阅读说明：本技术 （2s）-2-［（1h-吡唑-1-基）甲基］-1,3-噁嗪烷衍生物的制备方法 (Preparation method of (2S) -2- [ (1H-pyrazol-1-yl) methyl ] -1, 3-oxazinane derivative ) 是由 松原孝昌 浦部洋树 铃木亮 二村彩 木下僚 服部信隆 田伏英哲 伊村维晃 大岳宪一 于 2018-07-11 设计创作，主要内容包括：提供(2S)-2-［(1H-吡唑-1-基)甲基］-1,3-噁嗪烷衍生物的新的制备方法。具体地,提供式(1)所示的(2S)-2-［(1H-吡唑-1-基)甲基］-1,3-噁嗪烷衍生物的制备方法,其包含3-氨基丙烷-1-醇与乙醛酸的反应。<Image he="103" wi="198" file="DEST_PATH_IMAGE001.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(Provided is a novel method for producing a (2S) -2- [ (1H-pyrazol-1-yl) methyl ] -1, 3-oxazinane derivative. Specifically provided is a method for producing a (2S) -2- [ (1H-pyrazol-1-yl) methyl ] -1, 3-oxazinane derivative represented by formula (1), which comprises reacting 3-aminopropane-1-ol with glyoxylic acid.)

1. A process for producing (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone hydrate represented by the formula (1), which comprises the steps of:

[ chemical formula 1]

(a) A step of converting the compound represented by the formula (2) into a compound represented by the formula (3) by reacting glyoxylic acid,

[ chemical formula 2]

[ chemical formula 3]

(b) A step of condensing the compound represented by the formula (3) and the compound represented by the formula (4) to convert the compound represented by the formula (5),

[ chemical formula 4]

In the formula, R¹C which represents a hydrogen atom and may have a substituent_1-6Alkyl, C which may have a substituent_2-6Alkenyl, C which may have a substituent_2-6Alkynyl group, optionally substituted C_3-6Cycloalkyl group, optionally substituted C_3-6Cycloalkenyl group, and optionally substituted C_1-6Alkoxy, optionally substituted C_2-6Alkenyloxy group, optionally substituted C_2-6Alkynyloxy group, optionally substituted C_3-6Cycloalkoxy group, optionally substituted C_3-6Cycloalkenyloxy, aryl which may have a substituent, heteroaryl which may have a substituent, saturated or partially saturated heterocyclic group which may have a substituent, C which may have a substituent_7-12An aralkyloxy group, X represents a halogen atom,

[ chemical formula 5]

In the formula, R¹Means the same as the aforementioned meaning,

(c) a step of converting the compound represented by the formula (5) into a compound represented by the formula (6),

[ chemical formula 6]

In the formula, R¹The chiral amine means an optically active amine which forms a salt with a carboxylic acid,

(d) a step of converting the compound represented by the formula (6) into a compound represented by the formula (7),

[ chemical formula 7]

In the formula, R¹Means the same as the aforementioned meaning,

(e) a step of converting the compound represented by the formula (7) into a compound represented by the formula (8),

[ chemical formula 8]

In the formula, R¹Represents the same meaning as described above, R²Represents a protecting group of a carboxylic acid,

(f) a step of converting the compound represented by the formula (8) into a compound represented by the formula (9),

[ chemical formula 9]

In the formula, R²Means the same as the aforementioned meaning,

(g) a step of condensing the compound represented by the formula (9) with the compound represented by the formula (10) to convert the compound represented by the formula (11),

[ chemical formula 10]

[ chemical formula 11]

In the formula, R²Means the same as the aforementioned meaning,

(h) a step of converting the compound represented by the formula (11) into a compound represented by the formula (12),

[ chemical formula 12]

(i) A step of converting the compound represented by the formula (13) into the compound represented by the formula (15) by reacting the compound represented by the formula (14),

[ chemical formula 13]

In the formula, R³Represents a protecting group of pyrazole,

[ chemical formula 14]

Wherein X represents the same meaning as described above,

[ chemical formula 15]

In the formula, R³Means the same as the aforementioned meaning,

(j) a step of converting the compound represented by the formula (15) into a compound represented by the formula (16),

[ chemical formula 16]

(k) Reacting a compound represented by the formula (16) with R⁴SO₂-X or (R)⁴SO₂）₂A step of converting the resulting product into a compound represented by the formula (17) by reacting O,

[ chemical formula 17]

In the formula, R⁴Represents an alkyl group which may have a substituent, an aryl group which may have a substituent, and

(l) A step of converting the compound represented by the formula (12) into the compound represented by the formula (1) by reacting the compound represented by the formula (17).

2. A process for producing a compound represented by the formula (5),

[ chemical formula 18]

In the formula, R¹Means the same as the aforementioned meaning,

the method is characterized by comprising the following steps:

(m) a step of converting the compound represented by the formula (2) and the compound represented by the formula (4) into a compound represented by the formula (18) by condensation,

[ chemical formula 19]

In the formula, R¹Means the same as that described above, and

(n) a step of converting the compound represented by the formula (18) into a compound represented by the formula (5) by reacting the compound with glyoxylic acid.

3. A process for producing a compound represented by the formula (5),

[ chemical formula 20]

In the formula, R¹Means the same as the aforementioned meaning,

the method is characterized by comprising the following steps:

(o) a step of converting the compound represented by the formula (2) into a compound represented by the formula (19) by reacting the compound with a glyoxylic acid ester,

[ chemical formula 21]

In the formula, R²Means the same as the aforementioned meaning,

(p) a step of converting the compound represented by the formula (19) and the compound represented by the formula (4) into a compound represented by the formula (20) by condensation,

[ chemical formula 22]

In the formula, R¹、R²Means the same as that described above, and

(q) a step of converting the compound represented by the formula (20) into a compound represented by the formula (5).

4. A raw material or an intermediate for synthesizing an optically active oxazinane ring derivative, which is a compound represented by formula (21) or an enantiomer thereof, or a salt thereof,

[ chemical formula 23]

In the formula, R⁵Represents optionally substituted C_7-12An aralkyl group.

5. A compound represented by the formula (22) or an enantiomer thereof,

[ chemical formula 24]

In the formula, R²、R⁵The same meanings as described above are shown.

Technical Field

The present invention relates to a method for producing (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone hydrate which is useful as a compound having orexin (hereinafter sometimes referred to as OX) receptor antagonistic activity. In addition, the present invention relates to a novel intermediate compound produced in the production process thereof.

Background

Orexin is a neuropeptide spliced by orexin precursors specifically expressed in the lateral hypothalamic region. To date, OX-A formed of 33 amino acids and OX-B formed of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep/wake patterns, regulation of food intake.

Both OX-A and OX-B act on OX receptors. For the OX receptor, 2 subtypes, OX1 and OX2 receptors, which are 7-transmembrane G-protein coupled receptors mainly expressed in the brain, have been known to date to be cloned. The OX1 receptor specifically couples to Gq in the G protein subclass, while the OX2 receptor couples to Gq and Gi/o (see non-patent documents 1 and 2).

