JP2006188505A - Method for producing indole compound, and intermediate therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a suitable method for producing in high yield a compound useful as a β3-adrenoreceptor stimulant, and to provide the compound's intermediate easy to refine. <P>SOLUTION: The method comprises the following process: A compound of formula(1) [ wherein, R<SP>1</SP>is absent or a (substituted) alkyl or the like; R<SP>2</SP>is H or the like; R<SP>3</SP>is a OH-protecting group; R<SP>4</SP>is absent or a (substituted) alkyl; R<SP>5</SP>, R<SP>13</SP>and R<SP>14</SP>are each H or a (substituted) alkyl; R<SP>6</SP>and R<SP>6a</SP>are each H or an OH-protecting group; and R<SP>8</SP>is an amino-protecting group ] is reacted with a compound of formula(3) followed by, as necessary, deprotection to form a compound of formula(4), which is then reduced to obtain the objective compound of formula(5). <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for synthesizing indoles useful as β3-adrenergic receptor stimulants and synthetic intermediates.

There are several methods for synthesizing and synthesizing (2- (2-aryl-2-hydroxy) ethylamino) ethylindole derivatives and (2- (2-pyridyl-2-hydroxy) ethylamino) ethylindole derivatives. Known (see, for example, Patent Documents 1, 2, and 3).
JP-A-2-231486 JP-A-8-231504 International Publication No. 03/106418 Pamphlet

  International Publication No. 03/106418 pamphlet discloses that a compound represented by the following formula (10a) is useful as a β3-adrenergic receptor stimulant.

（式中、Ｒ^１ａは、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、水酸基、またはアミノ基を表す。
Ｒ^４ａは、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、水酸基、またはアミノ基を表す。
Ｒ^５は水素原子、または置換もしくは無置換のアルキル基を表す。
Ｒ^９は水素原子、または置換もしくは無置換のアルキル基を表す。
Ｒ^１１およびＲ^１２はそれぞれ独立して、水素原子、または置換もしくは無置換のアルキル基を表す）

(In the formula, R ^1a is not present, or is present in one or more, the same or different, and represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a hydroxyl group, or an amino group. .
R ^4a is not present, or is present in the same or different form, and represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a hydroxyl group, or an amino group.
R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl group.
R ⁹ represents a hydrogen atom or a substituted or unsubstituted alkyl group.
R ¹¹ and R ¹² each independently represents a hydrogen atom or a substituted or unsubstituted alkyl group)

  The pamphlet describes the following as a synthesis route of the above-mentioned compound.

（式中、Ｒ^１ａ、Ｒ^４ａ、Ｒ^９、Ｒ^１１およびＲ^１２は上記と同じ意味を表す。
Ｒ^１は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。
Ｒ^４は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。
Ｒ^２は水素原子、置換もしくは無置換のアルキル基、または窒素原子の保護基を表す。
Ｒ^３、Ｒ^６およびＲ^６ａは、同一または異なって水酸基の保護基を表す。
Ｒ^８はアミノ基の保護基を表す。
Ｒ^１０は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基を表す。
Ｘ^１は脱離基を表す。）

(In formula, R ^<1a> , R ^{<4a >} , R ^{< 9 >} , R ^{< 11 >} and R ^{< 12} > represent the same meaning as the above.
R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group Represents.
R ⁴ is absent, or is present in the same or different, one or more, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group Represents.
R ² represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a protecting group for a nitrogen atom.
R ³ , R ⁶ and R ^6a are the same or different and represent a hydroxyl-protecting group.
R ⁸ represents an amino-protecting group.
R ¹⁰ is not present, is one or more, is the same or different, and represents a substituted or unsubstituted alkyl group.
X ¹ represents a leaving group. )

As a result of studying general methods for producing the compounds described in JP-A-2-231486, JP-A-8-231504, and International Publication No. 03/106418, the present inventors have found some problems. It was.
Some of the issues found are: In either case, the present inventors have found the problem itself.
(A) The yield of the reduction reaction from the compound represented by formula (13) to the compound represented by formula (7a) is low, and separation from by-products is difficult.
(B) There are many steps of protection and deprotection, so that the number of steps increases and the overall yield is low.

As a result of intensive studies, the present inventors have conducted a new synthesis route for the compound represented by the following formula (5), an intermediate that can be easily purified, and a reaction suitable for the synthesis of the compound represented by the following formula (7). I found it.
That is, the present invention relates to the following.
[1] Formula (1):

（式中、Ｒ^１は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^２は水素原子、置換もしくは無置換のアルキル基、または窒素原子の保護基を表す。Ｒ^３は水酸基の保護基を表す。Ｒ^１３およびＲ^１４はそれぞれ独立して、水素原子、または置換もしくは無置換のアルキル基を表す。）で表される化合物と、式（３）：

(In the formula, R ¹ is absent, or is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ² represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a protecting group for a nitrogen atom, R ³ represents a protecting group for a hydroxyl group, and R ¹³ and R ¹⁴ are each independently , A hydrogen atom, or a substituted or unsubstituted alkyl group) and the formula (3):

（式中、Ｒ^４は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^５は水素原子、または置換もしくは無置換のアルキル基を表す。Ｒ^６は水素原子または水酸基の保護基を表す。Ｒ^８はアミノ基の保護基を表す。）で表される化合物を縮合剤を用いて反応させるか、または式（１）で表される化合物を、酸ハライドまたは酸無水物として、式（３）で表される化合物と縮合させ、必要に応じ脱保護して、式（４）：

(Wherein R ⁴ is absent, or is present in one or more, the same or different, substituted or unsubstituted alkyl group, substituted or unsubstituted alkoxy group, halogen atom, protected hydroxyl group, or protection R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ⁶ represents a hydrogen atom or a protecting group for a hydroxyl group, and R ⁸ represents a protecting group for an amino group. The compound represented by formula (1) is reacted with a compound represented by formula (3) as an acid halide or acid anhydride, and the compound represented by formula (1) is condensed as necessary. Deprotect to formula (4):

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^１３およびＲ^１４は前記と同じ意味を表す。Ｒ^６ａは水素原子または水酸基の保護基を表す。）で表される化合物とし、次いで、式（４）で表される化合物を還元することからなる、式（５）：

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as described above. R ^6a represents a hydrogen atom or a hydroxyl-protecting group). Consisting of reducing the compound represented by formula (4) and then the formula (5):

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６a、Ｒ^８、Ｒ^１３およびＲ^１４は前記と同じ意味を表す。）で表される化合物の製造方法。
［２］ 式（３）で表される化合物が、式（３ｂ）：

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as described above).
[2] The compound represented by the formula (3) is represented by the formula (3b):

で表される化合物である、［１］記載の製造方法。
［３］ 式（４ａ）：

The production method according to [1], which is a compound represented by the formula:
[3] Formula (4a):

（式中、Ｒ^１は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^３は水酸基の保護基を表す。Ｒ^４は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^５は水素原子、または置換もしくは無置換のアルキル基を表す。Ｒ^１３およびＲ^１４はそれぞれ独立して、水素原子、または置換もしくは無置換のアルキル基を表す。Ｒ^８はアミノ基の保護基を表す。）で表される化合物。
［４］ 式（４ｂ）：

(In the formula, R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ³ represents a hydroxyl-protecting group, and R ⁴ is absent, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, substituted or unsubstituted Represents an alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group, R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl group, and R ¹³ and R ¹⁴ each independently represents a hydrogen atom. Or a substituted or unsubstituted alkyl group, and R ⁸ represents an amino-protecting group.
[4] Formula (4b):

（式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^１３およびＲ^１４は［３］と同じ意味を表す。）で表される、［３］記載の化合物。
［５］ Ｒ^１およびＲ^４がともに存在しない、［３］または［４］記載の化合物。
［６］ 式（６）：

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as [3]), and the compound according to [3].
[5] The compound according to [3] or [4], wherein R ¹ and R ⁴ are both absent.
[6] Formula (6):

（式中、Ｒ^１は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^２は水素原子、置換もしくは無置換のアルキル基、または窒素原子の保護基を表す。Ｒ^３は水酸基の保護基を表す。Ｒ^４は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基、置換もしくは無置換のアルコキシ基、ハロゲン原子、保護された水酸基、または保護されたアミノ基を表す。Ｒ^５は水素原子、または置換もしくは無置換のアルキル基を表す。Ｒ^８はアミノ基の保護基を表す。Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は、それぞれ独立して、水素原子、または置換もしくは無置換のアルキル基を表す。）で表される化合物を脱保護して、式（７）：

(In the formula, R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ² represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a protecting group for a nitrogen atom, R ³ represents a protecting group for a hydroxyl group, and R ⁴ is absent or one Or a plurality, the same or different, each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group, and R ⁵ represents a hydrogen atom, or A substituted or unsubstituted alkyl group, R ⁸ represents an amino-protecting group, R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represents hydrogen; A compound represented by an atom or a substituted or unsubstituted alkyl group) is deprotected to obtain a compound represented by the formula (7):

（式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は前記と同じ意味を表す。）とし、次いで塩基の存在下、式（８）：

(Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as described above), and then in the presence of a base ( 8):

（式中、Ｒ^９は水素原子、または置換もしくは無置換のアルキル基を表す。Ｒ^１０は、存在しないか、１つまたは複数、同一もしくは異なって存在し、置換もしくは無置換のアルキル基を表す。Ｘ^１は脱離基を表す。）で表される化合物と反応させることからなる、式（９）：

(In the formula, R ⁹ represents a hydrogen atom or a substituted or unsubstituted alkyl group. R ¹⁰ is absent, or one or more, the same or different, and represents a substituted or unsubstituted alkyl group. X ¹ represents a leaving group), which is reacted with a compound represented by formula (9):

（式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は前記と同じ意味を表す。）で表される化合物の製造方法。
［７］ 式（６）で表される化合物が、式（６ｂ）：

(Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as described above). Compound production method.
[7] The compound represented by the formula (6) is represented by the formula (6b):

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は請求項６と同じ意味を表す。）
で表される化合物である、［６］記載の製造方法。

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as in claim 6).
The production method according to [6], which is a compound represented by the formula:

The production methods [1] to [2] have a high yield as a route for synthesizing the compound represented by the formula (5), and have few by-products.
The compounds [3] to [5] are intermediates via the route. Since this compound tends to form crystals, it is very easy to purify. Conventionally, no intermediate that can be crystallized has been found, so purification methods have been limited.
In addition, the steps of introducing and deprotecting protecting groups cause the number of steps to increase, leading to a decrease in overall yield. Therefore, reducing the steps of protection and deprotection as much as possible leads to an improvement in overall yield.
The production methods [6] to [7] include the compound represented by the formula (9) without protecting or deprotecting the hydroxyl group bonded to the carbon atom to which the pyridine ring is bonded. It can be synthesized efficiently.

