JP2000186077A - Production of 5-aminoisoxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a 5-aminoisoxazole derivative useful as a medicine, an agrochemical, or the like, or its synthetic intermediate with slight side reactions. SOLUTION: A compound represented by formula I (R denotes an organic group; R1 denotes a protecting group of carboxyl group; M+ denotes a cation) is reacted with a hydroxylamine salt to thereby produce a 5-aminoisoxazole derivative represented by formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing a 5-aminoisoxazole derivative which is useful as a pharmaceutical or agrochemical, etc. or a synthetic intermediate thereof.

[0002]

2. Description of the Related Art 5-aminoisoxazole derivatives include, for example, anti-inflammatory agents (JP-A-7-291972, JP-A-7-215952, JP-A-4-368375, JP-A-61-164508), cholesterol acyltransferase inhibitors Intermediate (203rd ACS
Natl. Meet. (April 5-10, SanFrancisco) 1992, Abst.
MEDI 142.).

[0003] With respect to a method for producing a 5-aminoisoxazole derivative, for example, as described below, an ester derivative (1) is reacted with an anion of acetonitrile, and
There is known a method of producing a 5-aminoisoxazole derivative (3) by converting the ketonitrile derivative (2) into a ketone nitrile derivative (2), followed by reaction with hydroxylamine (JP-A-4-368375).

Embedded image

[0004]

An object of the present invention is to provide a method for producing a 5-aminoisoxazole derivative with less side reaction. Another object of the present invention is to provide a method for producing an optically active 5-aminoisoxazole derivative from a carboxylic acid derivative having an asymmetric carbon by suppressing steric isomerization.

[0005]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, the formula:

Embedded image [In the formula, R represents an organic group. R ¹ represents a carboxyl-protecting group. M ⁺ represents a cation. By reacting a hydroxylamine salt with a compound represented by the formula The inventors have found that they can be manufactured and completed the present invention.

[0006] That is, the present invention is as follows. [1] Equation 1:

Embedded image By reacting a hydroxylamine salt with a compound represented by the formula:

Embedded image A method for producing a 5-aminoisoxazole derivative represented by the formula: [Wherein, R, R ¹ and M ⁺ are as defined above. ]

[2] An activator of a carboxyl group, represented by the formula 3:

Embedded image Activating the carboxyl group of the compound represented by the formula:

Embedded image By reacting a compound represented by the formula:

Embedded image By reacting a hydroxylamine salt with a compound represented by the formula:

Embedded image A method for producing a 5-aminoisoxazole derivative represented by the formula: [Wherein, R, R ¹ and M ⁺ are as defined above. ]

[3] R is a formula:

Embedded image [R ² , R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted Alkenyl group, optionally substituted alkynyl group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted alkoxy group, optionally substituted cycloalkoxy group, optionally substituted An aryloxy group, an optionally substituted heterocyclic oxy group,
—SR ⁵ (R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl Represents an optionally substituted aryl group, an optionally substituted acyl group, or an optionally substituted alkoxycarbonyl group) or an optionally substituted amino group. Also, R ² , R ³ and R ⁴
And any two of these may be bonded together to form, together with the carbon atom, an optionally substituted hydrocarbon ring or an optionally substituted heterocyclic ring. [1]
Or the production method according to [2].

[4] R is a formula:

Embedded image [R ³ and R ⁴ are as defined above. [1]
Or the production method according to [2]. [5] The production method according to any one of [1] to [4], wherein R ¹ is a tertiary alkyl group. [6] The production method according to any one of [1] to [4], wherein R ¹ is a t-butyl group. [7] M ⁺ is an alkali metal ion, an alkaline earth metal ion or an ammonium ion [1] to
The production method according to any one of [6]. [8] The production method according to any one of [1] to [6], wherein M ⁺ is a lithium ion or a sodium ion. [9] The method according to any one of [2] to [8], wherein the activator of the carboxyl group is an alkyl chloroformate, pivaloyl chloride or 1,1-carbonyldiimidazole.

[10] Formula:

Embedded image A compound represented by the formula: [Wherein, R ¹ , M ⁺ , R ² , R ³ and R ⁴ are as defined above. [11] The compound according to [10], wherein R ² is a hydrogen atom. [12] The compound according to [10] or [11], wherein R ¹ is a tertiary alkyl group. [13] The compound according to [10] or [11], wherein R ¹ is a t-butyl group. [14] M ⁺ is an alkali metal ion, an alkaline earth metal ion or an ammonium ion [10] to
[13] The compound according to [13]. [15] The compound according to any one of [10] to [13], wherein M ⁺ is a lithium ion or a sodium ion.

