JP2018095576A - Salt of isolated compound containing amide group, method for producing the same, and method for synthesizing amide compound using the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a salt of an isolated compound containing an amide group, a method for producing the same, and a method for synthesizing an amide compound using the same.SOLUTION: The present invention provides a salt of an isolated compound containing an amide group represented by formula (1) (M is an element belonging to group 1 in the periodic table; P is a first protective group of an amine represented by R1-O(C=O)-; Q is a second protective group of an amine represented by R2-(C=O)-; Rand Rindependently represent a substituted/unsubstituted hydrocarbon group).SELECTED DRAWING: None

Description

  The present specification relates to a salt of an isolated compound containing an amide group, a method for producing the salt, and a method for synthesizing an amide compound using the salt.

  As a method for introducing an acetamide group into an alkyl halide or alkyl sulfonate, a method in which a primary amine is synthesized by reduction after azidation and then acetylated is widely employed. In the above method, an explosive alkyl azide is routed as an intermediate product, and the number of steps is required, and there is room for improvement.

  The present inventors have heretofore introduced N-Cbz (benzyloxycarbonyl) -acetamide in a reaction system as a conventional method for introducing an acetamide group, and the resulting potassium salt is converted to trifluoromethanesulfonic acid ester. Have reported a method for nucleophilic substitution (Non-patent Document 1).

Sakai et al., J. Org. Chem. 2016, 81, 3799-3808

  However, the reaction of Non-Patent Document 1 needs to be performed under anhydrous and oxygen-free conditions. Furthermore, there is no known synthesis example in which a salt of a compound for introducing an acetamide group is isolated and used. The present specification provides a salt of an isolated compound containing an amide group into which an amide group can be easily introduced, a method for producing the same, and a method for synthesizing an amide compound using the same.

  As a simpler method for introducing an amide group, the present inventors have isolated and purified a salt of a compound containing an amide group rather than generating a salt of the compound containing an amide group in the reaction system. Various investigations were made. As a result, it was found that it is possible to easily synthesize and isolate a large amount of a salt of a compound containing an amide group. According to the present disclosure, the following means are provided.

（式中、Ｍは周期表１族に属する元素を示し、Ｐは以下の式（２）で表されるアミンの第１の保護基を示し、Ｑは以下の式（３）で表されるアミンの第２の保護基を示す。）

（式中、Ｒ^１、Ｒ^２は、それぞれ独立して置換基を有していてもよい炭化水素基を示す。）
（２）式（２）および（３）中のＲ^１、Ｒ^２が、それぞれ独立して、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基又は置換基を有していてもよいアラルキル基である、（１）に記載のアミド基を含む単離された化合物の塩。
（３）式（１）中のＰが、Ｃｂｚ（ベンジルオキシカルボニル）基、Ｂｏｃ（ｔｅｒｔ−ブトキシカルボニル）基、Ｔｒｏｃ（２，２，２−トリクロロエトキシカルボニル）基又はＡｌｌｏｃ（アリルオキシカルボニル）基である、（１）又は（２）に記載のアミド基を含む単離された化合物の塩。
（４）式（３）中のＲ^２が、炭素数１以上４以下のアルキル基である、（１）〜（３）のいずれかに記載のアミド基を含む単離された化合物の塩。
（５）（１）〜（４）のいずれかに記載のアミド基を含む単離された化合物の塩である、アミド基導入用試薬。
（６）（１）〜（４）のいずれかに記載のアミド基を含む単離された化合物の塩の製造方法であって、
以下の式（４）で表される化合物と、以下の式（５）で表される化合物を反応させて、

（式中、Ｒ^３は、ハロゲン原子又は-ＯＱを示す。）
以下の式（６）で表される化合物へ変換する工程と、

前記工程で得られた式（６）で表される化合物と、以下の式（７）で表される化合物を反応させる工程、

を備える製造方法。
（７）（１）〜（４）のいずれかに記載のアミド基を含む単離された化合物の塩と、電子求引基を有する化合物を反応させる工程、を備える、アミド基を含む単離された化合物の塩を用いたアミド化合物の合成方法。
（８）前記電子求引基は、ハロゲン原子、置換基を有していてもよいアルキルスルホニル基又は置換基を有していてもよいアリールスルホニル基である、（７）に記載の合成方法。 (1) A salt of an isolated compound containing an amide group represented by the following formula (1).

(In the formula, M represents an element belonging to Group 1 of the periodic table, P represents a first protecting group of an amine represented by the following formula (2), and Q is represented by the following formula (3). Represents the second protecting group of the amine.)

(In the formula, R ¹ and R ² each independently represents a hydrocarbon group which may have a substituent.)
(2) R ¹ and R ^{2 in} formulas (2) and (3) are each independently an optionally substituted alkyl group, an optionally substituted alkenyl group, and a substituted group. An alkynyl group optionally having a group, an aryl group optionally having a substituent, or an aralkyl group optionally having a substituent is isolated containing the amide group described in (1) Salt of the compound.
(3) P in the formula (1) is a Cbz (benzyloxycarbonyl) group, a Boc (tert-butoxycarbonyl) group, a Troc (2,2,2-trichloroethoxycarbonyl) group or an Alloc (allyloxycarbonyl) group. A salt of an isolated compound comprising the amide group according to (1) or (2).
(4) (3) R ² in is an alkyl group having 1 to 4 carbon atoms, the salts of the compounds isolated containing amide groups according to any one of (1) to (3).
(5) A reagent for introducing an amide group, which is a salt of an isolated compound containing the amide group according to any one of (1) to (4).
(6) A method for producing a salt of an isolated compound containing the amide group according to any one of (1) to (4),
The compound represented by the following formula (4) and the compound represented by the following formula (5) are reacted,

(In the formula, R ³ represents a halogen atom or —OQ.)
Converting to a compound represented by the following formula (6):

A step of reacting a compound represented by the formula (6) obtained in the step with a compound represented by the following formula (7):

A manufacturing method comprising:
(7) Isolation containing an amide group, comprising a step of reacting a salt of an isolated compound containing the amide group according to any one of (1) to (4) with a compound having an electron withdrawing group Of an amide compound using a salt of the prepared compound.
(8) The synthesis method according to (7), wherein the electron withdrawing group is a halogen atom, an alkylsulfonyl group which may have a substituent, or an arylsulfonyl group which may have a substituent.

  The disclosure of the present specification relates to a salt of an isolated compound containing an amide group, a production method thereof, a synthesis method of an amide compound using the same, and the like. The salt of an isolated compound containing an amide group disclosed in the present specification can introduce an amide group into various compounds and is a salt of a compound useful as an amide group introduction reagent.

  Hereinafter, the present disclosure will be described in detail. In addition, in this specification, carbon number of various functional groups represents the total carbon number including the substituent, when the said functional group has a substituent.

(Salts of compounds containing amide groups)
A salt of a compound containing an amide group of the present disclosure (hereinafter also referred to as a salt of the present compound) is represented by the following general formula (1). The salt of the present compound has a structure in which the first protecting group (P) and the second protecting group (Q) are bonded to one nitrogen atom (N). The first protecting group is an amine protecting group and is represented by the following formula (2). That is, P is a carbamate-based protecting group. The second protecting group is an amine protecting group and is represented by the following formula (3). That is, Q is an amide-type protecting group. In the formulas (2) and (3), R ¹ and R ² are each independently bonded to a hydrocarbon group R ¹ or R ² which may have a substituent.