  Various terms in the present invention will be described in detail as follows. Unless otherwise specified, the explanation of each group includes a case where it is a part of other substituents.

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

  Examples of the alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms. Specific examples include methyl, ethyl, propyl, isopropyl, butyl, 2-butyl, 2-methylpropyl. 1,1-dimethylethyl, pentyl, 3-pentyl, 3-methylbutyl, hexyl, 3-hexyl, 4-methylpentyl and the like.

  Examples of the alkenyl group include linear or branched alkenyl groups having 6 or less carbon atoms such as vinyl, allyl, propenyl, 2-propenyl, butenyl, pentenyl, hexenyl and the like.

  Examples of the alkoxy group include a group in which an oxygen atom is bonded to the bond of the alkyl group.

  Examples of the acyl group include a formyl group, for example, an alkanoyl group having 2 to 6 carbon atoms such as acetyl and propanoyl, for example, a cycloalkanecarbonyl having 4 to 7 carbon atoms such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, and cyclohexanecarbonyl. Groups such as cycloalkenecarbonyl groups having 3 to 6 carbon atoms such as cyclopentenecarbonyl and cyclohexenecarbonyl, such as aroyl groups having 6 to 10 carbon atoms such as benzoyl, toluoyl and naphthoyl, such as 2-piperidinecarbonyl and 3-morpholinecarbonyl A saturated heterocyclic-carbonyl group having a 5- or 6-membered saturated heterocyclic ring containing 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, such as furoyl, thenoyl, nicotinoyl, iso Nitrogen atom such as Kochinoiru, oxygen atom, such as heteroaromatic acyl groups having a heteroaromatic ring of 5 or 6 membered containing one or two hetero atoms selected from sulfur atom.

  The aryl part of the aralkyl group is, for example, an aryl group having 10 or less carbon atoms such as phenyl, 1- or 2-naphthyl, and the alkyl part is, for example, 6 or less carbon atoms such as methyl, ethyl, propyl or butyl. And the like. Representative aralkyl groups include, for example, benzyl group, 1- or 2-phenethyl group.

  The substituted alkyl group and the substituted alkoxy group may have one or the same or different substituents, and examples of the substituent include a halogen atom, a cyano group, a phenoxy group, a benzyloxy group, a trifluoromethyl group, a hydroxyl group. Lower alkoxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, carbamoyl group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, lower alkoxycarbonylamino group, carboxyl group, Lower alkoxycarbonyl group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, lower alkanoylamino group, lower alkylsulfonamide group, phthalimide group, aryl group (halogen atom, lower alkyl group, or lower group) 1 or more, which may be substituted by the same or different by an alkoxy group or the like, or a heteroaryl group (substituted by one or more, the same or different by a halogen atom, a lower alkyl group, or a lower alkoxy group, etc.) May be included).

  The term “lower” in the present invention means that the alkyl part of the group is a lower alkyl group, and examples of such lower alkyl group include methyl, ethyl, propyl, 2-propyl, butyl, tert-butyl, pentyl, hexyl. And a lower alkyl group having 1 to 6 carbon atoms. The number of carbon atoms is the carbon atom of the carbonyl group in the lower alkanoyloxy group, lower alkylaminocarbonyl group, di-lower alkylaminocarbonyl group, lower alkoxycarbonylamino group, lower alkoxycarbonyl group, and lower alkanoylamino group. Means the number of carbon atoms other than.

  Examples of the aryl group include aryl groups having 10 or less carbon atoms such as phenyl, 1- or 2-naphthyl.

  Examples of the heteroaryl group include a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms, a 5- to 6-membered single group containing 1 to 2 nitrogen atoms and one oxygen atom or one sulfur atom. Cyclic group, 5-membered monocyclic group containing 1 oxygen atom or 1 sulfur atom, or bicyclic containing 1 to 4 nitrogen atoms and condensed with 6-membered ring and 5- or 6-membered ring Specifically, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-imidazolyl, pyrazinyl, 2-pyrimidinyl, 3-pyridazinyl, 3-oxadiazolyl, 2-thiazolyl, 3- Examples include isothiazolyl, 2-oxazolyl, 3-isoxazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-quinolyl, 8-quinolyl, 2-quinazolinyl or 8-purinyl.

  As the substituent in the substituted aralkyl group, one or more, the same or different, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group and the like can be mentioned. Preferred substituents include lower alkyl groups such as methoxy.

  Examples of the hydroxyl-protecting group include trialkylsilyl groups such as trimethylsilyl, triethylsilyl, and tert-butyldimethylsilyl, acetal-type protecting groups such as tetrahydropyran-2-yl, methoxymethyl, and methoxyethoxymethyl, and tert-butoxycarbonyl. And an aralkyl group such as benzyl.

Examples of the protecting group for the amino group and the protecting group for the nitrogen atom represented by R ² include alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, tert-butoxycarbonyl, and vinyloxycarbonyl. Alkenyloxycarbonyl groups such as benzyloxycarbonyl, aralkyloxycarbonyl groups such as 9-fluorenylmethoxycarbonyl, aralkyl groups which may be substituted such as benzyl, 4-methoxybenzyl, formyl, acetyl, trifluoroacetyl, benzoyl And the like, arylsulfonyl groups such as p-toluenesulfonyl and benzenesulfonyl, and alkylsulfonyl groups such as methanesulfonyl.

Examples of the leaving group represented by X ¹ include halogen atoms such as chlorine atom, bromine atom and iodine atom, and optionally substituted alkylsulfonyloxy group such as methanesulfonyloxy, trifluoromethylsulfonyloxy, chloromethylsulfoxyoxy and the like. Or an arylsulfonyloxy group which may be substituted, such as a benzenesulfonyloxy group and a paratoluenesulfonyloxy group.

Next, the synthesis method and synthesis intermediate of the present invention will be described in detail.
(A) Synthesis method of [1] and synthesis intermediate of [3]

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^６a、Ｒ^８、Ｒ^１３およびＲ^１４は上記と同じ意味を表す）

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ^6a , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as above)

The compound represented by the formula (1) and the compound represented by the formula (3) in an amount of usually 1.0 to 2.0 mol times, preferably 1.0 to 1.5 mol times are usually 1. The compound represented by the formula (4) can be synthesized by reacting with 0 to 2.0 mol times, preferably 1.0 to 1.5 mol times of the condensing agent.
Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene and benzene, aprotic such as dimethylformamide and dimethyl sulfoxide. A polar solvent, water, etc. are mentioned, These solvents are used individually or in mixture of 2 or more types. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.
Examples of the condensing agent include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), N-ethyl-N′-3-dimethylaminopropylcarbodiimide (EDC = WSCI) and its hydrochloride (WSCI · HCl), benzotriazole-1 -Condensing agents frequently used for peptide bond formation such as yl-tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI), 2-ethoxy-1 -Ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), triphenylphosphine-carbon tetrachloride, diethyl cyanophosphonate, diphenylphosphoroazide and the like.
Examples of the additive used for the purpose of accelerating the speed of the condensation reaction or suppressing side reactions include N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt), and 3,4-dihydro. -3-hydroxy-4-oxo-1,2,3-benzotriazine (HOOBt) and the like.

Moreover, the compound of Formula (4) can be manufactured by making the carboxy group of the compound of Formula (1) into an acid chloride, and making the compound of Formula (3) react in an inert solvent. As a method for converting a carboxy group into an acid chloride, those commonly used can be used, and examples thereof include oxalyl chloride, thionyl chloride and the like.
A method for converting a carboxyl group using oxalyl chloride to acid chloride will be described below.
As usage-amount of an oxalyl chloride, the range of 1.0-3.0 mol times amount is mentioned with respect to the compound of Formula (1), for example. Examples of the base used at that time include triethylamine, diisopropylamine, ethylisopropylamine, pyridine, 4- (dimethylamino) pyridine, N-methylmorpholine, and the like. Preferred bases include N-methylmorpholine. . As the usage-amount of a base, the range of 1-3 mol times amount is mentioned with respect to the compound of Formula (1), for example, Preferably the range of 1.0-1.5 mol times amount is mentioned. Examples of the reaction solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl-t-butyl ether, ethylene glycol dimethyl ether, halogenated hydrocarbon solvents such as dichloromethane, and aromatic hydrocarbon solvents such as toluene. Solvents, aprotic polar solvents such as N, N-dimethylformamide, and the like are preferable, and tetrahydrofuran is preferable. The reaction temperature may be in the range of −78 to 30 ° C., preferably in the range of −30 to 10 ° C.
At this time, for example, when the resulting salt precipitates after converting the carboxy group to acid chloride, it can be removed by filtration.
The compound of the formula (4) can be produced by reacting the compound of the formula (3) with the compound of the formula (1) in which the carboxyl group is an acid chloride. As usage-amount of the compound of Formula (3), the range of 1-5 mole times amount is mentioned, for example with respect to the compound of Formula (1), Preferably the range of 1-2 mole times amount is mentioned. Examples of the reaction solvent include the same solvents as those used in the reaction for converting a carboxy group to an acid chloride. As reaction temperature, the range of -78-30 degreeC is mentioned, for example, Preferably the range of 0-30 degreeC is mentioned.