[16] Equation 5:

Embedded image Is reacted with a hydroxylamine salt to give a compound of formula 6:

Embedded image A 5-aminoisoxazole derivative represented by the following formula: Subsequently, a compound represented by the formula 7: NC—N (R ⁸ ) R ⁹ is reacted, and if necessary, further salified, whereby a formula 8:

Embedded image Or a pharmaceutically acceptable salt thereof. [Wherein, R ¹ and M ⁺ are as defined above. R ⁶ is 2-fluoro-biphenyl-4-
Represents yl, 3-benzoylphenyl, 2'-fluoro-biphenyl-4-yl or biphenyl-4-yl.
R ⁷ represents a hydrogen atom, a methyl group, a methoxy group or an ethoxy group. R ⁸ and R ⁹ are as described in the following (a), (b) or (c). (A) independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms. (B) one is hydrogen and the other - _{(CH 2) n} -
CO ₂ R ¹⁰ (n represents an integer of 1 to 3; R ¹⁰ represents an alkyl group having 1 to 3 carbon atoms), — (CH ₂ ) _m —O
R ¹¹ (m represents 2 or 3. R ¹¹ is a hydrogen atom,
Represents an alkyl group having 1 to 3 carbon atoms, 2-hydroxyethyl or 3-hydroxypropyl. ) Or-(C
^{_{H 2) m -N (R 12}} ) R 13 (m is as defined above ^{.R 12} and ^{R 13} are either independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or ^{R 12} and R ¹³ together with the nitrogen atom, pyrrolidine, piperidine, morpholine or N-methylpiperazine (wherein pyrrolidine, piperidine, morpholine and N-methylpiperazine may be substituted by one or two methyls. ). (C) together with the nitrogen atom, pyrrolidine, piperidine, morpholine or N-methylpiperazine (wherein pyrrolidine, piperidine, morpholine and N-methylpiperazine may be substituted by one or two methyls. ). [17] R ⁷ is a hydrogen atom or a methyl group, and -N
(R ⁸ ) R ⁹ is morpholino, 4-methyl-piperazinyl, 1,1-dioxo- [1,4] thiazin-4-yl, dimethylamino, diethylamino, methylamino,
The production method according to [16], which is ethylamino, hydroxyamino, 2-hydroxyethylamino, 2-morpholinoethylamino, 2-methoxyethylamino or 2- (2-hydroxyethyl) -ethylamino.

Hereinafter, the present invention will be described in detail. The organic group is not particularly limited.

Embedded image [R ² , R ³ and R ⁴ are as defined above. ] The group represented by this is mentioned.

As the carboxyl-protecting group, for example, known carboxyl-protecting groups (“Protective Groups in Or
ganic Synthesis ”second edition TW Greene and
PGMWuts, John Wiley & Sons, Inc. (1991)), and preferably a carboxyl-protecting group which is eliminated under acidic conditions. Specific examples include alkyl which may be substituted, silyl which may be substituted, and the like. Preferably, tertiary alkyl such as t-butyl and the like can be mentioned. Examples of the cation include a cation that forms a salt with an anion generated by extracting a hydrogen atom at the α-position from cyanoacetate, and specifically includes an alkali metal ion, an alkaline earth metal ion, and ammonium. Ions and the like. Examples of the alkali metal ion include a lithium ion, a sodium ion, a potassium ion, a cesium ion and the like, and preferably a lithium ion and a sodium ion. Examples of the alkaline earth metal ion include a magnesium ion. As ammonium ions,
For example, 4- (dimethylamino) pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5
And ammonium ions formed by addition of a hydrogen atom to amines such as -diazabicyclo [4.3.0] non-5-ene. Also, the cation can be exchanged for another cation. As the enol salt of the formula 1, etc.,
Including any geometric isomers or equilibrium mixtures, M ⁺ may be present on an oxygen atom, a carbon atom, or a nitrogen atom.

Examples of the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, phenanthryl, anthryl and the like. Preferably, phenyl, 1-naphthyl,
2-naphthyl is exemplified. Examples of the heterocyclic group include a 1 to 3 5- to 7-membered saturated or unsaturated heterocyclic group containing 1 to 6 nitrogen, oxygen and / or sulfur atoms. Specific examples of such a saturated heterocyclic group include tetrahydrofuryl, pyrrolidinyl,
One to three-membered saturated heterocyclic group such as pyrazolidinyl, imidazolidinyl, etc .; a one to three-membered six-membered saturated heterocyclic group such as piperidyl, morpholinyl, thiamorpholinyl, piperazinyl, hexahydro-pyrimidinyl;
And 3 to 7-membered saturated heterocyclic groups. As such unsaturated heterocyclic groups, specifically, furyl, thienyl,
Indolyl, isothiazolyl, benzothienyl, isobenzofuranyl, pyrrolyl, benzofuryl, imidazolyl, 4,5-dihydro-1H-imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, benzimidazolyl, benzothiazolyl,
1-3-membered 5-membered unsaturated heterocyclic group such as benzoxazolyl and carbazolyl, pyridyl, pyrazinyl, pyrimidinyl, 1,4,5,6-tetrahydro-pyrimidinyl,
3,6-dihydro-2H- [1,3,5] oxadiazinyl, pyridazinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, chromenyl,
1-3 ring 6-membered unsaturated heterocyclic group such as 2,3-dihydro-benzo [1,4] dioxanyl, and 1 such as 4,5,6,7-tetrahydro-1H- [1,3] diazepinyl ~ 3
And a 7-membered unsaturated heterocyclic group of a ring.