[R ¹ ]
Examples of the hydrocarbon group optionally having a substituent represented by R ¹ include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group.

(Alkyl group)
The alkyl group represented by R ¹ may be linear, branched or cyclic. As an alkyl group, C1-C20, for example, C5-C20, for example, C5-C10 linear or branched or cyclic alkyl group is mentioned, for example. For example, a C1-C4 alkyl group is mentioned. Specifically, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, neopentyl group, tert-pentyl group, Linear or branched alkyl group such as hexyl group, heptyl group, octyl group, nonyl group, decyl group, cetyl group, stearyl group; cyclopentyl group, methylcyclopentyl group, cyclohexyl group, methylcyclohexyl group, cycloheptyl group, cyclooctyl And a cycloalkyl group such as a group.

(Substituent of alkyl group)
These alkyl groups may have a substituent. Examples of the substituent include a hydrocarbon group, an aliphatic heterocyclic group, an aromatic heterocyclic group, an alkoxy group, an alkylenedioxy group, an aryloxy group, and an aralkyloxy group. Group, heteroaryloxy group, alkylthio group, arylthio group, aralkylthio group, heteroarylthio group, amino group, substituted amino group, cyano group, hydroxyl group, oxo group, nitro group, mercapto group, trisubstituted silyl group and halogen atom Etc.

  Examples of the hydrocarbon group substituted for the alkyl group include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group.

  The alkyl group substituted for the alkyl group may be linear, branched or cyclic, and is preferably a linear, branched or cyclic alkyl group having 1 to 20 carbon atoms, specifically, a methyl group. , Ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl group, tert-butyl group, n-pentyl group, neopentyl group, tert-pentyl group, hexyl group, heptyl group, octyl A linear or branched alkyl group such as a group, nonyl group, decyl group, cetyl group or stearyl group; a cycloalkyl group such as a cyclopentyl group, a cyclohexyl group or a cyclooctyl group.

  The alkenyl group substituted on the alkyl group may be linear or branched, and examples thereof include alkenyl groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. Specifically, an ethenyl group, a propenyl group, a 1-butenyl group, a pentenyl group, a hexenyl group, and the like can be given.

  The alkynyl group substituted for the alkyl group may be linear or branched, and examples thereof include alkynyl groups having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms. Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 3-butynyl group, pentynyl group, hexynyl group and the like can be mentioned.

  Examples of the aryl group substituted on the alkyl group include an aryl group having 6 to 20 carbon atoms, and specific examples include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group, and a terphenyl group.

  Examples of the aralkyl group substituted on the alkyl group include groups in which at least one hydrogen atom of the alkyl group is substituted with the above aryl group. For example, an aralkyl group having 7 to 12 carbon atoms is preferable. Group, 2-phenylethyl group, 1-phenylpropyl group, 3-naphthylpropyl group and the like.

  Examples of the aliphatic heterocyclic group to be substituted with an alkyl group include 2 to 14 carbon atoms and at least one, preferably 1 to 3 hetero atoms such as nitrogen, oxygen and sulfur atoms as hetero atoms. And a 5- to 8-membered, preferably 5- or 6-membered, monocyclic aliphatic heterocyclic group, or a polycyclic or condensed aliphatic heterocyclic group. Specific examples of the aliphatic heterocyclic group include pyrrolidyl-2-one group, piperidino group, piperazinyl group, morpholino group, tetrahydrofuryl group, tetrahydropyranyl group, tetrahydrothienyl group and the like.

  The aromatic heterocyclic group substituted for the alkyl group has, for example, 2 to 15 carbon atoms and includes at least one, preferably 1 to 3 heteroatoms such as nitrogen, oxygen and sulfur atoms as hetero atoms. A 5- to 8-membered, preferably 5- or 6-membered monocyclic heteroaryl group, or a polycyclic or condensed ring heteroaryl group, specifically, a furyl group, a thienyl group, or a pyridyl group. , Pyrimidyl group, pyrazyl group, pyridazyl group, pyrazolyl group, imidazolyl group, oxazolyl group, thiazolyl group, benzofuryl group, benzothienyl group, quinolyl group, isoquinolyl group, quinoxalyl group, phthalazyl group, quinazolyl group, naphthyridyl group, cinnolyl group, Examples thereof include a benzimidazolyl group, a benzoxazolyl group, and a benzothiazolyl group.

  The alkoxy group substituted for the alkyl group may be linear, branched or cyclic, and examples thereof include an alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, an n-propoxy group, Isopropoxy group, n-butoxy group, 2-butoxy group, isobutoxy group, tert-butoxy group, n-pentyloxy group, 2-methylbutoxy group, 3-methylbutoxy group, 2,2-dimethylpropyloxy group, n -Hexyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 5-methylpentyloxy group, cyclohexyloxy group, methoxymethoxy group, 2-ethoxyethoxy group, etc. .

  Examples of the alkylenedioxy group substituted for the alkyl group include an alkylenedioxy group having 1 to 3 carbon atoms, and specifically include a methylenedioxy group, an ethylenedioxy group, a trimethylenedioxy group, and propylenedioxy. Group, isopropylidenedioxy group and the like.

  Examples of the aryloxy group substituted on the alkyl group include an aryloxy group having 6 to 14 carbon atoms, and specific examples include a phenoxy group, a tolyloxy group, a xylyloxy group, a naphthoxy group, and an anthryloxy group.

  Examples of the aralkyloxy group substituted for the alkyl group include an aralkyloxy group having 7 to 12 carbon atoms, and specifically include a benzyloxy group, a 4-methoxyphenylmethoxy group, a 1-phenylethoxy group, and a 2-phenylethoxy group. Group, 1-phenylpropoxy group, 2-phenylpropoxy group, 3-phenylpropoxy group, 1-phenylbutoxy group, 3-phenylbutoxy group, 4-phenylbutoxy group, 1-phenylpentyloxy group, 2-phenylpentyloxy Group, 3-phenylpentyloxy group, 4-phenylpentyloxy group, 5-phenylpentyloxy group, 1-phenylhexyloxy group, 2-phenylhexyloxy group, 3-phenylhexyloxy group, 4-phenylhexyloxy group , 5-phenylhexyloxy group, 6-phen Hexyl group, and the like.

  The heteroaryloxy group substituted for the alkyl group includes, for example, at least one hetero atom, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom and a sulfur atom, and a carbon number of 2 to 14 Specific examples thereof include 2-pyridyloxy group, 2-pyrazyloxy group, 2-pyrimidyloxy group, 2-quinolyloxy group, and the like.

  The alkylthio group substituted for the alkyl group may be linear, branched or cyclic, and examples thereof include an alkylthio group having 1 to 6 carbon atoms, specifically, a methylthio group, an ethylthio group, an n-propylthio group, Examples include isopropylthio group, n-butylthio group, 2-butylthio group, isobutylthio group, tert-butylthio group, pentylthio group, hexylthio group, and cyclohexylthio group.