The tissue distribution varies depending on the subtype of the OX receptor, and the OX1 receptor is highly expressed in the locus coeruleus, which is the nucleus initiating the noradrenergic nerve, and the OX2 receptor is highly expressed in the nucleus of the papillary nodule, which is the nucleus initiating the histaminergic nerve (see non-patent documents 3,4 and 5). Expression of both OX1 receptor and OX2 receptor was observed in the dorsal tegmental area of the spinal nucleus, which is the initiation nucleus of serotonergic nerves, or the ventral tegmental area, which is the initiation nucleus of dopaminergic nerves (see non-patent document 3). Orexin nerves project to the monoaminergic nervous system of the brain stem and hypothalamus, and exert excitatory effects on these nerves, and further, the expression of OX2 receptor is observed in the acetylcholine nerve of the brain stem involved in the control of REM sleep, and also exerts an effect on the activity of these nuclei (see non-patent document 3 and non-patent document 4).

In recent years, the association of OX1 and OX2 receptors with sleep/wake regulation has been spotlighted, and the usefulness of compounds having OX receptor antagonistic action has been studied. When OX-a was administered into the ventricle of a rat, it was confirmed that there were an increase in the amount of spontaneous activity (see non-patent documents 6 and 7), an increase in stereotypic behavior (see non-patent document 7), an increase in the wake time (see non-patent document 6), and the like. The effect of shortening REM sleep time by administration of OX-a is completely antagonized by pretreatment with an OX receptor antagonist (see non-patent document 8). Further, it has been reported that administration of orally administrable substances that antagonize OX1 and OX2 receptors to the same extent results in a decrease in exercise amount, a decrease in sleep latency, and an increase in non-REM sleep amount and REM sleep (see non-patent documents 9 and 10).

Disclosed is a compound represented by formula (1), which has an OX receptor antagonistic activity, a hydrate of (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone (see patent document 1).

[ chemical formula 1]

Disclosed are methods for synthesizing a compound represented by the above formula (1) which binds to OX1 and a synthetic intermediate thereof (see patent documents 1,2 and 3). As a method for producing this compound, there is a method shown below (patent document 3).

[ chemical formula 2]

(wherein R 'is'¹Represents a protecting group of a carboxylic acid. R'²represents-B (OR'³）（OR′⁴) A group of (wherein, R'³And R'⁴The same or different, represent a hydrocarbon group, and R'³And R'⁴A cyclic group may be formed together with the oxygen atom and the boron atom. ). X represents a halogen atom. )

That is, the conventional production method of formula (1) shown in the above scheme is characterized in that 1, 3-oxazinane-2-carboxylic acid ester is synthesized from glyoxylic acid ester, reacted with 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoyl chloride, the ester is reduced, and the compound of formula (1) is synthesized by optical resolution using an enzymatic reaction.

However, the conventional production methods described above are disadvantageous in production cost and are not suitable for industrial mass production because, for example, glyoxylic acid esters are not industrially inexpensive, and the introduction of 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) benzoyl moiety followed by optical resolution and a silica gel column chromatography purification step are involved.

As a method for solving the problem of the production cost, for example, a method for directly synthesizing a 1, 3-oxazinane-2-carboxylic acid derivative from inexpensive glyoxylic acid, and a method for changing a functional group on a nitrogen atom while maintaining the steric configuration at the 2-position of an optically active 1, 3-oxazinane ring are required. However, as for the method for synthesizing a 1, 3-oxazinane-2-carboxylic acid derivative from glyoxylic acid, only a synthetic method for a polycyclic oxazinane-2-carboxylic acid derivative has been reported for these chemical transformations, and a monocyclic synthetic method which is susceptible to ring opening has not been reported (non-patent document 11). As a method for changing a functional group on a nitrogen atom while maintaining the configuration at the 2-position, neither polycyclic nor monocyclic methods have been confirmed.

Therefore, the value of inexpensive monocyclic 1, 3-oxazinane ring derivatives and conversion methods thereof, which are generally applicable to the synthesis of physiologically active substances having an oxazinane ring, can be said to be extremely high.

Disclosure of Invention

Problems to be solved by the invention

The purpose of the present invention is to provide a method for producing a hydrate of the compound (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone represented by formula (1) which is suitable for industrial mass production of a physiologically active compound having excellent physiological activity via an inexpensive intermediate of a monocyclic 1, 3-oxazinan-2-carboxylic acid derivative.

Means for solving the problems

The present inventors have made extensive studies to solve the above problems, and as a result, have found a novel method for producing a compound represented by formula (1) and a novel synthetic intermediate compound, thereby completing the present invention.

The present inventors have also obtained a stable chiral amine salt that is applicable even in industrial mass production by optically resolving a 1, 3-oxazinane-2-carboxylic acid derivative represented by formula (5) with an appropriate chiral amine.

Further, the present inventors have also found a method of changing a functional group on a nitrogen atom while maintaining the steric configuration of the 2-position of an optically active 1, 3-oxazine ring, and have completed the present invention by synthesizing (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazine-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone hydrate through conversion from (2S) -1, 3-oxazine-2-carboxylic acid represented by formula (7).

That is, the present invention is as follows.

(I) A process for producing (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinan-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone hydrate represented by the formula (1), which comprises the following steps:

[ chemical formula 3]

(a) A step of converting the compound represented by the formula (2) into a compound represented by the formula (3) by reacting glyoxylic acid,

[ chemical formula 4]

[ chemical formula 5]

(b) A step of condensing the compound represented by the formula (3) with the compound represented by the formula (4) to convert the compound represented by the formula (5),

[ chemical formula 6]

(in the formula, R¹C which represents a hydrogen atom and may have a substituent_1-6Alkyl, C which may have a substituent_2-6Alkenyl, C which may have a substituent_2-6Alkynyl group, optionally substituted C_3-6Cycloalkyl group, optionally substituted C_3-6Cycloalkenyl group, and optionally substituted C_1-6Alkoxy, optionally substituted C_2-6Alkenyloxy group, optionally substituted C_2-6Alkynyloxy group, optionally substituted C_3-6Cycloalkoxy group, optionally substituted C_3-6Cycloalkenyloxy, aryl which may have a substituent, heteroaryl which may have a substituent, saturated or partially saturated heterocyclic group which may have a substituent, C which may have a substituent_7-12Aralkyloxy group, and X represents a halogen atom. )

[ chemical formula 7]

(in the formula, R¹The same meanings as described above are shown. )

(c) A step of converting the compound represented by the formula (5) into a compound represented by the formula (6),

[ chemical formula 8]

(in the formula, R¹The same meanings as described above are shown. Chiral amine means an optically active amine that forms a salt with a carboxylic acid. )

(d) A step of converting the compound represented by the formula (6) into a compound represented by the formula (7),

[ chemical formula 9]

(in the formula, R¹The same meanings as described above are shown. )

(e) A step of converting the compound represented by the formula (7) into a compound represented by the formula (8),

[ chemical formula 10]

(in the formula, R¹The same meanings as described above are shown. R²Represents a protecting group of a carboxylic acid. )

(f) A step of converting the compound represented by the formula (8) into a compound represented by the formula (9),

[ chemical formula 11]

(in the formula, R²The same meanings as described above are shown. )

(g) A step of condensing the compound represented by the formula (9) with the compound represented by the formula (10) to convert the compound represented by the formula (11),

[ chemical formula 12]

[ chemical formula 13]

(in the formula, R²The same meanings as described above are shown. )

(h) A step of converting the compound represented by the formula (11) into a compound represented by the formula (12),

[ chemical formula 14]

(i) A step of converting the compound represented by the formula (13) into the compound represented by the formula (15) by reacting the compound represented by the formula (14),

[ chemical formula 15]

(in the formula, R³Represents a protecting group of pyrazole. )

[ chemical formula 16]

(wherein X represents the same meaning as described above.)

