WO2003089402A1

WO2003089402A1 - PROCESS FOR PRODUCING α-FLUORO-β-ALANINE COMPOUND AND PRODUCING INTERMEDIATE THEREFOR

Info

Publication number: WO2003089402A1
Application number: PCT/JP2003/003786
Authority: WO
Inventors: Yoshihiro Yamamoto; Kazuhiro Shimokawa
Original assignee: Daikin Industries, Ltd.
Priority date: 2002-04-19
Filing date: 2003-03-27
Publication date: 2003-10-30

Abstract

A process for producing an α-fluoro-β-alanine compound represented by the following formula (A) or a salt thereof, which comprises reacting an α-fluoroacrylic acid compound with ammonia and/or an amine at about 50 to 150˚C and optionally conducting hydrolysis: (A) wherein R1 and R2 are the same or different and each represents hydrogen, alkyl, or benzyl.

Description

Specification

—Process for producing fluoro-β-alanine compounds and intermediates thereof

The present invention relates to a method for producing an a-fluoro-β-araylene conjugate. The present invention also relates to a method for producing an amide compound which is an intermediate of the a-fluoro-β-alanine conjugate.

Background art

a-Fluoro-β-alanine is useful as an intermediate for pharmaceuticals, agricultural chemicals, chemicals, and the like. For example, Japanese Patent Application Laid-Open No. 63-060954 discloses a method for producing α-fluoro-13-alanine using 2-fluoromalonic acid as a starting material. J. Am. Chem. Soc. 1982, 104, 5836-5837 describes a method for producing monofluoro-β-alanine from L-serine.

Each of these methods requires a multi-step reaction process. Furthermore, since expensive reagents are used, these methods cannot produce α-fluoro-β-alanine industrially at low cost.

The present invention has been made in view of the problems of the prior art, and has as its main object to provide a method for inexpensively producing an α-fluoro-β-alanine conjugate.

The present invention also provides a method for inexpensively producing an amide compound as a raw material for producing an α-fluoro-β-alanine compound.

Disclosure of the invention

As a result of earnest studies, the present inventors have achieved the above object by reacting the α-fluoroacrylic acid conjugate with ammonia and Ζ or amine under specific temperature conditions, and hydrolyzing as needed. They have found that they can do this and have completed the present invention.

That is, the present invention relates to the following α-fluoro-β-alanine compound or a salt thereof, and a method for producing an amide compound as a raw material for producing the compound.

1. 50-150 of acrylic acid compound with ammonia and / or amine. A method for producing an a-fluoro-β-alanine conjugate represented by the following formula (A) or a salt thereof by reacting at about C and hydrolyzing as necessary.

[Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group, or a benzyl group. ]

2. The α-fluoroacrylic acid compound is at least one selected from the group consisting of α-fluoroacrylic acid halide, α-fluoroacrylic acid amide compound, α-fluoroacrylic acid ester, α-fluoroacrylic acid and monofluoroacrylic acid salt. 2. The method according to 1 above, which is a species.

3. The method according to the above item 1, wherein the α-fluoroacrylic acid compound is an α-fluoroacrylic acid halogenated compound, and the halogenated compound is reacted with ammonia.

4. a. At least one α-fluoroacrylic acid compound selected from the group consisting of monofluoroacrylic acid halide, α-fluoroacrylic acid amide compound and α-fluoroacrylic acid ester, and ammonia and / or amine 50 to: A method for producing an amide compound represented by the following formula (B) by reacting at about 150 ° C.

(B)

[Wherein, Ri to R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group, or a benzyl group. ]

5. The a-fluoroacrylic acid compound is at least one compound selected from the group consisting of α-fluoroacrylic acid ester and α-fluoroacrylic acid ester. The compound is reacted with ammonia to obtain the following compound. The method according to the above item 4, wherein the amide compound represented by the formula (B-1) is produced. NH ₂ -CH ₂ -CHF-C-NH ₂ (Bl)

O

6. a-Fluoroacrylic acid compound power The method according to the above item 4, wherein the compound is a fluoroacrylic acid amide compound, and the above compound is reacted with ammonia to produce an amide compound represented by the following formula (B-2).

