JP4776220B2 - Method for producing fluoroamide or fluoroamine from amino alcohol - Google Patents

Description

  The present invention relates to a method for producing fluoroamide or fluoroamine from aminoalcohol using α, α-difluoroamine. The fluorine compound such as fluoroamide or fluoroamine produced by the method of the present invention is useful as a fluorinating agent or a fluorine-containing building block for producing pharmaceuticals, other functional chemicals, or various fluorine compounds. I can do it.

As a method for producing a fluorine compound by introducing fluorine atoms into a substrate, there is a direct fluorination method using fluorine gas (F ₂ ). In the case of a substrate having a functional group such as oxygen, sulfur, and halogen, inorganic fluorine compounds such as hydrogen fluoride and sulfur tetrafluoride and other fluorinating agents such as hydrogen fluoride-pyridine (Olah reagent), fluoroalkylamine The functional group can be converted to fluorine using a type of Yarovenko reagent or an improved type of Ishikawa reagent, diethylaminosulfur trifluoride (DAST), or the like. A halogen-fluorine exchange method using an alkali metal salt of fluorine is also applicable. (For example, see Non-Patent Documents 1 and 2)

In the above fluorination technology, fluorine gas, hydrogen fluoride, and sulfur tetrafluoride have great toxicity, corrosiveness, and explosion risk, and have problems such as requiring special equipment and technology for handling. In order to avoid this problem and introduce fluorine safely and simply, various fluorinating agents have been developed. The inventors of the present invention are represented by the general formula (1), which is a nucleophilic fluorinating agent that has solved the drawbacks of the conventional fluorinating agent and has high thermal stability and easy industrial handling. α, α-Difluoroamine was proposed. This difluoroamine is characterized in that alcohols and saccharides having a hydroxyl group in the molecule can be selectively fluorinated in a safe and good yield (see, for example, Patent Documents 1, 2 , and 3).

On the other hand, with respect to the prior art and techniques relating to a method for producing fluoroamide or fluoroamine from an amino alcohol having an amino group in addition to a hydroxyl group, a method using a pyridine-HF complex known as an Olah reagent as a fluorinating agent (for example, Non-Patent Document 3 ), a method using SF ₄ or HF (for example, see Non-Patent Document 4 ) has only been reported. In the method of Non-Patent Document 4, α, β-amino alcohol can be converted to α, β-fluoroamine, or α-hydroxyaziridine can be dehydrooxyfluorinated. However, the yield and selectivity are relatively good, but there are problems such as that it takes several days to complete the reaction. In the non-patent document 5 method for fluorinating aminoalcohols using SF ₄ , the yield of the target fluorinated amine is at most 30 to 80%. In this way, it is extremely difficult to implement industrially from the viewpoint of economy, corrosivity, and safety. For example, the selectivity of the reaction is inadequate and it is necessary to carry out the reaction at a low temperature of -10 ° C. it is conceivable that.

As described above, there are few prior documents and techniques relating to methods for producing fluoroamides and fluoroamines from amino alcohols, and it is difficult to industrially produce fluoroamines from amino alcohols simply and safely. Further, there is no literature regarding a method for producing fluoroamide or fluoroamine from amino alcohol using α, α-difluoroamine.
Furthermore, there is no prior art or technique that describes stereospecific reaction examples, that is, that chiral fluoroamides or chiral fluoroamines can be produced from chiral (optically active) amino alcohols.

JP 2004-123605 A JP 2004-182665 A JP 2004-189655 A Yoshikazu Kimura, Journal of Organic Synthesis Society, 47, (1989) p258 G. A. Olah et al., Journal of Organic Chemistry, 44, 3872, 1979 G. Alvernhe et al., J. Chem. Res., 246, 1983 J. Kollonitsch et al., Journal of Organic Chemistry, 44, 771, 1979

（猶、一般式（１）で表されるα，α−ジフルオロアミンのＲ_０，Ｒ_１及びＲ_２は水素原子又は置換基を有する事のあるアルキル基、アリール基、アルキルアミノ基若しくはアリールアミノ基であり、それぞれが同一でも異なっていても良い。また、Ｒ_０，Ｒ_１及びＲ_２の二つ以上が結合して環を形成していても良い。一般式（２）、一般式（３）及び一般式（４）で表されるフッ素化合物並びにその基質中のＲ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７は水素原子又は置換基を有する事のあるアルキル基、アリール基、アルキルアミノ基若しくはアリールアミノ基であり、それぞれが同一でも異なっていても良い。また、Ｒ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７の二つ以上が結合して環を形成していても良い。） The object of the present invention is to use the α, α-difluoroamine represented by the general formula (1) from the racemic or chiral β or γ-aminoalcohol represented by the general formula (2). The present invention provides an industrial means for producing a racemic or chiral β or γ-fluoroamide represented by formula (4) or a racemic or chiral β or γ-fluoroamine represented by the general formula (4) safely and easily. There is.

(R, R ₀ , R ₁ and R ₂ of α, α-difluoroamine represented by the general formula (1) are a hydrogen atom or an alkyl group, aryl group, alkylamino group or arylamino which may have a substituent. Each of them may be the same or different, and two or more of R ₀ , R ₁ and R ₂ may be bonded to form a ring. 3) and the fluorine compound represented by the general formula (4) and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the substrate are a hydrogen atom or an alkyl group which may have a substituent, an aryl group, An alkylamino group or an arylamino group, each of which may be the same or different, and two or more of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are combined to form a ring; Is also good.)

  As a result of intensive studies to solve the above problems, the present inventors, for example, in the case where an alcohol having a secondary amino group at the β or γ position is used as a substrate, is represented by the general formula (1) used for fluorination. The α, α-difluoroamine represented can selectively convert a hydroxyl group into a fluorine group and a secondary amino group into an amide group, and can be used under normal heating means or microwave irradiation. It has been found that the reaction proceeds with a sufficient yield, and further, if this fluoroamide group is reduced with an appropriate reducing agent, a fluoroamine can be easily obtained. Moreover, when the said fluorination reaction was performed in water presence, it discovered that the amino ester in which the hydroxyl group was protected was obtained, and came to complete this invention.