[0015] Substitution in substituted aryl and substituted heterocyclic groups
Examples of the substituent include each of the following groups a) to g):
And any one or more of these
May be replaced. a): halogen atom, nitro group, cyano group, azide
Group, mercapto group, amino group which may be substituted,
An optionally substituted hydroxylamino group, an optionally substituted low
Secondary alkoxyamino group, hydroxyl group, acyl group, acyloxy
Si group, carboxyl group, carbamoyl which may be substituted
Group, carbamoyloxy group which may be substituted, sulfo
Group, a sulfamoyl group which may be substituted b): -R¹⁴, -OR¹⁴, -CO₂R¹⁴, -S
O₃R¹⁴, -SR^{1 4}, -OCH₂R¹⁴, -SCH
₂R¹⁴, -C (= NOH) R¹⁴  [Wherein, R¹⁴Represents a phenyl group or a monocyclic heterocyclic group
Represent. A phenyl group or a monocyclic heterocyclic group is, for example, halo
Gen atom, lower alkyl group, lower haloalkyl group, shea
No group, nitro group, azide group, hydroxyl group, lower alkoxy
Group, lower haloalkoxy group, optionally substituted amino
Group, carbamoyl group which may be substituted, carboxy group,
Lower alkylcarbonyl group, lower alkoxycarbonyl
Group, lower alkylthio group, lower alkylsulfinyl group
Arbitrarily selected from the group such as and lower alkylsulfonyl groups
May be substituted with one or more groups. ]

C): alkyl group, alkoxy group, alkoxy
Cicarbonyl group, alkoxy (thiocarbonyl) group,
Alkylthio group, (alkylthio) thiocarbonyl group,
(Alkylthio) carbonyl group, alkylcarbonyl
Group, alkylthioyl group, alkylsulfinyl group,
Alkylsulfonyl, alkylcarbonyloxy, a
Lucirch oiloxy group, alkylsulfonyloxy group
[Each group in this group is, for example, a halogen atom, a nitro group,
Ano, mercapto, oxo, thioxo, substituted
Amino group, hydroxyl group, acyl group, acyloxy
Group, carboxy group, carbamoyl group which may be substituted,
An optionally substituted carbamoyloxy group, a sulfo group,
An optionally substituted sulfamoyl group, -R^{1 4}, -OR
¹⁴, -SR¹⁴, -OCH₂R¹⁴, -SCH₂R
¹⁴(Where R ¹⁴Is as defined above. ), Low grade
Loalkyl group (lower cycloalkyl group is, for example, halogen
Atom, lower alkyl group, lower haloalkyl group, substituted
Amino group, hydroxyl group, lower alkoxy group and
One or more optionally selected from the group of lower haloalkoxy groups, etc.
May be substituted with a plurality of groups. ), Lower alkoxy
Group, lower alkoxycarbonyl group and lower alkylthio group
O group (lower alkoxy group, lower alkoxycarbonyl group
And a lower alkylthio group are, for example, a halogen atom,
Secondary cycloalkyl group, monocyclic heterocyclic group, phenyl group,
Ano group, nitro group, hydroxyl group, lower alkoxy group, lower
Alkoxy group, optionally substituted amino group, substituted
Carbamoyl group, carboxy group, lower alkyl
Carbonyl group, lower alkoxycarbonyl group, lower alkyl
Kirthio, lower alkylsulfinyl and lower alkyl groups
1 or any arbitrarily selected from the group of
It may be substituted with more than one group. Arbitrarily selected from the group
May be substituted with one or more groups. D): alkenyl group [alkenyl group is, for example, halogen
Atom, nitro group, cyano group, mercapto group, oxo
Group, thioxo group, amino group which may be substituted, hydroxyl group,
Lower alkoxy group, lower haloalkoxy group, lower alcohol
Xycarbonyl group, lower alkylthio group, acyl group,
Siloxy group, carboxy group, carba which may be substituted
Moyl group, -R¹⁴, -OR¹⁴, -SR¹⁴, -OC
H₂R¹⁴And -SCH₂R¹⁴(Where R¹⁴Is before
Synonymous with 1) or arbitrarily selected from the group of
It may be substituted with more than one group. ]