[Wherein, R ³ and R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group, or a benzyl group. ]

7. The method according to the above 1, 2, or 4, wherein the amine is at least one selected from the group consisting of monoalkylamines and dialkylamines.

8. A method for producing an a-fluoro-β-alanine conjugate represented by the following formula (A) or a salt thereof by hydrolyzing an amidig compound represented by the following formula (B).

[Wherein, RR ⁴ is the same or different and represents a hydrogen atom, an alkyl group or a benzyl group. ']

In the method of the present invention, the compound represented by the following formula (A) is obtained by reacting a-fluoroacrylic acid conjugate with ammonia and / or amine at about 50 to 150 ° C. and hydrolyzing as necessary. An a-fluoro-β-alanine compound or a salt thereof is produced.

[Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group or a benzyl group. ]

The compound obtained by the present invention may be a salt of the alanine conjugate represented by the formula (A). Salts include both acid addition salts of amino groups and base salts of carboxyl groups. For example, acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, hydrobromide, hydrofluoride, hydroiodide, perchlorate and phosphate, and methane sulfone. Organic acid salts such as acid salts and toluenesulfonic acid salts are exemplified. Examples of the base salt include salts such as ammonium salts and amine salts. Examples of the amine salt include a corresponding quaternary ammonium salt ([H ₂ NR ² ] +) obtained by adding a hydrogen atom to the amine (HNR ² ) used in the production.

A scheme showing a specific example of the method for producing the a-fluoro-β-alanine conjugate of the present invention or a salt thereof (Α) is shown below.

Step B (optional hydrolysis) R ¹

:--CH ₂ -CHF-COOH

acid / base

(A)

Wherein R ¹ and R ² are as defined above. R represents a halogen atom, an alkoxy group, aralkyloxy, aryloxy, OH, amino (NH ₂ ), NR ³ R ⁴ (R ³ and R ⁴ may be the same or different and represent a hydrogen atom, an alkyl group or a benzyl group. Or O (M ^{n +} ) _{1 / n} (M is an alkali metal such as sodium and potassium (n == l), an alkaline earth metal such as calcium and magnesium (n = 2), H ₂ NR¾ ² Ammonia ions (n = l) or transition metals such as Fe, Ni, Co, Zn, and Cu (n = 1 to 3). ^Ra is an alkoxy group, aralkyloxy, aryloxy, OH, amino (NH ₂ ), NR ⁴ (R ³ and R ⁴ are the same or different and represent a hydrogen atom, an alkyl group or a benzyl group) or ^{_{O (M n +) 1 /}} n (M is sodium, § alkali metal (n = l, such as potassium), calcium, alkaline earth metals such as magnesium metal (n = 2), ammonium Niu-ion, such as H _² NR¾ ₂ ( n = l) or transition metals such as Fe, Ni, Co, Zn, and Cu (indicating n = l to 3). ] In step A, an a-fluoro-β-alanine derivative is formed by adding an amine represented by HNR ² to the α-fluoroacrylic acid conjugate.

In the case where Ra of the derivative is not (or O (M "+) _{1 / n} (M is as defined above), in the case where α of the formula (A) Converted to fluoro-β-alanine compound.

Examples of the halogen atom include F, CI, Br and I.

Examples of the alkoxy group include linear or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentyloxy, and hexyloxy. Groups.

Examples of the aralkyloxy group include benzyloxy and phenethyl / reoxy. Examples of aryloxy include phenoxy and naphthoxy.

In the present invention, the alkyl group represented by R ¹ R ² , R ³ and R ⁴ is a linear or branched alkyl group, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, —Butyl, isobutyl, sec-butynole, t-butyl, pentyl, hexyl and the like, and an alkyl group having about 1 to 10 carbon atoms, and an alkyl group having about 1 to 5 carbon atoms is preferable. Alkyl groups of about several to three are particularly preferred.