[ chemical formula 17]

(in the formula, R³The same meanings as described above are shown. )

(j) A step of converting the compound represented by the formula (15) into a compound represented by the formula (16),

[ chemical formula 18]

(k) Reacting a compound represented by the formula (16) with R⁴SO₂-X or (R)⁴SO₂）₂A step of converting the resulting product into a compound represented by the formula (17) by reacting O,

[ chemical formula 19]

(in the formula, R⁴The term "aryl" refers to an optionally substituted alkyl group. ) And are and

(l) A step of converting the compound represented by the formula (12) into the compound represented by the formula (1) by reacting the compound represented by the formula (17).

(II) A method for producing a compound represented by the formula (5), which comprises the steps of:

[ chemical formula 20]

(in the formula, R¹The same meanings as described above are shown. )

(m) a step of converting the compound represented by the formula (2) into the compound represented by the formula (18) by condensing the compound represented by the formula (4),

[ chemical formula 21]

(in the formula, R¹The same meanings as described above are shown. ) And are and

(n) a step of converting the compound represented by the formula (18) into a compound represented by the formula (5) by reacting the compound with glyoxylic acid.

(III) A process for producing a compound represented by the formula (5), which comprises the steps of:

[ chemical formula 22]

(in the formula, R¹The same meanings as described above are shown. )

(o) a step of converting the compound represented by the formula (2) into a compound represented by the formula (19) by reacting with glyoxylic acid ester,

[ chemical formula 23]

(in the formula, R²The same meanings as described above are shown. ),

(p) a step of condensing the compound represented by the formula (19) with the compound represented by the formula (4) to convert the compound represented by the formula (20),

[ chemical formula 24]

(in the formula, R¹、R²The same meanings as described above are shown. ) And are and

(q) a step of converting the compound represented by the formula (20) into a compound represented by the formula (5).

(IV) A raw material or intermediate for synthesizing an optically active oxazinane ring derivative which is

A compound represented by the formula (21) or an enantiomer thereof, or a salt thereof,

[ chemical formula 25]

(in the formula, R⁵Represents optionally substituted C_7-12An aralkyl group. )

(V) a compound represented by the formula (22) or an enantiomer thereof,

[ chemical formula 26]

(in the formula, R²、R⁵The same meanings as described above are shown. )

ADVANTAGEOUS EFFECTS OF INVENTION

According to the production method of the present invention, an inexpensive synthesis method of monocyclic 1, 3-oxazinane-2-carboxylic acid which is applicable to the synthesis of a physiologically active substance having an oxazinane ring can be obtained, and (2S) - (2- { [ 3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl ] methyl } -1, 3-oxazinane-3-yl) [ 5-methyl-2- (2H-1, 2, 3-triazol-2-yl) phenyl ] methanone hydrate represented by formula (1) can be efficiently produced industrially in a large amount.

Detailed Description

The terms used in the present specification have the following meanings.

In the present invention, "n" represents normal (normal), "i" represents iso (iso), "s" and "sec" represent secondary (secondary), "t" and "tert" represent tertiary (tertiary), "c" represents cyclic (cyclo), "o" represents ortho (ortho), "m" represents meta (meta), and "p" represents para (para).

“C_1-6The "alkyl group" is an alkyl group having 1 to 6 carbon atoms and represents a linear or branched alkyl group. Examples thereof include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 2-methylbutyl group, 1-methylbutyl group, neopentyl group, 1, 2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 4-methylpentyl group, 3-methylpentyl groupPentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl and the like.

“C_2-6The "alkenyl group" represents a linear or branched alkenyl group having 2 to 6 carbon atoms. The number of double bonds contained in the alkenyl group is not particularly limited. Examples thereof include vinyl, prop-1-en-1-yl, allyl, isopropenyl, but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 2-methylprop-2-en-1-yl, 1-methylprop-2-en-1-yl, pent-1-en-1-yl, pent-2-en-1-yl, pent-3-en-1-yl, pent-4-en-1-yl, 3-methylbut-2-en-1-yl, 3-methylbut-3-en-1-yl, hex-1-en-1-yl, hex-2-en-1-yl, hex-3-en-1-yl, hex-4-en-1-yl, hex-5-en-1-yl, 4-methylpent-3-en-1-yl, 4-methylpent-4-en-1-yl and the like.

“C_2-6The alkynyl group "represents a linear or branched alkynyl group having 2 to 6 carbon atoms. Examples thereof include ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-1-yn-1-yl, but-3-yn-1-yl, 1-methylpropan-2-yn-1-yl, pent-1-yn-1-yl, pent-4-yn-1-yl, hex-1-yn-1-yl and hex-5-yn-1-yl.

“C_3-6Cycloalkyl "denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

“C_3-6Cycloalkenyl includes 2-cyclopen-1-yl, 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl and the like.

“C_1-6Alkoxy "is as defined above for C_1-6Examples of the group having an oxygen atom bonded to an alkyl group include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, 2-methylbutyloxy, 1-methylbutyloxy, neopentyloxy, 1, 2-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy1-methylpentyloxy, 3-dimethylbutoxy, 2-dimethylbutoxy, 1-dimethylbutoxy, 1, 2-dimethylbutoxy, 1, 3-dimethylbutoxy, 2-ethylbutoxy, 1-ethyl-1-methylpropoxy and the like.

“C_2-6Alkenyloxy "is as defined above for C_2-6Examples of the group having an oxygen atom bonded to an alkenyl group include a vinyloxy group and an allyloxy group.

“C_2-6Alkynyloxy "is as defined above for C_2-6Examples of the group having an oxygen atom bonded to an alkynyl group include an ethynyloxy group, a propynyloxy group and the like.

“C_3-6Cycloalkenyloxy "is as defined above for C_3-6The group having an oxygen atom bonded to the cycloalkenyl group represents, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

The "aryl group" represents a monocyclic or condensed polycyclic aromatic hydrocarbon group, and examples thereof include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthryl group, and a phenanthryl group.

