WO2012099184A1 - Method for producing fluoroamine - Google Patents

Abstract

A fluoroamine can be produced by: protecting an amino group of an amino alcohol with a nitrobenzenesulfonyl group, thereby converting into a protected amino alcohol (amino group protection step); causing the protected amino alcohol to react with sulfuryl fluoride (SO₂F₂) in the presence of an organic base, thereby converting into a protected fluoroamine (dehydroxyfluorination step); and eliminating the protective group of the amino group of the protected fluoroamine (deprotection step). Since a nitrobenzenesulfonyl group highly satisfies the conditions required for the protective group of an amino group of the present invention, an aimed fluoroamine can be obtained with high purity and high yield.

Description

Method for producing fluoroamines

The present invention relates to a method for producing fluoroamines.

Background of the Invention

The applicant of the present patent application removes alcohols by a combination of sulfuryl fluoride (SO ₂ F ₂ ) and an organic base (performed in the presence of a “salt or complex comprising an organic base and hydrogen fluoride” as necessary). A hydroxyfluorination reaction is disclosed (Patent Document 1). Moreover, the manufacturing method of optically active fluoroamines using this method is also disclosed (patent document 2).

In the dehydroxyfluorination reaction of amino alcohols using a combination of sulfuryl fluoride and an organic base, it is important to select a protective group for the amino group. If the nucleophilicity remains in the amino group protected by the protecting group, 1,2-rearrangement involving neighboring groups (Japanese Patent Laid-Open No. 2009-286777), intermolecular nucleophilic attack on the fluorosulfate ester intermediate, etc. Side reaction occurs. Patent Documents 1 and 2 disclose a phthaloyl group and a benzylidene group as amino-protecting groups, but these protecting groups can be applied only to primary amines and not secondary amines.

JP 2006-290870 A JP 2009-227596 A

Under such circumstances, there is a demand for a suitable amino-protecting group in which side reactions are unlikely to occur in the dehydroxyfluorination reaction of amino alcohols by a combination of sulfuryl fluoride and an organic base.

The present inventors have disclosed amino alcohols protected with typical amino-protecting groups [benzyl (Bn) group, tert-butoxycarbonyl (Boc) group, benzyloxycarbonyl (Cbz) group and acetyl (Ac) group]. The above-described dehydroxyfluorination reaction was examined, but the target reaction hardly proceeded (see Comparative Examples 1 to 4). The amino group protected with the Boc group, Cbz group and Ac group is considered to have sufficiently suppressed nucleophilicity, but this effect alone is a suitable amino group protecting group in the dehydroxyfluorination reaction. I couldn't.

On the other hand, it was found that the desired dehydroxyfluorination reaction proceeds well in amino alcohols protected with a methanesulfonyl group, a benzenesulfonyl group and a paratoluenesulfonyl group. However, these protecting groups could not be deprotected without side reactions, and the invention could not be completed from the viewpoint of a method for producing fluoroamines.

Under such circumstances, as a result of intensive studies, the present inventors have found a useful method for producing fluoroamines and have reached the present invention.

That is, the present invention includes [Invention 1] to [Invention 12] and provides a method for producing a fluoroamine.

［式中、Ｒ¹はアルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、Ｒ²はそれぞれ独立に水素原子、アルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、ｍは２、３または４の整数を表し、ｎは４、６または８の整数を表し、Ｐ¹はオルト、メタまたはパラ－ニトロベンゼンスルホニル基を表す。］
で示されるアミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させる脱ヒドロキシフッ素化工程を含む、一般式［２］：

［式中、Ｒ¹、Ｒ²、ｍ、ｎ、およびＰ¹は前記式［１］と同じである。］
で示されるフルオロアミン類保護体を製造する方法。 [Invention 1]
General formula [1]:

[Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, and R ² independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. M represents an integer of 2, 3 or 4, n represents an integer of 4, 6 or 8, and P ¹ represents an ortho, meta or para-nitrobenzenesulfonyl group. ]
Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by formula (2) is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

[Wherein R ¹ , R ² , m, n, and P ¹ are the same as those in the formula [1]. ]
A process for producing a protected fluoroamine compound represented by the formula:

[Invention 2]
The method according to invention 1, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

［式中、Ｒ¹はアルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、Ｒ²はそれぞれ独立に水素原子、アルキル基、置換アルキル基、芳香環基または置換芳香環基を表し、ｍは２、３または４の整数を表し、ｎは４、６または８の整数を表す。］
で示されるアミノアルコール類のアミノ基をニトロベンゼンスルホニル基で保護することにより、一般式［１］：

［式中、Ｒ¹、Ｒ²、ｍ、およびｎは前記式［３］と同じである。Ｐ¹はオルト、メタまたはパラ－ニトロベンゼンスルホニル基を表す。］
で示されるアミノアルコール類保護体に変換するアミノ基保護工程、
　該アミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させることにより、一般式［２］：

［式中、Ｒ¹、Ｒ²、ｍ、ｎ、およびＰ¹は前記式［１］と同じである。］
で示されるフルオロアミン類保護体に変換する脱ヒドロキシフッ素化工程、および
　該フルオロアミン類保護体のアミノ基の保護基を脱保護する脱保護工程を含む、一般式［４］：

［式中、Ｒ¹、Ｒ²、ｍ、およびｎは前記式［３］と同じである。］
で示されるフルオロアミン類を製造する方法。 [Invention 3]
General formula [3]:

[Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, and R ² independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. M represents an integer of 2, 3 or 4, and n represents an integer of 4, 6 or 8. ]
By protecting the amino group of the amino alcohol represented by general formula [1]:

[Wherein R ¹ , R ² , m and n are the same as those in the above-mentioned formula [3]. P ¹ represents an ortho, meta or para-nitrobenzenesulfonyl group. ]
An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [2]:

[Wherein R ¹ , R ² , m, n, and P ¹ are the same as those in the formula [1]. ]
And a deprotection step for deprotecting the protecting group of the amino group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [4]:

[Wherein R ¹ , R ² , m and n are the same as those in the above-mentioned formula [3]. ]
A process for producing a fluoroamine represented by the formula:

[Invention 4]
The method according to claim 3, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

［式中、Ｒ³はアルキル基または置換アルキル基を表し、Ｒ⁴はそれぞれ独立に水素原子、アルキル基または置換アルキル基を表し、ｘは２または３の整数を表し、ｙは４または６の整数を表し、Ｐ²はオルトまたはパラ－ニトロベンゼンスルホニル基を表す。］
で示されるアミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させる脱ヒドロキシフッ素化工程を含む、一般式［６］：

［式中、Ｒ³、Ｒ⁴、ｘ、ｙ、およびＰ²は前記式［５］と同じである。］
で示されるフルオロアミン類保護体を製造する方法。 [Invention 5]
General formula [5]:

[Wherein, R ³ represents an alkyl group or a substituted alkyl group, R ⁴ independently represents a hydrogen atom, an alkyl group or a substituted alkyl group, x represents an integer of 2 or 3, and y represents 4 or 6] Represents an integer, and P ² represents an ortho- or para-nitrobenzenesulfonyl group. ]
Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by formula ( _II ) is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

[Wherein R ³ , R ⁴ , x, y, and P ² are the same as those in the formula [5]. ]
A process for producing a protected fluoroamine compound represented by the formula:

[Invention 6]
6. The method according to claim 5, wherein the dehydroxyfluorination step is performed in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

［式中、Ｒ³はアルキル基または置換アルキル基を表し、Ｒ⁴はそれぞれ独立に水素原子、アルキル基または置換アルキル基を表し、ｘは２または３の整数を表し、ｙは４または６の整数を表す。］
で示されるアミノアルコール類のアミノ基をニトロベンゼンスルホニル基で保護することにより、一般式［５］：