  Examples of the arylthio group substituted on the alkyl group include an arylthio group having 6 to 14 carbon atoms, and specific examples include a phenylthio group, a tolylthio group, a xylylthio group, and a naphthylthio group.

  Examples of the aralkylthio group substituted on the alkyl group include an aralkylthio group having 7 to 12 carbon atoms, and specific examples include a benzylthio group and a 2-phenethylthio group.

  Examples of the heteroarylthio group substituted on the alkyl group include, for example, at least one hetero atom, preferably 1 to 3 hetero atoms such as a nitrogen atom, an oxygen atom, a sulfur atom, and the like. Specific examples thereof include 4-pyridylthio group, 2-benzimidazolylthio group, 2-benzoxazolylthio group, 2-benzthiazolylthio group and the like.

  Examples of the substituted amino group substituted on the alkyl group include an amino group in which one or two hydrogen atoms of the amino group are substituted with a substituent such as an alkyl group, an aryl group, or an aralkyl group. Specific examples of an amino group substituted with an alkyl group, that is, an alkyl group-substituted amino group include N-methylamino group, N, N-dimethylamino group, N, N-diethylamino group, N, N-diisopropylamino group, Examples thereof include mono- or dialkylamino groups such as N-cyclohexylamino group. Specific examples of the amino group substituted with an aryl group, that is, the aryl group-substituted amino group include N-phenylamino group, N, N-diphenylamino group, N, N-ditolylamino group, N-naphthylamino group, N- Examples thereof include mono- or diarylamino groups such as naphthyl-N-phenylamino group. Specific examples of the amino group substituted with an aralkyl group, that is, an aralkyl group-substituted amino group include mono- or diaralkylamino groups such as an N-benzylamino group and an N, N-dibenzylamino group.

  Examples of the trisubstituted silyl group substituted on the alkyl group include a trimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group, a tert-butyldimethylsilyl group, a tert-butyldiphenylsilyl group, and a triphenylsilyl group.

  Examples of the halogen atom substituted for the alkyl group include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Examples of the halogenated alkyl group include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a penta group. A fluoroethyl group etc. are mentioned.

  Among these substituents, hydrocarbon groups, aliphatic heterocyclic groups, aromatic heterocyclic groups, alkoxy groups, alkylenedioxy groups, aryloxy groups, aralkyloxy groups, heteroaryloxy groups, alkylthio groups, arylthio groups, The aralkylthio group, heteroarylthio group or substituted amino group may further have a substituent depending on the group selected from the above group of substituents.

(Alkenyl group)
The alkenyl group represented by R ¹ may be linear, branched or cyclic. As an alkenyl group, C2-C15, for example, C5-C15, for example, C5-C10 linear or branched or cyclic alkenyl group is mentioned, for example. Moreover, for example, an alkenyl group having 2 to 4 carbon atoms can be mentioned. Specifically, vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group Group, 1-cyclopentenyl group, 3-cyclopentenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group, 1-cyclohexenyl group, 3-cyclohexenyl group Etc.

  In addition, these alkenyl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group (aliphatic heterocyclic group, aromatic heterocyclic group), a halogen atom, and the like. Specific examples thereof include those described above as the substituent of the alkyl group.

(Alkynyl group)
The alkynyl group represented by R ¹ may be linear or branched. Examples of the alkynyl group include linear or branched alkynyl groups having 2 to 15 carbon atoms, for example 5 to 15 carbon atoms, and 5 to 10 carbon atoms, for example. For example, a C2-C4 alkynyl group is mentioned. Specifically, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-pentynyl group, 2-pentynyl group, 3-pentynyl group, 4- Examples include pentynyl group, 1-hexynyl group, 2-hexynyl group, 3-hexynyl group, 4-hexynyl group, 5-hexynyl group and the like.

  These alkynyl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group (aliphatic heterocyclic group, aromatic heterocyclic group), a trisubstituted silyl group, and the like. Specific examples thereof include those described above as substituents for the alkyl group.

(Aryl group)
Specific examples of the aryl group represented by R ¹ include the aryl groups as described above as the aryl group as the substituent of the alkyl group.

  These aryl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group (aliphatic heterocyclic group, aromatic heterocyclic group), a halogen atom, and the like. Specific examples thereof include those described above as substituents for the alkyl group.

(Aralkyl group)
Examples of the aralkyl group represented by R ¹ include aralkyl groups having 7 to 15 carbon atoms, preferably 7 to 10 carbon atoms. Specific examples include a benzyl group, a 2-phenylethyl group, and a 1-phenylpropyl group. , 3-naphthylpropyl group and the like.

  Further, these aralkyl groups may have a substituent, and examples of the substituent include an alkyl group, an aryl group, a heterocyclic group (aliphatic heterocyclic group, aromatic heterocyclic group), a halogen atom, and the like. Specific examples thereof include those described above as the substituent of the alkyl group.

Among the examples listed above, R ¹ is, for example, an alkyl group that may have a linear, branched, or cyclic substituent having 1 to 8 carbon atoms, or an alkenyl group that may have a substituent. An aryl group which may have a substituent and an aralkyl group which may have a substituent are preferable. Further, for example, an alkyl group which may have a linear or branched substituent having 1 to 4 carbon atoms and an alkenyl group which may have a substituent are preferable. More specifically, R ¹ is preferably, for example, a benzyl group, a tert-butyl group, a 2,2,2-trichloroethyl group, an allyl group, or the like. That is, as the first protective group P, for example, Cbz (benzyloxycarbonyl) group, Boc (tert-butoxycarbonyl) group, Troc (2,2,2-trichloroethoxycarbonyl) group or Alloc (allyloxycarbonyl) Groups etc. are preferred. Examples of R ¹ include a 4-methoxybenzyl group and a 2,4-dimethoxybenzyl group.

[R ² ]
Examples of the hydrocarbon group optionally having a substituent represented by R ² include an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and an aralkyl group.

(Alkyl group)
The alkyl group represented by R ² may be linear, branched or cyclic. As an alkyl group, C1-C20, for example, C1-C10, for example, C1-C6 linear or branched or cyclic alkyl group is mentioned, for example. Moreover, for example, a C1-C4 linear or branched alkyl group is mentioned. Alkyl groups R ² are exemplified as well as the alkyl groups for R ^1. R ² preferably has a relatively small steric hindrance compared to R ¹ . Preferably R ² is a methyl group. That is, as the second protecting group Q, an acetyl group is preferable.

(Other functional groups)
Other functional groups represented by R ² (alkenyl group, alkynyl group, aralkyl group, and aryl group) are exemplified in the same manner as in R ¹ . The number of carbon atoms of the alkenyl group represented by ^{R 2,} 2-15, preferably 2-10, more preferably 2-6. The carbon number of the alkynyl group represented by R ² is 2 to 15, preferably 2 to 10, and more preferably 2 to 6. Carbon number of the aralkyl group represented by R ² is, for example, 7-12. The number of carbon atoms of the aryl group represented by R ^2, for example, 6 to 20. It is preferable that these functional groups represented by R ² have relatively small steric hindrance as compared with R ¹ as described above.

