 10 wt% aqueous acetic acid solution and 5 wt% aqueous sodium bicarbonate solution in sequence. The organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off to obtain oily compound (2a-1).

[0842] Embodiment 13

[0843] [Step 1]

[0844] Preparation method of (2S, 5R)-1-acetyl-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0845] [Chemistry 61]

[0846]

[0847] Under nitrogen atmosphere, 1.05 g (1.01 g, 2.62 mmol in pure amount) of compound (1b) was dissolved in 4 mL of DMF in a separable flask. 0.873 g (2.83 mmol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 0.391 g (2.83 mmol) of potassium carbonate were added to the resulting solution, and the reaction temperature was set to 35° C. The mixture was stirred for 3 hours until the reaction conversion rate reached 99% or more.

[0848] To the obtained reaction solution, 9 mL of toluene was added under ice cooling, and the mixture was stirred for 30 minutes, and 4 mL of 40% aqueous acetic acid solution was added, and the mixture was allowed to stand for separation. The solvent of the obtained organic layer was distilled off to obtain compound (2b) as a light yellow oil.

[0849] ((2S,5R): (2R,5R)=98.8:1.2 (HPLC)).

[0850] Comparative Example 1: Step 8 → Step 9 → Step 1

[0851] [Step 8]

[0852] Preparation method of (2S, 5S)-1-(p-nitrobenzenesulfonyl)-5-hydroxy-piperidine-2-carboxylic acid methyl ester

[0853] [Chemistry 62]

[0854]

[0855] (1S,4S)-5-(p-nitrobenzenesulfonyl)-2-oxa-5-azabicyclo[2.2.2]octan-3-one (hereinafter referred to as compound (8c)) as a raw material was synthesized according to the method described in International Publication No. WO2014 / 200786.

[0856] In a 100 mL flask under nitrogen atmosphere, 2 g (6.4 mmol) of compound (8c) was suspended in 10 mL of methanol. 1.26 g (6.53 mmol) of 28% sodium methoxide methanol solution was added to the resulting suspension under ice cooling, and the reaction was allowed to react for 2 hours. The reaction conversion rate was confirmed to be 99% or higher.

[0857] 0.4 mL of acetic acid was added to the reaction solution under ice cooling, and the mixture was concentrated for 30 minutes using a high vacuum diaphragm pump. 14 mL of ethyl acetate was added to the resulting residue, and the mixture was washed with 6 mL of water and 6 mL of saturated sodium bicarbonate water in sequence. The resulting organic layer was dried over 0.4 g of magnesium sulfate, filtered, and the filtrate was concentrated to obtain 2.12 g of compound (9c) (yield 96%).

[0858] [Step 9]

[0859] Preparation method of (2S, 5R)-1-(p-nitrobenzenesulfonyl)-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester

[0860] [Chemistry 63]

[0861]

[0862] In a 100 mL flask under a nitrogen atmosphere, 2.03 g (5.9 mmol) of the compound (9c) obtained in the above [Step 8] was dissolved in 16 mL of ethyl acetate. 2.12 g (21.2 mmol) of triethylamine was added to the resulting solution at room temperature and stirred. Under ice cooling, 2.35 g (10.58 mmol) of p-nitrobenzenesulfonyl chloride was added, and the reaction was allowed to react for 4 hours. After that, the reaction conversion rate was confirmed to be 99% or more.

[0863] To the obtained reaction solution were added 0.4 mL of acetic acid and 6 mL of water under ice cooling for washing, and the obtained organic layer was concentrated to obtain 2.82 g of compound (1c) (yield 90%).

[0864] [Step 1]

[0865] Preparation method of (2S, 5R)-1-(p-nitrobenzenesulfonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0866] [Chemistry 64]

[0867]

[0868] Under nitrogen atmosphere, 1 g (1.88 mmol) of the compound (1c) obtained in the above [Step 9] was dissolved in 4 mL of DMF in a separable flask. 0.626 g (2.03 mmol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 0.281 g (2.03 mmol) of potassium carbonate were added to the resulting solution, and the reaction temperature was set to an internal temperature of 35°C and stirred for 102 hours until the reaction conversion rate reached 99% or more. The ratio of the 2-isomers in the resulting reaction solution was (2S, 5R): (2R, 5R) = 63:37 (HPLC).