E): alkynyl group [alkynyl group includes, for example, halogen atom, nitro group, cyano group, mercapto group,
Oxo group, thioxo group, amino group which may be substituted, hydroxyl group, lower alkoxy group, lower haloalkoxy group, lower alkoxycarbonyl group, lower alkylthio group, acyl group, acyloxy group, carboxy group, carbamoyl group which may be substituted ^{, -R 14, -OR 14, -SR} 14,
—OCH ₂ R ¹⁴ and —SCH ₂ R ¹⁴ (wherein, R
¹⁴ has the same meaning as described above. ) May be substituted with one or more groups arbitrarily selected from the group such as F): alkenyloxy group, alkenyloxycarbonyl group, alkenylcarbonyl group, alkenylcarbonyloxy group, alkynyloxy group, alkynyloxycarbonyl group [each group in this group is, for example, a halogen atom, an oxo group, or may be substituted] Arbitrarily selected from the group of amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group, carboxy group, carbamoyl group which may be substituted, lower alkoxycarbonyl group and phenyl group. It may be substituted with one or more groups. G): lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyloxycarbonyl group, lower cycloalkenyl group, lower cycloalkenyloxy group, lower cycloalkenylcarbonyl Group, lower cycloalkenylcarbonyloxy group, lower cycloalkenyloxycarbonyl group [each group in this group is
For example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy Group, a lower alkylthio group, a carboxy group, a carbamoyl group which may be substituted, a lower alkoxycarbonyl group, and the like. ]

Specific examples of the substituent of the substituted aryl group and the substituted heterocyclic group include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, phenyl, trifluoromethyl , 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 6,6,6-trifluorohexyl, hydroxymethyl, hydroxyethyl, methoxymethyl, hexyloxymethyl, cyclopropyl Methoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, 2- (1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxy Carbonylmethyl, carbamoylmethyl, amidinomethyl, Methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N-acetylaminomethyl, ethenyl, 2-propenyl, ethynyl, 2-propynyl, 2-methoxycarbonylethenyl, fluoro, chloro, bromo, nitro, cyano, hydroxy, amino, N, N-dimethylamino, mercapto, sulfo,
Carboxy, amidino, methoxy, cyclopropylmethoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 4,4,5
5,5-pentafluoropentoxy, 2-methanesulfinylethoxy, phenoxy, benzyloxy, 4-methoxybenzyloxy, methoxycarbonyloxy,
-Pyrrolidinyl, 3-hydroxy-1-pyrrolidinyl,
Acetylamino, N-acetyl-N-methylamino, N
-Methanesulfonylamino, N-methanesulfonyl-N
-Methylamino, methoxycarbonyl, 2-methyl-2
-Propyloxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, 2-thiazolidinyl, 2-oxazolidinyl, 5-tetrazolyl, methanesulfinyl, sulfamoyl, N, N-dimethylsulfamoyl , Acetyl, benzoyl, pivaloyl, trifluoroacetyl,
Formyl, ethylenedioxymethyl, imino, methoxyimino and the like can be mentioned.

Preferred examples of such a substituent include methyl, 2-methyl-1-propyl, hexyl, 2-methyl-2-propyl, 2-propyl, phenyl, trifluoromethyl, 2,2 , 2-trifluoroethyl, hydroxymethyl, hydroxyethyl, methoxymethyl, cyclopropylmethoxymethyl, acetoxymethyl, N, N-dimethylcarbamoyloxymethyl, methanesulfonyloxymethyl, N, N-dimethylsulfamoyloxymethyl, -(1-pyrrolidinyl) ethoxymethyl, 2-methoxyethyl, carboxymethyl, methoxycarbonylmethyl, carbamoylmethyl, amidinomethyl, methylthiomethyl, cyanomethyl, aminomethyl, aminoethyl, N-acetylaminomethyl, fluoro, chloro, Bromo, nitro, cyano,
Hydroxy, amino, N, N-dimethylamino, methoxy, 2- (1-pyrrolidinyl) ethoxy, methoxycarbonylmethoxy, 2-acetoxyethoxy, 2-hydroxyethoxy, 2-methoxyethoxy, 2-methanesulfinylethoxy, 1-pyrrolidinyl , 3-hydroxy-1-pyrrolidinyl, acetylamino, N-acetyl-
N-methylamino, N-methanesulfonylamino, N-
Methanesulfonyl-N-methylamino, methoxycarbonyl, 2-methyl-2-propyloxycarbonyl,
2,2,2-trifluoroethoxycarbonyl, carbamoyl, N, N-dimethylcarbamoyl, methanesulfinyl, acetyl, benzoyl, pivaloyl, trifluoroacetyl and the like. The preferred number of substituents in the aryl group and the heterocyclic group is 1, 2 or 3. Further, the aryl group and the heterocyclic group are preferably unsubstituted.