Among these, as R ² , for example, an alkyl group which may have a linear or branched substituent having 1 to 4 carbon atoms or an alkenyl group which may have a substituent is preferable. . More specifically, as R ² , for example, a methyl group, an ethyl group, a phenyl group and the like are preferable. That is, as the second protective group Q, for example, an acetyl group, a propionyl group, a benzoyl group, and the like are preferable.

  In the present invention, the second protecting group Q is preferably a substituent capable of leaving under relatively severe conditions such as the action of a strong acid or a strong base.

[M]
M represents an element (alkali metal element) of Group 1 of the periodic table. The alkali metal element represented by M is not particularly limited, and examples thereof include alkali metal elements such as Li, Na, K, and Rb. As the alkali metal element represented by M, K is preferably used.

  The salt of this compound is a useful reagent for introducing an amide group into various compounds as described later. The amidation reaction to which the salt of this compound can be applied is not particularly limited, but alkyl halides and alkyl sulfonates can be used as substrates. Various aspects in the amidation reaction will be described in detail later.

(Method for producing salt of this compound)
Those skilled in the art can appropriately synthesize the salt of this compound according to a known synthesis method.

For example, as shown in Scheme 1 below, the carbamic acid ester with a R ^1, by reacting the acid anhydride with a R ^2, synthesized an imide comprising R ^1, R ^2, contrast It can be obtained by reacting an alkali metal salt of tert-butyl alcohol. The carbamic acid ester and acid anhydride as raw materials can be appropriately selected depending on the target compound to be obtained. R ¹ and R ² may be the same or different.

  More specifically, in the synthesis of the salt of this compound, Amberlyst is added to the carbamate ester and the acid anhydride and stirred for 1 hour. After stirring, the Amberlyst is removed by filtration, the filtrate is concentrated, and the precipitated solid is recrystallized (for example, toluene / hexane = 1: 1) to obtain an imide as an intermediate product. This imide is dissolved in dimethoxyethane, cooled, added with an alkali metal salt of tert-butyl alcohol, and stirred for 10 minutes. The resulting precipitate is filtered off with suction, and washed with diethyl ether to give a salt of this compound. According to this production method, it is not necessary to purify the product of each step with a column, and purification of each step can be performed by simple steps of recrystallization and reprecipitation.

(Method for synthesizing amide compound using salt of this compound)
An amide compound using a salt of the present compound (hereinafter also referred to as the present amide compound) can be appropriately synthesized by those skilled in the art according to a known synthesis method.

  For example, as shown in Scheme 2 below, the present amide is reacted by reacting a salt of this compound with a substrate compound having an electron withdrawing group (for example, benzyl 3-bromopropyl ether shown in Scheme 2 below). A compound can be obtained. The substrate compound as a raw material can be appropriately selected depending on the target compound to be obtained.

  More specifically, in the present amide compound, the salt of the present compound and 18-crown-6 are dissolved in dimethylformamide, and then the substrate compound is added and stirred for 20 hours. After stirring, the organic layer containing the present amide compound is separated. The separated organic layer is washed with water and saturated brine, dried over anhydrous magnesium sulfate, and purified by flash silica gel chromatography (20% ethyl acetate / n-hexane) to give the amide compound.

(Substrate compound)
In the synthesis of the present amide compound, various compounds having an electron withdrawing group can be used as a substrate compound. If it is a compound having an electron withdrawing group, an amide group can be suitably introduced, and an amide compound corresponding to the substrate compound can be obtained.

[Electron withdrawing group]
Examples of the electron withdrawing group include a halogen atom, an alkylsulfonyl group which may have a substituent, or an arylsulfonyl group which may have a substituent.

  The halogen atom is not particularly limited, and examples thereof include halogen atoms such as Cl, Br, and I. As the halogen atom, it is preferable to use highly reactive I or Br.

  As an alkylsulfonyl group which may have a substituent, a C1-C20 alkylsulfonyl group is mentioned, for example. Specifically, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl, isopentylsulfonyl, neopentylsulfonyl, hexylsulfonyl, heptylsulfonyl, Examples include octylsulfonyl, nonylsulfonyl, decylsulfonyl, undecylsulfonyl, dodecylsulfonyl and the like.

Further, these alkylsulfonyl groups may have a substituent on the alkyl group, and examples of the substituent include an alkyl group, an aryl group, an alkoxy group, a halogen atom, and the like. Is the same as the substituent of the alkyl group in R ¹ . The alkylsulfonyl group is preferably a trifluoromethylsulfonyl group.

  As an arylsulfonyl group which may have a substituent, a C6-C20 arylsulfonyl group is mentioned, for example. Specifically, a phenylsulfonyl group, 1-naphthylsulfonyl group, 2-naphthylsulfonyl group and the like can be mentioned.

These arylsulfonyl groups may have a substituent on the aryl group, and examples of the substituent include an alkyl group, an aryl group, an alkoxy group, a halogen atom, and the like. Is the same as the substituent of the alkyl group in R ¹ . The arylsulfonyl group is preferably a p-toluenesulfonyl group.

  In the substrate compound, the carbon atom bonded to the electron withdrawing group is preferably a primary carbon atom. By reducing the steric hindrance, the present amide compound can be suitably obtained. Similarly, the substrate compound is preferably a compound having a relatively small volume.

(solvent)
In the synthesis of the present amide compound, a solvent can be used as necessary as long as the synthesis of the present amide compound is not inhibited. As a solvent, those skilled in the art can appropriately select from known solvents. Although it does not specifically limit, For example, halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, cyano-containing organic compounds, etc. are mentioned. These solvents may be used alone or in combination of two or more.

  When a solvent is used, the amount used varies depending on the type of the solvent, the salt of the present compound used, the substrate compound, etc., and therefore may be appropriately selected depending on the reaction. Among them, polar solvents such as acetonitrile and dimethylformamide are used. It is preferable to use it.

  The synthesis of the amide compound can be performed in the air or in an inert gas atmosphere. Examples of the inert gas include one or more of nitrogen gas, argon gas and the like. Moreover, a normal pressure may be sufficient and pressurization or pressure reduction conditions can also be selected suitably.

  The reaction temperature is usually appropriately selected from the range of 0 ° C to 100 ° C, preferably 0 ° C to 80 ° C, more preferably around room temperature to 80 ° C. The reaction time is usually about several minutes to several days, preferably about several minutes to 30 hours, more preferably about 1 hour to 20 hours. You may stir as needed during reaction.

  Hereinafter, the disclosure of the present specification will be described more specifically by way of examples. However, the disclosure of the present specification is not limited by the following examples unless it exceeds the gist.

[Synthesis of salt of isolated compound containing amide group]
(Synthesis of N- (benzyloxycarbonyl) acetamide potassium salt)
In this example, N- (benzyloxycarbonyl) acetamide potassium salt was synthesized by acetylating benzylcarbamate and then reacting with potassium tert-butoxide according to Scheme 3. In other words, N- (benzyloxycarbonyl) acetamide was synthesized by reacting benzylcarbamate with acetic anhydride in the presence of Amberlyst, and then the resulting N- (benzyloxycarbonyl) acetamide was dried. The target N- (benzyloxycarbonyl) acetamide potassium salt was synthesized by adding potassium tert-butoxide in dimethoxyethane.