"heteroaryl" refers to a monocyclic or fused polycyclic aromatic heterocyclic group. The number of the ring-forming hetero atoms is not particularly limited, and is 1 to several, preferably about 1 to 5. When 2 or more ring-forming heteroatoms are contained, these ring-forming heteroatoms may be the same or different. Examples of the hetero atom include, but are not limited to, an oxygen atom, a nitrogen atom, and a sulfur atom. Examples of the monocyclic heteroaryl group include a 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group, 1-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 3-isothiazolyl group, 4-isothiazolyl group, 5-isothiazolyl group, 1-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 1-pyrazolyl group, 3-pyrazolyl group, 4-pyrazolyl group, 5-pyrazolyl group, (1, 2, 3-oxadiazol) -4-yl group, and the like, (1, 2, 3-oxadiazole) -5-yl, (1, 2, 4-oxadiazole) -3-yl, (1, 2, 4-oxadiazole) -5-yl, (1, 2, 5-oxadiazole) -3-yl, (1, 2, 5-oxadiazole) -4-yl, (1, 3, 4-oxadiazole) -2-yl, (1, 3, 4-oxadiazole) -5-yl, furazanyl, (1, 2, 3-thiadiazole) -4-yl, (1, 2, 3-thiadiazole) -5-yl, (1, 2, 4-thiadiazole) -3-yl, (1, 2, 4-thiadiazole) -5-yl, (1, 2, 5-thiadiazole) -3-yl, and mixtures thereof, (1, 2, 5-thiadiazole) -4-yl, (1, 3, 4-thiadiazole) -2-yl, (1, 3, 4-thiadiazole) -5-yl, (1H-1, 2, 3-triazole) -1-yl, (1H-1, 2, 3-triazole) -4-yl, (1H-1, 2, 3-triazole) -5-yl, (2H-1, 2, 3-triazole) -2-yl, (2H-1, 2, 3-triazole) -4-yl, (1H-1, 2, 4-triazole) -1-yl, (1H-1, 2, 4-triazole) -3-yl, (1H-1, 2, 4-triazol-5-yl, (4H-1, 2, 4-triazol) -3-yl, (4H-1, 2, 4-triazol) -4-yl, (1H-tetrazol-1-yl, (1H-tetrazol) -5-yl, (2H-tetrazol) -2-yl, (2H-tetrazol) -5-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, (1, 2, 3-triazin-4-yl, (1, 2, 3-triazin-5-yl, (1, 2, 4-triazine) -3-yl, (1, 2, 4-triazine) -5-yl, (1, 2, 4-triazine) -6-yl, (1, 3, 5-triazine) -2-yl, 1-azepin, 2-azepin, 3-azepin, 4-azepin, 1, 4-azepin) -3-yl, (1, 4-azepin) -5-yl, (1, 4-azepin) -6-yl, (1, 4-azepin) -7-yl, (1, 4-thiazepin) -2-yl, (1, 4-thiazepan-3-yl, (1, 4-thiazepan) -5-yl, (1, 4-thiazepan) -6-yl, (1, 4-thiazepan) -7-yl, and the like, but is not limited thereto.

Examples of the fused polycyclic heteroaryl group include 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 1-isobenzofuranyl, 4-isobenzofuranyl, 5-isobenzofuranyl, 2-benzo [ b ] thienyl, 3-benzo [ b ] thienyl, 4-benzo [ b ] thienyl, 5-benzo [ b ] thienyl, 6-benzo [ b ] thienyl, 7-benzo [ b ] thienyl, 1-benzo [ c ] thienyl, 4-benzo [ c ] thienyl, 5-benzo [ c ] thienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl, (2H-isoindolyl) -2-yl, (2H-isoindolyl) -4-quinolinyl, (2H-indazolyl, 1-2-quinolyl, (2-1-7-1, 7-2-quinolyl, 3-1, 7-indazolyl, 1-2-indazolyl, 7-benzothiazolyl, 1-benzothiazolyl, 7-benzothiazolyl, 1-2-1, 7-indazolyl, 7-benzo [ b ] thienyl, (1, 7, 5-benzo [ b ] thienyl, 5-benzo [ b ] thienyl, 5, 4] thienyl, 5-2, 4, 1-2-1, 4-indazolyl, 4-2-indazolyl, 1,4, 7, 3-1-2-1, 7, 1-2-indazolyl, 1-2-1-2-1-2-1-2-1, 7, 1-2-1-2-1-2-1-2-1, 7, 6-1-2-1-2-1-2-1-2-1-2-1-2-1-indazolyl, 7, 2-1-2-1-2-1-2-1-2-1-2-1-2-1-6, 7, 6-1-2-1-2-1-2-1-6-1-2-1-2-1-2-1-2-1-2-1-2-1-2-1-2-1-2-.

"saturated or partially saturated heterocyclic group" means a saturated or partially saturated heterocyclic group containing 1 or more nitrogen atoms, oxygen atoms or sulfur atoms in the ring, and includes oxetan-3-yl, azetidin-1-yl, 1-pyrrolidinyl, piperidino, 2-piperidinyl, 3-piperidinyl, 1-piperazinyl, morpholin-4-yl, morpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-3-yl, azepan-1-yl, 1, 4-homomorpholine (oxazepan) -4-yl, and azocane-1-yl.

“C_7-12The "aralkyl group" represents a group having 7 to 12 carbon atoms, wherein the aforementioned alkyl group is substituted with the aforementioned aryl group, and examples thereof include, but are not limited to, benzyl, 1-naphthylmethyl, 2-naphthylmethyl, 1-phenylethyl, and the like.

“C_7-12Aralkyloxy "is represented by the aforementioned C_7-12Examples of the group having an oxygen atom bonded to the aralkyl group include, but are not limited to, a benzyloxy group, a 1-naphthylmethoxy group, a 2-naphthylmethoxy group, and a 1-phenethyloxy group.

The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The "protecting group for carboxylic acid" may be any group that forms a carboxylic acid ester, and examples thereof include an optionally substituted aryl group and an optionally substituted C_7-12Aralkyl group, optionally substituted C_1-6Alkyl, etc., but are not limited thereto.

Examples of the "protecting group of pyrazole" include C which may have a substituent_1-6Alkylsulfonyl group, optionally substituted C_1-6Alkylsulfonamide, and optionally substituted C_1-6Alkyl carbamate group, C which may have a substituent_1-6Alkyl group, aryl group which may have substituent(s), C which may have substituent(s)_7-12An aralkyl group, an aminoacetal group which may have a substituent, an amide which may have a substituent, and the like, but not limited thereto.

Examples of the "aminoacetal group" include N-hydroxymethyl, N-methoxymethyl, N-diethoxymethyl, N- (2-chloroethoxy) methyl, N- [ 2- (trimethylsilyl) ethoxy ] methyl, N-tert-butoxymethyl, N-tert-butyldimethylsiloxymethyl, N-pivaloyloxymethyl, n-benzyloxymethyl, N-4-methoxybenzyloxymethyl, N- [ 1- (6-nitro-1, 3-benzodioxole (benzodioxy) -5-yl) ethoxy ] methyl, N-dimethylaminomethyl, N-acetylaminomethyl, N-2-tetrahydropyranyl, N-2-tetrahydrofuranyl and the like.