Examples of the alkyl group include a linear or branched alkyl group having 1 to 10 carbon atoms. Specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methyl-1-propyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1-methylbutyl, 3-methylbutyl, hexyl, 2-methylpentyl, 3,3- Examples include dimethylbutyl, heptyl, 1-ethylpentyl, 5-methylhexyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, decyl and the like. As the lower alkyl group, one having 1 to carbon atoms
And 6 alkyl groups.

Examples of the substituent in the substituted alkyl group include, for example, any of the following groups a) to d), and these groups may be arbitrarily substituted one or more times. a): halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, optionally substituted amino group, optionally substituted hydroxylamino group, optionally substituted lower alkoxyamino group, hydroxyl group, acyl Group,
Acyloxy group, carboxy group, carbamoyl group which may be substituted, carbamoyloxy group which may be substituted,
Sulfo group, sulfamoyl group which may be substituted b): lower cycloalkyl group, lower cycloalkyloxy group, lower cycloalkylcarbonyl group, lower cycloalkylcarbonyloxy group, lower cycloalkyloxycarbonyl group, lower cycloalkenyl group, lower Cycloalkenyloxy group, lower cycloalkenylcarbonyl group, lower cycloalkenylcarbonyloxy group, lower cycloalkenyloxycarbonyl group [each group in this group is
For example, halogen atom, nitro group, cyano group, mercapto group, oxo group, thioxo group, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy Group, a lower alkylthio group, a carboxy group, a carbamoyl group which may be substituted, a lower alkoxycarbonyl group, and the like. ]

C): alkoxy group, alkoxycarbonyl
Group, alkoxy (thiocarbonyl) group, alkylthio
Group, (alkylthio) thiocarbonyl group, (alkylthio
E) carbonyl group, alkylcarbonyl group, alkylthio
Oil group, alkylsulfinyl group, alkylsulfonate
Group, alkylcarbonyloxy group, alkylthioyl
Oxy group, alkylsulfonyloxy group [each group in this group
Represents, for example, a halogen atom, a nitro group, a cyano group,
Group, oxo group, thioxo group,
Group, hydroxyl group, acyl group, acyloxy group, carboxy
Group, an optionally substituted carbamoyl group, an optionally substituted
Carbamoyloxy group, sulfo group, may be substituted
Sulfamoyl group, -R^{1 4}, -OR¹⁴, -S
R¹⁴, -OCH₂R¹⁴, -SCH₂R¹⁴(Where
R ¹⁴Is as defined above. ), Lower cycloalkyl group
(Lower cycloalkyl groups include, for example, halogen atom, lower
Alkyl group, lower haloalkyl group,
Mino group, hydroxyl group, lower alkoxy group and lower haloal
One or more groups arbitrarily selected from the group of
It may be replaced. ), Lower alkoxy group, lower alcohol
Xycarbonyl and lower alkylthio groups (lower alkyl
Coxy group, lower alkoxycarbonyl group and lower alkyl
The quinthio group is, for example, a halogen atom, a lower cycloalkyl.
Group, monocyclic heterocyclic group, phenyl group, cyano group, nitro
Group, hydroxyl group, lower alkoxy group, lower haloalkoxy
Group, optionally substituted amino group, optionally substituted cal
Bamoyl group, carboxy group, lower alkylcarbonyl
Group, lower alkoxycarbonyl group, lower alkylthio
Group, lower alkylsulfinyl group and lower alkyls
One or more groups arbitrarily selected from a group such as a rufonyl group
May be substituted. ))
Or a plurality of groups. D): -R¹⁴, -OR¹⁴, -SR¹⁴, -OCH
₂R¹⁴, -SCH₂R ¹⁴(Where R¹⁴Is the same as above
Righteous. )

Examples of the substituted alkyl group include trifluoromethyl, 2-nitroethyl, 2-cyanopropyl,
4-mercaptobutyl, 3-oxobutyl, 2-piperidinoethyl, 2-hydroxyethyl, 3-methoxypropyl, ethoxycarbonylmethyl, cyclopropylmethyl, cyclohexylmethyl, 6-cyclohexylhexyl, 3-cyclohexenylbutyl, 2-phenylbutyl, Benzyl, 2-naphthylmethyl, phenethyl, 2-
Pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2-quinolylmethyl, 3-quinolylmethyl, 3-
Thienylpropyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, carboxymethyl,
Ethoxycarbonylmethyl, carbamoylmethyl and the like. In addition, a lower haloalkyl group refers to a lower alkyl group substituted with 1 to 5 halogen atoms.