Furthermore, the compound of Formula (4) can be manufactured by making the carboxy group of the compound of Formula (1) into a mixed acid anhydride, and reacting the compound of Formula (3) in an inert solvent. As a method for converting a carboxy group into a mixed acid anhydride, those usually used can be used, and examples thereof include alkyl chloroformate and pivaloyl chloride. Examples of the alkyl chloroformate include isopropyl chloroformate, isobutyl chloroformate, n-butyl chloroformate and the like, and preferably isopropyl chloroformate and isobutyl chloroformate.
A method for converting a carboxy group using alkyl chloroformate or pivaloyl chloride into a mixed acid anhydride will be described below.
As the usage-amount of alkyl chloroformate or pivaloyl chloride, the range of 1.0-1.5 mol times with respect to the compound of Formula (1) is mentioned, for example. Examples of the base used at that time include triethylamine, diisopropylamine, ethylisopropylamine, pyridine, 4- (dimethylamino) pyridine, N-methylmorpholine, and the like. Preferred bases include N-methylmorpholine. . As the usage-amount of a base, the range of 1-3 mol times amount is mentioned with respect to the compound of Formula (1), for example, Preferably the range of 1.0-1.5 mol times amount is mentioned. Examples of the reaction solvent include ether solvents such as tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl-t-butyl ether, ethylene glycol dimethyl ether, halogenated hydrocarbon solvents such as dichloromethane, and aromatic hydrocarbon solvents such as toluene. Solvents, aprotic polar solvents such as N, N-dimethylformamide, and the like are preferable, and tetrahydrofuran is preferable. The reaction temperature may be in the range of −78 to 30 ° C., preferably in the range of −30 to 10 ° C.
At this time, for example, when the resulting salt precipitates after the carboxy group is converted to a mixed acid anhydride, it can be removed by filtration.
The compound of Formula (4) can be manufactured by making the compound of Formula (3) react with the compound of Formula (1) which made the carboxy group the mixed acid anhydride. As usage-amount of the compound of Formula (3), the range of 1-5 mole times amount is mentioned, for example with respect to the compound of Formula (1), Preferably the range of 1-2 mole times amount is mentioned. As a reaction solvent, the solvent similar to the solvent used by reaction which makes a carboxyl group a mixed acid anhydride, for example is mentioned. As reaction temperature, the range of -78-30 degreeC is mentioned, for example, Preferably the range of -20-10 degreeC is mentioned.

The compound represented by the formula (4) thus obtained can be deprotected as necessary to synthesize a compound represented by the formula (4) in which R ⁶ is a hydrogen atom. . Reaction conditions include methods known in the literature (for example, Green, TW and Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)).

  Specifically, for example, when deprotecting a trialkylsilyl group such as a tert-butyldimethylsilyl group, a triethylsilyl group, or a trimethylsilyl group, it can be carried out by reacting with a reagent for deprotection. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. Examples of the reagent include inorganic substances such as hydrochloric acid (for example, 2 N aqueous solution), hydrobromic acid (for example, 2 N aqueous solution), 1 to 5 mol times, preferably 2 to 3 mol times hydrofluoric acid. Examples thereof include organic acids such as acid, acetic acid and trifluoroacetic acid, or fluorine salts such as 1 to 5 mol times, preferably 2 to 3 mol times tetra-n-butylammonium fluoride. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

  When deprotecting an aralkyl group such as a benzyl group, it can be carried out, for example, by a hydrogenation reaction. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. Examples of the hydrogenation reaction include a catalytic hydrogenation reaction that reacts with hydrogen in the presence of a catalyst. Examples of the catalyst include heterogeneous catalysts such as palladium carbon and palladium hydroxide. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

  When deprotecting an acetal type protecting group such as tetrahydropyran-2-yl, methoxymethyl, methoxyethoxymethyl, etc., it can be carried out by reacting with a reagent for deprotection. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. Examples of the reagent include inorganic acids such as hydrochloric acid (for example, 2N aqueous solution) and hydrobromic acid (for example, 2N aqueous solution), and organic acids such as acetic acid and trifluoroacetic acid. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

By reducing the compound represented by Formula (4), the compound represented by Formula (5) can be synthesized. Examples of the reducing agent include borane reducing agents such as diborane, borane tetrahydrofuran (BH ₃ · THF) complex, borane dimethyl sulfide (BH ₃ · S (CH ₃ ) ₂ ) complex, borane (BH ₃ ) · pyridine complex, And aluminum hydride-based reducing agents such as lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. 0 mole times, preferably 3.0 to 10.0 mole times are used. Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, and these solvents are used alone or in combination. The reaction temperature is generally −20 ° C. to 110 ° C., preferably −10 ° C. to 40 ° C. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 8 hours.

  Among the compounds represented by the above formula (4), in particular, the formula (4a):

（式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^１３およびＲ^１４は上記と同じ意味を表す）で表される化合物は、結晶になりやすく、再結晶により容易に精製することができる。再結晶溶媒としては、例えば水、エタノール、メタノール等のアルコール系溶媒、ジエチルエーテル、テトラヒドロフランなどのエーテル系溶媒、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、アセトン、メチルエチルケトンなどのケトン系溶媒、酢酸エチルなどのエステル系溶媒、ｎ−ヘキサン、ｎ−ヘプタンなどの炭化水素系溶媒、トルエン、ベンゼン等の芳香族炭化水素系溶媒等が挙げられる。これらの溶媒は単独でまたは２種以上混合して用いられる。

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as described above), the compound represented by can do. Examples of the recrystallization solvent include alcohol solvents such as water, ethanol and methanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, ketone solvents such as acetone and methyl ethyl ketone, and acetic acid. Examples thereof include ester solvents such as ethyl, hydrocarbon solvents such as n-hexane and n-heptane, and aromatic hydrocarbon solvents such as toluene and benzene. These solvents are used alone or in combination of two or more.

(B) Synthesis method of [6]

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３およびＲ^１４は上記と同じ意味を表す）
式（６）で表される化合物を、Ｒ^３とＲ^８の組み合わせを考慮して、適当な条件でＲ^３を選択的に脱保護することにより、式（７）で表される化合物を合成することができる。

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ and R ¹⁴ represent the same meaning as above)
A compound represented by formula (6) is synthesized by selectively deprotecting R ³ under appropriate conditions in consideration of the combination of R ³ and R ^8. can do.

When R ³ is, for example, a trialkylsilyl group such as a tert-butyldimethylsilyl group, a triethylsilyl group, or a trimethylsilyl group, deprotection can be performed by reacting with a reagent for deprotection. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. Examples of the reagent include inorganic acids such as hydrochloric acid (for example, 2 N aqueous solution) and hydrobromic acid (for example, 2 N aqueous solution), organic acids such as acetic acid and trifluoroacetic acid, and 1 to 5 mol times, preferably Includes 2 to 3 mole times hydrofluoric acid, or 1 to 5 mole times amount, preferably 2 to 3 mole times fluorine salt such as tetra-n-butylammonium fluoride. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

In addition, when R ³ is an aralkyl group which may be substituted, such as a benzyl group or a 4-methoxybenzyl group, deprotection can be performed by, for example, a hydrogenation reaction. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, and water. These solvents are used alone or in admixture of two or more. The reaction temperature is generally −20 ° C. to 60 ° C., preferably −10 ° C. to 40 ° C. Examples of the hydrogenation reaction include a catalytic hydrogenation reaction that reacts with hydrogen in the presence of a catalyst. Examples of the catalyst include heterogeneous catalysts such as palladium carbon and palladium hydroxide. R ⁸ is a benzyl group, when the optionally substituted aralkyl group such as 4-methoxybenzyl group, which may R ⁸ is also deprotected. In that case, it is better to put a base in the reaction system. Examples of the base include alkali carbonates such as potassium carbonate and sodium carbonate, inorganic bases such as alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and organic bases such as triethylamine, tributylamine and N-methylmorpholine. The amount of the base used is 1.0 to 20.0 mol times, preferably 3.0 to 10.0 mol times based on the compound represented by formula (6). The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

When R ³ is an alkyl group such as a methyl group, the deprotection can be carried out by reacting with a reagent for deprotection such as a Lewis acid. Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene and benzene, and nitrile solvents such as acetonitrile. These solvents are used alone or in combination of two or more. The reaction temperature is usually 0 ° C to 100 ° C, preferably 20 ° C to 70 ° C. Examples of the Lewis acid include boron tribromide, trimethylsilyl iodine, aluminum chloride and the like. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

When R ³ is an acetal type protecting group such as tetrahydropyran-2-yl, methoxymethyl, methoxyethoxymethyl, etc., deprotection can be performed by reacting with a reagent for deprotection. Examples of the reaction solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aromatic hydrocarbons such as toluene and benzene. Examples include solvents, aprotic polar solvents such as dimethylformamide, dimethyl sulfoxide and the like, and these solvents are used alone or in combination of two or more. The reaction temperature is generally 0 ° C to 40 ° C, preferably 20 ° C to 30 ° C. Examples of the reagent include inorganic acids such as hydrochloric acid (for example, 2N aqueous solution) and hydrobromic acid (for example, 2N aqueous solution), and organic acids such as acetic acid and trifluoroacetic acid. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 3 hours.

The compound represented by the formula (9) can be synthesized by reacting the compound represented by the formula (7) with the compound represented by the formula (8) in the presence of a base.
Examples of the base used include carbonates such as potassium carbonate and cesium carbonate, bicarbonates such as sodium bicarbonate and potassium bicarbonate, inorganic bases such as alkali hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine and tributylamine , Organic bases such as diisopropylethylamine and the like. The amount used is usually 1.0 to 5.0 moles, preferably 1.5 to 2.0 moles, relative to the compound represented by the formula (7). Double the amount.
As the usage-amount of the compound represented by Formula (8), it is 1.0-3.0 mol times normally with respect to the compound represented by Formula (7), Preferably it is 1.0-1.5 mol times amount Is mentioned.
Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide. The reaction temperature is usually 0 ° C to 100 ° C, preferably 0 ° C to 30 ° C.
The reaction time is usually about 10 minutes to 1 day, preferably about 10 minutes to 3 hours.

(C) Conversion from a compound represented by formula (9) to a compound represented by formula (10)

（式中、Ｒ^１、Ｒ^２、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^８、Ｒ^９、Ｒ^１０、Ｒ^１１、Ｒ^１２、Ｒ^１３、Ｒ^１４、Ｒ^１ａ、Ｒ^４ａ、およびＸ^１は上記と同じ意味を表す）
式（９）で表される化合物の、Ｒ^８で表されるアミノ基の保護基を脱保護して、式（９ｂ）で表される化合物を合成することができる。反応条件としては文献公知の方法（例えば、Green, T. W.およびWuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)等）が挙げられる。
このようにして得られる式（９ｂ）で表される化合物を、塩基性条件下または酸性条件下で処理することにより、式（１０）で表される化合物を合成することができる。
塩基としては、例えば水酸化リチウムなどのアルカリ金属水酸化物等、酸としては、例えば塩酸、硫酸等の無機酸等が挙げられ、塩基または酸の使用量としては、通常１．０〜１０．０モル倍量、好ましくは２．０〜５．０モル倍量が挙げられる。
反応溶媒としては、例えば水、ジエチルエーテル、テトラヒドロフランなどのエーテル系溶媒、メタノール、エタノールなどのアルコール系溶媒、ジメチルホルムアミド、ジメチルスルホキシドなどの非プロトン性極性溶媒、またはそれらの混合溶媒等が挙げられる。反応温度としては通常０℃〜１００℃、好ましくは１０℃〜３０℃が挙げられる。
反応時間としては通常１０分から１日程度であり、好ましくは１０分から３時間程度で反応が終了する。

(Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ^1a , R ^4a , and X ¹ are (Same meaning as above)
The compound represented by the formula (9b) can be synthesized by deprotecting the protecting group of the amino group represented by R ⁸ of the compound represented by the formula (9). Reaction conditions include methods known in the literature (for example, Green, TW and Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)).
The compound represented by the formula (10) can be synthesized by treating the compound represented by the formula (9b) thus obtained under a basic condition or an acidic condition.
Examples of the base include alkali metal hydroxides such as lithium hydroxide. Examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid. The amount of the base or acid used is usually 1.0 to 10. 0 mole times amount, Preferably 2.0-5.0 mole times amount is mentioned.
Examples of the reaction solvent include water-based ether solvents such as diethyl ether and tetrahydrofuran, alcohol solvents such as methanol and ethanol, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, and mixed solvents thereof. The reaction temperature is usually 0 ° C to 100 ° C, preferably 10 ° C to 30 ° C.
The reaction time is usually about 10 minutes to 1 day, preferably about 10 minutes to 3 hours.