Examples of the "amide" include formamide, N' -diethylureide, dichloroacetamide, pivaloamide, and tert-butoxycarbonyl-N-methyl-4-aminobutanamide.

In the present specification, the term "optionally substituted" with respect to a functional group means that 1 or 2 or more substituents are present at chemically possible positions on the functional group. The kind of the substituent present on the functional group, the number of the substituents, and the substitution position are not particularly limited, and when 2 or more substituents are present, these substituents may be the same or different. Examples of the substituent present on the functional group include a halogen atom, an oxo group, a thioxo group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanato group, an isothiocyanato group, a hydroxyl group, a sulfanyl group, a carboxyl group, a sulfanylcarbonyl group, an oxalyl group, a meso-oxalyl group, a thiocarboxyl group, a dithiocarboxyl group, a carbamoyl group, a thiocarbamoyl group, a sulfo group, a sulfamoyl group, a sulfino group, an aminosulfinyl group, a sulfenyl group, an aminosulfonyl group, a phosphono group, a hydroxyphosphonyl group, a phosphono group, a cyano group, an isocyano group, a hydroxyl group, a_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_1-6Alkylidene, aryl, C_7-12Aralkyl radical, C_7-12Aralkylene, C_1-6Alkoxy, aryloxy, C_7-12Aralkyloxy radical, C_1-6Alkylsulfanyl, arylsulfanyl, C_7-12Aralkyloxysulfanyl, C_1-6Alkanoyl, arylcarbonyl, C_1-6Alkylsulfonyl, arylsulfonyl, C_1-6Alkoxycarbonyl, amino, hydrazino, hydrazono, diazenyl, ureido, thioureido, guanidino, carbamimidoyl (amidino group), azido, imino, hydroxyamino, hydroxyimino, aminooxy, diazo, uretmino (semicarbazo group)A micrbazono group), a urea carbonyl group, a hydantoin group, a phosphine group, a phospho group, a boroxy group, a silyl group, an oxy group, a heteroaryl group, a saturated or partially saturated heterocyclic group, or the like, but is not limited thereto.

These substituents may be further substituted with one or two or more other substituents. Such an example includes C_1-6Haloalkyl, C_1-6Haloalkoxy, carboxy substituted C_1-6Alkyl radical, C_1-6Alkyl-substituted amino groups, and the like, but are not limited thereto.

Examples of the "chiral amine" include, but are not limited to, (R) -phenylethylamine, (R) -1- (p-tolyl) ethylamine, (R) -1- (4-methoxyphenyl) -ethylamine, (R) -1- (4-chlorophenyl) -ethylamine, (S) -3, 3-dimethyl-2-butylamine, (1S, 2R) -2-amino-1-phenyl-1, 3-propanediol, L-phenylalaninol, (R) -phenylglycinol, (R) -2-amino-1-propanol, and cinchonidine, which have an asymmetric optical activity at the α -position of the amino group.

The salt of the compound (21) includes, in addition to the salt with the aforementioned "chiral amine", a salt with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, and aluminum ion, and a salt with an amine such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, and benzathine.

The salt of an enantiomer of compound (21) includes salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, calcium ion, magnesium ion, zinc ion, aluminum ion, etc., and salts with amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine, etc.

Preferred embodiments of the present invention are described below.

Preferably R is¹Is C which may have a substituent_2-6Alkenyloxy group, optionally substituted C_7-12Compounds of aralkyloxy, more preferably R¹Is allyloxy,A benzyloxy compound.

Preferably R is²Is C which may have a substituent_1-6Alkyl compounds, more preferably R²Is a compound of methyl, ethyl and isopropyl.

Preferably R is³Is C which may have a substituent_1-6Alkylsulfonamide group, optionally substituted C_1-6Alkoxycarbonyl group, optionally substituted C_1-6Alkyl group, aryl group which may have substituent(s), C which may have substituent(s)_7-12Aralkyl group, amino acetal group which may have a substituent, more preferably R³The compound is an aminoacetal group which may have a substituent, and a tetrahydropyranyl group is particularly preferable.

Preferably R is⁴Is C which may have a substituent_1-6Alkyl group, aryl group which may have a substituent, and more preferably R⁴Is C which may have a substituent_1-6Alkyl compounds.

Preferably R is⁵Is C which may have a substituent_7-12Aralkyl, more preferably R⁵Is a benzyl compound or a 1-phenethyl compound.

Preferred are compounds in which X is a chlorine atom or a bromine atom, and more preferred are compounds in which X is a chlorine atom.

Preferred chiral amines (chiral amines) are compounds having an asymmetric optically active amine at position α of the amino group, more preferred chiral amines are compounds of (1S, 2R) -2-amino-1-phenyl-1, 3-propanediol, L-phenylalaninol, (R) -phenylglycinol, (R) -2-amino-1-propanol.

In a preferred one of the modes of execution,

R¹is C which may have a substituent_2-6Alkenyloxy group, or C which may have a substituent_7-12An aralkyloxy group;

R²is C which may have a substituent_1-6An alkyl group;

R³is C which may have a substituent_1-6Alkylsulfonamide group, optionally substituted C_1-6Alkoxycarbonyl group, optionally substituted C_1-6Alkyl, may have a substituentAryl of substituent, C which may have substituent_7-12An aralkyl group, or an aminoacetal group which may have a substituent; and is

R⁴Is C which may have a substituent_1-6An alkyl group or an aryl group which may have a substituent; and is

Chiral amines are amines having asymmetric optical activity at the α position of the amino group.

In a further preferred manner, the first and second,

R¹is allyloxy, or benzyloxy;

R²is C which may have a substituent_1-6An alkyl group;

R³is C which may have a substituent_1-6Alkylsulfonamide group, optionally substituted C_1-6Alkoxycarbonyl group, optionally substituted C_1-6Alkyl group, aryl group which may have substituent(s), C which may have substituent(s)_7-12An aralkyl group, or an aminoacetal group which may have a substituent;

R⁴is C which may have a substituent_1-6An alkyl group or an aryl group which may have a substituent; and is

The chiral amine is (1S, 2R) -2-amino-1-phenyl-1, 3-propanediol, L-phenylalaninol, (R) -phenylglycinol, or (R) -2-amino-1-propanol.

In a further preferred manner, the first and second,

R¹is allyloxy, or benzyloxy;

R²is C which may have a substituent_1-6An alkyl group;

R³is an aminoacetal group which may have a substituent;

R⁴is C which may have a substituent_1-6An alkyl group or an aryl group which may have a substituent; and is

The chiral amine is (1S, 2R) -2-amino-1-phenyl-1, 3-propanediol, L-phenylalaninol, (R) -phenylglycinol, or (R) -2-amino-1-propanol.

In a further preferred manner, the first and second,

R¹is benzyloxy;

R²is C which may have a substituent_1-6An alkyl group;

R³is an aminoacetal group which may have a substituent;

R⁴is C which may have a substituent_1-6An alkyl group or an aryl group which may have a substituent; and is

The chiral amine is (R) -phenylglycinol.