[0024] The alkoxy group means an oxy group to which an alkyl group is bonded. Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like. Examples of the substituent of the substituted alkoxy group include the same substituents as those of the substituted alkyl group. Specific examples of the substituted alkoxy group include cyclopropylmethoxy, trifluoromethoxy, 2-pyrrolidinoethoxy, benzyloxy, 2-pyridylmethoxy and the like. In addition, the haloalkoxy group refers to an alkoxy group substituted with 1 to 5 halogen atoms. An alkoxycarbonyl group refers to a carbonyl group to which an alkoxy group is bonded. Specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl and the like. Examples of the substituent in the substituted alkoxycarbonyl group include the same substituents as those in the substituted alkyl group.

Examples of the alkenyl group include a linear or branched alkenyl group having 2 to 10 carbon atoms and having 1 to 3 double bonds. Specifically, ethenyl, 1-propenyl, 2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl , 3-methyl-2-butenyl, 1-hexenyl,
2-hexenyl, 1-heptenyl, 2-heptenyl, 1
-Octenyl, 2-octenyl, 1,3-octadienyl, 2-nonenyl, 1,3-nonadienyl, 2-decenyl and the like. Preferred alkenyl groups include, for example, ethenyl, 1-propenyl and 1-butenyl groups. Examples of the lower alkenyl group include alkenyl groups having 2 to 6 carbon atoms. Examples of the substituent of the substituted alkenyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, and a lower alkoxycarbonyl group. A lower alkylthio group, an acyl group, an acyloxy group, a carboxy group, a carbamoyl group which may be substituted, -R ¹⁴ , -OR ¹⁴ , -S
R ¹⁴ , —OCH ₂ R ¹⁴ , —SCH ₂ R ¹⁴ (wherein,
R ¹⁴ has the same meaning as described above. ) And the like. Also,
An alkenyloxy group refers to an oxy group to which an alkenyl group is bonded.

Examples of the alkynyl group include a linear or branched alkynyl group having 2 to 10 carbon atoms and having 1 to 3 triple bonds. Specifically, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3
-Butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-octynyl, 6-methyl-1-heptynyl, 2-decynyl and the like. Preferred alkynyl groups include, for example, 1-propynyl, 1-butynyl and the like. The lower alkynyl group has 2 to 2 carbon atoms.
And 6 alkynyl groups. Examples of the substituent of the substituted alkynyl group include a halogen atom, a nitro group, a cyano group, a mercapto group, an oxo group, a thioxo group, an amino group which may be substituted, a hydroxyl group, a lower alkoxy group, a lower haloalkoxy group, an acyl group, and an acyloxy group. Group, lower alkylthio group, carboxy group, carbamoyl group which may be substituted, lower alkoxycarbonyl group, -R ¹⁴ , -OR
_{^{14, -SR 14, -OCH 2 R}} 14, -SCH 2 R
¹⁴ (wherein, R ¹⁴ has the same meaning as described above). Further, an alkynyloxy group refers to an oxy group to which an alkynyl group is bonded.

As the cycloalkyl group, for example, a compound having 3 to 3 carbon atoms
10 cycloalkyl groups, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Examples of the lower cycloalkyl group include a cycloalkyl group having 3 to 6 carbon atoms. Further, a cycloalkyloxy group refers to an oxy group to which a cycloalkyl group is bonded. Examples of the cycloalkenyl group include those having 3 to 10 carbon atoms, and specific examples include cyclohexenyl. Examples of the lower cycloalkenyl group include cycloalkenyl groups having 3 to 6 carbon atoms. Further, a cycloalkenyloxy group refers to an oxy group to which a cycloalkenyl group is bonded. Examples of the substituent of the substituted cycloalkyl group and the substituted cycloalkenyl group include a halogen atom, a nitro group,
Cyano group, mercapto group, oxo group, thioxo group, lower alkyl group, lower haloalkyl group, optionally substituted amino group, hydroxyl group, lower alkoxy group, lower haloalkoxy group, acyl group, acyloxy group, lower alkylthio group,
Examples thereof include a carboxy group, a carbamoyl group which may be substituted, and a lower alkoxycarbonyl group.

As the acyl group, for example, a group represented by the formula -ZR
¹⁵ (wherein, Z represents —CO—, —CS—, —SO—, or —SO ₂ —, and R ¹⁵ is an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted And an acyl group represented by the following formula: Specific examples of the acyl group include formyl, acetyl, propanoyl, 2-propanoyl, pivaloyl, valeryl, pivaloyl, trifluoroacetyl, benzoyl, naphthoyl, nicotinoyl, methanesulfonyl, trifluoromethanesulfonyl, and p-toluenesulfonyl. . Preferred acyl groups include an acetyl group. An acyloxy group refers to an oxy group to which an acyl group is bonded.