［式中、Ｒ³、Ｒ⁴、ｘ、およびｙは前記式［７］と同じである。Ｐ²はオルトまたはパラ－ニトロベンゼンスルホニル基を表す。］
で示されるアミノアルコール類保護体に変換するアミノ基保護工程、
　該アミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させることにより、一般式［６］：

［式中、Ｒ³、Ｒ⁴、ｘ、ｙ、およびＰ²は前記式［５］と同じである。］
で示されるフルオロアミン類保護体に変換する脱ヒドロキシフッ素化工程、および
　該フルオロアミン類保護体のアミノ基の保護基を脱保護する脱保護工程を含む、一般式［８］：

［式中、Ｒ³、Ｒ⁴、ｘ、およびｙは前記式［７］と同じである。］
で示されるフルオロアミン類を製造する方法。 [Invention 7]
General formula [7]:

[Wherein, R ³ represents an alkyl group or a substituted alkyl group, R ⁴ independently represents a hydrogen atom, an alkyl group or a substituted alkyl group, x represents an integer of 2 or 3, and y represents 4 or 6] Represents an integer. ]
By protecting the amino group of the amino alcohol represented by general formula [5]:

[Wherein R ³ , R ⁴ , x, and y are the same as those in the formula [7]. P ² represents an ortho or para-nitrobenzenesulfonyl group. ]
An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [6]:

[Wherein R ³ , R ⁴ , x, y, and P ² are the same as those in the formula [5]. ]
And a deprotection step of deprotecting the protecting group of the amino group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [8]:

[Wherein R ³ , R ⁴ , x, and y are the same as those in the formula [7]. ]
A process for producing a fluoroamine represented by the formula:

[Invention 8]
The method according to invention 7, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

で示されるアミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させる脱ヒドロキシフッ素化工程を含む、一般式［１０］：

で示されるフルオロアミン類保護体を製造する方法。
［式中、Ｍｅはメチル基を表す。］ [Invention 9]
General formula [9]:

Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by the above formula is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

A process for producing a protected fluoroamine compound represented by the formula:
[Wherein, Me represents a methyl group. ]

[Invention 10]
The method according to invention 9, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

で示されるアミノアルコール類のアミノ基をニトロベンゼンスルホニル基で保護することにより、一般式［９］：

で示されるアミノアルコール類保護体に変換するアミノ基保護工程、
　該アミノアルコール類保護体を有機塩基の存在下にスルフリルフルオリド（ＳＯ₂Ｆ₂）と反応させることにより、一般式［１０］：

で示されるフルオロアミン類保護体に変換する脱ヒドロキシフッ素化工程、および
　該フルオロアミン類保護体のアミノ基の保護基を脱保護する脱保護工程を含む、一般式［１２］：

で示されるフルオロアミン類を製造する方法。
［式中、Ｍｅはメチル基を表す。］ [Invention 11]
General formula [11]:

By protecting the amino group of the amino alcohol represented by general formula [9]:

An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [10]:

And a deprotection step of deprotecting an amino-protecting group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [12]:

A process for producing a fluoroamine represented by the formula:
[Wherein, Me represents a methyl group. ]

[Invention 12]
The method according to invention 11, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.

According to the preferred embodiment of the present invention, it is possible to provide a suitable protecting group for an amino group that hardly causes a side reaction in the dehydroxyfluorination reaction of amino alcohols by a combination of sulfuryl fluoride and an organic base. Further, according to a preferred embodiment of the present invention, an amino group and a hydroxyl group coexist in the amino alcohol of the raw material substrate, but only the amino group can be selectively protected in the amino group protecting step. Furthermore, according to a preferred embodiment of the present invention, deprotection can be performed without side reactions under mild reaction conditions in the deprotection step. Finally, according to the preferred embodiment of the present invention, fluoroamines can be obtained with high purity and good yield.

Detailed description

The method for producing the fluoroamines of the present invention will be described in detail.

A preferred method for producing fluoroamines of the present invention includes an amino group protecting step of protecting an amino group of an amino alcohol represented by the general formula [3] with a nitrobenzenesulfonyl group, and an amino alcohol protecting method represented by the general formula [1]. 3 steps: a dehydroxyfluorination step for reacting the product with sulfuryl fluoride in the presence of an organic base, and a deprotection step for deprotecting the protecting group of the amino group of the protected fluoroamine represented by the general formula [2] including.

1 Amino Group Protection Step First, the amino group protection step will be specifically described.

R ^{1 of the} amino alcohol represented by the general formula [3] represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. The alkyl group is a linear or branched chain or cyclic group (having 3 or more carbon atoms) having 1 to 18 carbon atoms. The aromatic ring group is an aromatic hydrocarbon group having 1 to 18 carbon atoms such as a phenyl group, a naphthyl group and an anthryl group, or a pyrrolyl group (including a nitrogen protector), a pyridyl group, a furyl group, a thienyl group, an indolyl group. An aromatic heterocyclic group containing a hetero atom such as a nitrogen atom, oxygen atom or sulfur atom such as a group (including a nitrogen-protected form), a quinolyl group, a benzofuryl group and a benzothienyl group. The substituted alkyl group and the substituted aromatic ring group each have a substituent in any number and in any combination on any carbon atom or nitrogen atom of the above alkyl group and aromatic ring group. Such substituents include halogen atoms such as fluorine, chlorine and bromine, lower alkyl groups such as methyl, ethyl and propyl, lower haloalkyl groups such as fluoromethyl, chloromethyl and bromomethyl, methoxy and ethoxy Lower alkoxy groups such as propoxy group, lower haloalkoxy groups such as fluoromethoxy group, chloromethoxy group and bromomethoxy group, lower alkoxycarbonyl groups such as cyano group, methoxycarbonyl group, ethoxycarbonyl group and propoxycarbonyl group, phenyl group , Aromatic groups such as naphthyl, anthryl, pyrrolyl (including nitrogen protected), pyridyl, furyl, thienyl, indolyl (including nitrogen protected), quinolyl, benzofuryl and benzothienyl , Protector of carboxyl group, Protection of amino groups, as well as protection and the like of the hydroxyl groups. In the present specification, “lower” means a linear or branched chain or cyclic group (in the case of 3 or more carbon atoms) having 1 to 6 carbon atoms. In addition, the aromatic ring group of the “substituent” is a protected form of a halogen atom, a lower alkyl group, a lower haloalkyl group, a lower alkoxy group, a lower haloalkoxy group, a cyano group, a lower alkoxycarbonyl group, or a carboxyl group. The amino group protector and the hydroxyl group protector can be substituted. Furthermore, pyrrolyl, indolyl, carboxyl, amino and hydroxyl protecting groups are described in Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. And the like. Among these, an alkyl group and a substituted alkyl group are preferable, and a methyl group is particularly preferable.

R ^{2 in the} aminoalcohols represented by the general formula [3] each independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R ¹ of the amino alcohol represented by the general formula [3]. Is the same. When the carbon atom substituted by R ² is an asymmetric carbon, any stereochemistry (R-form, S-form or racemic form) can be adopted. In addition, when a plurality of asymmetric carbons are present, any combination of stereochemistry can be taken (for example, when two asymmetric carbons are present, R, R isomer, R, S isomer, S, R form, S, S form, or any diastereomeric mixture thereof). Furthermore, two R ² of the aminoalcohols represented by the general formula [3] are each directly between arbitrary carbon atoms or nitrogen atoms [including amino group protectors, and the protecting group is a nitrobenzenesulfonyl group. It is not limited, and the protecting group described in the above-mentioned book of the protecting group can be taken], and a cyclic structure can be taken by a covalent bond through an oxygen atom or a sulfur atom. Is also included in the claims. Among these, a hydrogen atom, an alkyl group, and a substituted alkyl group are preferable, and a hydrogen atom is particularly preferable.

M in the amino alcohol represented by the general formula [3] represents an integer of 2, 3 or 4. Among them, integers of 2 and 3 are preferable, and integer 2 is particularly preferable.