α- Furuoroakuriru acid compound (1) with ammonia and / or Amin; temperature of reacting the (I HNR¾ ²⁾ is usually 50 to 150 ° about C, preferably 60 to 100 [° C, more preferably about 70 About 90 ° C. The reaction time is not particularly limited, but is usually about 5 to 20 hours, preferably 10 to 15 hours. Although the reaction pressure is not particularly limited, it is generally about 0.1 to 2 MPa, preferably about 0.3 to 1 MPa. The reaction proceeds even at normal pressure.

In the production method of the present invention, ammonia and / or amine (I; HNR ² ) are used. In one of the preferred embodiments, the α-fluoroacrylic acid compound is reacted with ammoair at about 50 to 150 ° C. and, if necessary, hydrolyzed to obtain a-fluoro-β-alanine. it can.

Examples of the ammonia or amine used in the present invention include a compound represented by the following formula (I).

NHR ² (I) [In the formula, R ¹ and R ² are the same or different and each represent a hydrogen atom, an alkyl group or a benzyl group. ]

The alkyl group represented by R ¹ or R ² in the formula (I) is a linear or branched alkynole group, for example, having about 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, and an isopropyl group. And an alkyl group having about 1 to 5 carbon atoms is preferred, and an alkyl group having about 1 to 3 carbon atoms is particularly preferred.

Examples of the amine of the formula (I) used in the present invention include monoalkylamine, dialkylamine and the like. Examples of the monoalkylamine include, for example, monomethylamine, monoethylamine, monopropylamine, benzinoleamine and the like, and among these, benzylamine is particularly preferred.

Examples of dialkynoleamine include, for example, amines represented by the following formula (II).

NH R ^ R ² '(II)

[Wherein, R ¹ ′ and R ² ′ are the same or different and represent an alkyl group. ]

In the formula (Π), examples of the alkyl group represented by R ¹ ′ or R ² ′ include, for example, an alkyl group having about 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, and an isopropyl group. Of these, an alkyl group having about 1 to 3 carbon atoms is particularly preferable.

Examples of the monofluoroacrylic acid compound used in the present invention include, for example, a-fluoroacrylic acid halide, a-fluoroacrylamide compound, α-fluoroacrylic acid ester, a-fluoroacrylic acid or a salt thereof, and the like. Of these, α-fluoroacrylamide compounds are preferred. As the α-fluoroacrylic acid conjugate, one kind may be used alone, or two or more kinds may be used in combination.

Examples of the α-fluoroacrylic acid halide include α-fluoroacrylic acid fluoride, α-fluoroacrylic acid chloride, CK-fluoroacrylic acid bromide, and _α -fluoroacrylic acid iodide. Among these, α-fluoroacrylic acid fluoride But preferred.

When an a-fluoroacrylic acid halide represented by the following formula (a) is reacted with ammonia or an amine (HNR ² ) at about 50 to 150 ° C, an amide compound represented by the following formula (B) is obtained. Generate. By hydrolyzing the obtained amide compound of the formula (B), the a-fluoro-β-alanine conjugate represented by the above formula (A) or a salt thereof can be obtained.

CH ₂ CF two one

(a) (B)

[In the formula, X represents a halogen atom such as F, Cl, Br, and I, and R ¹ and R ² are as defined above. ]

As the a-fluoroacrylamide amide compound used in the present invention, for example, a primary amide, a secondary amide, a tertiary amide and the like can be used, and an amide amide represented by the following formula (b) can be used. Compounds can be exemplified.

Roh R ³

CH ₂ CF ₂ C 1 N '(b)

II \ „A

0 R wherein R ³ and R ⁴ are the same or different and each represent a hydrogen atom, an alkyl group or a benzyl group. ]

The alkyl group represented by R ³ and R ⁴ in the formula (b) is a linear or branched alkyl group, and includes, for example, a C ^{1 to} C ⁴ alkyl group such as a methyl group, an ethyl group, a propyl group, and an isopropyl group. An alkyl group having about 10 carbon atoms can be exemplified, and an alkyl group having about 1 to 3 carbon atoms, particularly an alkyl group having from about!

— Specific examples of the fluoroacrylamide compound include, for example, monofluoroacrylamide, α-fluorobenzoyl amide, a-fluoroacrylic acid dimethylamide, a-fluoroacrylic acid getylamide, and monofluoroacrylic acid diisopropylamide. Of these, α-fluoroacrylamide is preferred.