As the substituent in the substituted carbamoyl group,
Examples thereof include an alkyl group which may be substituted with an aryl group or a heterocyclic group, an aryl group, a heterocyclic group, and the like, or a plurality of identical or different groups may be independently substituted. Specific examples of the substituted carbamoyl group include ethylcarbamoyl, dimethylcarbamoyl, phenylcarbamoyl, 2-pyridylcarbamoyl, benzylcarbamoyl, (3-pyridylmethyl) carbamoyl, and the like. Examples of the substituent in the substituted sulfamoyl group include an alkyl group, an aryl group, and a heterocyclic group. A plurality of the same or different substituents may be independently substituted. Specific examples of the substituted sulfamoyl group include ethylsulfamoyl, dimethylsulfamoyl, phenylsulfamoyl, 2-pyridylsulfamoyl and the like. Examples of the substituent in the substituted amino group include an acyl group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group, a heterocyclic group, an alkoxycarbonyl group, and the like.
A plurality of the same or different ones may be independently substituted. Specific examples of the substituted amino group include acetamido, propionamido, butylamido, 2-butylamido, methylamino, 2-methyl-1-propylamino, diethylamino and the like. The substituent in the substituted hydroxylamino group may be substituted with any of a nitrogen atom and an oxygen atom, and examples of the substituent include the same substituents as those in the substituted amino group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

Examples of the optionally substituted hydrocarbon ring formed by bonding any ^two of R ² , R ³ and R ⁴ together with a carbon atom include, for example, the number of carbon atoms which may be substituted. Examples thereof include a cycloalkane ring having 3 to 8 carbon atoms and a cycloalkene ring having 3 to 8 carbon atoms which may be substituted. Specific examples of such a cycloalkane ring or cycloalkene ring include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and the like. Examples of the substituent in the substituted hydrocarbon ring include the same substituents as those in the substituted cycloalkyl group. R ² , R ³ and R
^{As the} heterocyclic ring in the optionally substituted heterocyclic ring formed by bonding any two of ⁴ together with a carbon atom, for example, 1 to 6 nitrogen atoms, oxygen atoms and / or sulfur atoms (Containing at least one nitrogen atom), a 5- to 7-membered monocyclic or bicyclic saturated or unsaturated heterocyclic ring. Specifically, pyrrolidine, imidazolidin, 4,5-dihydro-1H-imidazole, piperidine, piperidin-4-one, piperazine, morpholine, thiamorpholine, 1,4,5,6-
Tetrahydro-pyrimidine, hexahydro-pyrimidine, 3,6-dihydro-2H- [1,3,5] oxadiazine and the like. Examples of the substituent in the substituted heterocyclic ring include the same substituents as those in the substituted heterocyclic group.

[0031] Pharmaceutically acceptable salts of the isoxazole derivative of Formula 8 include acid addition salts and base addition salts. Examples of the acid addition salt include hydrochloride, hydrobromide,
Inorganic acid salts such as sulfate, hydroiodide, nitrate and phosphate, citrate, oxalate, acetate, formate, propionate, benzoate, trifluoroacetate, fumarate , Maleate, tartrate, aspartate, glutamate, methanesulfonate, benzenesulfonate, camphor-sulfonate, and other organic acid salts. Base addition salts include sodium salts, potassium salts,
Inorganic base salts such as calcium salts, magnesium salts, and ammonium salts; and organic base salts such as triethylammonium salts, triethanolammonium salts, pyridinium salts, and diisopropylammonium salts. The present invention
It includes all stereoisomers, optically active forms and tautomers of the isoxazole derivative of the formula 8. The present invention also encompasses solvates such as hydrates of the isoxazole derivative of the formula 8 or a pharmaceutically acceptable salt thereof, and all forms of the crystalline form.