N in the amino alcohol represented by the general formula [3] represents an integer of 4, 6 or 8. Among these, integers of 4 and 6 are preferable, and integer 4 is particularly preferable. Regarding the relationship between the integers m and n, when m is the integer 2, n takes the integer 4, when m is the integer 3, n takes the integer 6, and when m is the integer 4, n takes the integer 8.

Among amino alcohols represented by the general formula [3], amino alcohols represented by the general formula [7] are preferable, and amino alcohols represented by the general formula [11] are particularly preferable. Many of the aminoalcohols represented by the general formula [7] are commercially available and are easily available on a large scale. Of the amino alcohols represented by the general formula [11], the fluoroamines represented by the general formula [12] obtained therefrom are important as intermediates for medicines and agrochemicals.

The aminoalcohols represented by the general formula [3] can also be used in the form of salts with inorganic acids such as hydrogen chloride, hydrogen bromide and sulfuric acid or organic acids such as oxalic acid, phthalic acid and paratoluenesulfonic acid. .

［式中、ニトロ基はオルト、メタまたはパラ位に置換し、Ｘはハロゲン原子を表す。］
で示されるニトロベンゼンスルホニルハライドと反応させることにより、一般式［１］で示されるアミノアルコール類保護体を製造することができる。 The amino group protecting step can be carried out by employing a general method in organic synthesis [for example, the above-mentioned book of protecting groups, the Chemical Society of Japan, 5th edition experimental chemistry course (Maruzen), etc.]. Specifically, the amino alcohol represented by the general formula [3] is added in the presence of a base to the general formula [13]:

[Wherein the nitro group is substituted at the ortho, meta or para position, and X represents a halogen atom. ]
A protected amino alcohol represented by the general formula [1] can be produced by reacting with a nitrobenzenesulfonyl halide represented by the general formula [1].

R ^1, R ^2, m, and n in the general formula [1] is the same as R ^1, R ^2, m, and n in the general formula [3]. In the general formula [1], P ¹ represents an ortho, meta, or para-nitrobenzenesulfonyl group.

The nitro group of the nitrobenzenesulfonyl halide represented by the general formula [13] is substituted at the ortho, meta or para position. Of these, the ortho and para positions are preferred, and the ortho position is particularly preferred.

X in the nitrobenzenesulfonyl halide represented by the general formula [13] represents a halogen atom. The halogen atom is the same as the halogen atom described in the “substituents for R ¹ ” of R ¹ of the amino alcohol represented by the general formula [3]. Of these, chlorine and bromine are preferable, and chlorine is particularly preferable.

Among the nitrobenzenesulfonyl halides represented by the general formula [13], ortho and para-nitrobenzenesulfonyl chloride are preferable, and ortho-nitrobenzenesulfonyl chloride is particularly preferable. Ortho and para-nitrobenzenesulfonyl chloride are commercially available and are readily available. Ortho-nitrobenzenesulfonyl chloride is less expensive and is suitable for production on a large scale.

The amount of the nitrobenzenesulfonyl halide represented by the general formula [13] may be 0.7 mol or more, preferably 0.8 to 5 mol, based on 1 mol of the amino alcohol represented by the general formula [3]. 9 to 3 mol is particularly preferred.

The base is an inorganic base such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and cesium hydroxide. , And triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine, 1,5-diazabicyclo [4.3. Organic bases such as 0] non-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene. Among them, organic bases are preferable, and triethylamine, diisopropylethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethylaminopyridine and 1,8-diazabicyclo [5.4.0] undec-7- En is particularly preferred. These bases can be used alone or in combination.

The amount of the base used may be 0.35 mol or more, preferably 0.4 to 20 mol, particularly preferably 0.45 to 15 mol, relative to 1 mol of the aminoalcohol represented by the general formula [3]. When the amino alcohol represented by the general formula [3] is used in the form of a salt with an inorganic acid or an organic acid, it is added in consideration of the amount of base necessary for neutralizing the acid, It is convenient to continuously protect the amino group in the same reaction system. The base used for acid neutralization is the same as the above base.

The order of addition of the base is not particularly limited, and an amino alcohol represented by the general formula [3] and a nitrobenzenesulfonyl halide represented by the general formula [13] are added to the reaction solvent and finally a base is added to achieve a good result. May be obtained.

Reaction solvents include aliphatic hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as toluene and xylene, halogens such as methylene chloride and 1,2-dichloroethane, tetrahydrofuran and tert-butyl methyl ether Ethers such as ethyl acetate and esters such as ethyl acetate and n-butyl acetate, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone Amides such as acetonitrile, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide and water. Of these, n-heptane, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetonitrile, dimethyl sulfoxide and water are preferable. Toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetonitrile And water are particularly preferred. These reaction solvents can be used alone or in combination. When used in combination with water, the reaction can be carried out in a two-phase system.

The reaction solvent may be used in an amount of 0.05 L (liter) or more, preferably 0.1 to 20 L, particularly preferably 0.15 to 10 L with respect to 1 mol of the aminoalcohol represented by the general formula [3]. . This reaction can also be carried out neat without using a reaction solvent.

The reaction temperature may be in the range of −80 to + 200 ° C., preferably −60 to + 150 ° C., particularly preferably −40 to + 100 ° C.

The reaction time may be within a range of 24 hours or less, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

In the post-treatment, a protected amino alcohol represented by the general formula [1] can be obtained by employing a general operation in organic synthesis. The crude product can be purified to a high purity by activated carbon treatment, fractional distillation, recrystallization, column chromatography or the like, if necessary. In particular, a salt of an amino alcohol represented by the general formula [3] with an inorganic acid or a halide ion derived from the nitrobenzenesulfonyl halide represented by the general formula [13] may cause impurities as a by-product (special feature). (See Kai 2010-163422). In such a case, water washing of the organic layer containing the target product, a short column, etc. are effective.

2 Dehydroxyfluorination process Next, a dehydroxyfluorination process is demonstrated concretely.

In the dehydroxyfluorination step, the protected amino alcohol represented by the general formula [1] is reacted with sulfuryl fluoride in the presence of an organic base to obtain the protected fluoroamine represented by the general formula [2]. Can be manufactured.

R ^1, R ^2, m, n, and P ¹ in the general formula [2] are the same as R ^1, R ^2, m, n, and P ¹ in the general formula [1].

The amount of sulfuryl fluoride used may be 0.7 mol or more, preferably 0.8 to 20 mol, particularly preferably 0.9 to 15 mol, based on 1 mol of the protected amino alcohol represented by the general formula [1]. .

The organic base is the same as the organic base described in the base in the amino group protecting step. However, the organic base is not limited to these, and organic bases generally used in organic synthesis can also be employed. Among them, triethylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine and 1,8-diazabicyclo [5.4.0] undec-7-ene are preferable, triethylamine, Diisopropylethylamine, tri-n-butylamine, pyridine and 1,8-diazabicyclo [5.4.0] undec-7-ene are particularly preferred. These organic bases can be used alone or in combination.

The amount of the organic base used may be 0.7 mol or more, preferably 0.8 to 20 mol, particularly preferably 0.9 to 15 mol, based on 1 mol of the protected amino alcohol represented by the general formula [1].

The organic base of the “salt or complex comprising an organic base and hydrogen fluoride” is the same as the organic base described in the dehydroxyfluorination step, and the “preferred” and “particularly preferable” organic bases are also the same. These organic bases of “a salt or complex comprising an organic base and hydrogen fluoride” can be used alone or in combination.

The molar ratio of the organic base to hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” may be used in the range of 100: 1 to 1: 100, preferably 50: 1 to 1:50, Particularly preferred is 25: 1 to 1:25. Commercially available from Aldrich (2009-2010 catalog) “complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride” or “from pyridine˜30% (˜10 mol%) and hydrogen fluoride˜70% (˜90 mol%) It is convenient to use "complex".