（猶、一般式（１）で表されるα，α−ジフルオロアミンのＲ_０，Ｒ_１及びＲ_２は水素原子又は置換基を有する事のあるアルキル基、アリール基、アルキルアミノ基若しくはアリールアミノ基であり、それぞれが同一でも異なっていても良い。また、Ｒ_０，Ｒ_１及びＲ_２の二つ以上が結合して環を形成していても良い。一般式（２）、一般式（３）で表されるフッ素化合物並びにその基質中のＲ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７は水素原子又は置換基を有する事のあるアルキル基、アリール基、アルキルアミノ基若しくはアリールアミノ基であり、それぞれが同一でも異なっていても良い。また、Ｒ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７の二つ以上が結合して環を形成していても良い。）
２．一般式（１）で表されるα，α−ジフルオロアミンのＲ_０が、フェニル基、３−メチルフェニル基、又は２−メトキシフェニル基であり、Ｒ_１及びＲ_２が、炭素数１から１６迄のアルキル基である、１に記載のアミノアルコールからフルオロアミドを製造する方法。
３．一般式（２）で表されるアミノアルコールから、一般式（３）で示されるフルオロアミドを製造する際、マイクロ波照射下に反応を行う、１又は２に記載のアミノアルコールからフルオロアミドを製造する方法。
４．一般式（２）で表されるアミノアルコールが群１に属するものである、１から３の何れかに記載のアミノアルコールからフルオロアミドを製造する方法。
［群１］
Ｎ−メチルエタノールアミン、Ｎ−メチルジエタノールアミン、Ｎ−（β−アミノエチル）エタノールアミン、Ｎ−（β−アミノエチル）ジエタノールアミン、Ｎ−ｎ−ブチルエタノールアミン、Ｎ−ｎ−ブチルジエタノールアミン、Ｎ−t−ブチルエタノールアミン、Ｎ−t−ブチルジエタノールアミン、Ｎ，Ｎ−ジメチルエタノールアミン、２−（メチルアミノ）エタノール、２−（アニリノ）エタノール、２−（ベンジルアミノ）エタノール、３−（ベンジルアミノ）プロパン−１−オール、１−（ベンジルアミノ）オクタン−２−オール、２−（ベンジルアミノ）−２−フェニルエタノール、２−（ベンジルアミノ）−１−フェニルプロパン−１−オール、（２−（イソブチルアミノ）フェニル）メタノール、２−（ベンジルアミノ）シクロヘキサノール、３−（ベンジルアミノ）−４−イソプロポキシブタン−２−オール、ピロリジン−３−オール、t−アミノアルコール、Ｎ，Ｎ−ジアルキルノルエフェドリン、ジフェニル（１−メチルピロリジン−２−イル）メタノール、-フェニル−２−ピロリジニル−１−プロパノール、Ｄ−バリノール、Ｌ−バリノール、Ｌ−アラニノール、Ｌ−メチオニノール、Ｌ−ロイシノール、Ｌ−イソロイシノール、Ｄ−フェニルアラニノール、Ｌ−フェニルアラニノール、Ｄ−プロリノール、Ｌ−プロリノール、Ｌ−トリプトファノール、（Ｒ）−２−フェニルグリシノール、（Ｓ）−２−フェニルグリシノール、Ｌ−t−ロイシノール、（R）−３−ピロリジノール、（R）−１−アミノ−２−プロパノール、（Ｓ）−１−アミノ−２−プロパノール、（Ｒ）−２−アミノ−１−ブタノール、（Ｓ）−２−アミノ−１−ブタノール、（1R,2R）−２−アミノ−１−フェニル−１，３−プロパンジオール、（1S,2S）−２−アミノ−１−フェニル−１，３−プロパンジオール、（1R,2S）−２−アミノ−１，２−ジフェニルエタノール、（1S,2R）−２−アミノ−１，２−ジフェニルエタノール
５．一般式（２）で表されるアミノアルコールが光学活性アミノアルコールである、１から４の何れかに記載のアミノアルコールからフルオロアミドを製造する方法。
６．１から５の何れかに記載の方法によって製造された一般式（３）で表されるフルオロアミドを還元して、一般式（４）で表されるフルオロアミンを得る、アミノアルコールからフルオロアミンを製造する方法。

（猶、一般式（４）で表されるフッ素化合物並びにその基質中のＲ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７は水素原子又は置換基を有する事のあるアルキル基、アリール基、アルキルアミノ基若しくはアリールアミノ基であり、それぞれが同一でも異なっていても良い。また、Ｒ_３，Ｒ_４，Ｒ_５，Ｒ_６及びＲ_７の二つ以上が結合して環を形成していても良い。） That is, the present invention relates to a method for producing fluoroamide or fluoroamine from amino alcohol using α, α-difluoroamine represented by the general formula (1), characterized by comprising 1 to 6 below. .
1. Using the α, α-difluoroamine represented by the general formula (1) to obtain the fluoroamide represented by the general formula (3) from the amino alcohol represented by the general formula (2), A method for producing a fluoroamide from an amino alcohol.