When a- Furuoroakuriru acid amide compound (b) with ammonia and / or Amin (HNR¾ ²⁾ and is reacted at about 50 to 150 ° C, amide compounds represented by the following formula (B) is produced. Profit By hydrolyzing the obtained amido conjugate of the formula (B), the a-funoleolol β-alanine compound represented by the above formula (A) or a salt thereof can be obtained.

(b) (B)

[Wherein, R ¹ to R are as defined above. ]

As the α-fluoroacrylic acid ester used in the present invention, for example, an ester / Reich compound represented by the following formula (c) can be exemplified.

CH ₂ : CF-C- OR ^y (c)

o

[Wherein, R ⁵ represents an alkyl group. ]

R ⁵ in the formula (c) is a linear or branched alkyl group, for example, having 1 to 5 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and a t-butyl group. Examples of the degree of the alkyl group can be given.

Specific examples of a-fluoroacrylic acid ester include, for example, a-fluoroacrylic acid methyl ester, _a- fluoroacrylic acid ethyl ester, a-fluoroacrylic acid propynoleester, and a-fluoroacrylic acid-t_butyl ester. Of these, a-fluoroacrylic acid methyl ester is preferred.

When the a-fluoroacrylic acid ester is reacted with ammonia and / or amine at 50 to 150 ° C., an amide compound in which part or all of the ester is represented by the following formula (B) is formed. By hydrolyzing the obtained amide compound of the formula (B), the α-fluoro-β-alanine conjugate represented by the above formula (A) or a salt thereof can be obtained.

(c) (B)

[Wherein, R ¹ and R ² are the same or different and each represent a hydrogen atom or an alkyl group, and R ⁵ represents an alkyl group. ]

As the salt of a-fluoroacrylic acid used in the present invention, for example, an ammonium salt, a sodium salt, a potassium salt and the like can be exemplified, and among these, an ammonium salt is preferable.

a When monofluoroacrylic acid or a salt thereof is reacted with ammonia and / or amine (HNR ² ) at about 50 to 150 ° C, an α-fluoro-jS-alanine compound represented by the following formula (A) or a salt thereof is obtained. Is generated. _{When a} -fluoroacrylic acid or a salt thereof is used, a salt corresponding to the used ammonia or amine is obtained. Examples of the salt of the α-fluoroβ-alanine compound obtained in this case include an ammonium salt and a quaternary ammonium salt corresponding to the used amine. The reaction formula is shown below when a-fluoroacrylic acid is used.

(A)

[Wherein, R ¹ and R ² are the same as above. ]

(a) When a fluoroacrylic acid conjugate is used, a compound that produces an amido conjugate represented by the following formula (C) by mixing with ammonia or an amine represented by the above formula (I) is used. For example, before reacting at about 50 to 150 ° C, α-fluoroacrylic should be preliminarily reduced to about 50 ° C (preferably about -10 ° C to less than 50 ° C, more preferably about 0 to 30 ° C). The acid conjugate may be mixed with ammonia and / or amine.

(c)

[Wherein, R ¹ and R ² are the same as described above. ]

Examples of the α-fluoroacrylic acid compound which reacts with ammonia or amine to produce an amide compound represented by the formula (C) include _α -fluoroacrylic acid halide, α-fluoroacrylic acid ester and the like.

At less than about 50 ° C., the time for mixing the α-fluoroacrylic acid compound with ammonia and / or amine is not particularly limited, but is usually about 0.1 to 5 hours, preferably about 0.1 to 1 hour. It is. The pressure is not particularly limited and is usually about 0.1 to: IMpa, preferably about 0.1 to 0.5 Mpa.

Further, even when a compound having a boiling point of about 50 ° C. or less is used as the monofluoroacrylic acid conjugate, a-fluoroacrylic acid compound and ammonia and / or And amines. The mixing temperature is a force which can be appropriately set according to the boiling point of the a-fluoroacrylic acid compound to be used. The mixing temperature is usually about less than 50 ° C, preferably about -10 ° C or more and less than 50 ° C, more preferably about 0 to 10 ° C. Alternatively, the temperature may be lower than the boiling point of the α-fluoro acrylate compound, preferably about 10 to 20 ° C. lower than the boiling point.