The amount used in the case of using “a salt or complex comprising an organic base and hydrogen fluoride” is 0.001 as fluoride ion (F ⁻ ) with respect to 1 mol of the protected amino alcohol represented by the general formula [1]. 05 mol or more may be used, preferably 0.07 to 30 mol, particularly preferably 0.09 to 15 mol.

The reaction solvent is the same as the reaction solvent excluding water described in the amino group protecting step, and the “preferred” and “particularly preferable” reaction solvents are the same (of course, excluding water). These reaction solvents can be used alone or in combination.

The amount of the reaction solvent used may be 0.05 L or more, preferably 0.1 to 20 L, particularly preferably 0.15 to 10 L with respect to 1 mol of the protected amino alcohol represented by the general formula [1]. This reaction can also be carried out neat without using a reaction solvent.

The reaction temperature may be in the range of −50 to + 200 ° C., preferably −40 to + 150 ° C., particularly preferably −30 to + 100 ° C.

The reaction time may be within a range of 48 hours, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, and nuclear magnetic resonance. It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

The post-treatment can employ a general operation in organic synthesis to obtain a protected fluoroamine represented by the general formula [2]. The crude product can be purified to a high purity by activated carbon treatment, fractional distillation, recrystallization, column chromatography or the like, if necessary. The dehydroxyfluorination reaction in this step proceeds by a bimolecular nucleophilic substitution (S _N 2) reaction. Therefore, when the raw material substrate is an optically active alcohol, the target product can be obtained as an optically active fluorinated product having an inverted stereochemistry. In particular, in the case of an optically active secondary alcohol, the reaction proceeds at a high inversion rate.

3 Deprotection Step Finally, the deprotection step will be specifically described.

［式中、Ｒ⁵はアルキル基、置換アルキル基、芳香環基または置換芳香環基を表す。］
で示されるチオール類と反応させることにより、一般式［４］で示されるフルオロアミン類を製造することができる。 The deprotection step can be performed by employing a general method in organic synthesis [for example, the above-mentioned book of protecting groups, the Chemical Society of Japan, 5th edition, Experimental Chemistry Course (Maruzen), etc.]. Specifically, the protected fluoroamine represented by the general formula [2] is added in the presence of a base to the general formula [14]:

[Wherein R ⁵ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. ]
The fluoroamine represented by the general formula [4] can be produced by reacting with the thiol represented by the general formula [4].

R ^1, R ^2, m, and n in the general formula [4] are the same as R ^1, R ^2, m, and n in the general formula [3].

R ⁵ of the thiols represented by the general formula [14] represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. The alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group are the alkyl group, substituted alkyl group, aromatic ring group and substituted aromatic ring group described in R ¹ of the amino alcohol represented by the general formula [3]. Is the same. Among these, an alkyl group and an aromatic ring group are preferable, and a phenyl group is particularly preferable. Thiophenol is highly reactive and is commercially available as an industrial chemical.

The amount of the thiol represented by the general formula [14] may be 0.7 mol or more with respect to 1 mol of the protected fluoroamine represented by the general formula [2], preferably 0.8 to 20 mol, .9 to 15 mol is particularly preferred.

The base is the same as the base described in the amino group protecting step. Among these, an inorganic base is preferable, and lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate are particularly preferable. These bases can be used alone or in combination. In general organic synthesis, when a nitrobenzenesulfonyl group is used as a protecting group for an amino group, the organic base 1,8-diazabicyclo [5.4.0] undec-7-ene is frequently used as a deprotecting base. . However, in the deprotection step of the present invention, it is possible to employ milder reaction conditions when using an inorganic base, and it is possible to perform deprotection with good yield without side reactions (preferred embodiment of the present invention).

The amount of the base used may be 0.35 mol or more, preferably 0.4 to 20 mol, particularly preferably 0.45 to 15 mol, relative to 1 mol of the protected fluoroamine represented by the general formula [2].

The reaction solvent is the same as the reaction solvent described in the amino group protection step. Among them, n-heptane, toluene, methylene chloride, tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl Sulfoxides are preferred, tetrahydrofuran, N, N-dimethylformamide, 1-methyl-2-pyrrolidinone, N, N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile and dimethyl sulfoxide are particularly preferred. These reaction solvents can be used alone or in combination.

The amount of the reaction solvent used may be 0.05 L or more, preferably 0.1 to 20 L, particularly preferably 0.15 to 10 L, relative to 1 mol of the protected fluoroamine represented by the general formula [2]. This reaction can also be carried out neat without using a reaction solvent.

The reaction temperature may be in the range of −50 to + 100 ° C., preferably −40 to + 90 ° C., particularly preferably −30 to + 80 ° C.

The reaction time may be performed within 36 hours, and varies depending on the raw material substrate, the reactants, and the reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, nuclear magnetic resonance, It is preferable to set the end point when the decrease in the raw material substrate is hardly recognized.

In the post-treatment, a fluoroamine represented by the general formula [4] can be obtained by employing a general operation in organic synthesis. The crude product can be purified to a high purity by activated carbon treatment, fractional distillation, recrystallization, column chromatography or the like, if necessary. If the target product has a low boiling point, it is convenient to directly recover and distill the reaction-terminated liquid. The target product can also be obtained by purification in the form of a salt with an inorganic acid such as hydrogen chloride, hydrogen bromide and sulfuric acid or an organic acid such as oxalic acid, phthalic acid and paratoluenesulfonic acid.

[Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples. Comparative Examples 1 to 4 are the results when an amino-protecting group different from the present invention was used.

で示されるアミノアルコール類３．００ｇ（３９．９ｍｍｏｌ、１．００ｅｑ）とトリエチルアミン２９．０ｇ（２８７ｍｍｏｌ、７．１９ｅｑ）を加えて溶解し、オルト－ニトロベンゼンスルホニルクロリド８．８９ｇ（４０．１ｍｍｏｌ、１．０１ｅｑ）を０℃で加え、室温で１時間攪拌した。反応終了液に水４０．０ｍＬを加え、酢酸エチル８０．０ｍＬで抽出し、回収水層を酢酸エチル８０．０ｍＬで再抽出し、回収有機層を合わせて無水硫酸ナトリウムで乾燥し、減圧濃縮し、真空乾燥し、カラムクロマトグラフィー（シリカゲル／酢酸エチル：ｎ－ヘキサン＝２：１）で精製することにより、下記式：

で示されるアミノアルコール類保護体（精製品）を７．９３ｇ得た。収率は７６％であった。ガスクロマトグラフィー純度は９５．８％であった。¹Ｈ－ＮＭＲを下に示す。 To 30.0 mL (0.752 L / mol) of methylene chloride, the following formula:

And 3.09 g (39.9 mmol, 1.00 eq) of amino alcohol and 29.0 g (287 mmol, 7.19 eq) of triethylamine were added and dissolved, and 8.89 g (40.1 mmol, 1) of ortho-nitrobenzenesulfonyl chloride was dissolved. .01eq) at 0 ° C. and stirred at room temperature for 1 hour. 40.0 mL of water was added to the reaction completed solution, extracted with 80.0 mL of ethyl acetate, the recovered aqueous layer was re-extracted with 80.0 mL of ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. By vacuum drying and purification by column chromatography (silica gel / ethyl acetate: n-hexane = 2: 1), the following formula:

As a result, 7.93 g of a protected amino alcohol (purified product) was obtained. The yield was 76%. The gas chromatography purity was 95.8%. ¹ H-NMR is shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 1.97 (br, 1H), 3.00 (s, 3H), 3.42 (m, 2H), 3 .80 (m, 2H), 7.84 (Ar, 4H).