(R, R ₀ , R ₁ and R ₂ of α, α-difluoroamine represented by the general formula (1) are a hydrogen atom or an alkyl group, aryl group, alkylamino group or arylamino which may have a substituent. Each of them may be the same or different, and two or more of R ₀ , R ₁ and R ₂ may be bonded to form a ring. 3) R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the fluorine compound represented by 3) and a substrate thereof are a hydrogen atom or an alkyl group, aryl group, alkylamino group or arylamino which may have a substituent. And each of them may be the same or different, and two or more of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ may be bonded to form a ring.)
2. R ₀ of the α, α-difluoroamine represented by the general formula (1) is a phenyl group, a 3-methylphenyl group, or a 2-methoxyphenyl group, and R ₁ and R _{2 each} have 1 to 16 carbon atoms. A process for producing a fluoroamide from an amino alcohol according to 1, which is an alkyl group up to.
3. When the fluoroamide represented by the general formula (3) is produced from the amino alcohol represented by the general formula (2), the reaction is performed under microwave irradiation, and the fluoroamide is produced from the amino alcohol according to 1 or 2. how to.
4). A method for producing a fluoroamide from an amino alcohol according to any one of 1 to 3, wherein the amino alcohol represented by the general formula (2) belongs to Group 1.
[Group 1]
N-methylethanolamine, N-methyldiethanolamine, N- (β-aminoethyl) ethanolamine, N- (β-aminoethyl) diethanolamine, Nn-butylethanolamine, Nn-butyldiethanolamine, Nt -Butylethanolamine, Nt-butyldiethanolamine, N, N-dimethylethanolamine, 2- (methylamino) ethanol, 2- (anilino) ethanol, 2- (benzylamino) ethanol, 3- (benzylamino) propane -1-ol, 1- (benzylamino) octan-2-ol, 2- (benzylamino) -2-phenylethanol, 2- (benzylamino) -1-phenylpropan-1-ol, (2- (isobutyl Amino) phenyl) methanol, 2- (benzylamino) si Lohexanol, 3- (benzylamino) -4-isopropoxybutan-2-ol, pyrrolidin-3-ol, t-aminoalcohol, N, N-dialkylnorephedrine, diphenyl (1-methylpyrrolidin-2-yl) Methanol, -phenyl-2-pyrrolidinyl-1-propanol, D-valinol, L-valinol, L-alaninol, L-methioninol, L-leucinol, L-isoleucinol, D-phenylalaninol, L-phenylalaninol, D -Prolinol, L-prolinol, L-tryptophanol, (R) -2-phenylglycinol, (S) -2-phenylglycinol, L-t-leucinol, (R) -3-pyrrolidinol, ( R) -1-amino-2-propanol, (S) -1-amino-2-propa (R) -2-amino-1-butanol, (S) -2-amino-1-butanol, (1R, 2R) -2-amino-1-phenyl-1,3-propanediol, (1S, 2S) -2-amino-1-phenyl-1,3-propanediol, (1R, 2S) -2-amino-1,2-diphenylethanol, (1S, 2R) -2-amino-1,2-diphenyl Ethanol 5. The method for producing a fluoroamide from an amino alcohol according to any one of 1 to 4, wherein the amino alcohol represented by the general formula (2) is an optically active amino alcohol.
The fluoroamide represented by the general formula (3) produced by the method according to any one of 6.1 to 5 is reduced to obtain the fluoroamine represented by the general formula (4). A method for producing an amine.

(Ryo, R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the fluorine compound represented by the general formula (4) and its substrate are a hydrogen atom or an alkyl group which may have a substituent, an aryl group, An alkylamino group or an arylamino group, each of which may be the same or different, and two or more of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are combined to form a ring; Is also good.)

According to the present invention, there is no danger of corrosion or explosion in the conventional fluorination of aminoalcohols using HF-pyridine, SF ₄ , DAST, etc., and it can be carried out safely on an industrial scale. A new route to synthesize fluoroamides or fluoroamines can be provided. In addition, the method of the present invention can stereoselectively dehydroxy-fluorinate an amino alcohol having a chiral hydroxyl group and / or a chiral amino group, and simultaneously introduce fluorine into the amino alcohol and protect the hydroxyl group. In particular, it has high utility as a method for introducing a fluorine group for a chiral drug or a production of a fluorine-containing building block, for which stereospecificity is strongly demanded from the standpoint of medicinal properties.

The present invention will be described in detail below. The α, α-difluoroamine used in the reaction with the substrate amino alcohol is a compound represented by the general formula (1).
R ₀ , R ₁ and R ₂ of the α, α-difluoroamine are a hydrogen atom or an alkyl group, aryl group, alkylamino group or arylamino group which may have a substituent, and each is the same or different. May be. Two or more of R ₀ , R ₁ , and R ₂ may be bonded to form a ring.
Examples of the alkyl group include linear or branched ones having 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl. , Neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4 -Methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-me Rupropyl, 1-ethyl-2-methylpropyl, 1-ethyl-3-methylpropyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, n-decyl, n-dodecyl, cyclohexyl, decalyl, norbornyl, There are bicyclohexyl, adamantyl, menthyl and isomers thereof, and other preferable examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl, cyclohexyloxy and the like. In addition, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,2-cyclopentylene, 1,2-cyclohexylene, etc. I can do it. Moreover, one part or all part of an alkyl group may have an unsaturated bond.

Aryl groups include phenyl, o-tolyl, m-tolyl, p-tolyl, dimethylphenyl, naphthyl, fluorenyl, anthryl, phenanthrenyl and their positional isomers, cumyl, mesityl, trimethylphenyl, hydroxyphenyl, methoxyphenyl and their positions Isomers, naphthyl, methyl naphthyl, dimethyl naphthyl, hydroxy naphthyl, biphenyl, tetralyl, t-phenyl and the like, and aryl groups containing heteroatoms include furanyl, oxazolyl, pyridinyl, quinolyl, isoquinolyl, benzofuranyl, dibenzofuranyl, Examples include benzothienyl, chromenyl, indoyl and the like.
These alkyl groups and aryl groups include other functional groups such as hydroxyl groups, halogens, nitro groups, mercapto groups, amino groups, amide groups, cyano groups, carbonyl groups, carboxyl groups, acetyl groups, acyl groups, alkoxy groups. Or a sulfone group, or other atoms or atomic groups may be contained. Examples of aryl groups containing other atoms and atomic groups include alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, 1-methylbutoxy, 2- Methylbutoxy, 3-methylbutoxy, neopentoxy, 1-ethylpropoxy, cyclopentoxy, n-hexoxy, cyclohexoxy, n-heptoxy, n-octoxy, n-decoxy, n-dedecoxy, menthoxy and their isomers and adamantyl Oxy is mentioned. Examples thereof include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, alkyl substitution products thereof, halogen substitution products, and the like.