At about less than 50 ° C., the time for mixing the α-fluoroacrylic acid conjugate with ammonia and 7 or amine is not particularly limited, but is usually 0 :! ~ 5 hours, preferably

It is about 0.1-1 hour. The pressure is not particularly limited and is usually about 0.;! To IMpa, preferably about 0.1 to 0.5 Mpa.

(The molar ratio of the total amount of ammonia and amine to the fluoroacrylic acid compound is not particularly limited, but is usually about 1: 0.5 to 100, preferably 1: 1 to 100).

It is about 50, more preferably 1: 5 to about 20.

When reacting the α-fluoroacrylic acid compound with ammonia and / or amine, a solvent may be used as necessary, or no solvent may be used. Examples of the solvent include water; lower alcohols such as methanol, ethanol, and propanol; Ν, Ν-dimethylformamide (DMF), N-methyl-

Examples thereof include 2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), diglyme, and a mixed solvent thereof. The concentrations of ammonia and amine are not particularly limited as long as the reaction proceeds. For example, the concentration of ammonia water is usually about 20 to 30%, which is 28 ° / commercially available. You can use Ammoyua water.

As described above, a-fluoroacrylic acid compound such as α-fluoroacrylic acid halide, α-fluoroacrylic acid amide compound, α-fluoroacrylic acid ester, etc., and ammonia and / or amine at about 50 to 150 ° C. When reacted, an amide compound represented by the following formula (B) is produced.

[Wherein R ^ R ⁴ is the same as above. ]

The α-fluoro-1-β-alanine compound represented by the formula (A) or a salt thereof can be produced by hydrolyzing the amido conjugate represented by the formula (B). The hydrolysis proceeds, for example, by mixing an acidic aqueous solution of hydrochloric acid, sulfuric acid, hydrobromic acid or the like with an amide compound represented by the formula (Β). Examples of the salt of the α-fluoro-13-alanine conjugate obtained by hydrolysis include salts corresponding to the acid used, and more specifically, hydrochloride, sulfate, bromide and the like. Salts such as hydrochloride can be exemplified.

The concentration of the acidic aqueous solution is not particularly limited as long as the hydrolysis proceeds, but is usually about 1 to 95%, preferably about 10 to 35%. The amount of the acidic aqueous solution is not particularly limited as long as the hydrolysis proceeds, but is usually about 2 to 50 equivalents, preferably about 10 to 20 equivalents, based on the amide compound.

The hydrolysis may be, for example, a method in which an amide compound represented by the formula (Β) is purified in advance, and then mixed with an aqueous acid solution.a The reaction is carried out by reacting a reaction solution of monofluoroacrylic acid conjugate with ammonia and / or amine The process proceeds by a method of adding an acid until the liquid becomes acidic. When the acid is added to the reaction solution, the amount of the acid can be appropriately set according to the solvent and the like, and the pH of the reaction solution is usually about 1 to 4, preferably about 1 to 2. The acid may be added up to that. The temperature at which the hydrolysis is performed is not particularly limited as long as the reaction proceeds, but is usually about 20 to 120 ° C, preferably about 60 to 110 ° C. The hydrolysis time is not particularly limited, but is usually about 1 to 20 hours, preferably about 1 to 10 hours. The pressure during hydrolysis is normal pressure Usually 0.1 to: about LMPa, preferably about 0.1 to 0.2 MPa. Hydrolysis proceeds even at normal pressure.