で示されるフルオロアミン類保護体（精製品）を５．５５ｇ得た。収率は９３％であった。精製品は結晶であった。ガスクロマトグラフィー純度は９８．０％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 In a pressure resistant reaction vessel made of stainless steel (SUS), 5.93 g (22.8 mmol, 1.00 eq) of the amino alcohol protector (purified product) obtained above, 23.0 mL (1.01 L / mol) of acetonitrile, Add and dissolve 4.95 g (38.3 mmol, 1.68 eq) of diisopropylethylamine and 1.43 g (7.56 mmol, 0.332 eq) of diisopropylethylamine / hydrogen trifluoride, soak in a refrigerant bath at −78 ° C. 6.30 g (61.7 mmol, 2.71 eq) of fluoride was blown from the bomb and stirred at room temperature for 4 hours. A potassium carbonate aqueous solution [prepared from 3.00 g (21.7 mmol, 0.952 eq) of potassium carbonate and 30.0 mL of water] was added to the reaction completion solution, followed by extraction with 60.0 mL of ethyl acetate, and the recovered organic layer was washed with anhydrous sodium sulfate. After drying, concentration under reduced pressure, vacuum drying, and purification with a short column (silica gel / ethyl acetate: n-hexane = 2: 1), the following formula:

5.55 g of a protected fluoroamine (purified product) represented by the formula (1) was obtained. The yield was 93%. The purified product was a crystal. The gas chromatography purity was 98.0%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 3.03 (s, 3H), 3.61 (m, 2H), 4.62 (m, 2H), 7 .83 (Ar, 4H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; −58.84 (m, 1F).

で示されるフルオロアミン類（粗生成物）を９８７ｍｇ得た。粗生成物の¹⁹Ｆ－ＮＭＲ分析より内部標準法（内部標準物質α，α，α－トリフルオロトルエン）で定量したところ、目的物が６２２ｍｇ含まれていた。残り３６５ｍｇはＮ，Ｎ－ジメチルホルムアミドであった。収率は８２％であった。Ｎ，Ｎ－ジメチルホルムアミドを除くガスクロマトグラフィー純度は９４．２％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 To 20.0 mL (2.03 L / mol) of N, N-dimethylformamide, 2.58 g (9.84 mmol, 1.00 eq) of the protected fluoroamines (purified product) obtained above and 4.09 g of potassium carbonate (29.6 mmol / 3.01 eq) was added, 2.69 g (24.4 mmol, 2.48 eq) of thiophenol was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. By directly collecting and distilling the reaction end solution, the following formula:

As a result, 987 mg of a fluoroamine (crude product) was obtained. When quantified by an internal standard method (internal standard substance α, α, α-trifluorotoluene) from ¹⁹ F-NMR analysis of the crude product, 622 mg of the target product was contained. The remaining 365 mg was N, N-dimethylformamide. The yield was 82%. The gas chromatographic purity excluding N, N-dimethylformamide was 94.2%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 2.48 (s, 3H), 2.87 (m, 2H), 4.54 (m, 2H), amino Proton cannot be assigned.

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; −61.95 (m, 1F).

で示されるアミノアルコール類１８０ｇ（２．４０ｍｏｌ、１．１３ｅｑ）とトリエチルアミン２４１ｇ（２．３８ｍｏｌ、１．１２ｅｑ）を加えて溶解し、オルト－ニトロベンゼンスルホニルクロリド４７３ｇ（２．１３ｍｏｌ、１．００ｅｑ）を０℃で加え、室温で終夜攪拌した。反応終了後、析出したトリエチルアミン塩化水素塩を濾過により取り除き、酢酸エチル１．００Ｌを用いて塩を洗浄した。濾液と洗浄液を合わせ、減圧濃縮により容量をおよそ１／３に濃縮した後に水１．００Ｌを加え、酢酸エチル１．５０Ｌにて抽出した。水層を酢酸エチル５００ｍＬにて２回再抽出を行い、有機層を合わせて減圧濃縮を行った。濃縮後トルエン２００ｍＬを加えてさらに減圧濃縮を行い、下記式：

で示されるアミノアルコール類保護体を５３３ｇ得た。収率は９６％であった。ガスクロマトグラフィー純度は９２．０％であった。 To 2.20 L (1.03 L / mol) of acetonitrile, the following formula:

180 g (2.40 mol, 1.13 eq) of amino alcohol represented by the above and 241 g (2.38 mol, 1.12 eq) of triethylamine were added and dissolved, and 473 g (2.13 mol, 1.00 eq) of ortho-nitrobenzenesulfonyl chloride was dissolved. Added at 0 ° C. and stirred at room temperature overnight. After completion of the reaction, the precipitated triethylamine hydrochloride was removed by filtration, and the salt was washed with 1.00 L of ethyl acetate. The filtrate and the washing solution were combined, and the volume was concentrated to about 1/3 by concentration under reduced pressure, 1.00 L of water was added, and the mixture was extracted with 1.50 L of ethyl acetate. The aqueous layer was re-extracted twice with 500 mL of ethyl acetate, and the organic layers were combined and concentrated under reduced pressure. After concentration, 200 mL of toluene is added and further concentrated under reduced pressure.

As a result, 533 g of a protected amino alcohol was obtained. The yield was 96%. The gas chromatography purity was 92.0%.

で示されるフルオロアミン類保護体を結晶として５１７ｇ得た。収率は９６％であった。ガスクロマトグラフィー純度は９８．０％であった。 In a pressure-resistant reaction vessel made of stainless steel (SUS), 533 g (2.05 mol, 1.00 eq) of the amino alcohol protector obtained above, 500 mL (0.244 L / mol) of acetonitrile, 329 g (2.55 mol, diisopropylethylamine) 1.24 eq) and 39.7 g (0.210 mol, 0.102 eq) of diisopropylethylamine / hydrogen trifluoride were added and dissolved, and immersed in an ice bath to 246 g (2.41 mol, 1.18 eq) of sulfuryl fluoride. The mixture was further blown and stirred at room temperature for 2.5 hours. After the reaction completion solution was concentrated under reduced pressure, 500 mL of ethyl acetate and 500 mL of water were added. After the resulting crystals were collected by filtration, 1.00 L of ethyl acetate and 500 mL of water were added to the filtrate to separate the two layers. The obtained organic layer was washed twice with 1.00 L of water, and then with 500 mL of brine containing 50.0 g of sodium chloride. After concentration under reduced pressure, reprecipitation was performed with 1.20 L of ethyl acetate and 1.20 L of n-heptane, and vacuum drying was performed together with the previously collected crystals.

As a result, 517 g of a protected fluoroamine compound represented by the formula: The yield was 96%. The gas chromatography purity was 98.0%.

で示されるフルオロアミン類（粗生成物）を２１．４ｇ得た。収率は９１％であった。ガスクロマトグラフィー純度は９２．７％であった。 To 300 mL (0.987 L / mol) of 1,3-dimethyl-2-imidazolidinone, 79.6 g (304 mmol, 1.00 eq) of the protected fluoroamine obtained above, 53.7 g (487 mmol, thiophenol) 1.60 eq) and 82.2 g (595 mmol, 1.96 eq) of potassium carbonate were added at 0 ° C., and the mixture was stirred at room temperature for 3 hours. By directly collecting and distilling the reaction end solution, the following formula:

21.4 g of a fluoroamine represented by (crude product) was obtained. The yield was 91%. The gas chromatography purity was 92.7%.