(Synthesis method)
Benzyl carbamate (10 g, 66.2 mmol) was dissolved in acetic anhydride (100 mL), Amberlyst 15DRY (1 g, 1/10 amount of raw material) was added, and the mixture was stirred at room temperature for 1 hour. Amberlyst was removed by filtration, and the filtrate was concentrated under reduced pressure to stop the reaction. N- (benzyloxycarbonyl) acetamide (11.4 g, 89%) was obtained by recrystallization using about 100 mL of a toluene / hexane = 1: 1 solution to the precipitated solid. A solution of the obtained N- (benzyloxycarbonyl) acetamide (11.4 g, 59.1 mmol) in dimethoxyethane (60 mL) was cooled to 0 ° C., potassium tert-butoxide (6.63 g, 59.1 mmol) was added, and 0 ° C. was added. For 10 minutes. The resulting precipitate was collected by suction filtration and washed thoroughly with diethyl ether to give a powdery white solid of N- (benzyloxycarbonyl) acetamide potassium salt (13.5 g, 99%).
¹ H NMR (DMSO-d ₆ , 600 MHz) d 7.33-7.30 (4H, m), 7.24 (1H, m), 4.85 (2H, s), 1.80 (3H, s); ¹³ C NMR (DMSO-d ₍₆ , 150 MHz) d 178.5, 161.7, 139.3, 128.0, 127.2, 126.9, 64.3, 26.6; IR (KBr disk) 1676, 1569, 1398, 1344, 1231 cm ^-1 ;

(Synthesis of N- (tert-butoxycarbonyl) acetamide potassium salt)
In this example, N- (tert-butoxycarbonyl) acetamide was synthesized according to Scheme 4 using tert-butylcarbamate and various ligands, and then the resulting N- (tert-butoxycarbonyl) acetamide was dimethoxylated. The target N- (tert-butoxycarbonyl) acetamide potassium salt was synthesized by adding potassium tert-butoxide in ethane.

(Synthesis method)
Acetic anhydride (8.8 mL, 43 mmol) and pyridine (18 mL) were added to tert-butyl carbamate (2.19 g, 18.7 mmol) and DMAP (228 mg, 1.87 mmol), and the mixture was stirred at 70 ° C. for 23 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and then saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash silica gel chromatography (20% → 30% diethyl ether / hexane) gave N- (tert-butoxycarbonyl) acetamide (1.25 g, 52%). A solution of the obtained N- (tert-butoxycarbonyl) acetamide (200 mg, 1.26 mmol) in dimethoxyethane (1.3 mL) was cooled to 0 ° C., potassium tert-butoxide (141 mg, 1.26 mmol) was added, and 0 was added. Stir at 5 ° C. for 5 minutes. The resulting precipitate was collected by suction filtration and washed thoroughly with diethyl ether to give a powdery white solid of N- (benzyloxycarbonyl) acetamide potassium salt (204 g, 82%).
¹ H NMR (DMSO-d ₆ , 600 MHz) d 1.31 (9H, s), 1.75 (3H, s) ¹³ C NMR (DMSO-d ₆ , 150 MHz) d 175.2, 159.2, 75.3, 28.4, 25.9.

  Compared to Example 1, although the yield of the intermediate product (N- (tert-butoxycarbonyl) acetamide) was reduced, the salt of the isolated compound containing the desired amide group (N- (tert- Butoxycarbonyl) acetamide potassium salt) could be obtained.

[Substrate examination]
(Synthesis of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (amide compound using salt of compound containing amide group))
Using N- (benzyloxycarbonyl) acetamide potassium salt and benzyl 3-bromopropyl ether synthesized in Example 1, an amide compound using N- (benzyloxycarbonyl) acetamide potassium salt is prepared according to Scheme 5 shown below. Synthesized.

In entry 15, N- (benzyloxycarbonyl) acetamide potassium salt (76 mg, 0.33 mmol) and 18-crown-6 (79 mg, 0.30 mmol) were dissolved in dimethylformamide (1.7 mL). After adding benzyl 3-bromopropyl ether (50 mL, 0.30 mmol), the mixture was stirred at room temperature for 20 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / n-hexane) gave a colorless oil of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (91 mg, 89%). It was.
¹ H NMR (CDCl ₃ , 500 MHz) d 7.39-7.25 (10H, m), 5.21 (2H, s), 4.43 (2H, s), 3.88 (2H, t, J = 7.3 Hz), 3.47 (2H, t, J = 6.2 Hz), 2.48 (3H, s), 1.85 (2H, tt, J = 7.3, 6.2 Hz); ¹³ C NMR (CDCl ₃ , 125 MHz) d 172.9, 154.5, 138.4, 135.1, 128.7, 128.5, 128.3, 128.2, 127.52, 127.46, 72.7, 68.4, 68.0, 41.9, 28.8, 26.8; IR (film) 1738, 1702, 1349, 1197 cm ^-1 ; HRFABMS m / z calcd for C ₂₀ H ₂₃ NO ₄ Na (MNa ⁺ ) 364.1525, found 364.1530.

  Hereinafter, N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide was synthesized according to the conditions specified in Scheme 5 and entries 1-14. These results (entries 1 to 15) are also shown below.

  As described above, bromine is used as an electron-withdrawing group, and N-amide compounds of compounds containing the desired amide group using various solvents (ie, N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide) could be synthesized. In particular, when a polar solvent was used, the reaction proceeded rapidly and the target compound could be obtained in high yield (entries 8 and 9). In the examination of equivalents of N- (benzyloxycarbonyl) acetamide potassium salt and 18-crown-6 using a polar solvent (entries 10 to 15), when acetonitrile was used as the solvent and 18-crown-6 was used as the catalyst amount, The rate decreased (entry 11), but the others yielded the target compound in a generally high yield.

(Synthesis of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (amide compound using salt of compound containing amide group))
Using N- (benzyloxycarbonyl) acetamide potassium salt and benzyl 3-bromopropyl ether synthesized in Example 1, according to the following schemes 6 and 7, amide using N- (benzyloxycarbonyl) acetamide potassium salt The compound was synthesized.

  Benzyl-3-bromopropyl ether (175 mL, 1.00 mmol) was dissolved in dimethylformamide (1 mL). N- (Benzyloxycarbonyl) acetamide potassium salt (256 mg, 1.10 mmol) was added, and the mixture was stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10% ethyl acetate / n-hexane) gave a colorless oil of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (311 mg, 91%). It was.

  Benzyl-3-bromopropyl ether (175 mL, 1.00 mmol) was dissolved in dimethylformamide (1 mL). N- (Benzyloxycarbonyl) acetamide potassium salt (256 mg, 1.10 mmol) was added, and the mixture was stirred at 80 ° C. for 0.5 hr. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10% ethyl acetate / n-hexane) gave a colorless oil of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (307 mg, 90%). It was.

  As described above, even when 18-crown-6 was not used, the target compound was obtained in a high yield.

(Synthesis of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (amide compound using salt of compound containing amide group))
Using N- (benzyloxycarbonyl) acetamide potassium salt and benzyl 3-iodopropyl ether synthesized in Example 1, an amide compound using N- (benzyloxycarbonyl) acetamide potassium salt is prepared according to Scheme 8 shown below. Synthesized.