Examples in which any two or more of R ₀ , R ₁ and R ₂ are bonded include pyrrolidin-1-yl, 3-methylimidazolidin-1-yl, morpholin-4-yl, N-piperidinyl, 4-methyl Examples include piperazin-1-yl. In addition, the overall structure containing nitrogen of the general formula (1) includes 2,2-difluoropyrrolidine, 2,2-difluoropiperidine, 2,2-difluoroimidazolidine, [2,2,2] -2,2, Also applicable are 5,5-tetrafluoro-1,4-diazabicyclooctane, [2,2,2] -2,2,6,6-tetrafluoro-1,4-diazabicyclooctane and the like.
In addition, there are fluoroalkyl, fluoroaryl in which part of the aforementioned alkyl group, aryl group and the like are substituted with fluorine, trifluoromethylalkyl, trifluoromethylaryl, etc. substituted with trifluoromethyl group.

Specific examples of the compound include the following fluoroamines as described in Japanese Patent Application Publication No. 2003-066404 or 2004-182665.
That is, difluoro-N, N-dimethylmethanamine, difluoro-N, N-diethylmethanamine, difluoro-N, N-di (n-propyl) methanamine, difluoro-N, N-di (i-propyl) methanamine, Difluoro-N, N-di (n-butyl) methanamine, difluoro-N, N-dipentylmethanamine, 1,1-difluoro-N, N-dimethylethanamine, 1,1-difluoro-N, N-diethylethane Amine, 1,1-difluoro-N, N-di (n-propyl) ethanamine, 1,1-difluoro-N, N-di (isopropyl) ethanamine, 1,1-difluoro-N, N-di (n- Butyl) ethanamine, 1,1-difluoro-N, N-di (i-butyl) ethanamine, 2,2-difluoro-N, N-dimethylpropane 1-amine, 1,1,2,2,2-pentafluoro-N, N-dimethylethanamine, 1,1,2,2,2-pentafluoro-N, N-diethylethanamine, 1-cyano- 1,1-difluoro-N, N-dimethylmethanamine, cyclopropyldifluoro-N, N-dimethylmethanamine, cyclopropyldifluoro-N, N-diethylmethanamine, difluoro-N, N-dimethyl (phenyl) methanamine, Difluoro-N, N-diethyl (phenyl) methanamine, 1,1-difluoro-N, N-dimethylbutane-1-amine-3-one, 1,1-difluoro-N, N-diethylbutane-1-amine 3-one, 2,2-dichloro-1,1-difluoro-N, N-dimethylbutan-1-amine-3-one, 1,1-difluoro-N N-dimethyl-2-phenoxyethanamine, N, N-diethyl-1,1-difluoropropan-1-amine, N, N-diethyl-1,1-difluorobutan-1-amine, N, N-bis ( 2-hydroxymethyl) -1,1-difluorododecan-1-amine, N, N-bis (aminoethyl) -1,1-difluoro-2-methyl-2-propen-1-amine, N, N-diethyl -1,1-difluoro-2- (naphthyl-1-yloxy) propan-1-amine, (N- (decahydronaphthalen-1-yl) difluoromethyl) -N-ethylethanamine, difluoro-N-methylmethane Amine, 1,1-difluoro-N-methylethanamine, N- (difluoromethyl) -N-methylbenzenamine, 1,1-difluoro-N, N-dimethyl Tan-1-amine, 1,1-difluoro-N, N, 2-trimethylpropan-1-amine, N, N-diethyl-1,1-difluoro-2-methylpropan-1-amine, N, N- Dimethyl-1,1-difluoropentan-1-amine, difluoro-N, N-dimethyl (phenyl) methanamine, N- (difluoro (phenyl) methyl) -N-ethylethanamine, N- (difluoro (m-tolyl)) Methyl) -N-ethylethanamine, N- (difluoro (o-tolyl) methyl) -N-ethylethanamine, N- (difluoro (p-tolyl) methyl) -N-ethylethanamine, 2,4- ( Dimethylphenyl) difluoro-N, N-dimethylmethanamine, 2,4- (dimethylphenyl) difluoro-N, N-diethylmethanamine, 2,6- (Dimethylphenyl) difluoro-N, N-dimethylmethanamine, 2,6- (dimethylphenyl) difluoro-N, N-diethylmethanamine, N- (aminoethyl) -N- (1,1-difluoro-2- Methylallyl) methanediamine, (E) -1,1-difluoro-N, N-dimethyl-3-p-loploen-1-amine, difluoro (tetrahydrofuran-2-yl) -N, N-dimethylmethanamine , Difluoro (tetrahydrofuran-3-yl) -N, N-dimethylmethanamine, N- (difluoro (2-methoxyphenyl) methyl) -N-ethylethanamine, (4-chlorophenyl) difluoro-N, N-dimethylmethane Amine, (4-bromophenyl) difluoro-N, N-dimethylmethanamine, (4-fluorophenyl) Difluoro-N, N-dimethylmethanamine, N- (difluoro (mesityl) methyl) -N-ethylethanamine, difluoro-N, N-diethyl (naphthalen-2-yl) methanamine, difluoro (4-biphenyl) -N , N-diethylmethanamine, anthracen-2-yldifluoro-N, N-diethylmethanamine, cyclohexyldifluoro-N, N-diethylmethanamine, N, N-dimethyl-1,1-difluorodecane-1-amine, N, N-diethyl-1,1-difluorodecan-1-amine, difluoro-N, N-dimethyl (pyridin-2-yl) methanamine, difluoro-N, N-diethyl (pyridin-2-yl) methanamine, 1 -(Difluoro (phenyl) methyl) piperidine, 4- (difluoro (phenyl) Methyl) morpholine.

Among these, R ₀ is a 3-methylphenyl group or 2-methoxyphenyl group, and R ₁ and R ₂ are ethyl groups, N, N-diethyl-α, α-difluoro- (3-methyl ) Benzylamine and N, N-diethyl-α, α-difluoro- (2-methoxy) benzylamine have high thermal stability and are stable even at a high temperature of 150 ° C. or higher. It is particularly preferable since the reaction can be carried out.