In a further preferred manner, the first and second,

R¹is benzyloxy;

R²is methyl, ethyl, or isopropyl;

R³is tetrahydropyranyl;

R⁴is C which may have a substituent_1-6An alkyl group; and is

The chiral amine is (R) -phenylglycinol.

The invention relates to a preparation method of a compound shown as a formula (1). The present invention also relates to compounds represented by formula (3), formula (5), formula (6), formula (7), formula (8), formula (9), formula (11), formula (12), formula (15), formula (16), and formula (17), which are intermediates for the production thereof.

The present invention can be carried out by the following methods. One embodiment of the present invention is shown in scheme 1 below.

Scheme 1

[ chemical formula 27]

(in the formula, R¹、R²、R³、R⁴And X represents the same meaning as described above. )

Step 1: the compound of formula (2) is reacted with glyoxylic acid in a polar solvent in the presence of a base to produce formula (3), and then the compound of formula (5) is reacted with formula (4) by further adding a polar solvent and a base.

As the polar solvent, for example, an alcohol solvent such as methanol, ethanol, or isopropanol, tetrahydrofuran, acetonitrile, or water, or a mixed solvent thereof can be used in the syntheses of formulae (3) and (5).

As the base, inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like can be used in both the syntheses of the formulae (3) and (5).

The reaction temperature in the synthesis of the formulae (3) and (5) may be generally from-20 ℃ to the boiling point of the solvent used, preferably in the range of-15 to 60 ℃, and more preferably in the range of-10 to 10 ℃.

The amount of the base used in the synthesis of formula (3) may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1 to 1.5 molar equivalents, relative to the compound of formula (2) as a raw material. In the synthesis of formula (5), the compound of formula (2) may be used in an amount of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1.3 to 2.0 molar equivalents, based on the starting material.

The amount of glyoxylic acid used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1 to 1.5 molar equivalents, relative to the compound of formula (2) as the starting material.

The amount of the compound of formula (4) used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1 to 2.5 molar equivalents, relative to the compound of formula (2) as a raw material.

The amount of the solvent used in the synthesis of formula (3) may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, based on the amount of the compound of formula (2) as the raw material. In the synthesis of formula (5), the compound of formula (2) may be used in an amount of 1 to 100 times by mass, preferably 1 to 50 times by mass, and more preferably 1 to 30 times by mass, based on the starting material.

The compound of formula (5) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurrying, crystallization, or the like.

And a step 2: the compound of formula (5) is added dropwise to a chiral amine in an inert solvent and stirred to obtain a compound of formula (6).

Examples of the inert solvent include ester solvents such as ethyl acetate and isopropyl acetate, alcohol solvents such as methanol, ethanol and isopropyl alcohol, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane and 1, 4-dioxane, acetonitrile and a mixed solvent thereof.

As the chiral amine, a compound having an asymmetry at the α -position of the amino group, such as (R) -phenylethylamine, (R) -1- (p-tolyl) ethylamine, (R) -1- (4-methoxyphenyl) -ethylamine, (R) -1- (4-chlorophenyl) -ethylamine, (S) -3, 3-dimethyl-2-butylamine, (1S, 2R) -2-amino-1-phenyl-1, 3-propanediol, L-phenylalaninol, (R) -phenylglycinol, (R) -2-amino-1-propanol, and cinchonidine, can be used.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-15 to 15 ℃, and more preferably in the range of-10 to 10 ℃.

The equivalent of the chiral amine may be used in the range of 0.2 to 2 molar equivalents, preferably 0.45 to 0.65 molar equivalent, and more preferably 0.50 to 0.60 molar equivalent to the compound of formula (5).

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 5 to 10 times by mass, relative to the compound of formula (5).

The compound of formula (6) can be obtained as a purified product formed by recrystallization, reslurry, or neutralization crystallization.

Step 3: the compound of formula (7) is obtained by reacting the compound of formula (6) with an acid in a mixed solvent of water and an inert solvent.

Examples of the inert solvent include alcohol solvents such as methanol, ethanol, and 2-propanol, hydrocarbon solvents such as toluene and xylene, halogen solvents such as chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, 1, 2-dichlorobenzene, and trifluorotoluene, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, and 1, 4-dioxane, and solvents such as acetonitrile, dimethyl sulfoxide, and mixtures thereof.

As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, etc. can be used.

The reaction temperature may be generally from-10 ℃ to the boiling point of the solvent used, and is preferably in the range of-5 to 50 ℃, and more preferably in the range of 0 to 40 ℃.

The amount of the acid to be used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1 to 2 molar equivalents, relative to the compound of formula (6) as a raw material.

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 5 to 15 times by mass, based on the amount of the compound of formula (6) as the raw material.

The compound of formula (7) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, or neutralization crystallization.

And step 4: by reacting a compound of formula (7) with R in an inert solvent in the presence of an acid²OH to obtain the compound of formula (8) according to the present invention.

Examples of the inert solvent include hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, cyclohexane, and petroleum ether, halogen solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, and trifluorotoluene, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, and 1, 4-dioxane, and acetonitrile, or a mixed solvent thereof.

The acid can be hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, or trisFluoroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, methanesulfonic acid, or with R²Acid chlorides (thionyl chloride, oxalyl chloride) which react with OH to generate an acid, and the like.

R²R in OH²As defined above, as R²As OH, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, allyl alcohol, benzyl alcohol and the like can be used.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-5 to 40 ℃, and more preferably in the range of 10 to 30 ℃.

The amount of the acid to be used may be in the range of 0.1 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 2 molar equivalents, relative to the compound of formula (7) as a raw material.

R²The amount of OH used may be in the range of 0.1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (7).

The amount of the solvent used may be in the range of 0 to 100 times by mass, preferably 0 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (7).

The compound of formula (8) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, or neutralization crystallization.

Step 5: in this step, a compound of formula (9) can be produced by deprotection of the amino group at position 1 of the compound of formula (8), and a compound of formula (11) can be obtained by reacting the compound of formula (9) with a compound of formula (10).

The deprotection reaction in this reaction may be carried out by appropriately selecting and using deprotection conditions according to the nature of the protecting group. For example, R¹In the case of a benzyloxy group, the compound of formula (8) is reacted with palladium on carbon catalyst and hydrogen in an inert solvent in the presence of a base to prepare formula (9), and then the formula (9) is condensed with an acid chloride of formula (10), whereby formula (11) can be obtained. As a direction ofThe method for converting an acyl chloride of formula (10) may be prepared by reacting an acyl chloride in an inert solvent.

As the inert solvent, for example, a hydrocarbon solvent such as toluene, xylene, benzene, heptane, hexane, petroleum ether, etc., a halogen solvent such as methylene chloride, chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, trifluorotoluene, etc., an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, etc., an ester solvent such as ethyl acetate, isopropyl acetate, etc., or a mixed solvent thereof can be used in the production of formula (9). In the production of the acid chloride compound of formula (10), for example, a hydrocarbon solvent such as toluene, xylene, benzene, heptane, or the like, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, or the like, or a mixed solvent thereof can be used. In synthesizing formula (11), for example, hydrocarbon solvents such as toluene, xylene, benzene, and heptane, halogen solvents such as methylene chloride, chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, and trifluorotoluene, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, ester solvents such as ethyl acetate and isopropyl acetate, and mixed solvents thereof can be used.