  In entry 4, benzyl 3-iodopropyl ether (83 mg, 0.30 mmol) and 18-crown-6 (79 mg, 0.30 mmol) were dissolved in dimethylformamide (1.7 mL). N- (Benzyloxycarbonyl) acetamide potassium salt (69 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / n-hexane) gave a colorless oil of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (94 mg, 91%). It was.

  Hereinafter, N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide was synthesized according to the conditions specified in Scheme 8 and entries 1 to 3. These results (entries 1 to 4) are also shown below.

  As described above, when iodine was employed as the electron withdrawing group, the reaction time and yield were generally good as compared with Example 3.

(Synthesis of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (amide compound using salt of compound containing amide group))
Using N- (benzyloxycarbonyl) acetamide potassium salt synthesized in Example 1 and 3- (benzyloxy) propyl p-toluenesulfonate, according to Scheme 9 shown below, N- (benzyloxycarbonyl) acetamide potassium salt An amide compound using was synthesized.

  In entry 4, 3- (benzyloxy) propyl p-toluenesulfonate (96 mg, 0.30 mmol) and 18-crown-6 (79 mg, 0.30 mmol) were dissolved in dimethylformamide (1.7 mL). N- (Benzyloxycarbonyl) acetamide potassium salt (76 mg, 0.33 mmol) was added, and the mixture was stirred at room temperature for 7 hr. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / n-hexane) gave a colorless oil of N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (87 mg, 85%). It was.

  Hereinafter, N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide was synthesized according to the conditions specified in Scheme 9 and entries 1 to 3. These results (entries 1 to 4) are also shown below.

  As described above, when a tosyl group was employed as the electron withdrawing group, the reaction time was extended as compared with Example 3, but the target compound was obtained in a yield of approximately the same level.

(Synthesis of N- (3- (benzyloxy) propyl) -N- (tert-butoxycarbonyl) acetamide (N-amide compound of a salt of a compound containing an amide group))
Using N- (tert-butoxycarbonyl) acetamide potassium salt and benzyl 3-iodopropyl ether synthesized in Example 2 according to Scheme 10 shown below, an amide using N- (tert-butoxycarbonyl) acetamide potassium salt The compound was synthesized.

  In the entry, benzyl 3-iodopropyl ether (83 mg, 0.300 mmol) and 18-crown-6 (79 mg, 0.300 mmol) were dissolved in dimethylformamide (1.7 mL) and then N- (tert-butoxycarbonyl) acetamide potassium Salt (59 mg 0.300 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours. However, since the reaction was not completed, N- (tert-butoxycarbonyl) acetamide potassium salt (30 mg) was added, and the total was 7 Stir for hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash silica gel chromatography (1% diethyl ether / dichloromethane) gave 40% (isolation: 36.6 mg) of N-alkylated product by NMR ratio and 37% (isolation: 13.5 mg) of by-products. It was.

  Hereinafter, N- (3- (benzyloxy) propyl) -N- (tert-butoxycarbonyl) acetamide was synthesized according to the conditions specified in Scheme 10 and Entry 2. These results (entries 1 and 2) are also shown below.

  As shown above, when the reaction was performed in an open system, the yield of the target compound was slightly reduced (entry 1). On the other hand, when the reaction was carried out in an Ar atmosphere, the yield of the target compound was improved.

(Synthesis of amide compounds using salts of compounds containing amide groups using various substrates)
Using the N- (benzyloxycarbonyl) acetamide potassium salt synthesized in Example 1 and various substrates, amide compounds using N- (benzyloxycarbonyl) acetamide potassium salt were synthesized according to Scheme 11 shown below. These results (entries 1 to 13) are also shown below.

  In entry 1, N- (benzyloxycarbonyl) acetamide potassium salt (76 mg, 0.33 mmol) and 18-crown-6 (79 mg, 0.33 mmol) were dissolved in dimethylformamide (0.3 mL). After adding benzyl 3-bromopropyl ether (52 mL, 0.30 mmol), the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous ammonium chloride was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10 → 20% ethyl acetate / n-hexane), N- (3- (benzyloxy) propyl) -N- (benzyloxycarbonyl) acetamide (87 mg, 85%) colorless oil Got.

  In entry 2, N- (benzyloxycarbonyl) acetamide potassium salt (254 mg, 1.10 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding n-dodecyl bromide (250 mL, 1.00 mmol), the mixture was stirred at room temperature for 24.5 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10% ethyl acetate / n-hexane) gave a colorless oil of N- (benzyloxycarbonyl) -N-dodecylacetamide (361 mg, 100%).

  In entry 3, N- (benzyloxycarbonyl) acetamide potassium salt (255 mg, 1.10 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After allyl bromide (120 mL, 1.00 mmol) was added, the mixture was stirred at room temperature for 0.5 hour. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10% ethyl acetate / n-hexane) gave a colorless oil of N-allyl-N- (benzyloxycarbonyl) acetamide (209 mg, 90%).

  In entry 4, N- (benzyloxycarbonyl) acetamide potassium salt (255 mg, 1.10 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding ethyl bromoacetate (111 mL, 1.00 mmol), the mixture was stirred at room temperature for 10 minutes. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (10% ethyl acetate / n-hexane) gave a colorless oil of synthesis of N-acetyl-N- (benzyloxycarbonyl) aminoacetate (270 mg, 97%).

  In entry 5, N- (benzyloxycarbonyl) acetamide potassium salt (255 mg, 1.10 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding benzyl bromide (120 mL, 1.00 mmol), the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / n-hexane) gave a colorless oil of N-benzyl-N- (benzyloxycarbonyl) acetamide (283 mg, 100%).

  In entry 6, N- (benzyloxycarbonyl) acetamide potassium salt (231 mg, 1.00 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). 1-Bromo-2-chloroethane (83 mL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 19.5 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% → 40% ethyl acetate / n-hexane) gave a colorless oil of N- (benzyloxycarbonyl) -N- (2-chloroethyl) acetamide (137 mg, 54%) .

  In entry 7, N- (benzyloxycarbonyl) acetamide potassium salt (231 mg, 1.00 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). Neopentyl bromide (140 μL 1.11 mmol) was added, and the mixture was stirred at room temperature for 5 hours, but the reaction did not proceed, so neopentyl bromide (50 μL 0.4 mmol) was added, the temperature was raised to 80 ° C., and the total was 36.5. Stir for hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / benzene) gave an N-alkylated product (24.7 mg, 9%).

  In entry 8, triflate (105.7 mg, 0.332 mmol) and 18-crown-6 (83 mg, 0.314 mmol) were dissolved in dimethylformamide (1 mL) and then N- (benzyloxycarbonyl) acetamide potassium salt (109 mg, 0.472 mmol) was added and stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. When purified by flash silica gel chromatography (5 → 20% ethyl acetate / hexane), an N-alkylated product was not obtained, and 21.4 mg (30%) of the aldehyde compound as a by-product was obtained. mg, (55%) was obtained.