で示されるアミノアルコール類５．１２ｇ（５７．４ｍｍｏｌ、１．０７ｅｑ）とトリエチルアミン５．６６ｇ（５５．９ｍｍｏｌ、１．０４ｅｑ）を加えて溶解し、オルト－ニトロベンゼンスルホニルクロリド１１．９ｇ（５３．７ｍｍｏｌ、１．００ｅｑ）を０℃で加え、室温で終夜攪拌した。反応終了後、酢酸エチル１００ｍＬと水３０．０ｍＬを加えて２層分離し、水層を酢酸エチル３０．０ｍＬにて２回再抽出した。有機層を合わせ、少量のシリカゲルカラムに有機層を通した後に、減圧濃縮を行い、下記式：

で示されるアミノアルコール類保護体を１３．２ｇ得た。収率は９０％であった。ガスクロマトグラフィー純度は９９．０％であった。¹Ｈ－ＮＭＲを下に示す。 To 53.0 mL (0.987 L / mol) of acetonitrile, the following formula:

Aminoalcohol 5.12 g (57.4 mmol, 1.07 eq) and triethylamine 5.66 g (55.9 mmol, 1.04 eq) were added and dissolved, and 11.9 g (53.7 mmol) of ortho-nitrobenzenesulfonyl chloride was dissolved. 1.00 eq) at 0 ° C. and stirred at room temperature overnight. After completion of the reaction, 100 mL of ethyl acetate and 30.0 mL of water were added to separate two layers, and the aqueous layer was re-extracted twice with 30.0 mL of ethyl acetate. The organic layers are combined, passed through a small amount of silica gel column, and then concentrated under reduced pressure.

As a result, 13.2 g of a protected amino alcohol was obtained. The yield was 90%. The gas chromatographic purity was 99.0%. ¹ H-NMR is shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 1.82 (m, 2H), 2.65 (br, 1H), 2.93 (s, 3H), 3 .38 (m, 2H), 3.70 (m, 2H), 7.60-7.70 (Ar, 3H), 7.96 (Ar, 1H).

で示されるフルオロアミン類保護体（精製品）を２．５２ｇ得た。収率は８６％であった。ガスクロマトグラフィー純度は９８．８％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 In a pressure resistant reaction vessel made of stainless steel (SUS), 2.91 g (10.6 mmol, 1.00 eq) of the amino alcohol protector obtained above, 11.0 mL (1.04 L / mol) of acetonitrile, diisopropylethylamine 1. 65 g (12.8 mmol, 1.21 eq) and diisopropylethylamine / hydrogen trifluoride 200 mg (1.06 mmol, 0.100 eq) were added and dissolved, and at 0 ° C., sulfuryl fluoride 4.60 g (45.1 mmol, 4.1 eq). 25 eq) was blown from the cylinder and stirred at room temperature for 3.5 hours. A potassium carbonate aqueous solution [prepared from 830 mg (6.01 mmol, 0.567 eq) of potassium carbonate and 10.0 mL of water] was added to the reaction completion solution, and the mixture was extracted with 40.0 mL of ethyl acetate. The organic layer was washed with 20.0 mL of water and 20.0 mL of brine and then dried over anhydrous sodium sulfate. This was concentrated under reduced pressure and purified by a short column (silica gel / ethyl acetate: n-hexane = 2: 1) to obtain the following formula:

As a result, 2.52 g of a protected fluoroamine (refined product) was obtained. The yield was 86%. The gas chromatography purity was 98.8%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, heavy solvent; CDCl ₃ ), δ ppm; 1.95-2.06 (m, 2H), 2.94 (s, 3H), 3.39 (m, 2H), 4.46 (m, 1H), 4.58 (m, 1H), 7.60-7.70 (Ar, 3H), 7.99 (Ar, 1H).

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; −59.85 (m, 1F).

で示されるフルオロアミン類（粗生成物）を７５０ｍｇ得た。収率は９７％であった。ガスクロマトグラフィー純度は８４．７％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 To 8.50 mL (1.0 L / mol) of 1,3-dimethyl-2-imidazolidinone, 2.34 g (8.47 mmol, 1.00 eq) of the protected fluoroamines (purified product) obtained above and 2.28 g (16.5 mmol, 1.95 eq) of potassium carbonate was added, 1.50 g (13.6 mmol, 1.61 eq) of thiophenol was added at 0 ° C., and the mixture was stirred at room temperature for 3 days. By directly collecting and distilling the reaction end solution, the following formula:

As a result, 750 mg of a fluoroamine (crude product) was obtained. The yield was 97%. The gas chromatographic purity was 84.7%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 2.00 (m, 2H), 2.46 (s, 3H), 2.75 (m, 2H), 4 .48 (m, 1H), 4.59 (m, 1H), amino proton cannot be assigned.

¹⁹ F-NMR (reference material; C ₆ F ₆ , deuterated solvent; CDCl ₃ ), δ ppm; −59.82 (m, 1F).

で示されるアミノアルコール類保護体を１０．９ｇ得た。収率は７２％であった。ガスクロマトグラフィー純度は９２．０％であった。¹Ｈ－ＮＭＲを下に示す。 In 50.0 mL (0.998 L / mol) of acetonitrile, 5.70 g (55.3 mmol, 1.10 eq) of valinol and 5.52 g (54.6 mmol, 1.09 eq) of triethylamine were added and dissolved, and ortho-nitrobenzenesulfonyl was dissolved. 11.1 g (50.1 mmol, 1.00 eq) of chloride was added at 0 ° C. and stirred at room temperature overnight. After completion of the reaction, 40.0 mL of ethyl acetate and 20.0 mL of water were added to separate two layers, and the aqueous layer was re-extracted twice with 30.0 mL of ethyl acetate. The organic layers were combined, passed through a small amount of silica gel column, and concentrated under reduced pressure. The obtained concentrate was dissolved in 50.0 mL of acetonitrile and 50.0 mL of N, N-dimethylformamide, and then 10.9 g (76.8 mmol, 1.53 eq) of iodomethane and 2.39 g (59.59 of 60% sodium hydride). After adding 8 mmol, 1.19 eq), the mixture was stirred at 50 ° C. for 3 hours. After completion of the reaction, 300 mL of ethyl acetate and 40.0 mL of water were added to separate two layers, and the aqueous layer was re-extracted with 40.0 mL of ethyl acetate. The organic layers are combined, and the organic layer is passed through a small amount of silica gel column, followed by concentration under reduced pressure.

As a result, 10.9 g of a protected amino alcohol was obtained. The yield was 72%. The gas chromatography purity was 92.0%. ¹ H-NMR is shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 0.83 (d, 3H), 0.96 (d, 3H), 1.77 (m, 1H), 1 .97 (m, 1H), 2.93 (s, 3H), 3.57 (m, 2H), 3.85 (m, 1H), 7.60-7.70 (Ar, 3H), 8. 05 (Ar, 1H).

で示されるフルオロアミン類保護体を３．２６ｇ得た。収率は９７％であった。ガスクロマトグラフィー純度は８６．７％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 In a pressure resistant reaction vessel made of stainless steel (SUS), 3.33 g (11.0 mmol, 1.00 eq) of the amino alcohol protector obtained above, 11.0 mL (1.00 L / mol) of acetonitrile, 1. 76 g (13.6 mmol, 1.24 eq) and 200 mg (1.06 mmol, 0.0964 eq) of diisopropylethylamine / hydrogen trifluoride were added and dissolved, and 4.00 g (39.2 mmol, 3.9.2 mmol) of sulfuryl fluoride was added at 0 ° C. 56 eq) was blown from a cylinder and stirred at room temperature for 3 hours. A potassium carbonate aqueous solution [prepared from 820 mg (5.93 mmol, 0.539 eq) of potassium carbonate and 20.0 mL of water] was added to the reaction completion solution, and the mixture was extracted with 30.0 mL of ethyl acetate. The organic layer was washed twice with 20.0 mL of water and then dried over anhydrous sodium sulfate. After concentration under reduced pressure, purification with a short column (silica gel / ethyl acetate: n-hexane = 1: 1) yields the following formula:

3.26 g of a protected fluoroamine represented by the following formula was obtained. The yield was 97%. The gas chromatographic purity was 86.7%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 0.92 (d, 3H), 1.04 (d, 3H), 2.04 (m, 1H), 2 .97 (s, 3H), 3.72 (m, 1H), 4.49-4.71 (m, 2H), 7.60-7.70 (Ar, 3H), 8.00 (Ar, 1H) ).

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; −66.71 (m, 1F).