The reaction temperature in the preparation of formula (9) may be generally a temperature from-20 ℃ to the boiling point of the solvent used, preferably in the range of-5 to 50 ℃, and more preferably in the range of 0 to 40 ℃.

In the preparation of the acyl chloride of formula (10), the reaction temperature may be generally from 0 ℃ to the boiling point of the solvent used, preferably in the range of 10 to 70 ℃, more preferably in the range of 30 to 60 ℃. In synthesizing formula (11), the reaction temperature may be usually from 0 ℃ to the boiling point of the solvent used, preferably in the range of 0 to 50 ℃, and more preferably in the range of 0 to 30 ℃.

As the base, triethylamine, diisopropylamine, pyridine, 2,4, 6-tetramethylpyridine, etc. can be used.

The amount of the base used may be in the range of 0 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (8) as a raw material.

The amount of palladium on carbon used may be in the range of 0.001 to 1 molar equivalent, preferably 0.005 to 0.5 molar equivalent, and more preferably 0.01 to 0.4 molar equivalent, relative to the compound of formula (8) as a raw material.

The amount of the compound of formula (10) used may be in the range of 0.7 to 3 molar equivalents, preferably 0.8 to 2 molar equivalents, and more preferably 0.9 to 1.5 molar equivalents, relative to the compound of formula (8) as a raw material.

As the acid chloride used for the conversion to the acid chloride of formula (10), thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride, and the like can be used.

The amount of acid chloride used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 2 molar equivalents, and more preferably 1 to 1.5 molar equivalents, relative to the compound of formula (10) as a raw material.

The amount of the solvent used in the preparation of formula (9) may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, based on the compound of formula (7). In the preparation of the acyl chloride of formula (10), the amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (10).

The compound of formula (11) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, crystallization, or the like.

Step 6: the compound of formula (12) is obtained by reacting the compound of formula (11) with a reducing agent in an alcohol-based or ether-based solvent.

As the alcohol solvent, for example, methanol, ethanol, propanol, isopropanol, or a mixed solvent thereof can be used. As the ether solvent, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, and 1, 4-dioxane can be used.

As the reducing agent, for example, sodium borohydride, lithium aluminum hydride, lithium triethylborohydride, sodium bis (2-methoxyethoxy) aluminum hydride, lithium tri-sec-butylborohydride, potassium tri-sec-butylborohydride, diisobutylaluminum hydride, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, or the like can be used.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-5 to 40 ℃, and more preferably in the range of 0 to 20 ℃.

The amount of the reducing agent to be used may be in the range of 0.5 to 8 molar equivalents, preferably 2 to 6 molar equivalents, and more preferably 3 to 5 molar equivalents, relative to the compound of formula (11).

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (11).

The compound of formula (12) can be obtained as a purified product or unpurified product by chromatography, recrystallization, reslurry, or neutralization crystallization.

Step 7: after an aryl zinc reagent is prepared by adding a base and a zinc reagent to the compound of formula (13) in an inert solvent, the compound of formula (15) can be obtained by a radical-to-radical reaction with the compound of formula (14) using a catalyst.

Examples of the inert solvent used in the preparation of the arylzinc reagent include hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, and cyclohexane, ester solvents such as ethyl acetate and isopropyl acetate, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, and 1, 4-dioxane, and mixed solvents thereof.

Examples of the inert solvent used in the preparation of the zinc reagent in the root-bank reaction include hydrocarbon solvents such as toluene, xylene, benzene, heptane, hexane, and cyclohexane, ester solvents such as ethyl acetate and isopropyl acetate, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, and 1, 4-dioxane, amide solvents such as N, N-dimethylformamide, N-dimethylacetoamide, and N-methyl-2-pyrrolidone, and mixed solvents thereof.

Examples of the base include n-butyllithium, n-hexyllithium, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, and the like.

As the zinc reagent, for example, zinc chloride, zinc bromide, or the like can be used.

As the catalyst, for example, palladium catalysts such as palladium chloride, palladium acetate, bis (triphenylphosphine) palladium dichloride, tetrakis (triphenylphosphine) palladium and the like, or nickel catalysts such as bis (triphenylphosphine) nickel dichloride and the like can be used. If necessary, a phosphine ligand such as triphenylphosphine or tris (2-methylphenyl) phosphine may be added together with the catalyst.

The preparation temperature of the arylzinc reagent may be generally from-78 ℃ to the boiling point of the solvent used, preferably in the range of-78 to 30 ℃, and more preferably in the range of-20 to 10 ℃. The reaction temperature of the bank reaction may be usually 0 ℃ to the boiling point of the solvent used, and is preferably in the range of 20 to 100 ℃, and more preferably in the range of 40 to 70 ℃.

The amount of the base to be used may be in the range of 0.1 to 5 molar equivalents, preferably 0.2 to 3 molar equivalents, and more preferably 1 to 2 molar equivalents, relative to the compound of formula (14).

The amount of the zinc reagent to be used may be in the range of 0.1 to 5 molar equivalents, preferably 0.2 to 3 molar equivalents, and more preferably 1 to 2 molar equivalents, relative to the compound of formula (14).

The amount of the catalyst to be used may be in the range of 0.001 to 1.0 molar equivalent, preferably 0.001 to 0.1 molar equivalent, and more preferably 0.01 to 0.04 molar equivalent, relative to the compound of formula (14). Further, it is preferable to add a phosphine ligand, and the amount of the phosphine ligand to be used may be in the range of 0.001 to 1.0 molar equivalent to the compound of formula (14). Preferably 0.001 to 0.1 molar equivalent, and more preferably 0.01 to 0.04 molar equivalent.

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, relative to the compound of formula (13).

The compound of formula (15) can be obtained as a purified product or unpurified product by chromatography, recrystallization, reslurry, or neutralization crystallization.

Step 8: the deprotection reaction in this reaction may be carried out by appropriately selecting and using deprotection conditions according to the nature of the protecting group. Specifically, R³In the case of the dioxane-2-yl group (tetrahydropyran (THP) group), in general, the compound of formula (15) is reacted with an acid in an inert solvent, whereby formula (16) can be obtained. Instead of inert solvents, other solvents may also be used.

Examples of the acid include bronsted acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, and trifluoroacetic acid, and lewis acids such as boron trifluoride diethyl ether complex and aluminum chloride.

Examples of the inert solvent include halogen-based solvents such as dichloromethane, chloroform, 1, 2-dichloroethane and chlorobenzene, hydrocarbon-based solvents such as toluene, xylene, benzene, heptane, hexane and cyclohexane, ester-based solvents such as ethyl acetate and isopropyl acetate, ether-based solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane and 1, 4-dioxane, amide-based solvents such as N, N-dimethylformamide, N-dimethylacetoxyamide and N-methyl-2-pyrrolidone, and mixed solvents thereof. Water or an alcohol such as methanol, ethanol, or propanol may be used as the solvent, or one or more of these may be used in combination with an inert solvent.