When an ammonium is reacted with α-fluoroacrylic acid fluoride, which is a monofluoroacrylic acid compound, and the like, ammonium fluoride, which is a corrosive conjugate, is produced as a by-product. In such a case, the corrosive compound in the reaction system may be removed as necessary. For example, when α-fluoroacrylic acid fluoride and ammonia are used, first, α-fluoroacrylic acid fluoride and ammonia are mixed at about less than 50 ° C., mixed, and subjected to amidation. After the removal of the ammonium fluoride, the amido conjugate is reacted with ammonia or amine at about 50 to 150 ° C. More specifically, the reaction solution after the amidation is concentrated if necessary, and the concentrated residue is added to alcohol to precipitate Futi-dani ammonium. After removing this by filtration, a method of reacting the filtrate at about 50 to 150 ° C can be exemplified. If necessary, ammonia or an amine may be further added to the filtrate. The filtrate may be concentrated if necessary, and then reacted at about 50 to about 50 ° C. By removing the ammonium fluoride, it is possible to suppress the deterioration of a reactor made of glass, stainless steel, or the like.

According to the present invention, it is possible to provide a method for producing a monofluoro-β-alanine conjugate from inexpensive raw materials.

According to the present invention, an a-fluoro-β-alanine compound can be easily produced. In the method of the present invention, since the number of reaction steps is small, an α-fluoro-1-β-alanine compound can be produced at lower cost.

It is considered that the polymerization reaction of the α-fluoro-acrylic acid conjugate proceeds when heated. However, according to the present invention, the polymerization reaction of the a-fluoroacrylic acid conjugate does not proceed, and the desired compound can be obtained in low yield.

According to the present invention, an amide compound useful as an intermediate for producing an _α -fluoro-β-alanine compound can be produced from inexpensive raw materials.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to Examples of the present invention and Comparative Examples. The present invention is not limited to the following examples.

Example 1 50 ml (about 0.9 mol) of 28% aqueous ammonia was put into a 100 ml eggplant flask in which a Dimroth was set. While cooling and stirring the aqueous ammonia, 10 g (about 92 mmol) of α-fluoroacrylic acid fluoride (GC85%) was slowly added dropwise to the aqueous ammonia, taking care not to generate heat. After completion of the dropwise addition, the mixture was further stirred for 1 hour while cooling with ice. Next, the mixed solution was put in a 200 ml autoclave, and kept at 80 ° C for 15 hours while stirring. The reaction pressure was 0.4 MPa. After completion of the reaction, insolubles contained in the reaction solution were removed by filtration, and the filtrate was concentrated at 80 ° C or lower using an evaporator to obtain 3.6 g of a syrup-like crude water-containing product.

A crude product composition product (3.6 g) and concentrated hydrochloric acid (100 ml) were placed in a 200 ml eggplant flask, heated to 100 ° C. using an oil bath, and reacted for 4 to 5 hours with stirring.

After completion of the reaction, the reaction solution was concentrated to 20 ml at a temperature of 80 ° C. or lower using an evaporator, left overnight in a 7-year storage, and filtered to obtain 760 mg of α-fluoro-β-alanine hydrochloride as crystals. (Yield: 5.8%).

The obtained compound was identified using NMR and TLC. The results of NMR and TLC are shown below. These results were consistent with a sample of a-fluoro-] 3-alanine (manufactured by Tokyo Chemical Industry).

-NMR (TMS standard)

CHF: 5.33ppm (ddd, J = 47.98, 7.91, 3.49)

CHN: 3.55ppm (m)

1 ⁹ F- orchid R (CFC1 ₃ standard)

CHF: -196.4ppm (m)

TLC (silica gel 254) conditions and analysis results

Developing solvent n-butanol: acetic acid: water = 4: 2: l (v / v)

Coloring reagent Ninhydrin

Rf = 0.36

Example 2

10 g of a mixture of monofluoroacrylamide and α-fluoroacrylic acid ammonium salt (molar ratio of amide compound: ammonium salt = 73:27, total number of both: 107 mmol) and 50 ml (about 0.9 mol) of 28% ammonia water It was placed in a 200 ml autoclave and kept at 80 ° C for 7 hours with stirring. The reaction pressure was 0.5MPa. After completion of the reaction, insolubles contained in the reaction solution were removed by filtration, and the filtrate was concentrated at 80 ° C. or lower using an evaporator to obtain 12 g of a syrup-like crude water-containing product.

As a result of confirming the structure of the compound contained in the crude product by NMR, the conversion of ammonia to olefin was about 50 to 60%.