で示されるフルオロアミン類（粗生成物）を７９０ｍｇ得た。収率は６２％であった。ガスクロマトグラフィー純度は７４．４％であった。¹Ｈと¹⁹Ｆ－ＮＭＲを下に示す。 To 10.0 mL (0.935 L / mol) of 1,3-dimethyl-2-imidazolidinone, 3.26 g (10.7 mmol, 1.00 eq) of the protected fluoroamine obtained above and 2. 66 g (19.2 mmol, 1.79 eq) was added, 1.68 g (15.2 mmol, 1.42 eq) of thiophenol was added at 0 ° C., and the mixture was stirred at room temperature overnight. By directly collecting and distilling the reaction end solution, the following formula:

As a result, 790 mg of a fluoroamine (crude product) was obtained. The yield was 62%. The gas chromatography purity was 74.4%. ¹ H and ¹⁹ F-NMR are shown below.

¹ H-NMR (reference material; Me ₄ Si, deuterated solvent; CDCl ₃ ), δ ppm; 0.96 (m, 6H), 1.88 (m, 1H), 2.48 (m, 4H), 4 .30-4.60 (m, 2H), amino proton cannot be assigned.

¹⁹ F-NMR (reference material; C ₆ F ₆ , heavy solvent; CDCl ₃ ), δ ppm; −67.57 (m, 1F).

で示されるアミノアルコール類Ｂｎ保護体２．９５ｇ（１７．９ｍｍｏｌ、１．００ｅｑ）、アセトニトリル２０．０ｍＬ（１．１２Ｌ／ｍｏｌ）、ジイソプロピルエチルアミン７．０６ｇ（５４．６ｍｍｏｌ、３．０５ｅｑ）とジイソプロピルエチルアミン・三フッ化水素３．３６ｇ（１７．８ｍｍｏｌ、０．９９４ｅｑ）を加えて溶解し、－７８℃の冷媒浴に浸し、スルフリルフルオリド３．５０ｇ（３４．３ｍｍｏｌ、１．９２ｅｑ）をボンベより吹き込み、室温で４時間攪拌した。反応終了液に炭酸カリウム水溶液［炭酸カリウム１５．０ｇ（１０９ｍｍｏｌ、６．０９ｅｑ）と水３０．０ｍＬから調製］を加え、酢酸エチル６０．０ｍＬで抽出し、回収有機層を無水硫酸ナトリウムで乾燥し、減圧濃縮し、真空乾燥することにより、下記式：

で示されるフルオロアミン類Ｂｎ保護体（粗生成物）を３．３６ｇ得た。粗生成物の¹⁹Ｆ－ＮＭＲ分析より内部標準法（内部標準物質α，α，α－トリフルオロトルエン）で定量したところ、目的物の存在は確認できたものの最大でも１５０ｍｇしか含まれていなかった。収率は５％未満であった。 [Comparative Example 1]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula:

2.95 g (17.9 mmol, 1.00 eq) of amino alcohols represented by the following formula: 20.0 mL (1.12 L / mol) of acetonitrile, 7.06 g (54.6 mmol, 3.05 eq) of diisopropylethylamine and diisopropyl Ethylamine / hydrogen trifluoride (3.36 g, 17.8 mmol, 0.994 eq) was added and dissolved, immersed in a −78 ° C. refrigerant bath, and sulfuryl fluoride (3.50 g, 34.3 mmol, 1.92 eq) was bombed. The mixture was further blown and stirred at room temperature for 4 hours. A potassium carbonate aqueous solution [prepared from 15.0 g (109 mmol, 6.09 eq) of potassium carbonate and 30.0 mL of water] was added to the reaction completion solution, and the mixture was extracted with 60.0 mL of ethyl acetate, and the recovered organic layer was dried over anhydrous sodium sulfate. By vacuum concentration and vacuum drying, the following formula:

3.36 g of a protected Bn protected product (crude product) was obtained. As a result of ¹⁹ F-NMR analysis of the crude product, quantified by an internal standard method (internal standard substance α, α, α-trifluorotoluene), the presence of the target product was confirmed, but it contained only 150 mg at the maximum. . The yield was less than 5%.

で示されるアミノアルコール類Ｂｏｃ保護体１．７４ｇ（９．９３ｍｍｏｌ、１．００ｅｑ）、アセトニトリル１０．０ｍＬ（１．０１Ｌ／ｍｏｌ）、ジイソプロピルエチルアミン１．５７ｇ（１２．１ｍｍｏｌ、１．２２ｅｑ）とジイソプロピルエチルアミン・三フッ化水素２０５ｍｇ（１．０８ｍｍｏｌ、０．１０９ｅｑ）を加えて溶解し、－７８℃の冷媒浴に浸し、スルフリルフルオリド２．００ｇ（１９．６ｍｍｏｌ、１．９７ｅｑ）をボンベより吹き込み、室温で３時間攪拌した。反応終了液に炭酸カリウム水溶液［炭酸カリウム３００ｍｇ（２．１７ｍｍｏｌ、０．２１９ｅｑ）と水２０．０ｍＬから調製］を加え、酢酸エチル３０．０ｍＬで抽出し、回収有機層を水２０．０ｍＬで洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮し、真空乾燥することにより、下記式：

で示されるフルオロアミン類Ｂｏｃ保護体（粗生成物）を１．１２ｇ得た。粗生成物の¹⁹Ｆ－ＮＭＲ分析より内部標準法（内部標準物質α，α，α－トリフルオロトルエン）で定量したところ、目的物の存在は確認できたものの最大でも８８．０ｍｇしか含まれていなかった。収率は５％未満であった。 [Comparative Example 2]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula:

1.74 g (9.93 mmol, 1.00 eq) of the amino alcohols Boc protector represented by the following: 10.0 mL (1.01 L / mol) of acetonitrile, 1.57 g (12.1 mmol, 1.22 eq) of diisopropylethylamine and diisopropyl 205 mg (1.08 mmol, 0.109 eq) of ethylamine / hydrogen trifluoride was added and dissolved, immersed in a refrigerant bath at −78 ° C., and 2.00 g (19.6 mmol, 1.97 eq) of sulfuryl fluoride was blown from the cylinder. And stirred at room temperature for 3 hours. Potassium carbonate aqueous solution [prepared from 300 mg (2.17 mmol, 0.219 eq) of potassium carbonate and 20.0 mL of water] was added to the reaction completion solution, extracted with 30.0 mL of ethyl acetate, and the recovered organic layer was washed with 20.0 mL of water. Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the following formula:

As a result, 1.12 g of a Boc protected product (crude product) was obtained. The amount of the target product was confirmed by the internal standard method (internal standard substance α, α, α-trifluorotoluene) from ¹⁹ F-NMR analysis of the crude product, but it contained only 88.0 mg at the maximum. There wasn't. The yield was less than 5%.

で示されるアミノアルコール類Ｃｂｚ保護体２．１２ｇ（１０．１ｍｍｏｌ、１．００ｅｑ）、アセトニトリル１０．０ｍＬ（０．９９０Ｌ／ｍｏｌ）、ジイソプロピルエチルアミン１．５８ｇ（１２．２ｍｍｏｌ、１．２１ｅｑ）とジイソプロピルエチルアミン・三フッ化水素１８７ｍｇ（９８８μｍｏｌ、０．０９７８ｅｑ）を加えて溶解し、－７８℃の冷媒浴に浸し、スルフリルフルオリド５．００ｇ（４９．０ｍｍｏｌ、４．８５ｅｑ）をボンベより吹き込み、室温で３時間３０分攪拌した。反応終了液に炭酸カリウム水溶液［炭酸カリウム３９０ｍｇ（２．８２ｍｍｏｌ、０．２７９ｅｑ）と水２０．０ｍＬから調製］を加え、酢酸エチル３０．０ｍＬで抽出し、回収有機層を水２０．０ｍＬで洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮し、真空乾燥することにより、下記式：