In the formula (9b), when R ¹ and / or R ⁴ is a protected hydroxyl group and / or a protected amino group, respectively, a method known in the literature (for example, Green, TW and Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999), etc.) and can be converted into a hydroxyl group or an amino group, respectively, to synthesize a compound represented by the formula (10).
The protecting group for the protected hydroxyl group and the protected amino group in R ¹ and R ⁴ may be any protecting group as long as it is not deprotected in the reaction until the synthesis of the formula (9b).

(D) Raw material compound in each step The compound represented by the formula (1) which is the raw material compound in the above step (A) is a known compound or a known method (for example, literature (J. Biol. Chem. 260, 12585 (1985)), etc.). Similarly, the compound represented by the formula (3) is also a known compound or a known method (for example, literature (Organic Process Research & Development 2003, 7, 285-288 and Bull. Chem. Soc. Jpn. , 1986, 59, 2537) and the like.

  The compound represented by the formula (6) which is the raw material compound in the step (B) can be synthesized from a known compound by a known method. As an example, when the compound represented by the formula (6b) is given, it can be synthesized, for example, by the following method.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^８、Ｒ^１１、Ｒ^１２、Ｒ^１３、およびＲ^１４は上記と同じ意味を表す。Ｒ^７は水素原子または水酸基の保護基を表す。）
式（１１）で表される化合物を、通常１〜３モル倍量、好ましくは１．２〜１．５モル倍量の縮合剤の存在下、通常１〜３モル倍量、好ましくは１．２〜１．５モル倍量の式（１２）で表される化合物と反応させることにより、式（１３）で表される化合物を合成することができる。
縮合剤としては、例えばＮ，Ｎ'−ジシクロヘキシルカルボジイミド、１−エチル−３−(３−ジメチルアミノプロピル)カルボジイミド塩酸塩、Ｎ，Ｎ'−カルボニルジイミダゾール、Ｎ，Ｎ'−カルボニルジコハク酸イミド、１−エトキシカルボニル−２−エトキシ−１，２−ジヒドロキノリン、ジフェニルホスホリルアジド、プロパンホスホン酸無水物等が挙げられる。
反応溶媒としては、例えばジエチルエーテル、テトラヒドロフランなどのエーテル系溶媒、ジクロロメタン、クロロホルムなどのハロゲン化炭化水素系溶媒、ジメチルホルムアミド、ジメチルスルホキシドなどの非プロトン性極性溶媒および水等が挙げられる。反応温度としては通常０℃〜１００℃、好ましくは０℃〜３０℃で行う。
反応時間としては通常１０分から１日程度であり、好ましくは１０分から３時間程度で反応が終了する。

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as described above. R ⁷ represents a hydrogen atom or a hydroxyl group protecting group. To express.)
The compound represented by the formula (11) is usually 1 to 3 mol times, preferably 1 to 3 mol times, preferably 1.2 to 1.5 mol times in the presence of a condensing agent. A compound represented by the formula (13) can be synthesized by reacting with a compound represented by the formula (12) in an amount of 2 to 1.5 moles.
Examples of the condensing agent include N, N′-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N, N′-carbonyldiimidazole, N, N′-carbonyldisuccinic acid imide. 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanephosphonic anhydride and the like.
Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aprotic polar solvents such as dimethylformamide and dimethyl sulfoxide, and water. The reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 30 ° C.
The reaction time is usually about 10 minutes to 1 day, preferably about 10 minutes to 3 hours.

The compound represented by the formula (13) thus obtained can be reduced and deprotected as necessary to synthesize the compound represented by the formula (6a). Examples of the reducing agent include borane reducing agents such as diborane, borane tetrahydrofuran (BH ₃ · THF) complex, borane dimethyl sulfide (BH ₃ · S (CH ₃ ) ₂ ) complex, borane (BH ₃ ) · pyridine complex, and Examples include aluminum hydride-based reducing agents such as lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, and the like. A molar amount, preferably 3.0 to 10.0 molar times, is used. Examples of the reaction solvent include ether solvents such as diethyl ether and tetrahydrofuran, and these solvents are used alone or in admixture of two or more. The reaction temperature is generally −20 ° C. to 110 ° C., preferably −10 ° C. to 40 ° C. The reaction time is about 10 minutes to 1 day, and the reaction is usually completed in about 10 minutes to 8 hours.

  Examples of methods for deprotecting protecting groups include methods known in the literature (for example, Green, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)).

  A compound represented by the formula (6b) can be synthesized by introducing a protecting group into the amino group of the compound represented by the formula (6a) thus obtained. Reaction conditions include methods known in the literature (for example, Green, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)).

The compound obtained by each reaction described above can be isolated and purified by a fractional recrystallization method which is a conventional separation means, a purification method using chromatography, a solvent extraction method, reprecipitation or the like.
The product obtained in any reaction takes the form of an acid addition salt or a free base depending on the reaction conditions. These products can be converted into the desired acid addition salt or free base form by conventional methods.
When the compound of the present invention or the raw material compound obtained by each reaction is a racemate or a mixture of diastereomers, each stereoisomer is prepared according to a conventional method, for example, the method described in European Patent Application Publication No. 455006. Can be separated.
In the reactions described above, not only when specific protecting groups are exemplified, but when each starting compound has a reactive group such as a carboxyl group, a hydroxyl group, and an amino group, these groups are The target compound can be synthesized by protecting with an appropriate protecting group in advance and removing the protecting group after carrying out this reaction. The protection and deprotection are performed according to the method described in the literature (for example, Green, TW and Wuts, PGM, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. (1999)) according to each protecting group. be able to.

  The compounds represented by the formula (10) thus obtained can be administered orally or parenterally when they are used as a medicament. That is, it can be administered orally in dosage forms such as powders, granules, tablets, capsules, syrups, suspensions or the like that are usually used, or, for example, solutions, emulsions, suspensions thereof The dosage form can be administered parenterally in the form of an injection. Rectal administration can also be performed in the form of suppositories. The above-mentioned appropriate dosage form can be produced, for example, by blending the compound of the present invention into an acceptable ordinary carrier, excipient, binder, stabilizer, or diluent. When used in an injection form, for example, an acceptable buffer, solubilizer, and isotonic agent can be added. The dose and frequency of administration vary depending on, for example, the target disease, symptoms, age, body weight, and dosage form, but are usually 0.1 to 2000 mg, preferably 1 to 200 mg per day for an adult once or several times (for example, 2 to 2). (4 times) can be divided and administered.

  The production method and production intermediate of the present invention will be described in more detail with reference to the following examples and reference examples, but the present invention is not limited to these specific examples.

Reference Example 1-1
Synthesis of (2R) -N-benzyl-2-hydroxy-2- (3-pyridyl) acetamide To a solution of benzylamine (4.4 g) in tetrahydrofuran (78 g), (2R) -2-hydroxy- (3-pyridyl) Acetic acid / sulfate (10 g), triethylamine (5.6 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (11.5 g) and 1-hydroxybenzotriazole hydrate (8. 1 g) was added and stirred at 20-25 ° C. for 1 hour 35 minutes. Water (50 mL), saturated aqueous sodium hydrogen carbonate (50 mL) and ethyl acetate (200 mL) were added to the reaction mixture, and the mixture was partitioned and extracted. The aqueous layer was further partitioned and extracted with ethyl acetate. The organic layers were combined, washed with 10% brine and saturated brine, and dried over anhydrous sodium sulfate. After filtration, 2-propanol (29 g) was added to the crude product obtained by distilling off the solvent, and the mixture was stirred at 80 ° C. for 30 minutes, then cooled to 50 ° C., seed crystals were added, and the mixture was stirred for 1 hour and 25 minutes. . The mixture was further cooled to 20 to 25 ° C., n-heptane (116 g) was added dropwise, the mixture was further cooled to 0 ° C., and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (9.3 g, yield 96%). Got.
¹ H-NMR (CDCl ₃ ) δ: 8.55 (1H, d, J = 2.2 Hz), 8.42 (1H, dd, J = 4.9, 1.6 Hz), 7.83 (1H, ddd, J = 7.9, 2.2, 1.6 Hz), 7.15-7.33 (7H, m), 5.13 (1H, s), 4.39-4.48 (2H, m ).

Reference Example 1-2
Synthesis of (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride (2R) -N-benzyl-2-hydroxy-2- (3-pyridyl) acetamide (18. To a solution of 76 g, 77.4 mmol) in tetrahydrofuran (190 mL), a 2 mol / L borane-dimethyl sulfide complex tetrahydrofuran solution (232 mL) was added dropwise over 40 minutes under ice cooling, and the mixture was heated to reflux for 30 minutes. The reaction solution was brought to 50 ° C., 10% hydrochloric acid methanol solution (263 mL) was added dropwise over 20 minutes, and the mixture was heated to reflux for 1 hour. The mixture was allowed to stand overnight at 20 to 25 ° C., and the precipitated crystals were collected by filtration and dried under reduced pressure to obtain the title compound (16.20 g, 53.8 mmol, 69%).
¹ H-NMR (DMSO-d ₆ ) δ: 9.77 (1H, brs), 9.62 (1H, brs), 8.89 (1H, d, J = 1.4 Hz), 8.85 (1H , D, J = 5.6 Hz), 8.52 (1H, d, J = 8.0 Hz), 8.01 (1H, dd, J = 8.0, 5.6 Hz), 7.59-7. 63 (2H, m), 7.36-7.45 (3H, m), 5.38 (1H, dd, J = 8.4, 3.2 Hz), 4.21 (2H, s), 3. 28-3.31 (1H, m), 3.11-3.13 (1H, m).
In the following Reference Examples and Examples, when used in a free form, (1R) -2-benzylamino-1- (3-pyridyl) ethanol can be obtained by freezing the above hydrochloride by a known method. it can.