  In entry 9, triflate (105.7 mg, 0.332 mmol) and 18-crown-6 (70 mg, 0.265 mmol) were dissolved in acetonitrile (1 mL), and then N- (benzyloxycarbonyl) acetamide potassium salt (92 mg, 0.396 mmol) was added and stirred at room temperature for 30 min. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification by flash silica gel chromatography (5% ethyl acetate / hexane) gave 67.5 mg (71%) of the N-alkylated product and 3.3 mg (2%) of lauryl alcohol as a decomposition product.

  In entry 10, N- (benzyloxycarbonyl) acetamide potassium salt (255 mg, 1.104 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding isopropyl bromide (94 μL 1.00 mmol), the mixture was stirred at room temperature for 23 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over magnesium sulfate. Purified by flash silica gel chromatography (30% diethyl ether / hexane), N-alkylated product was 32% from NMR ratio (isolation: 57.3 mg), O-alkylated product was 5% (isolation: 2.9 mg) ) Obtained.

  In entry 11, N- (benzyloxycarbonyl) acetamide potassium salt (231 mg, 1.00 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding isopropyl iodide (110 mL, 1.10 mmol), the mixture was stirred at room temperature for 18.5 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (5 → 10% ethyl acetate / benzene) gave a colorless oil of N- (benzyloxycarbonyl) -N-isopropylacetamide (105 mg, 47%). At the same time, a colorless oil of isopropyl N- (benzyloxycarbonyl) acetimidate (26 mg, 9%) as an O-alkylated product was also obtained.

  In entry 12, N- (benzyloxycarbonyl) acetamide potassium salt (254 mg, 1.10 mmol) and 18-crown-6 (264 mg, 1.00 mmol) were dissolved in dimethylformamide (1 mL). After adding methyl 2-bromopropionate (111 mL, 1.00 mmol), the mixture was stirred at room temperature for 19.5 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (20% ethyl acetate / n-hexane) gave a colorless oil of methyl 2- (N-acetyl-N- (benzyloxycarbonyl) amino) propionate (217 mg, 80%) . Simultaneously, a colorless oil of O-alkylated methyl 2- (1-((benzyloxycarbonyl) imino) ethoxy) propionate (41 mg, 19%) was also obtained.

  In entry 13, N- (benzyloxycarbonyl) acetamide potassium salt (150 mg, 0.761 mmol) and 18-crown-6 (134 mg, 0.507 mmol) were dissolved in dimethylformamide (1 mL). After adding 2-dodecanoyl o-nitrobenzenesulfonate (188 mg, 0.507 mmol), the mixture was stirred at room temperature for 1.2 hours. Saturated aqueous ammonium chloride solution (about 3 mL) was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. Purification by flash silica gel chromatography (80% benzene / n-hexane) gave a colorless oil of N- (benzyloxycarbonyl) -N- (2-dodecanyl) acetamide (84 mg, 46%). At the same time, a colorless oil of N- (benzyloxycarbonyl) acetimidic acid 2-dodecanyl (22 mg, 12%) as an O-alkylated product was also obtained.

  As described above, when the primary alkyl halide was used as a substrate, the target N-amide compound was obtained in a single and high yield (entries 1 to 5). When the selectivity of the reaction was examined using 1-bromo-2-chloroethane as a substrate, an N-alkylated product substituted with bromine was obtained (entry 6). The substrate with large steric hindrance decreased the reactivity (entry 7). When triflate with higher elimination ability was used as a substrate, it reacted with the solvent (DMF) (entry 8), so the solvent was changed to acetonitrile and examined again (entry 9) to obtain the target compound. I was able to.

  When the secondary alkyl halide is used as a substrate, the target compound can be obtained although the reaction time is extended and the yield is reduced as compared with the case where the primary alkyl halide is used as the substrate. did it. Moreover, O-alkyl body was obtained as a by-product (entry 10-13).

[Examination of selective deprotection of first protecting group and second protecting group]
(Selective deprotection of the second protecting group)
According to scheme 12 shown below, selective deprotection of an amide compound using this compound was examined.

  N-((2R, 3S)-(3- (tert-butyldimethylsilyloxy) tetrahydro-2H-pyran-2-yl) methyl) -N- (benzyloxycarbonyl) acetamide (27.7 mg, 0.066 mmol) in methanol After dissolving in (1 mL), potassium carbonate (1.6 mg, 0.012 mmol) was added and stirred at room temperature for 15 hours. After removing potassium carbonate by filtration with a cotton plug, the filtrate was concentrated under reduced pressure, purified by flash silica gel chromatography (6 → 20% ethyl acetate / hexane), and N-((2R, 3S)-(3- (tert- A colorless oil of butyldimethylsilyloxy) tetrahydro-2H-pyran-2-yl) methyl) benzyl carbamate (19.7 mg, 79%) was obtained.

The NMR data, MS data, etc. of the obtained compound are shown below.
[a] ²⁴ _D +47.7 (c 1.64, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 600 MHz) d 7.37-7.33 (4H, m), 7.30 (1H, m), 5.14 (1H, brs), 5.11 and 5.10 (each 1H, d, J = 12.3 Hz), 3.86 (1H, dtd, J = 10.3, 3.3, 1.5 Hz), 3.70 (1H, m), 3.37-3.27 (2H, m), 3.14-3.09 ( 2H, m), 2.00 (1H, m), 1.65--1.61 (2H, m), 1.43 (1H, qd, J = 10.8, 7.7 Hz), 0.89 (6H, s), 0.07 (3H, s), 0.05 (3H, s); ¹³ C NMR (CDCl ₃ , 150 MHz) d 156.3, 136.7, 128.5, 128.1, 128.0, 81.1, 69.0, 67.6, 66.5, 42.8, 33.2, 25.8, 25.4, 17.9, -4.1,- 4.9; IR (film) 3345, 2951, 2929, 2856, 1728, 1508, 1252, 1098 cm ^-1 ; HRFABMS m / z calcd for C ₂₀ H ₃₄ NO ₄ Si (MH ⁺ ) 380.2257, found 380.2241

  N-((2R, 3S)-(3- (tert-butyldimethylsilyloxy) tetrahydro-2H-pyran-2-yl) methyl) -N- (benzyloxycarbonyl) acetamide is described in the literature (Sakai, T. et al. Fukuta, A .; Nakamura, K .; Nakano, M .; Mori, YJ Org. Chem. 2016, 81, 3799-3808.).

  As described above, the acetyl group could be selectively deprotected by a general hydrolysis reaction in the presence of the first protective group (Cbz group) and the second protective group (acetyl group).

(Selective deprotection of the first protecting group)
According to the following scheme 13, selective deprotection of an amide compound using this compound was examined.

  N-((2R, 3S)-(3- (tert-butyldimethylsilyloxy) tetrahydro-2H-pyran-2-yl) methyl) -N- (benzyloxycarbonyl) acetamide (20.0 mg, 0.048 mmol) After dissolving in ethyl (1.5 mL), 5% palladium-carbon (2.0 mg) was added, and the mixture was stirred at room temperature for 18 hours in a hydrogen atmosphere. 5% Palladium-carbon was removed by Celite filtration, concentrated under reduced pressure, purified by flash silica gel chromatography (ethyl acetate), N-((2R, 3S)-(3- (tert-butyldimethylsilyloxy) A colorless amorphous solid of tetrahydro-2H-pyran-2-yl) methyl) acetamide (13.9 mg, 100%) was obtained.