で示されるフルオロアミン類Ｃｂｚ保護体（粗生成物）を１．６９ｇ得た。粗生成物の¹⁹Ｆ－ＮＭＲ分析より内部標準法（内部標準物質α，α，α－トリフルオロトルエン）で定量したところ、目的物の存在は確認できたものの最大でも１０７ｍｇしか含まれていなかった。収率は５％未満であった。 [Comparative Example 3]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula:

2.12 g (10.1 mmol, 1.00 eq) of protected amino alcohols represented by the following formula: 10.0 mL (0.990 L / mol) of acetonitrile, 1.58 g (12.2 mmol, 1.21 eq) of diisopropylethylamine and diisopropyl Ethylamine / hydrogen trifluoride 187 mg (988 μmol, 0.0978 eq) was added and dissolved, immersed in a −78 ° C. refrigerant bath, and sulfuryl fluoride 5.00 g (49.0 mmol, 4.85 eq) was blown from the bomb. For 3 hours 30 minutes. Potassium carbonate aqueous solution [prepared from 390 mg (2.82 mmol, 0.279 eq) of potassium carbonate and 20.0 mL of water] was added to the reaction completion solution, extracted with 30.0 mL of ethyl acetate, and the recovered organic layer was washed with 20.0 mL of water. Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the following formula:

1.69 g of a Cbz protected product (crude product) was obtained. As a result of ¹⁹ F-NMR analysis of the crude product, quantified by the internal standard method (internal standard substance α, α, α-trifluorotoluene), the presence of the target product was confirmed, but it contained only 107 mg at the maximum. . The yield was less than 5%.

で示されるアミノアルコール類Ａｃ保護体１．１９ｇ（１０．２ｍｍｏｌ、１．００ｅｑ）、アセトニトリル１０．０ｍＬ（０．９８０Ｌ／ｍｏｌ）、ジイソプロピルエチルアミン１．５７ｇ（１２．１ｍｍｏｌ、１．１９ｅｑ）とジイソプロピルエチルアミン・三フッ化水素１９９ｍｇ（１．０５ｍｍｏｌ、０．１０３ｅｑ）を加えて溶解し、－７８℃の冷媒浴に浸し、スルフリルフルオリド３．４０ｇ（３３．３ｍｍｏｌ、３．２６ｅｑ）をボンベより吹き込み、室温で４時間攪拌した。反応終了液に炭酸カリウム水溶液［炭酸カリウム３２０ｍｇ（２．３２ｍｍｏｌ、０．２２７ｅｑ）と水２０．０ｍＬから調製］を加え、酢酸エチル３０．０ｍＬで抽出し、回収有機層を水２０．０ｍＬで洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮し、真空乾燥することにより、下記式：

で示されるフルオロアミン類Ａｃ保護体（粗生成物）を５７５ｍｇ得た。粗生成物の¹⁹Ｆ－ＮＭＲ分析より内部標準法（内部標準物質α，α，α－トリフルオロトルエン）で定量したところ、目的物の存在は確認できたものの最大でも６１．０ｍｇしか含まれていなかった。収率は５％未満であった。 [Comparative Example 4]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula:

1.19 g (10.2 mmol, 1.00 eq) of protected amino alcohols represented by the formula: 10.0 mL (0.980 L / mol) of acetonitrile, 1.57 g (12.1 mmol, 1.19 eq) of diisopropylethylamine and diisopropyl 199 mg (1.05 mmol, 0.103 eq) of ethylamine / hydrogen trifluoride was added and dissolved, immersed in a −78 ° C. refrigerant bath, and 3.40 g (33.3 mmol, 3.26 eq) of sulfuryl fluoride was blown from the cylinder. And stirred at room temperature for 4 hours. Potassium carbonate aqueous solution [prepared from 320 mg (2.32 mmol, 0.227 eq) of potassium carbonate and 20.0 mL of water] was added to the reaction completion solution, extracted with 30.0 mL of ethyl acetate, and the recovered organic layer was washed with 20.0 mL of water. Dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried under vacuum to obtain the following formula:

As a result, 575 mg of a protected Acamine (crude product) was obtained. The amount of the target product was confirmed by ¹⁹ F-NMR analysis of the crude product by internal standard method (internal standard substance α, α, α-trifluorotoluene). There wasn't. The yield was less than 5%.

Fluoroamines targeted in the present invention can be used as intermediates for medicines and agricultural chemicals.

Claims (12)

General formula [1]:

[Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, and R ² independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. M represents an integer of 2, 3 or 4, n represents an integer of 4, 6 or 8, and P ¹ represents an ortho, meta or para-nitrobenzenesulfonyl group. ]
Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by formula (2) is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

[Wherein R ¹ , R ² , m, n, and P ¹ are the same as those in the formula [1]. ]
A process for producing a protected fluoroamine compound represented by the formula: The method according to claim 1, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride. General formula [3]:

[Wherein R ¹ represents an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group, and R ² independently represents a hydrogen atom, an alkyl group, a substituted alkyl group, an aromatic ring group or a substituted aromatic ring group. M represents an integer of 2, 3 or 4, and n represents an integer of 4, 6 or 8. ]
By protecting the amino group of the amino alcohol represented by general formula [1]:

[Wherein R ¹ , R ² , m and n are the same as those in the above-mentioned formula [3]. P ¹ represents an ortho, meta or para-nitrobenzenesulfonyl group. ]
An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [2]:

[Wherein R ¹ , R ² , m, n, and P ¹ are the same as those in the formula [1]. ]
And a deprotection step for deprotecting the protecting group of the amino group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [4]:

[Wherein R ¹ , R ² , m and n are the same as those in the above-mentioned formula [3]. ]
A process for producing a fluoroamine represented by the formula: The method according to claim 3, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride. General formula [5]:

[Wherein, R ³ represents an alkyl group or a substituted alkyl group, R ⁴ independently represents a hydrogen atom, an alkyl group or a substituted alkyl group, x represents an integer of 2 or 3, and y represents 4 or 6] Represents an integer, and P ² represents an ortho- or para-nitrobenzenesulfonyl group. ]
Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by formula ( _II ) is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

[Wherein R ³ , R ⁴ , x, y, and P ² are the same as those in the formula [5]. ]
A process for producing a protected fluoroamine compound represented by the formula: 6. The method according to claim 5, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride. General formula [7]:

[Wherein, R ³ represents an alkyl group or a substituted alkyl group, R ⁴ independently represents a hydrogen atom, an alkyl group or a substituted alkyl group, x represents an integer of 2 or 3, and y represents 4 or 6] Represents an integer. ]
By protecting the amino group of the amino alcohol represented by general formula [5]:

[Wherein R ³ , R ⁴ , x, and y are the same as those in the formula [7]. P ² represents an ortho or para-nitrobenzenesulfonyl group. ]
An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [6]:

[Wherein R ³ , R ⁴ , x, y, and P ² are the same as those in the formula [5]. ]
And a deprotection step of deprotecting the protecting group of the amino group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [8]:

[Wherein R ³ , R ⁴ , x, and y are the same as those in the formula [7]. ]
A process for producing a fluoroamine represented by the formula: The method according to claim 7, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride. General formula [9]:

Which includes a dehydroxyfluorination step in which a protected amino alcohol represented by the above formula is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base:

A process for producing a protected fluoroamine compound represented by the formula:
[Wherein, Me represents a methyl group. ] The method according to claim 9, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride. General formula [11]:

By protecting the amino group of the amino alcohol represented by general formula [9]:

An amino group protecting step for converting into a protected amino alcohol represented by
By reacting the protected amino alcohol with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base, the general formula [10]:

And a deprotection step of deprotecting an amino-protecting group of the protected fluoroamines, which is converted to a protected fluoroamines represented by the general formula [12]:

A process for producing a fluoroamine represented by the formula:
[Wherein, Me represents a methyl group. ] The method according to claim 11, wherein the dehydroxyfluorination step is carried out in the presence of a salt or complex comprising an organic base and hydrogen fluoride.