Reference Example 1-3
Synthesis of (2R) -N-benzyl-2-triethylsilyloxy-2- (3-pyridyl) ethylamine (1R) -2-benzylamino-1- (3-pyridyl) ethanol dihydrochloride under nitrogen atmosphere ( To an N, N-dimethylformamide (5 mL) solution of 600 mg, 1.99 mmol), imidazole (814 mg, 12.0 mmol) was added at 20 to 25 ° C., and triethylsilane chloride (1.34 mL, 7.97 mmol) was added dropwise. The mixture was stirred at 20 to 25 ° C. for 2 hours and 45 minutes. The reaction mixture was poured into water (6 mL), and toluene (6 mL) and saturated aqueous sodium bicarbonate (1.4 mL) were added for partition extraction. The aqueous layer was further partitioned and extracted twice with toluene (6 mL). The organic layers were combined, washed twice with saturated aqueous sodium hydrogen carbonate (1.4 mL) -5% brine (6 mL), twice with 5% brine (6 mL), and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 1: 1 → 0: 1 → saturated ammonia chloroform-methanol = 10: 1). The title compound (571 mg, 1.67 mmol, 84% yield) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.57 (1H, dd = 2.1 Hz), 8.51 (1H, dd, J = 4.8, 1.7 Hz), 7.67 (1H, ddd, J = 7.8, 2.1, 1.7 Hz), 7.21-7.34 (6H, m), 4.87 (1H, dd, J = 7.7, 4.2 Hz), 3 .83 (1H, d, J = 13.5 Hz), 3.79 (1H, d, J = 13.5 Hz), 2.84 (1H, dd, J = 12.0, 7.7 Hz), 2. 74 (1H, dd, 12.0, 4.2 Hz), 0.87 (9H, t, J = 7.9 Hz), 0.46-0.61 (6H, m).

Example 1-1
Synthesis of N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl] -N-[(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide (1)
Under a nitrogen atmosphere, (2R) -N-benzyl-2-triethylsilyloxy-2- (3-pyridyl) ethylamine (2.5 g, 7.30 mmol) in a N, N-dimethylformamide (50 mL) solution (7 -(Benzyloxy) -1H-indol-3-yl) acetic acid (2.26 g, 8.03 mmol), 1-hydroxybenzotriazole (1.39 g, 9.11 mmol), 1-ethyl-3- (3-dimethyl) Aminopropyl) carbodiimide hydrochloride (1.75 g, 9.11 mmol) was added and stirred at 20-25 ° C. for 15 hours. The reaction mixture was poured into water and extracted twice with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was dissolved in tetrahydrofuran (50 mL), 2M aqueous hydrochloric acid (20 mL) was added, and the mixture was stirred at 20 to 25 ° C. for 5 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate-methanol = 10: 1) to give the title compound (3.39 g, 6.90 mmol, yield). 95%) was obtained as white crystals.
¹ H-NMR (CDCl ₃ ) δ: 8.46 (1H, dd, J = 4.8, 1.6 Hz), 8.43 (1H, brs), 8.39 (1H, d, J = 2. 1 Hz), 7.60 (1H, ddd, J = 7.9, 2.1, 1.6 Hz), 7.47-7.49 (2H, s), 7.32-7.43 (6H, m), 7.20 (1H, d, J = 8.1 Hz), 7.14 (1H, dd, J = 7.9, 4.8 Hz), 7.06-7.11 (3H, m) 7.04 (1H, dd, J = 8.1, 7.7 Hz), 5.22 (2H, s), 4.90 (1H, dd, J = 8.0, 2.4 Hz), 4 .65 (1H, d, J = 16.7 Hz), 4.26 (1 H, d, J = 16.7 Hz), 3.89 (2H, s), 3.79 (1 H, dd, J = 14. 5, 8.0 Hz), 3.49 ( 1H, dd, J = 14.5, 2.4 Hz).

Example 1-2
Synthesis of N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl] -N-[(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide (2)
Under a nitrogen atmosphere, a solution of (1R) -2-benzylamino-1- (3-pyridyl) ethanol (5.00 g, 21.90 mmol) in N, N-dimethylformamide (50 mL) was added to 1-hydroxybenzotriazole (1 .68 g, 12.4 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.05 g, 26.28 mmol) was added, and 7- (benzyloxy) -1H-indole was further added. A solution of -3-yl) acetic acid (6.47 g, 23.00 mmol) in N, N-dimethylformamide (10 mL) was added dropwise and stirred at 20-25 ° C. for 15 hours. Ethyl acetate and 20% aqueous sodium hydroxide solution were added to the reaction solution, and the mixture was partitioned. The aqueous layer was further partitioned and extracted with ethyl acetate. The organic layers were combined and washed with 5% brine. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), seed crystals were added, and the mixture was stirred for 2 and a half hours under ice cooling. Further heptane (50 mL) was added dropwise, and the mixture was stirred for 30 minutes under ice cooling. The crystals were collected by filtration and dried under reduced pressure to give the title compound (8.14 g, 16.6 mmol, yield 76%).

Example 1-3
Synthesis of (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol (1)
Under a nitrogen atmosphere, a suspension of lithium aluminum hydride (155 mg, 4.08 mmol) in tetrahydrofuran (2 mL) was charged with N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl] -N—. A solution of [(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide (500 mg, 1.02 mmol) in tetrahydrofuran (10 mL) was added dropwise over 15 minutes, and the mixture was stirred at 20 to 25 ° C. for 3 hours. Under ice-cooling, water (155 μL), 15% aqueous sodium hydroxide solution (155 μL) and water (465 μL) were sequentially added to the reaction solution, and the mixture was stirred at 20 to 25 ° C. for 1 hour. The insoluble material was filtered off, and the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 1: 1) to give the title compound (403.2 mg, 0. 884 mmol, yield 83%).
¹ H-NMR (CDCl ₃ ) δ: 8.49-8.51 (2H, m), 8.23 (1H, brs), 7.61 (1H, dt, J = 7.9, 1.8 Hz) ), 7.46-7.49 (2H, m), 7.27-7.42 (8H, m), 7.21-7.25 (1H, m), 7.09 (1H, d, J) = 8.0 Hz), 6.99 (1H, dd, J = 8.0, 7.5 Hz), 6.95 (1H, d, J = 2.3 Hz), 6.71 (1H, d, J = 7.5 Hz), 5.20 (1 H, s), 4.64 (1 H, dd, J = 10.5, 3.6 Hz), 4.01 (1 H, d, J = 13.4 Hz), 3. 97 (1H, brs), 3.64 (1H, d, J = 13.4 Hz), 2.86-3.09 (4H, m), 2.75 (1H, dd, J = 12.8, 3 .6 Hz), 2.63 ( 1H, dd, J = 12.8, 10.5 Hz).

Example 1-4
Synthesis of (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol (2)
A suspension of lithium aluminum hydride (9.4 g, 247 mmol) and tetrahydrofuran (162 mL) was cooled to an internal temperature of 10 ° C., and N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl ] -N-[(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide (24.1 g, 49.0 mmol) in tetrahydrofuran (109 mL) was added dropwise at the same temperature over 1 hour and 38 minutes, The mixture was stirred and reacted at the same temperature for 5 hours and 45 minutes. Thereafter, the internal temperature was cooled to 0 ° C. The reaction mixture after cooling was dropped into ethyl acetate (72 mL) at an internal temperature of -14 to -1 ° C over 1 hour and 20 minutes. Then, it heated up to 40 degreeC of internal temperature, and stirred at the same temperature for 1 hour. To this, sodium sulfate (78 g) and water (71 mL) were added and stirred at an internal temperature of 25 ° C., and the insoluble material was filtered off. To the obtained filtrate, toluene (270 mL), water (68 mL) and 35 wt% hydrochloric acid (27 g) were added at an internal temperature of 40 ° C., followed by liquid separation treatment to obtain an organic layer and an aqueous layer. The organic layer was further extracted with 3.6 wt% hydrochloric acid (27 g), and the resulting aqueous layer was combined with the previously obtained aqueous layer. Toluene (202 mL) and tetrahydrofuran (202 mL) were added to the combined aqueous layer, and 15 wt% aqueous sodium hydroxide solution (74 g) was added dropwise at an internal temperature of 40 ° C. to adjust the pH to 6.8, followed by liquid separation treatment. Thus, an organic layer and an aqueous layer were obtained. The aqueous layer was further extracted with toluene (81 mL), and the resulting toluene layer was combined with the previously obtained organic layer. The combined organic layer was concentrated to 261 g. Activated carbon (2.7 g) was added to the concentrated residue, and the temperature was raised to an internal temperature of 65 ° C. After adding n-heptane (216 mL) to this, insoluble matter was filtered off at the same temperature, and the insoluble matter was washed with a mixed solution of toluene (17 mL) and n-heptane (17 mL). The obtained filtrate and washings were cooled to an internal temperature of 50 ° C., seed crystals were added, and the mixture was stirred at the same temperature for 1 hour and 15 minutes. Furthermore, it cooled over 20 hours and 15 minutes to internal temperature 0 degreeC, and n-heptane (108 mL) was dripped over 1 hour and 30 minutes at the same temperature. The mixture was further stirred and maintained at the same temperature for 2 hours, and the precipitated crystals were collected by filtration, washed and dried to obtain the title compound (18.3 g, 38.3 mmol, yield 78%).