The substrate used for the fluorination is an amino alcohol represented by the general formula (6), and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are a hydrogen atom or an alkyl group which may have a substituent, aryl A group, an alkylamino group or an arylamino group, which may be the same or different. Two or more of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ may be bonded to form a ring.

Examples of the alkyl group in R ₃ , R ₄ , R ₅ , R ₆ and R ₇ include linear or branched alkyl groups having 1 to 30 carbon atoms, such as methyl, ethyl, propyl, isopropyl and butyl. , Isobutyl, t-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1,3-dimethylpropyl, 1-ethylpropyl, n-to Xyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1 2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1-ethyl-3-methylpropyl, n-heptyl, n-octyl, 2-ethylhexyl, n-nonyl, There are n-decyl, n-dodecyl, cyclohexyl, decalyl, norbornyl, bicyclohexyl, adamantyl, menthyl and isomers thereof. Besides, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxyphenyl, cyclohexyloxy, etc. A preferred example is given. In addition, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,5-pentylene, 1,6-hexylene, 1,2-cyclopentylene, 1,2-cyclohexylene, etc. I can do it. Moreover, one part or all part of an alkyl group may have an unsaturated bond.

Aryl groups include phenyl, o-tolyl, m-tolyl, p-tolyl, dimethylphenyl, naphthyl, fluorenyl, anthryl, phenanthrenyl and their positional isomers, cumyl, mesityl, trimethylphenyl, hydroxyphenyl, methoxyphenyl and their positions Isomers, naphthyl, methyl naphthyl, dimethyl naphthyl, hydroxy naphthyl, biphenyl, tetralyl, t-phenyl and the like, and aryl groups containing heteroatoms include furanyl, oxazolyl, pyridinyl, quinolyl, isoquinolyl, benzofuranyl, dibenzofuranyl, Examples include benzothienyl, chromenyl, indoyl and the like.
These alkyl groups and aryl groups include other functional groups such as hydroxyl groups, halogens, nitro groups, mercapto groups, amino groups, amide groups, cyano groups, carbonyl groups, carboxyl groups, acetyl groups, acyl groups, alkoxy groups. Or a sulfone group, or other atoms or atomic groups may be contained. Examples of aryl groups containing other atoms and atomic groups include alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, n-pentoxy, 1-methylbutoxy, 2- Methylbutoxy, 3-methylbutoxy, neopentoxy, 1-ethylpropoxy, cyclopentoxy, n-hexoxy, cyclohexoxy, n-heptoxy, n-octoxy, n-decoxy, n-dedecoxy, menthoxy and their isomers and adamantyl Oxy is mentioned. Examples thereof include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, alkyl substitution products thereof, halogen substitution products, and the like.

Examples in which any two or more of R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are bonded include pyrrolidin-1-yl, 3-methylimidazolidin-1-yl, morpholin-4-yl, N -Piperidinyl, 4-methylpiperazin-1-yl and the like, and when viewed as an overall ring structure in which two or more of R ₅ , R ₆ and R ₇ are bonded, pyrrolidine, imidazolidine, morpholine, piperidine and piperazine are each Applicable to 2,2-difluoropyrrolidine, 2,2-difluoropiperidine, 2,2-difluoroimidazolidine, [2,2,2] -2,2,5,5-tetrafluoro-1,4-diaza Bicyclooctane, [2,2,2] -2,2,6,6-tetrafluoro-1,4-diazabicyclooctane and the like can also be mentioned.
In addition, there are fluoroalkyl, fluoroaryl substituted with fluorine, trifluoromethylalkyl substituted with a trifluoromethyl group, trifluoromethylaryl, and the like.

Generally speaking, the amino group of the amino alcohol in the present invention may be any of primary, secondary and tertiary. However, when the number of carbon atoms is small, an amino alcohol having a secondary amino group rather than a primary may be preferable. For example, in the case of monoethanolamine, a ring-closed compound is obtained. That is, in the reaction of monoethanol aion with N, N-diethyl-α, α-difluoro- (3-methyl) benzylamine (hereinafter sometimes abbreviated as DFMBA), 2-m-tolyl-4, 5-dihydrooxazole is formed.
Carbohydrates having an amino group at the α-position or β-position are also a kind of amino alcohol. And fructose, sorbose, tagatose, unsaturated sugars such as hexaenos having an unsaturated bond, and amino sugars such as branched sugars such as apiose or polysaccharides. Preferred amino alcohols include those belonging to the following group 1.
(Group 1)
N-methylethanolamine, N-methyldiethanolamine, N- (β-aminoethyl) ethanolamine, N- (β-aminoethyl) diethanolamine, Nn-butylethanolamine, Nn-butyldiethanolamine, Nt -Butylethanolamine, Nt-butyldiethanolamine, N, N-dimethylethanolamine, 2- (methylamino) ethanol, 2- (anilino) ethanol, 2- (benzylamino) ethanol, 3- (benzylamino) propane -1-ol, 1- (benzylamino) octan-2-ol, 2- (benzylamino) -2-phenylethanol, 2- (benzylamino) -1-phenylpropan-1-ol, (2- (isobutyl Amino) phenyl) methanol, 2- (benzylamino) si Lohexanol, 3- (benzylamino) -4-isopropoxybutan-2-ol, pyrrolidin-3-ol, t-aminoalcohol, N, N-dialkylnorephedrine, diphenyl (1-methylpyrrolidin-2-yl) Methanol, -phenyl-2-pyrrolidinyl-1-propanol, D-valinol, L-valinol, L-alaninol, L-methioninol, L-leucinol, L-isoleucinol, D-phenylalaninol, L-phenylalaninol, D -Prolinol, L-prolinol, L-tryptophanol, (R) -2-phenylglycinol, (S) -2-phenylglycinol, L-t-leucinol, (R) -3-pyrrolidinol, ( R) -1-amino-2-propanol, (S) -1-amino-2-propa (R) -2-amino-1-butanol, (S) -2-amino-1-butanol, (1R, 2R) -2-amino-1-phenyl-1,3-propanediol, (1S, 2S) -2-amino-1-phenyl-1,3-propanediol, (1R, 2S) -2-amino-1,2-diphenylethanol, (1S, 2R) -2-amino-1,2-diphenyl ethanol.