The reaction temperature may be generally from-80 ℃ to the boiling point of the solvent used, and is preferably in the range of 0 to 100 ℃, and more preferably in the range of 15 to 30 ℃.

The amount of the acid to be used may be in the range of 0.01 to 20 molar equivalents, preferably 0.1 to 10 molar equivalents, and more preferably 0.1 to 5 molar equivalents, relative to the compound (15) as a raw material.

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, based on the compound (2) as the raw material.

The compound of formula (16) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, or neutralization crystallization.

Step 9: by reacting a compound of formula (16) with R in a basic solvent⁴SO₂-X or (R)⁴SO₂）₂O reaction to give the compound of formula (17).

Examples of the basic solvent include triethylamine, diisopropylamine, pyridine, and 2,4, 6-tetramethylpyridine.

R⁴SO₂-X or (R)⁴SO₂）₂R in O⁴And X are the same as defined above, and for example, methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride and the like can be used.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-5 to 40 ℃, and more preferably in the range of 0 to 30 ℃.

R⁴SO₂-X or (R)⁴SO₂）₂The amount of O used may be in the range of 0.5 to 7 molar equivalents, preferably 1 to 5 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (16).

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (16).

The compound of formula (17) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, crystallization, or the like.

Step 10: the compound of formula (1) can be obtained by reacting the compound of formula (12) with the compound of formula (17) in an inert solvent in the presence of a base.

Examples of the inert solvent include hydrocarbon solvents such as toluene, xylene, benzene, and heptane, ether solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, and tetrahydropyran, acetonitrile, pyridine, 2,4, 6-tetramethylpyridine, and a mixed solvent thereof.

Examples of the base include sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, n-butyllithium, and n-hexyllithium.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-5 to 80 ℃, and more preferably in the range of 0 to 70 ℃.

The amount of the compound of formula (17) may be in the range of 0.5 to 7 molar equivalents, preferably 1 to 5 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (12).

The amount of the base to be used may be in the range of 0.5 to 7 molar equivalents, preferably 1 to 5 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (12).

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 10 times by mass, relative to the compound of formula (12).

The compound of formula (1) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurrying, crystallization, or the like.

[ chemical formula 28]

(in the formula, R¹The same meanings as described above are shown. )

Step 1': formula (18) can be obtained by reacting the compound of formula (2) with formula (4) in a polar solvent in the presence of a base.

Examples of the polar solvent include alcohol solvents such as methanol, ethanol, and isopropanol, tetrahydrofuran, acetonitrile, and water, and mixed solvents thereof.

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium phosphate, potassium phosphate, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, and potassium hydrogencarbonate.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-10 to 60 ℃, and more preferably in the range of 0 to 30 ℃.

The amount of the base to be used may be in the range of 0.5 to 7 molar equivalents, preferably 1 to 6 molar equivalents, and more preferably 1 to 5 molar equivalents, relative to the compound of formula (2).

The amount of the compound of formula (4) may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (2).

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, relative to the compound of formula (2).

The compound of formula (18) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, crystallization, or the like.

Step 2': the compound of formula (18) is reacted with glyoxylic acid in an acidic solvent to give the compound of formula (5).

As the acidic solvent, for example, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, or the like can be used.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of 0 to 70 ℃, and more preferably in the range of 20 to 60 ℃.

The amount of glyoxylic acid used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (18) as the starting material.

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, relative to the compound of formula (2).

The compound of formula (5) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurrying, crystallization, or the like.

[ chemical formula 29]

(in the formula, R¹、R²The same meanings as described above are shown. )

Step 1': formula (20) can be obtained by reacting the compound of formula (2) with glyoxylic acid ester in an inert solvent to synthesize formula (19), and then further adding an inert solvent and a base to react with formula (4).

As the inert solvent, a hydrocarbon solvent such as toluene, xylene, benzene, heptane, etc., a halogen solvent such as chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, 1, 2-dichlorobenzene, trifluorotoluene, etc., an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, 1, 4-dioxane, etc., acetonitrile, or a mixed solvent thereof, etc., can be used in the syntheses of the formulae (19) and (20).

Examples of the base include triethylamine, diisopropylamine, pyridine, and 2,4, 6-tetramethylpyridine.

As the glyoxylic acid ester, there can be used alkyl esters and aralkyl esters of glyoxylic acid such as methyl glyoxylate, ethyl glyoxylate, propyl glyoxylate, isopropyl glyoxylate, n-butyl glyoxylate, t-butyl glyoxylate, allyl glyoxylate, hexyl glyoxylate, benzyl glyoxylate and menthyl glyoxylate.

The reaction temperature in the synthesis of the formulae (19) and (20) may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-10 to 70 ℃, and more preferably in the range of 0 to 60 ℃.

The amount of glyoxylic acid ester to be used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 3 molar equivalents, and more preferably 1 to 1.5 molar equivalents, relative to the compound of formula (2).

The amount of the base to be used may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (2).

The amount of the compound of formula (4) may be in the range of 0.5 to 5 molar equivalents, preferably 1 to 4 molar equivalents, and more preferably 1 to 3 molar equivalents, relative to the compound of formula (2).

The amount of the solvent used in the synthesis of the compounds of the formulae (19) and (20) may be 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, based on the compound of the formula (2).

The compound of formula (20) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurry, crystallization, or the like.

Step 2': formula (5) can be obtained by reacting a compound of formula (20) with a base and water in an inert solvent.

As the inert solvent, an alcohol solvent such as methanol, ethanol, or isopropanol, a hydrocarbon solvent such as toluene, xylene, benzene, or heptane, a halogen solvent such as chloroform, 1, 2-dichloroethane, carbon tetrachloride, chlorobenzene, 1, 2-dichlorobenzene, or trifluorotoluene, an ether solvent such as tetrahydrofuran, 2-methyltetrahydrofuran, tetrahydropyran, diethyl ether, diisopropyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 2-dimethoxyethane, diethoxymethane, or 1, 4-dioxane, acetonitrile, or a mixed solvent thereof, or the like can be used.

Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, and lithium hydroxide.

The reaction temperature may be generally from-20 ℃ to the boiling point of the solvent used, and is preferably in the range of-10 to 70 ℃, and more preferably in the range of 0 to 40 ℃.

The amount of the base used may be in the range of 0.5 to 7 molar equivalents, preferably 1 to 6 molar equivalents, and more preferably 1 to 5 molar equivalents, relative to the compound of formula (20) as a raw material.

The amount of the solvent used may be in the range of 1 to 100 times by mass, preferably 1 to 30 times by mass, and more preferably 1 to 20 times by mass, relative to the compound of formula (20).

The compound of formula (5) can be obtained as a purified product or an unpurified product by chromatography, recrystallization, reslurrying, crystallization, or the like.