[0869] To the obtained reaction solution, 5 mL of toluene was added under ice cooling, and the mixture was stirred for 30 minutes, and 4 mL of 40% aqueous acetic acid solution was added, and the mixture was allowed to stand for separation. The solvent of the obtained organic layer was distilled off to obtain a crude product of compound (2c) as a light yellow oil.

[0870] Comparative Example 2

[0871] [Step 1]

[0872] Preparation method of (2S, 5R)-1-(p-nitrobenzenesulfonyl)-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0873] [Chemistry 65]

[0874]

[0875] In [Step 1] of Comparative Example 1, the same experiment was carried out except that the reaction temperature was changed from 35° C. to 65° C. and the reaction time was changed from 102 hours to 6 hours, thereby obtaining Compound (2c) as a light yellow oil.

[0876] The ratio of the 2-isomers in the obtained reaction solution was (2S, 5R):(2R, 5R)=53:47 (HPLC).

[0877] Comparative Example 3: Step 9 → Step 1

[0878] [Step 9]

[0879] Preparation method of (2S, 5S)-1-trifluoroacetyl-5-(p-nitrobenzenesulfonyloxy)-piperidine-2-carboxylic acid methyl ester

[0880] [Chemistry 66]

[0881]

[0882] Methyl (2S,5S)-1-(trifluoroacetyl)-5-hydroxypiperidine-2-carboxylate (hereinafter referred to as compound (9d)) as a raw material was synthesized according to the method described in International Publication No. WO2013 / 180197.

[0883] In a flask under a nitrogen atmosphere, 14.5 g (56.2 mmol) of compound (9d) was dissolved in 115 mL of ethyl acetate. 20.5 g (202 mmol) of triethylamine was added to the resulting solution, and 22.7 g (101 mmol) of p-nitrobenzenesulfonyl chloride was added under ice cooling. After reacting for 3 hours, the reaction conversion rate was confirmed to be 99% or more.

[0884] To the obtained reaction solution, 4.7 ml of acetic acid and 43 ml of water were added under ice cooling, and after washing, the obtained organic layer was washed twice with 43 ml of saturated sodium bicarbonate water and further washed with 14 mL of water, and the organic layer was concentrated to obtain 24.6 g of compound (1d) (yield 99%).

[0885] [Step 1]

[0886] Preparation method of (2S, 5R)-1-trifluoroacetyl-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0887] [Chemistry 67]

[0888]

[0889] Under nitrogen atmosphere, 1.11 g (1.01 g, 2.29 mmol in pure amount) of the compound (1d) obtained in the above [Step 9] was dissolved in 4 mL of DMF in a separable flask. 0.763 g (2.47 mmol) of N-(p-nitrobenzenesulfonyl)-O-benzyl-hydroxylamine and 0.342 g (2.47 mmol) of potassium carbonate were added to the resulting solution, and the reaction temperature was set to an internal temperature of 35°C, and stirred for 21 hours until the reaction conversion rate reached 99% or more. The ratio of the 2-isomers in the resulting reaction solution was (2S, 5R): (2R, 5R) = 92:8 (HPLC).

[0890] To the obtained reaction solution, 5 mL of toluene was added under ice cooling, and the mixture was stirred for 30 minutes, and 4 mL of 40% aqueous acetic acid solution was added, and the mixture was allowed to stand for separation. The solvent of the obtained organic layer was distilled off to obtain compound (2d) as a light yellow oil.

[0891] Comparative Example 4

[0892] [Step 1]

[0893] Preparation method of (2S, 5R)-1-trifluoroacetyl-5-(N-benzyloxy-p-nitrobenzenesulfonylamino)-piperidine-2-carboxylic acid methyl ester

[0894] [Chemistry 68]

[0895]

[0896] In [Step 1] of Comparative Example 3, the same experiment was carried out except that the reaction temperature was changed from 35° C. to 65° C. and the reaction time was changed from 21 hours to 2 hours, thereby obtaining Compound (2d) as a light yellow oil.

[0897] The ratio of the 2-isomers in the obtained reaction solution was (2S, 5R): (2R, 5R) = 80:20 (HPLC).

[0898] [Table 2]

[0899]

[0900] The results of Examples 3, 6 to 10 and 13, and Comparative Examples 11 to 14 are summarized in Table 2.