  Of these, 2- (methylamino) ethanol, 2- (anilino) ethanol, 2- (benzylamino) ethanol, 3- (benzylamino) propan-1-ol, 1- (benzylamino) octane- are more preferable. 2-ol, 2- (benzylamino) -2-phenylethanol, 2- (benzylamino) -1-phenylpropan-1-ol, (2- (isobutylamino) phenyl) methanol, 2- (benzylamino) cyclo Hexanol, 3- (benzylamino) -4-isopropoxybutan-2-ol, pyrrolidin-3-ol and the like.

  The reaction between α, α-difluoroamine and amino alcohol can be carried out in a batch, semi-batch or continuous manner, and the reaction can be carried out under normal heating, ultrasonic waves or microwave irradiation. The reaction temperature can be safely implemented as long as it is equal to or lower than the thermal runaway temperature (according to the ARC test). Usually, it is preferable to carry out the reaction at a temperature of 200 ° C. or lower, and a temperature range from room temperature to 150 ° C. is particularly preferable. The reaction is desirably carried out at a temperature below the thermal runaway temperature in this temperature range. Moreover, it can react by irradiating an ultrasonic wave, the microwave of 0.3-300 GHz, and the electromagnetic wave of a microwave vicinity. The electromagnetic wave can be irradiated, for example, by continuously or intermittently controlling the temperature. The amount of α, α-difluoroamine used is preferably 1 mol or more with respect to 1 mol of the functional group of the target substrate. However, the reaction may be carried out with an excess or a stoichiometric deficiency. The reaction time is preferably in the range of 10 to 360 minutes for the thermal reaction. When the reaction is performed under ultrasonic or microwave irradiation, the range of 0.1 to 180 minutes is preferable, but irradiation can be performed for a longer time. It is not necessary to use a solvent for the progress of the fluorination reaction, but a solvent may be used to sufficiently stir or prevent a temperature rise.

Preferred solvents include aliphatic alcohols, aromatic hydrocarbons, halogenated hydrocarbons, and aromatic halogenated hydrocarbons that are inert to the substrate, amino alcohol, fluorinating agent α, α-difluoroamine, and products. , Nitriles, ethers and the like, which can be appropriately selected and used in combination. If water is present during the fluorination reaction, an ester may be formed by introducing a residue derived from α, α-difluoroamine instead of fluorine. Usually, when the reaction is carried out in the presence of 10,000 ppm or more of water, the hydroxyl group of the substrate is acylated. That is, in the presence of water, aminoesters are obtained if the substrate is an amino alcohol, and hydroxyesters are obtained if the substrate is a diol. Therefore, it is necessary to carry out the reaction under dehydration conditions in order to obtain a fluorinated product in which the hydroxyl group is converted to fluorine by suppressing the formation of ester. The standard of the dehydration conditions is preferably 3,000 ppm or less, and particularly preferably 1,000 ppm or less.
After completion of the fluorination reaction, the product can be recovered by, for example, neutralizing with a dilute alkaline aqueous solution such as sodium hydrogen carbonate and extracting with a suitable solvent. The separated / recovered product can be made into high-purity fluoroamide by purifying it using usual means such as column chromatography, recrystallization or distillation, if necessary.

  Next, in order to obtain a fluoroamine, the amide is reduced. Reduction methods include catalytic reduction and reagent reduction, and any method may be used. For small scale, metal hydrides such as lithium aluminum hydride, sodium borohydride, sodium hydride, sodium aluminum hydride, diethyl aluminum sodium hydride, tris (t-butoxy) lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum It is preferred to carry out a reagent reduction by For industrial-scale reagent reduction, for example, a 70% toluene solution (trade name: Vitride) of bis (2-methoxyethoxy) aluminum sodium hydride can be used. In the case of carrying out reduction on a large scale, hydrogen catalytic reduction using a catalyst such as platinum, palladium, rhodium, nickel, etc. is usually applicable, although there are disadvantages such as high temperature or high pressure conditions.

  Hereinafter, although the method of this invention is demonstrated in more detail by an Example and a comparative example, this invention is not limited by these examples.

Example 1
Synthesis of N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide 2-anilinoethanol (1.0 mmol: 0.137 g) as a substrate and N, N-diethyl-α, α as a fluorinating agent -After adding 2.4 mmol (0.511 g) of difluoro- (3-methyl) benzylamine (DFMBA), microwave irradiation was performed at a temperature of 70 ° C. for 10 minutes without stirring. After completion of the reaction, the reaction mixture was cooled to room temperature and neutralized by adding the reaction product to 15 ml of an aqueous solution containing sodium hydrogen carbonate. Next, extraction was performed three times with ether, and the extract was dried with an appropriate amount of potassium carbonate, the solvent was removed, and the residue was purified by column chromatography. As a product, N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide was obtained with a yield of 90%.

Example 2
Synthesis of N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide In Example 1, the reaction was carried out at 70 ° C. for 10 minutes under ordinary heating conditions instead of irradiation with microwaves. After cooling to room temperature, the reaction product was neutralized by adding to 15 ml of an aqueous solution containing sodium hydrogen carbonate, and then extracted three times with ether. The extract was dried with an appropriate amount of potassium carbonate, the solvent was removed, and quantitative analysis of N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide was performed using 19F-NMR. The yield was 98%.

Comparative Example 1
DAST (2.4 mmol) was added at −78 ° C. using anilinoethanol (1.0 mmol) as a substrate, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, ether (10 ml) was added to the reaction solution to precipitate an insoluble matter, but formation of the amide in Examples 1 and 2 was not observed at all.
Furthermore, no gas-chromo peak derived from organic substances was observed in the ether-soluble component.
For comparison, examples have been described, but it is apparent that amides cannot be obtained as in the present invention as long as the DAST and Olah reagents of the prior art are used in the case of other substrates as well.