Next, 12 g of the crude product and 40 ml of concentrated hydrochloric acid were placed in a 100-ml eggplant flask, heated to 100 ° C. using an oil bath, and reacted for 4 to 5 hours while stirring.

After completion of the reaction, the reaction solution was concentrated at 80 ° C. or lower using an evaporator, and 100 ml of ethanol was added thereto, whereby a solid precipitated. The precipitated solid was collected by filtration. The obtained solid was dried at 100 mmHg and 80 ° C for 1 hour, suspended in 30 ml of methanol, washed, and filtered again to collect crystals.

Next, the recovered crystals were dried at 100 mmHg and 80 ° C for 3 hours to obtain 4.4 g (yield 28%) of crystals of a-fluoro-β-alanine 'hydrochloride. The obtained compound was identified using NMR and TLC. The results of NR and TLC are shown below. These results were consistent with the standard (manufactured by Tokyo Chemical Reagents).

-NMR (TMS standard)

CHF: 5.33ppm (ddd, J = 47.98, 7.91, 3.49)

CHN: 3.55ppm (m)

1 ⁹ F- NMR (CFC1 ₃ standard)

CHF:-196.4ppm (m)

TLC (silica gel 254) conditions and analysis results

Developing solvent n-butanol: acetic acid: water = 4: 2: l (v / v)

Coloring reagent Ninhydrin

Rf = 0.36

Comparative Example 1

In a 100 ml eggplant flask set with a Dimroth, 50 ml (about 1.4 mol) of 28% aqueous ammonia was placed. While stirring the ammonia water under ice-cooling, 10 g (about 92 mmol) of monofluoric acrylate fluoride (GC85%) was slowly added dropwise to the aqueous ammonia, taking care not to generate heat. After the completion of the dropwise addition, the mixture was further stirred at 20 to 25 ° C for 24 hours. The mixture was concentrated at 80 ° C. or lower using an evaporator, and the obtained solid was analyzed by NMR. As a result, a peak observed when alumination occurred in olefin was not confirmed.

Claims

The scope of the claims

1. a-Fluoroacrylic acid compound and ammonia and / or amine are reacted at about 50 to 150 ° C. and, if necessary, hydrolyzed to obtain α- represented by the following formula (A). Fluoro-process for producing a β-alanine compound or a salt thereof.

2. The α-fluoroacrylic acid compound is selected from the group consisting of α-fluoroacrylic acid halide, monofluoroacrylic acid amide compound, monofluoroacrylic acid ester, α-fluoroacrylic acid and α-fluoroacrylic acid salt. 2. The method according to claim 1, wherein the method is at least one.

3. The method according to claim 1, wherein the a-fluoroacrylic acid compound is a-fluoroacrylic acid halide, and the halide is reacted with ammonia.

4. at least one α-fluoroacrylic acid compound selected from the group consisting of a-fluoroacrylic acid halide, α-fluoroacrylic acid amide compound and a-fluoroacrylic acid ester, and ammonia and / or amine at 50 to 50%; A method for producing an amide compound represented by the following formula (B) by reacting at about 150 ° C.

(B)

[In the formulas,-represents the same or different and represents a hydrogen atom, an alkyl group or a benzyl group. ]

5. The a-fluoroacrylic acid compound is at least one compound selected from the group consisting of α-fluoroacrylic acid esters, 5. The method according to claim 4, wherein the compound is reacted with ammonia to produce an amido conjugate represented by the following formula (B-1).

NH ₂ -CH ₂ -CHF-C-NH (B-1)

〇

6. The α-fluoroacrylic acid conjugate is an α-fluoroacrylamide compound, and reacts the amide compound with ammonia to produce an amide compound represented by the following formula (Β-2). The method of claim 4.

(Β-2)

7. The method according to claim 1, 2 or 4, wherein the amine is at least one selected from the group consisting of monoalkylamine and dialkylamine.

8. A method for producing an α-fluorinated β-alanine conjugate represented by the following formula (Α) or a salt thereof by hydrolyzing an amide compound represented by the following formula (Β).