The NMR data, MS data, etc. of the obtained compound are shown below.
[a] ²⁴ _D +54.8 (c 1.15, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 600 MHz) d 5.82 (1H, brs), 3.89 (1H, dtd, J = 10.6, 3.3, 1.5 Hz), 3.80 (1H, m), 3.38-3.30 (2H, m), 3.14-3.08 (2H, m), 2.02 (1H, m), 1.98 (3H, s), 1.68-1.63 (2H, m), 1.44 (1H , dtd, J = 12.8, 10.6, 7.7 Hz), 0.89 (9H, s), 0.08 (3H, s), 0.06 (3H, s); ¹³ C NMR (CDCl ₃ , 150 MHz) d 169.8, 80.9, 69.3 , 67.7, 41.3, 33.2, 25.8, 25.4, 23.3, 17.9, -4.1, -4.9; IR (film) 3294, 2952, 2930, 2857, 1652, 1550, 1252, 1096 cm ^-1 ; HRFABMS m / z calcd for C ₁₄ H ₃₀ NO ₃ Si (MH ⁺ ) 288.1995, found 288.1984

  N-((2R, 3S)-(3- (tert-butyldimethylsilyloxy) tetrahydro-2H-pyran-2-yl) methyl) -N- (benzyloxycarbonyl) acetamide is described in the literature (Sakai, T .; Fukuta , A .; Nakamura, K .; Nakano, M .; Mori, YJ Org. Chem. 2016, 81, 3799-3808.).

  As described above, when the reduction was carried out in a hydrogen atmosphere in the presence of the first protective group (Cbz group) and the second protective group (acetyl group), the Cbz group could be selectively deprotected.

(Selective deprotection of the first protecting group in the presence of benzyl ether)
According to the scheme 14 shown below, selective deprotection of amide compounds using this compound was examined.

  N- (benzyloxycarbonyl) -N-(((2R, 3S, 5S, 6S) -6- (3- (benzyloxy) propyl) -3- (tert-butyldimethylsilyloxy) -5-methyltetrahydro- 2H-pyran-2-yl) methyl) acetamide (57.0 mg, 0.098 mmol) was dissolved in ethyl acetate, 5% Pd-C (6.0 mg) was added, and the mixture was stirred at room temperature for 4 hours under hydrogen atmosphere. 5% Palladium-carbon was removed by Celite filtration, concentrated under reduced pressure, purified by flash silica gel chromatography (70 → 80% ethyl acetate / hexane), and N-((((2R, 3S, 5S, 6S)- 6- (3- (Benzyloxy) propyl) -3- (tert-butyldimethylsilyloxy) -5-methyltetrahydro-2H-pyran-2-yl) methyl) acetamide (34.5 mg, 79%) colorless amorphous Quality solid was obtained.

The NMR data, MS data, etc. of the obtained compound are shown below.
[a] ²⁶ _D +24.6 (c 1.11, CHCl ₃ ); ¹ H NMR (CDCl ₃ , 600 MHz) d 7.36-7.32 (4H, m), 7.28 (1H, m), 5.83 (1H, brs), 4.51 (2H, s), 3.75 (1H, m), 3.53 (1H, ddd, J = 11.0, 8.6, 4.6 Hz), 3.48 (1H, dt, J = 9.1, 6.3 Hz), 3.51 (1H, dt, J = 9.1, 6.3 Hz), 3.40 (1H, ddd, J = 7.9, 5.3, 2.2 Hz), 3.14-3.07 (2H, m), 1.95 (3H, s), 1.87 (1H, ddd, J = 12.7, 4.8 , 2.6 Hz), 1.83 (1H, qdt, J = 7.0, 4.5, 2.2 Hz), 1.71 (1H, m), 1.65-1.54 (3H, m), 1.42 (1H, m), 0.94 (3H, d, J = 7.0 Hz), 0.88 (9H, s), 0.07 (3H, s), 0.05 (3H, s); ¹³ C NMR (CDCl ₃ , 150 MHz) d 169.7, 138.4, 128.3, 127.61, 127.55, 81.2, 79.5, 72.9, 70.1, 65.7, 41.4, 40.8, 32.5, 29.3, 26.5, 25.7, 23.3, 17.9, 12.6, -4.2, -4.8; IR (film) 3302, 3031, 2928, 2883, 2856, 1652, 1254, 1104 cm ^-1 ; HRFABMS m / z calcd for C ₂₅ H ₄₄ NO ₄ Si (MH ⁺ ) 450.3040, found 450.3022

  N- (benzyloxycarbonyl) -N-(((2R, 3S, 5S, 6S) -6- (3- (benzyloxy) propyl) -3- (tert-butyldimethylsilyloxy) -5-methyltetrahydro- 2H-pyran-2-yl) methyl) acetamide is a literature (Sakai, T .; Fukuta, A .; Nakamura, K .; Nakano, M .; Mori, YJ Org. Chem. 2016, 81, 3799-3808.) It was synthesized according to the method.

As described above, when the reduction is performed in a hydrogen atmosphere in the presence of the first protective group (Cbz group), the second protective group (acetyl group) and the benzyl ether group, only the Cbz group can be selectively deprotected. did it.

Claims (8)

The salt of the isolated compound containing the amide group represented by the following formula | equation (1).

(In the formula, M represents an element belonging to Group 1 of the periodic table, P represents a first protecting group of an amine represented by the following formula (2), and Q is represented by the following formula (3). Represents the second protecting group of the amine.)

(In the formula, R ¹ and R ² each independently represents a hydrocarbon group which may have a substituent.) R ¹ and R ^{2 in} formulas (2) and (3) each independently have an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. Of the isolated compound containing an amide group according to claim 1, which is an alkynyl group which may be substituted, an aryl group which may have a substituent or an aralkyl group which may have a substituent. salt.   P in the formula (1) is a Cbz (benzyloxycarbonyl) group, a Boc (tert-butoxycarbonyl) group, a Troc (2,2,2-trichloroethoxycarbonyl) group or an Alloc (allyloxycarbonyl) group. A salt of an isolated compound comprising the amide group according to claim 1 or 2. Salts of R ² in the formula (3) is an alkyl group having 1 to 4 carbon atoms, a compound isolated containing amide groups according to claim 1.   The reagent for amide group introduction | transduction which is a salt of the isolated compound containing the amide group in any one of Claims 1-4. A method for producing a salt of an isolated compound comprising the amide group according to any one of claims 1 to 4,
The compound represented by the following formula (4) and the compound represented by the following formula (5) are reacted,

(In the formula, R ³ represents a halogen atom or —OQ.)
Converting to a compound represented by the following formula (6):

A step of reacting a compound represented by the formula (6) obtained in the step with a compound represented by the following formula (7):

A manufacturing method comprising: Reacting a salt of an isolated compound comprising the amide group according to any one of claims 1 to 4 with a substrate compound having an electron withdrawing group;
A method for synthesizing an amide compound using a salt of an isolated compound containing an amide group.   The synthesis method according to claim 7, wherein the electron withdrawing group is a halogen atom, an alkylsulfonyl group which may have a substituent, or an arylsulfonyl group which may have a substituent.