Example 3
Synthesis of N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide As in Example 1, except that 1.2 mmol (0.255 g) of DFMBA was used as α, α-difluoroamine. The operation was performed. As a result, N- (2 fluoroethyl) -N-phenyl- (3-methyl) benzamide was obtained with a yield of 45%.

Example 4
Synthesis of N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide The same operation as in Example 1 was carried out except that DMFBA was changed to 3.6 mmol (0.766 g) as a fluorinating agent. . N- (2-fluoroethyl) -N-phenyl- (3-methyl) benzamide was obtained with a yield of 94%.

Example 5
Synthesis of N- (2-fluoroethyl) -N-methyl- (3-methyl) benzamide benzamide 1 mmol (0.137 g) of N-methylethanolamine as a substrate and 2.4 mmol (0.511 g) of DFMBA as a fluorinating agent The reaction was performed at 70 ° C. for 10 minutes under microwave irradiation. The operation was performed in the same manner as in Example 1. A 59% yield of N- (2-fluoroethyl) -N-methyl- (3-methyl) benzamide was obtained as the product.

Example 6
Synthesis of N- (2-fluoroethyl) -N-benzyl- (3-methyl) benzamide 1 mmol (0.137 g) of N-benzylethanolamine as a substrate and 2.4 mmol (0.511 g) of D FMBA as a fluorinating agent The reaction was performed at 70 ° C. for 10 minutes under microwave irradiation. The operation was performed in the same manner as in Example 1. N- (2-fluoroethyl) -N-benzyl- (3-methyl) benzamide was obtained as a product in a yield of 66%.

Example 7
Synthesis of N-benzyl-N- (2-fluorooctyl) benzamide 1 mmol (0.137 g) of 1-benzylamino-octan-2-ol as a substrate and N, N-diethyl-α, α-difluorobenzyl as a fluorinating agent 2.4 mmol (0.478 g) of amine (hereinafter abbreviated as DFBA) was added, and microwave irradiation was performed at 100 ° C. for 10 minutes without stirring. The treatment after completion of the reaction is the same as in Example 1. N-benzyl-N- (2-fluorooctyl) benzamide was obtained as a product in a yield of 76%.

Example 8
Synthesis of dibenzyl- (2-fluorooctyl) amine 0.76 mmol (0.137 g) of N-benzyl-N- (2-fluorooctyl) benzamide obtained in Example 7 was dissolved in anhydrous THF (20 ml), lithium After adding 0.8 mmol (0.478 g) of aluminum hydride (LAH) at 0 ° C. with stirring, the mixture was reacted at room temperature for 1 hour. The reaction solution was poured into 3N-potassium hydroxide aqueous solution (10 ml) to neutralize, and extracted with ether three times. The extract was dried with an appropriate amount of potassium carbonate, the solvent was removed, and the residue was purified by column chromatography. Dibenzyl- (2-fluorooctyl) amine was obtained as a product in a yield of 65%.

Reference Example Synthesis of α, α-difluoroamine 1) Synthesis of N, N-diethyl-α, α-difluoro-3-pyridylmethanamine 200 ml of N, N-diethylnicotinamide 12.9 g (72 mmol) The flask was charged with 50 ml of dichloromethane. Under slightly pressurized nitrogen, the flask was cooled with ice water, and a solution of oxalyl chloride in dichloromethane (9.85 g of oxalyl chloride, 78 mmol dissolved in 20 ml of dichloromethane) was added dropwise at about 5 ° C. After completion of the dropwise addition, the reaction solution was heated to about 40 ° C. to carry out a reaction between the two. After completion of the chlorination reaction, the reaction solution was cooled with ice water, and 8.7 g (53 mmol) of TEA · 3HF complex was added dropwise at about 3 ° C. About 10 g of triethylamine was added, and the reaction was further performed at 25 ° C. for 1 hour. After completion of the reaction, the salt precipitated in the system was removed by filtration. The filtrate was concentrated, extracted with hexane, and distilled to obtain 9 g of N, N-diethyl-α, α-difluoro-3-pyridylmethanamine (isolation yield 60%).
The structure of the product was confirmed by NMR and IR.
1H-NMR: δ value (ppm), TMS standard, measured in CDCl ₃ 1.06 (t, —CH ₃ ), 2.87 (q, —CH ₂ —),
7.3, 7.9, 8.6, 8.8 (aromatic ring hydrogen)

2) 4-Difluoromethylmorpholine was synthesized in the same manner as in Reference Example 1 except that 72 mmol of N-formylmorpholine was used instead of 4-difluoromethylmorpholine N, N-diethylnicotinamide (isolated yield). 70%). The structure of the product was confirmed by NMR and IR.
1H-NMR: δ value (ppm), TMS standard, measured in CDCl ₃ 2.85 (t, 4H, —CH ₂ —N— × 2),
3.71 (t, 4H, —O—CH ₂ — × 2), 5.93 (s, 1H, —CF ₂ —H)
¹³ C-NMR: δ value (ppm), TMS standard, -50 ° C., measured in CDCl ₃ 43.46 (s, —CH ₂ —N— × 2), 66.0 (s, —O—CH ₂ − × 2),
_{116.78 (t, 244Hz, -CF 2} )
¹⁹ F-NMR: δ value (ppm), CF ₃ COOH standard, measured at −50 ° C. in CDCl ₃ −102.89, −103.01 (d, ═CF ₂ )

3) 1-Difluoromethylpiperidine was synthesized in the same manner as in Reference Example 1 except that 72 mmol of N-formylpiperidine was used instead of 1-difluoromethylpiperidine N, N-diethylnicotinamide (isolated yield) 68%). The structure of the product was confirmed by NMR and IR.
1H-NMR: δ value (ppm), TMS standard, measured in CDCl ₃ 2.81 (m, 4H, —CH ₂ —N— × 2),
1.55 (m, 6H, - CH 2 -CH 2 -CH 2 -N -, - CH 2 - CH 2 -CH 2 -N- × 2),
_{5.90 (s, 1H, -CF 2} -H)
¹³ C-NMR: ^δ value (ppm), TMS standard, -50 ° C., measured in _{CDCl 3 24.12 (s, - CH} 2 -CH 2 -N- × 2), 24.76 (s, - CH ₂ -CH ₂ -CH ₂ -N-),
_{44.38 (s, - CH 2 -N-} × 2), 117.66 (t, 246Hz, -CF 2)
¹⁹ F-NMR: δ value (ppm), CF ₃ COOH standard, measured at −50 ° C. in CDCl ₃ −101.03, −101.18 (d, ═CF ₂ )