Example 1-5
Synthesis of (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol mono-oxalate under nitrogen atmosphere To a suspension of lithium aluminum hydride (367 mg, 9.67 mmol) in tetrahydrofuran (5 mL) at 20-25 ° C., N-benzyl-2- [7- (benzyloxy) -1H-indol-3-yl] -N -A solution of [(2R) -2-hydroxy-2-pyridin-3-ylethyl] acetamide (1.19 g, 2.42 mmol) in tetrahydrofuran (25 mL) was added dropwise over 30 minutes. Stir at 20-25 ° C. Under ice-cooling, water (367 μL), 15% aqueous sodium hydroxide solution (367 μL) and water (1.10 mL) were successively added dropwise to the reaction solution, and the temperature was raised to 20 to 25 ° C. and stirred for 1 hour. The insoluble material was filtered off, and the solvent was distilled off. The residue was partitioned and extracted with toluene and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with 5% aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, a solution of oxalic acid (217 mg, 2.41 mmol) in ethyl acetate (5 mL) was added, and the precipitate was collected by filtration and dried to give the title compound (1.02 g, 1.80 mmol, 74% yield). It was.
¹ H-NMR (DMSO-d ₆ ) δ: 10.96 (1H, brs), 8.52 (1H, d, J = 2.0 Hz), 8.48 (1H, dd, J = 4.8, 1.6 Hz), 7.70 (1H, ddd, J = 7.8, 2.0, 1.6 Hz), 7.54-7.56 (2H, m), 7.20-7.42 (8H) M), 7.04 (1H, brs), 6.99 (1H, d, J = 7.9 Hz), 6.84 (1H, dd, J = 7.9, 7.5 Hz), 6.71 (1H, d, J = 7.5 Hz), 5.24 (2H, s), 4.89 (1H, m), 4.10 (2H, brs), 2.95 (6H, m).

Example 1-6
Synthesis of 3- (2- {benzyl [(2R) -2-hydroxy-2-pyridin-3-ylethyl] amino} ethyl) -1H-indol-7-ol (1)
(1R) -2- (Benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol mono-oxalate (837 mg, 1.48 mmol ) In methanol-tetrahydrofuran (1: 1, 30 mL), potassium carbonate (614 mg, 4.44 mmol) and 10% palladium carbon (50% water, 80 mg) were added, and the mixture was heated at 20-25 ° C. under a hydrogen atmosphere. Stir for hours. A 0.5 M phosphate buffer solution (pH 6.86, 30 mL) was added to the reaction solution, followed by filtration through celite. Tetrahydrofuran and methanol in the filtrate were distilled off, followed by partition extraction with ethyl acetate twice. The organic layer was washed with 5% brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated to give the title compound (562 mg, 1.45 mmol, yield 98%).
¹ H-NMR (CDCl ₃ ) δ: 8.48 (1H, dd, J = 4.8, 1.6 Hz), 8.37 (1H, d, J = 1.9 Hz), 8.30 (1H, brs), 7.59 (1H, ddd, J = 7.8, 1.9, 1.6 Hz), 7.26-7.35 (5H, m), 7.23 (1H, dd, J = 7). .8, 4.8 Hz), 7.07 (1H, d, J = 8.0 Hz), 6.98 (1H, s), 6.91 (1H, dd, J = 8.0, 7.4 Hz) ), 6.58 (1H, d, J = 7.4 Hz), 4.59 (1H, dd, J = 10.3, 3.6 Hz), 3.99 (1H, d, J = 13.5 Hz) 3.65 (1H, d, J = 13.5 Hz), 2.88-3.07 (4H, m), 2.72 (1H, dd, J = 12.8, 3.6 Hz), 2. 58 (1H, dd, J = 2.8,10.3Hz).

Example 1-7
Synthesis of 3- (2- {benzyl [(2R) -2-hydroxy-2-pyridin-3-ylethyl] amino} ethyl) -1H-indol-7-ol (2)
Under a nitrogen atmosphere, (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol (50.7 mg, 0 .106 mmol) in acetonitrile (4 mL) was added trimethylsilyl iodine (75.5 μL, 0.530 mmol), and the mixture was stirred at 40 ° C. for 1 hour. To the reaction solution was added 1M aqueous hydrochloric acid (2 mL), and the mixture was further stirred for 15 minutes. The reaction solution was poured into saturated aqueous sodium hydrogen carbonate, and partitioned and extracted with ethyl acetate, washed with 5% aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (saturated ammonia chloroform solution → saturated ammonia chloroform solution-methanol = 50: 1 → 20: 1 → 10: 1), The title compound (26.8 mg, 0.0692 mmol, yield 65%) was obtained.

Example 1-8
(1R) -2- [Benzyl (2- {7-[(1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy] -1H-indol-3-yl} ethyl) amino]- Synthesis of 1-pyridin-3-ylethanol (1)
Of 3- (2- {benzyl [(2R) -2-hydroxy-2-pyridin-3-ylethyl] amino} ethyl) -1H-indol-7-ol (73.0 mg, 0.188 mmol) under nitrogen atmosphere. To a solution of N, N-dimethylformamide (1 mL), (1R) -1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonate (64.9 mg, 0.207 mmol) and cesium carbonate (92.0 mg, 0.282 mmol) was added, and the mixture was stirred at 20 to 25 ° C. for 2 hours. The reaction solution was poured into saturated aqueous ammonium chloride-water (1: 1) and extracted twice with ethyl acetate. The organic layer was washed with 5% brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (chloroform → saturated ammonia chloroform) to obtain the title compound (71.1 mg, 0.134 mmol, yield 72%). .
¹ H-NMR (CDCl ₃ ) δ: 8.49-8.51 (3H, m), 7.61 (1H, ddd, J = 7.9, 2.0, 1.6 Hz), 7.28- 7.36 (5H, m), 7.24 (1H, dd, J = 7.9, 4.9 Hz), 7.11 (1H, d, J = 8.0 Hz), 6.94-6. 98 (2H, m), 6.63 (1H, d, J = 7.7 Hz), 5.12 (1H, q, J = 6.7 Hz), 4.63 (1H, dd, J = 10.4) 3.5 Hz), 4.00 (1H, d, J = 13.4 Hz), 3.64 (1 H, d, J = 13.4 Hz), 3.53-3.63 (6H, m), 3 .45-3.50 (1H, m), 3.36-3.41 (1H, m), 2.81-3.07 (4H, m), 2.75 (1H, dd, J = 12. 8, 3.5 Hz).

Example 1-9
(1R) -2- [Benzyl (2- {7-[(1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy] -1H-indol-3-yl} ethyl) amino]- Synthesis of 1-pyridin-3-ylethanol (2)
Of (1R) -2- (benzyl {2- [7- (benzyloxy) -1H-indol-3-yl] ethyl} amino) -1-pyridin-3-ylethanol (5.9 g, 12.4 mmol) To a mixed solution of methanol (12 mL) and N, N-dimethylformamide (8.9 mL), potassium carbonate (8.7 g, 62.8 mmol) and 10% palladium carbon (50% moisture, 0.6 g) are added, and hydrogen is added. After stirring for 3 hours at 0 to 5 ° C. in an atmosphere, the insoluble matter was filtered off. To the filtrate, cesium carbonate (6.1 g, 18.8 mmol), N, N-dimethylformamide (51 mL), (1R) -1-methyl-2-morpholin-4-yl-2-oxoethyl 4-methylbenzenesulfonic acid ester (4.7 g, 15.1 mmol) was added, and the mixture was stirred at an internal temperature of 15 to 18 ° C. for 5.5 hours. The reaction solution was added to a mixed solution of toluene (60 mL) and 10 wt% hydrochloric acid (30 g) at an internal temperature of 0 to 5 ° C., followed by liquid separation treatment, and the resulting aqueous layer was further washed with toluene (30 mL). Ethyl acetate (60 mL) was added to the aqueous layer, and 15 wt% aqueous sodium hydroxide solution (13.9 g) was added dropwise at an internal temperature of 0 ° C. to adjust the pH to 8.8, followed by heating to 40 ° C. and liquid separation treatment. An organic layer and an aqueous layer were obtained. The aqueous layer was further extracted twice with ethyl acetate (30 mL), and the obtained organic layer was combined with the previously obtained organic layer. N, N-dimethylformamide (18 mL) was added to the combined organic layer, and then concentrated to 36.6 g. The concentrated residue was heated to 40 ° C., water (30 mL) and seed crystals were added, then cooled to an internal temperature of 0 ° C. over 2 hours and 5 minutes, and stirred at the same temperature for 2 hours. Water (30 mL) was further added, and the mixture was stirred for 2 hr. The precipitated crystals were collected by filtration, washed and dried to give the title compound (4.9 g, 9.31 mmol, yield: 75%).

Reference Example 1-4
(1R) -2-((2- (7-((1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy) -1H-indol-3-yl) ethyl) amino) -1 Synthesis of Pyridin-3-ylethanol (1R) -2- [Benzyl (2- {7-[(1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy] -1H-indole- 3-yl} ethyl) amino] -1-pyridin-3-ylethanol (71.1 mg, 0.134 mmol) in methanol (2 mL) was added 20% palladium hydroxide on carbon (10 mg) under a hydrogen atmosphere. , And stirred at 40 degrees for 9 hours. The reaction solution was filtered through Celite, and the solvent was distilled off to obtain the title compound (51.6 mg, 0.118 mmol, yield 88%).
¹ H-NMR (CDCl ₃ ) δ: 8.83 (brs, 1H), 8.85 (d, 1H, J = 1.8 Hz), 8.49 (dd, 1H, J = 4.8, 1. 3 Hz), 7.69 (d, 1 H, J = 7.9 Hz), 7.23-7.26 (m, 2 H), 7.01 (d, 1 H, J = 1.8 Hz), 6.99 ( dd, 1H, J = 8.0, 7.7 Hz), 6.63 (d, 1H, J = 7.7 Hz), 5.15 (q, 1H, J = 6.6 Hz), 4.70 (dd , 1H, J = 9.3, 3.4 Hz), 3.41-3.61 (m, 8H), 2.94-3.08 (m, 4H), 2.93 (dd, 1H, J = 12.2, 3.4 Hz), 2.69 (dd, 1H, J = 12.2, 9.3 Hz), 1.65 (d, 3H, J = 6.6 Hz).

Reference Example 2-1
Synthesis of N-((7-benzyloxy) -1H-indol-3-yl) methyl) -N, N-dimethylamine Under nitrogen atmosphere, 40% dimethylamine aqueous solution (7.88 g, 69.9 mmol) and 37% To a solution of formaldehyde aqueous solution (5.92 g, 72.9 mmol) in acetic acid (70 mL), 7- (benzyloxy) -1H-indole (14.2 g, 63.6 mmol) was added at 0 ° C. Stir for 3.5 hours. Water was added to the reaction solution, which was washed with diethyl ether. The aqueous layer was adjusted to pH 12 with 3N aqueous sodium hydroxide solution and partitioned and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous potassium carbonate. After filtration, the crude product obtained by distilling off the solvent was dissolved in ethyl acetate (100 mL), crystallized by adding n-hexane (100 mL), and collected by filtration to give N-((7-benzyl). Oxy) -1H-indol-3-yl) methyl) -N, N-dimethylamine (14.3 g, 50.9 mmol, yield 80%) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.35 (1H, brs), 7.47-7.49 (2H, m), 7.35-7.43 (3H, m), 7.32 (1H , D, J = 8.0 Hz), 7.10 (1H, d, J = 2.3 Hz), 7.03 (1H, dd, J = 7.9, 7.7 Hz), 6.73 (1H, d, J = 7.7 Hz), 5.20 (2H, s), 3.61 (2H, s), 2.27 (6H, s).