[0901] It is obvious from Table 2 that PG 1When the protecting group is a highly electron-withdrawing protecting group such as Ns or TFA, the ratio of the 2-isomer (2R, 5R) of the compound (2) tends to increase. Also, when the reaction temperature is high, the ratio of the 2-isomer (2R, 5R) of the compound (2) tends to increase.

[0902] Industrial Applicability

[0903] The method of the present invention is a method for preparing a (2S,5R)-5-(protected oxyamino)-piperidine-2-carboxylic acid derivative that can be carried out under mild reaction conditions without the need for extremely low temperature equipment and is safer, has easy quality control of the target product, good operability at the preparation site, and is cheaper.

[0904] This application is based on Japanese patent application No. 2018-177774, the contents of which are incorporated herein in their entirety.

Claims

1. A method for preparing a compound represented by general formula (4), characterized in that: The method comprises the steps of reacting a compound represented by the general formula (6) with an amino protecting agent to obtain a compound represented by the general formula (7) or a salt thereof; A step of reacting the compound represented by the general formula (7) with a lactonization agent to obtain a compound represented by the general formula (8); A step of reacting the compound represented by the general formula (8) with an esterifying agent to obtain a compound represented by the general formula (9); A step of reacting the compound represented by the general formula (9) with a leaving group-introducing agent to obtain a compound represented by the general formula (1); The compound represented by the general formula (1) and the general formula PG 2 NHOPG 3 The step of reacting a hydroxylamine derivative shown in the embodiment of the present invention with a pyridine, a carbonate, a metal hydride or a metal alkoxide in an amide solvent, an ether solvent or a hydrocarbon solvent at a temperature of 10° C. to 70° C. to obtain a compound shown in the general formula (2), wherein PG 2 Indicates benzenesulfonyl or nitrobenzenesulfonyl protecting group, PG 3 represents an ether protecting group; Removal of PG from the compound represented by the general formula (2) 2 A step of obtaining a compound represented by the general formula (3) or a salt thereof; and Removal of PG from the compound represented by the general formula (3) 1 The step of obtaining the compound represented by the general formula (4) or a salt thereof, or Removal of PG from the compound represented by the general formula (2) 1 A step of obtaining a compound represented by the general formula (5) or a salt thereof; and Removal of PG from the compound represented by the general formula (5) 2 The step of obtaining the compound represented by the general formula (4) or a salt thereof, In the formula, PG 1 represents a tert-butyloxycarbonyl group or an acetyl group, In the formula, PG 1 As defined above, In the formula, R represents a hydrocarbon group having 1 to 8 carbon atoms, PG 1 As defined above, In the formula, LG represents an arylsulfonyloxy group or a nitroarylsulfonyloxy group, and the other symbols are as defined above, In the formula, the symbols are as defined above, In the formula, the symbols are as defined above, In the formula, the symbols are as defined above, In the formula, each symbol is as defined above.

2. A compound represented by the following formula (2b), (3b) or (5a), In the formula, Ac represents an acetyl group, Ns represents a p-nitrobenzenesulfonyl group, and Bn represents a benzyl group.

3. A method for preparing a compound represented by general formula (1), characterized in that: The method comprises the steps of reacting a compound represented by the general formula (8) with an esterifying agent to obtain a compound represented by the general formula (9); and reacting the compound represented by the general formula (9) with a leaving group introducing agent. In the formula, PG 1 represents a tert-butyloxycarbonyl group or an acetyl group, In the formula, R represents a hydrocarbon group having 1 to 8 carbon atoms, PG 1 As defined above, In the formula, LG represents an arylsulfonyloxy group or a nitroarylsulfonyloxy group, and the other symbols are as defined above.

4. The preparation method according to claim 3, characterized in that: The method further comprises the step of reacting the compound represented by the general formula (6) with an amino protecting agent to obtain the compound represented by the general formula (7) or a salt thereof; and a step of reacting the compound represented by the general formula (7) with a lactonization agent to obtain a compound represented by the general formula (8), In the formula, PG 1 represents a tert-butyloxycarbonyl group or an acetyl group, In the formula, PG 1 As defined above.

5. A compound represented by the following formula (1a), (1b) or (9b), In the formula, Boc represents tert-butoxycarbonyl, Ac represents acetyl, and Ns represents p-nitrobenzenesulfonyl.

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