The following equipment was used for structure identification of the products of Reference Examples 1 to 3.
¹ H-NMR measurement JMN-EX270 (270MNz) manufactured by JEOL: measured with deuterated chloroform solvent
¹³ C-NMR, ¹⁹ F-NMR
JEOL NMR-LA500SS (500 MHz): measured with deuterated chloroform solvent

Examples 9-14
The reaction was performed in the same manner as in Example 1 except that the kind of α, α-difluoroamine used in the fluorination reaction was changed. The results are shown below. The reaction time was 10 minutes, the reaction temperature was 70 ° C., and no solvent was used.
Example Substrate α, α-Difluoroamine Product Type Isolation Yield%
9 1 DFBA Amide 1 71
10 2 DFMBA Amide 2 86
11 3 DFMBA Amide 3 42
12 4 DFBA Amide 4 76
13 2-anilinoethanol DFEP amide 5 72
14 2-anilinoethanol DFBA amide 6 85

The amino alcohols as substrates in the above Examples 9 to 14 are as follows.
1: (benzylamino) propan-1-ol 2: 2- (benzylamino) -2-phenylethanol 3: 2- (benzylamino) -1-phenylpropan-1-ol 4: 1- (benzylamino)- 3-Benzyloxy-propan-2-ol

The compound names of α, α-difluoroamine which are abbreviated in the above Examples 9 to 14 are as follows.
DFEP: Difluoro-N, N-diethyl (pyridin-2-yl) methanamine

The names of the compounds of amides 1 to 6 which are the products in Examples 9 to 14 are as follows.
1: N-benzyl-N- (3-fluoropropyl) benzamide 2: N-benzyl-N- (2-fluoro-1-phenylethyl) -3-methylbenzamide 3: N-benzyl-N- (1-fluoro -Phenylpropan-2-yl) -3-methylbenzamide 4: N-benzyl-N- (3-benzyloxy-2-fluoropropyl) -benzamide 5: N- (2-fluoroethyl) -N-phenylpicolinamide 6 : N- (2-fluoroethyl) -N-phenylbenzamide

  By using the method of the present invention in which α, α-difluoroamino compounds are used as a fluorinating agent, racemic or chiral aminoamide having both an amino group and a hydroxyl group in the molecule is converted into a racemic or chiral fluoroamide or fluoroamine. Can be obtained in a simple and high yield. The method of the present invention is particularly useful as a fluorination method for pharmaceutical synthesis, which often requires positional specificity and stereospecificity.

Claims (5)

Using the α, α-difluoroamine represented by the general formula (1) to obtain the fluoroamide represented by the general formula (3) from the amino alcohol represented by the general formula (2), A method for producing a fluoroamide from an amino alcohol.

(R, R ₀ of α, α-difluoroamine represented by the general formula (1) is a phenyl group or pyridinyl group which may have a substituent, and R ₁ and R ₂ are ethyl groups. (2), the fluorine compound represented by the general formula (3) and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the substrate are a hydrogen atom or a phenyl group or carbon number which may have a substituent 1-6 alkyl groups, each of which may be the same or different.) R ₀ of the α, α-difluoroamine represented by the general formula (1) is a phenyl group, a 3-methylphenyl group, or a 2-methoxyphenyl group, and R ₁ and R _{2 each} have 1 to 16 carbon atoms. A process for producing a fluoroamide from an aminoalcohol according to claim 1, which is an alkyl group up to. The aminoalcohol to fluoroamide according to claim 1 or 2, wherein when the fluoroamide represented by the general formula (3) is produced from the aminoalcohol represented by the general formula (2), the reaction is performed under microwave irradiation. How to manufacture. The method for producing a fluoroamide from an amino alcohol according to any one of claims 1 to 3, wherein the amino alcohol represented by the general formula (2) belongs to Group 1.
[Group 1]
N-methylethanolamine, Nn-butylethanolamine, Nt-butylethanolamine, 2- (anilino) ethanol, 2- (benzylamino) ethanol, 3- (benzylamino) propan-1-ol, 1 -(Benzylamino) octan-2-ol, 2- (benzylamino) -2-phenylethanol, 2- (benzylamino) -1-phenylpropan-1-ol, 3- (benzylamino) -4-isopropoxy Butan-2-ol, D-valinol, L-valinol, L-alaninol, L-methioninol, L-leucinol, L-isoleucinol, D-phenylalaninol, L-phenylalaninol, (R) -2-phenyl Ricinol, (S) -2-phenylglycinol, L-t-leucinol, (R)- -Amino-2-propanol, (S) -1-amino-2-propanol, (R) -2-amino-1-butanol, (S) -2-amino-1-butanol, (1R, 2R) -2 -Amino-1-phenyl-1,3-propanediol, (1S, 2S) -2-amino-1-phenyl-1,3-propanediol, (1R, 2S) -2-amino-1,2-diphenyl Ethanol, (1S, 2R) -2-amino-1,2-diphenylethanol After producing a fluoro amide represented by the general formula Ri by the method described (3) to any one of claims 1 to 4, through a reduction process to obtain a fluoro amine represented by the general formula (4), A method for producing a fluoroamine from an amino alcohol.

(Gei, the fluorine compound represented by the general formula (4) and R ₃ , R ₄ , R ₅ , R ₆ and R ₇ in the substrate are a hydrogen atom or a phenyl group which may have a substituent or a carbon number of 1 -6 an alkyl group, each of which may be the same or different. _{also, R 3, R 4, R} 5, two or more of R ₆ and R ₇ may bond to form a ring .)