Reference Example 2-2
Synthesis of (7- (benzyloxy) -1H-indol-3-yl) acetonitrile Under nitrogen atmosphere, N-((7-benzyloxy) -1H-indol-3-yl) methyl) -N, N-dimethylamine A solution of potassium cyanide (13.2 g, 202.7 mmol) in water (25 ml) was added to a solution of (14.2 g, 50.6 mmol) in N, N-dimethylformamide (150 mL), and after cooling with ice, methyl iodide (34. 5 g, 243.1 mmol) was added dropwise, and the mixture was stirred at 20 to 25 ° C. for 14 hours. The reaction solution was poured into water and partitioned and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 2: 1) to give (7- (benzyloxy) -1H-indole-3. -Yl) acetonitrile (12.0 g, 45.7 mmol, 90% yield) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.42 (1H, brs), 7.46-7.48 (2H, m), 7.34-7.43 (3H, m), 7.19-7 .21 (2H, m), 7.08 (1H, t, J = 7.9 Hz), 7.68 (1H, d, J = 7.7 Hz), 5.21 (2H, s), 3.83 (2H, d, J = 0.84 Hz).

Reference Example 2-3
Synthesis of (7- (benzyloxy) -1H-indol-3-yl) acetic acid Under a nitrogen atmosphere, (7- (benzyloxy) -1H-indol-3-yl) acetonitrile (13.2 g, 50.3 mmol) A 10N aqueous sodium hydroxide solution (130 mL) was added to the methanol (400 mL) suspension, and the mixture was heated to reflux for 5 hours. The reaction solution was returned to 20-25 ° C, methanol alone was distilled off, and the pH was adjusted to 1 with concentrated hydrochloric acid while cooling with ice. The resulting precipitate was collected by filtration, and the product on the filter was dissolved in chloroform and dried over anhydrous sodium sulfate. After filtration, the solvent was distilled off to obtain (7- (benzyloxy) -1H-indol-3-yl) acetic acid (12.2 g, 43.4 mmol, yield 86%).
¹ H-NMR (DMSO-d ₆ ) δ: 12.09 (1H, brs), 11.04 (1H, s), 7.55-7.57 (2H, m), 7.39-7.42 (2H, m), 7.31-7.35 (1H, m), 7.14 (1H, d, J = 2.4 Hz), 7.09 (1H, d, J = 7.9 Hz), 6 .88 (1H, dd, J = 7.9, 7.6 Hz), 6.73 (1H, d, J = 7.6 Hz), 5.26 (2H, s), 3.61 (2H, s) .

Reference Example 2-4
Synthesis of 2- (7- (benzyloxy) -1H-indol-3-yl) ethanol Under a nitrogen atmosphere, (7- (benzyloxy) -1H-indol-3-yl) acetic acid (7.21 g, 27.4 mmol) ) In tetrahydrofuran (150 mL) was added 1M borane / tetrahydrofuran complex tetrahydrofuran solution (55 ml, 55 mmol), and the mixture was stirred at 20 to 25 ° C. for 17 hours. Methanol (100 mL) was added to the reaction solution, and the mixture was stirred at 20 to 25 ° C. for 1 hour, and the solvent was distilled off. The obtained crude product was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 2: 1 → 1: 1) to give 2- (7- (benzyloxy) -1H-indol-3-yl. ) Ethanol (6.37 g, 23.8 mmol, 87% yield) was obtained.
¹ H-NMR (CDCl ₃ ) δ: 8.31 (1H, s), 7.47-7.49 (2H, m), 7.34-7.43 (3H, m), 7.24 (1H , D, J = 8.1 Hz), 7.06 (1H, d, J = 3.2 Hz), 7.03 (1H, dd, J = 8.1, 7.7 Hz), 6.74 (1H, dJ = 7.7 Hz), 5.21 (2H, s), 3.90 (2H, td, J = 6.3, 5.3 Hz), 3.03 (2H, t, J = 6.3 Hz), 1.48 (1H, t, J = 5.3 Hz).

Reference Example 2-5
Synthesis of 3- (2-azidoethyl) -7- (benzyloxy) -1H-indole 2- (7- (benzyloxy) -1H-indol-3-yl) ethanol (1.65 g, 6. To a solution of 17 mmol) in dichloromethane (20 mL), triethylamine (1.72 mL, 12.3 mmol) and methanesulfonyl chloride (0.6 mL, 7.78 mmol) were added and stirred at 20-25 ° C. for 16 hours. The reaction solution was poured into water and partitioned and extracted with chloroform. The organic layer was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was dissolved in N, N-dimethylformamide (20 mL), sodium azide (1.00 g, 15.4 mmol) was added, and the mixture was reacted at 60 ° C. for 3 hours. . The reaction solution was poured into water and partitioned and extracted with ethyl acetate. The organic layer was washed successively with 1N aqueous hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 10: 1 → 3: 1 → 1: 1) to give the title compound (1.52 g Yield 84%).
¹ H-NMR (CDCl ₃ ) δ: 3.05 (2H, t, J = 7.2 Hz), 3.56 (2H, t, J = 7.2 Hz), 5.20 (2H, s), 6 .74 (1H, d, J = 7.7 Hz), 7.02-7.06 (2H, m), 7.21 (1H, d, J = 8.0 Hz), 7.34-7.43 ( 3H, m), 7.47-7.49 (2H, m), 8.42 (1H, brs).

Reference Example 2-6
Synthesis of 2- (7- (benzyloxy) -1H-indol-3-yl) ethylamine Under nitrogen atmosphere, 3- (2-azidoethyl) -7- (benzyloxy) -1H-indole (5.10 g, 17. 4 mmol) in pyridine (100 mL) -water (100 mL) was added triphenylphosphine (5.02 g, 19.1 mmol) and stirred at 20-25 ° C. for 18 hours. The reaction solution was poured into water and partitioned and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (saturated ammonia chloroform solution → saturated ammonia chloroform solution-methanol = 50: 1 → 10: 1) to give the title compound (4. 38 g, yield 95%).
¹ H-NMR (CDCl ₃ ) δ: 2.89 (2H, t, J = 6.8 Hz), 3.02 (2H, t, J = 6.8 Hz), 5.21 (2H, s), 6 .73 (1H, d, J = 7.7 Hz), 7.01 (1H, d, J = 2.1 Hz), 7.02 (1H, dd, J = 8.0, 7.7 Hz), 7. 24 (1H, d, J = 8.0 Hz), 7.34-7.43 (3H, m), 7.47-7.49 (2H, m), 8.29 (1H, brs).

Reference Example 2-7
Synthesis of (2R) -N- (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) -2-hydroxy-2-pyridin-3-ylacetamide 2- (7- (benzyloxy ) -1H-Indol-3-yl) ethylamine (11.1 g, 41.7 mmol) in N, N-dimethylformamide (300 mL) with stirring at 20-25 ° C. under (R) -2-hydroxy-2- ( 3-pyridyl) acetic acid / sulfate (12.6 g, 50 mmol), triethylamine (20 mL, 143 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride (10.0 g, 52.1 mmol), And 1-hydroxybenzotriazole (7.04 g, 52.1 mmol) were sequentially added, and the mixture was stirred at 20 to 25 ° C. for 14 hours. The reaction mixture was diluted with a 1: 1 mixture of saturated aqueous sodium hydrogen carbonate and water, and extracted three times with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate → ethyl acetate-methanol = 10: 1) to obtain the title compound (11.5 g, yield 69%).
¹ H-NMR (CDCl ₃ ) δ: 2.82-2.97 (2H, m), 3.54-3.65 (2H, m), 4.99 (1H, s), 5.20 (2H , S), 6.37 (1H, t, J = 5.3 Hz), 6.73 (1H, d, J = 7.6 Hz), 6.80 (1H, d, J = 2.2 Hz), 7 .02 (1H, dd, J = 8.0, 7.6 Hz), 7.16 (1H, d, J = 8.0 Hz), 7.22 (1H, dd, J = 7.9, 4.8 Hz) ), 7.33-7.42 (3H, m), 7.47-7.49 (2H, m), 7.65 (1H, dt, J = 7.9, 1.8 Hz), 8.44. (1H, brs), 8.47 (1H, dd, J = 4.8, 1.6 Hz), 8.52 (1H, d, J = 2.1 Hz).

Reference Example 2-8
Synthesis of tert-butyl (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) ((2R) -2-hydroxy-2-pyridin-3-ylethyl) carbamate (2R) -N- To a solution of (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) -2-hydroxy-2-pyridin-3-ylacetamide (32.6 g, 81.2 mmol) in tetrahydrofuran (650 mL) 2M borane dimethyl sulfide complex tetrahydrofuran solution (122 mL, 244 mmol) was added and heated to reflux for 4 hours. A 10% hydrochloric acid methanol solution (200 mL) was added to the reaction solution, and the mixture was heated to reflux for 1 hour, and the solvent was distilled off. The residue was partitioned by adding saturated aqueous sodium bicarbonate and chloroform. The organic layer was washed with saturated brine and dried over sodium sulfate. After filtration, the solvent was distilled off to obtain a reduced product.
The obtained reduced product was dissolved in tetrahydrofuran (520 mL), di-tert-butyl dicarbonate (17.5 mL, 76.2 mmol) was added at 20 to 25 ° C., and the mixture was stirred as it was for 1 hour. A 70% ethylamine aqueous solution (10 mL) was added, and the mixture was further stirred at 20 to 25 ° C. for 1 hour, and then saturated sodium bicarbonate water was added for partition extraction. The aqueous layer was further partitioned and extracted with ethyl acetate, and the organic layers were combined and washed with saturated brine. The organic layer is dried over anhydrous magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography (hexane-ethyl acetate = 1: 1 → 1: 3) to give the title compound (20.0 g, 41.1 mol, yield 51%) was obtained.
IR (ATR (total reflection absorption method) / FT-IR, cm ⁻¹ ): 3320, 1670, 1577, 1411, 1365, 1257, 1226, 1161, 1045, 1026.

Reference Example 2-9
of tert-butyl (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) ((2R) -2-pyridin-3-yl-2-((triethylsilyl) oxy) ethyl) carbamate Synthesis Under a nitrogen atmosphere, tert-butyl (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) ((2R) -2-hydroxy-2-pyridin-3-ylethyl) carbamate (20. 0 g, 41.1 mmol) in a solution of N, N-dimethylformamide (200 mL) was added imidazole (3.50 g, 51.4 mmol) and triethylsilane chloride (8.74 mL, 51.4 mmol), and 20-25 ° C. For 2 hours. The reaction solution was poured into water and partitioned and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 5: 1 → 3: 1) to give the title compound (23.6 g, yield 95). %).
IR (ATR (total reflection absorption method) / FT-IR, cm ⁻¹ ): 1685, 1577, 1454, 1408, 1365, 1230, 1164, 1087.

Reference Example 2-10
Synthesis of tert-butyl (2- (7-hydroxy-1H-indol-3-yl) ethyl) ((2R) -2-pyridin-3-yl-2-((triethylsilyl) oxy) ethyl) carbamate tert- Butyl (2- (7- (benzyloxy) -1H-indol-3-yl) ethyl) ((2R) -2-pyridin-3-yl-2-((triethylsilyl) oxy) ethyl) carbamate (12. 8 g, 21.3 mmol) in methanol (130 mL) was added with phosphate standard buffer (pH 6.86, 13 mL) and 10% palladium carbon (50% wet, 12 g), and at 20-25 ° C. under hydrogen atmosphere. Stir for 1.5 hours. The reaction solution was filtered through Celite, and the solvent of the filtrate was distilled off under reduced pressure. Water and ethyl acetate were added to the residue for partitioning, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the crude product obtained by distilling off the solvent was separated and purified by silica gel column chromatography (n-hexane-ethyl acetate = 3: 1 → 3: 2) to give the title compound (8.37 g, yield 77). %).
IR (ATR (total reflection absorption method) / FT-IR, cm ⁻¹ ): 3340, 1670, 1577, 1473, 1457, 1411, 1365, 1238, 1161, 1088.

Reference Example 2-11
(1R) -2-((2- (7-((1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy) -1H-indol-3-yl) ethyl) amino) -1 Synthesis of -pyridin-3-ylethanol tert-butyl (2- (7-hydroxy-1H-indol-3-yl) ethyl) ((2R) -2-pyridin-3-yl-2-((triethylsilyl)) To a solution of (oxy) ethyl) carbamate (10.0 g, 19.6 mmol) in N, N-dimethylformamide (150 mL), potassium carbonate (8.13 g, 58.8 mmol), (1R) -1-methyl-2-morpholine. -4-yl-2-oxoethyl 4-methylbenzenesulfonate (see JP 2000-273085 A) (7.68 g, 24.5 mmol) was added, and 70 In the mixture was stirred for 1 hour. After standing to cool, the reaction solution was poured into water and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate = 3/1 to 0/1). , Tert-butyl (2- (7-((1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy) -1H-indol-3-yl) ethyl) ((2R) -2- Pyridin-3-yl-2-((triethylsilyl) oxy) ethyl) carbamate (8.91 g) was obtained.
Furthermore, tert-butyl (2- (7-((1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy) -1H-indol-3-yl) ethyl) ((2R) -2 To a 1,4-dioxane solution (100 mL) of 4-pyridin-3-yl-2-((triethylsilyl) oxy) ethyl) carbamate (8.91 g), 4N hydrochloric acid / 1,4-dioxane solution (75 mL, 300 mmol) ) Was added and stirred at 20-25 ° C. for 14 hours. The solvent in the reaction solution was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was partitioned and extracted three times with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was obtained by silica gel column chromatography (saturated ammonia chloroform solution). / Methanol = 100/1 to 100/4) to give the title compound (12.9 g, yield 66%).
¹ H-NMR (CDCl ₃ ) δ: 1.65 (3H, d, J = 6.6 Hz), 2.69 (1H, dd, J = 12.2, 9.3 Hz), 2.93 (1H, dd, J = 12.2, 3.4 Hz), 2.94-3.08 (4H, m), 3.41-3.61 (8H, m), 4.70 (1H, dd, J = 9) .3, 3.4 Hz), 5.15 (1H, q, J = 6.6 Hz), 6.63 (1H, d, J = 7.7 Hz), 6.99 (1H, dd, J = 8. 0, 7.7 Hz), 7.01 (1 H, d, J = 1.8 Hz), 7.23-7.26 (2 H, m), 7.69 (1 H, d, J = 7.9 Hz), 8.49 (1H, dd, J = 4.8, 1.3 Hz), 8.55 (1H, d, J = 1.8 Hz), 8.83 (1H, brs).

Reference Example 2-12
Synthesis of (2S) -2-((3- (2-(((2R) -2-hydroxy-2-pyridin-3-ylethyl) amino) ethyl) -1H-indol-7-yl) oxy) propanoic acid
(1R) -2-((2- (7-((1S) -1-methyl-2-morpholin-4-yl-2-oxoethoxy) -1H-indol-3-yl) ethyl) amino) -1- Tetrahydrofuran (30 mL) and 2N lithium hydroxide (30 mL) were added to a methanol (30 mL) solution of pyridin-3-ylethanol (5.63 g, 12.8 mmol), and the mixture was stirred at 20 to 25 ° C. for 2 hours. 1N hydrochloric acid was added to the reaction solution at 0 ° C. to neutralize it, and a phosphate standard buffer solution (pH 6.8, 10 mL) was added. The mixture was concentrated under reduced pressure, further toluene added, and azeotroped. Water was added to the residue, and the precipitate was collected by filtration and dried under reduced pressure to give the title compound (4.17 g, yield 88%).
¹ H-NMR (DMSO-d ₆ ) δ: 1.55 (3H, d, J = 6.6 Hz), 2.60-2.90 (5H, m), 3.02 (1H, dd, J = 12.3, 3.3 Hz), 4.60 (1H, q, J = 6.6 Hz), 4.93 (1H, dd, J = 9.9, 3.3 Hz), 6.50 (1H, d) , J = 7.7 Hz), 6.70 (1H, dd, J = 7.9, 7.7 Hz), 6.78 (1H, d, J = 1.8 Hz), 6.91 (1H, d, J = 7.9 Hz), 7.38 (1H, dd, J = 7.7, 4.7 Hz), 7.79 (1H, ddd, J = 7.7, 1.8, 1.5 Hz), 8 .49 (1H, dd, J = 4.7, 1.5 Hz), 8.59 (1H, d, J = 1.8 Hz), 10.87 (1H, d, J = 1.6 Hz).

Compare the yield of Example 1-1 and Example 1-3 with 95% × 83% = 79% to the yield of Reference Example 2-7 to Reference Example 2-8 with 69% × 51% = 35%. Thus, it can be seen that the production method [1] of the present invention is an excellent production method with a high yield.
In addition, as shown in Examples 1-2 and 1-4 above, the compounds represented by the formulas (4) and (5) of the present invention are easily crystallized, and thus are easily purified. I know that there is.
Further, as shown in Examples 1-8 to 1-5 and Reference Example 2-11, the hydroxyl group bonded to the carbon atom to which the pyridine ring is bonded is protected and deprotected. It can be seen that it can be synthesized with good yield even without it.

The production method of the present invention is an advantageous production method with a high yield, and the compound of the present invention is an excellent intermediate which can be easily purified. Therefore, they are suitable for the production of a compound represented by the above formula (10) which is useful as a β3-adrenergic receptor stimulant.

Claims (7)

Formula (1):

(In the formula, R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ² represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a protecting group for a nitrogen atom, R ³ represents a protecting group for a hydroxyl group, and R ¹³ and R ¹⁴ are each independently , A hydrogen atom, or a substituted or unsubstituted alkyl group) and the formula (3):

(Wherein R ⁴ is absent, or is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl group, R ⁶ represents a hydrogen atom or a protecting group for a hydroxyl group, and R ⁸ represents a protecting group for an amino group. The compound represented by formula (1) is reacted with a compound represented by formula (3) as an acid halide or acid anhydride, and the compound represented by formula (1) is condensed as necessary. Deprotect, formula (4):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as described above. R ^6a represents a hydrogen atom or a hydroxyl-protecting group). Consisting of reducing the compound represented by formula (4) and then the formula (5):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ^6a , R ⁸ , R ¹³ and R ¹⁴ represent the same meaning as described above). The compound represented by formula (3) is represented by formula (3b):

The manufacturing method of Claim 1 which is a compound represented by these. Formula (4a):

(In the formula, R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ³ represents a hydroxyl-protecting group, and R ⁴ is absent, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, substituted or unsubstituted Represents an alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group, R ⁵ represents a hydrogen atom or a substituted or unsubstituted alkyl group, and R ¹³ and R ¹⁴ each independently represents a hydrogen atom. Or a substituted or unsubstituted alkyl group, and R ⁸ represents an amino-protecting group. Formula (4b):

(Wherein R ¹ , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹³ and R ¹⁴ have the same meaning as in claim 3). R ¹ and ^{R 4} are both absent, claim 3 or 4 compounds described. Formula (6):

(In the formula, R ¹ is not present, is present in one or more, the same or different, and is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected group. R ² represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a protecting group for a nitrogen atom, R ³ represents a protecting group for a hydroxyl group, and R ⁴ is absent or one Or a plurality, the same or different, each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkoxy group, a halogen atom, a protected hydroxyl group, or a protected amino group, and R ⁵ represents a hydrogen atom, or A substituted or unsubstituted alkyl group, R ⁸ represents an amino-protecting group, R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ each independently represents hydrogen; A compound represented by an atom or a substituted or unsubstituted alkyl group) is deprotected to obtain a compound represented by the formula (7):

(Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as described above), and then in the presence of a base ( 8):

(In the formula, R ⁹ represents a hydrogen atom or a substituted or unsubstituted alkyl group. R ¹⁰ is absent, or one or more, the same or different, and represents a substituted or unsubstituted alkyl group. X ¹ represents a leaving group), which is reacted with a compound represented by formula (9):

(Wherein R ¹ , R ² , R ⁴ , R ⁵ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ have the same meaning as described above). Compound production method. The compound represented by formula (6) is represented by formula (6b):

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁸ , R ¹¹ , R ¹² , R ¹³ , and R ¹⁴ represent the same meaning as in claim 6).
The manufacturing method of Claim 6 which is a compound represented by these.