Preparation of 5-aminoisoxazole derivative of formula 2
Method

Embedded image [Wherein, R, R ¹ and M ⁺ are as defined above. The 5-aminoisoxazole derivative of the formula 2 can be produced by reacting the compound of the formula 1 with a hydroxylamine salt in a water-containing hydrophilic solvent. Examples of hydroxylamine salts include salts of hydroxylamine with inorganic or organic acids. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid and the like. Examples of the organic acid include methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, formic acid, oxalic acid, acetic acid, propionic acid, butyric acid, tartaric acid, lactic acid, citric acid, phthalic acid, succinic acid, and monochloroacetic acid. It is also possible to use a mixture of two or more of these. Preferred acids include hydrochloric acid, sulfuric acid, oxalic acid, phosphoric acid and the like, and particularly preferred is hydrochloric acid. The hydroxylamine salt can also be adjusted in the reaction system. The amount of the hydroxylamine salt to be used is, for example, in the range of 1 to 5 equivalents, preferably 3 to 4 equivalents, relative to the compound of the formula 1. As the hydrophilic solvent, for example, dimethylformamide (DM
F), amide solvents such as dimethylacetamide (DMA), alcohol solvents such as methanol, ethanol, isopropyl alcohol, s-butanol and t-butanol; ether solvents such as tetrahydrofuran (THF) and 1,4-dioxane; Acetone and the like can be mentioned. Preferred hydrophilic solvents include alcohol solvents, amide solvents and the like, particularly preferably isopropyl alcohol, DMF and the like. The hydrophilic solvent may be a mixed solvent of several kinds of the above-mentioned hydrophilic solvents. The amount of the hydrophilic solvent is, for example, in the range of 3 to 30 times by weight based on the compound of the formula 1, preferably 5
The range is up to 15 times by weight. The amount of water to be added to the hydrophilic solvent is, for example, in the range of 0 to 5 times by weight, preferably in the range of 0.5 to 2 times by weight, relative to the hydrophilic solvent. The reaction temperature is, for example, 20 to 1
50 ° C, preferably 50 to 100 ° C. The above-mentioned acids can be further added to the reaction solvent. Preferred acids include hydrochloric acid, phosphoric acid and the like. The amount of the acid added is, for example, 0.1 to 1.5 equivalents to the compound of the formula 1, preferably 0.1 to 1.5 equivalents.
1.0 equivalent. When the reaction solvent is an amide solvent, it is preferable to add an acid. Additives such as salts can also be added to the reaction solvent. Examples of the salts include phosphates such as sodium dihydrogen phosphate and potassium dihydrogen phosphate, borates such as sodium borate, formates such as sodium formate and potassium formate, and oxalic acids such as lithium oxalate and sodium oxalate. Salt, lithium acetate, acetate such as sodium acetate, sodium tartrate, tartrate such as potassium tartrate, lactate such as sodium lactate, potassium lactate, potassium citrate such as sodium citrate;
Examples include hydrochlorides such as lithium chloride and sodium chloride, and hydrobromides such as lithium bromide and sodium bromide, and preferably sodium phosphate and the like. The amount of the additive is, for example, in the range of 0.3 to 3 equivalents, preferably 0.3 to 0.5 equivalents, relative to the compound of the formula 1. When the reaction solvent is an alcohol solvent, it is preferable to add salts and the like.

Method for producing compound of formula 1

Embedded image [Wherein, R, R ¹ and M ⁺ are as defined above. (1) Activation of the carboxyl group of the compound of formula 3 With the activator of the carboxyl group, the carboxyl group of the compound of formula 3 is activated, and the compound of formula 4 is converted into an inert solvent by
By reacting, the compound of the formula 1 can be produced. As a method for activating a carboxyl group, a commonly used method can be used. For example, “Comprehe
nsive Organic Transformations ”RC Larock, VCH
Publishers, Inc., New York (1989), p. 963-976. As a specific method for activating a carboxyl group, a compound of the formula 3 is prepared by acid azide, phosphate, sulfonate, amide,
A method of converting into a thioester, an acid halide, an acid anhydride, a mixed acid anhydride, and the like can be given. Specific examples of the carboxyl group activator include alkyl chloroformate, pivaloyl chloride, 2,4,6-trichlorobenzoyl chloride,
3-dicyclohexylcarbodiimide, 1,1-carbonyldiimidazole, 2,2′-dithiodipyridine, cyanodiethyl phosphate, and the like, preferably, alkyl chloroformate, pivaloyl chloride, 1,1-carbonyldiimidazole, and the like. No. Examples of the alkyl chloroformate include isopropyl chloroformate, isobutyl chloroformate, n-butyl chloroformate and the like, and preferably isopropyl chloroformate and isobutyl chloroformate. A method for activating a carboxyl group using alkyl chloroformate or pivaloyl chloride will be described below. The amounts of the alkyl chloroformate and pivaloylisobutyl chloride used are, for example, in the range of 1.0 to 1.5 equivalents to the compound of the formula 3. Examples of the base used at that time include triethylamine, diisopropylamine, ethylisopropylamine, pyridine, 4- (dimethylamino) pyridine, N-methylmorpholine and the like.
-Methylmorpholine. The amount of the base to be used is, for example, in the range of 1 to 3 equivalents, preferably 1.0 to 1.5 equivalents, relative to the compound of the formula 3. Examples of the reaction solvent include ether solvents such as THF, 1,4-dioxane, diethyl ether, methyl-t-butyl ether, and ethylene glycol dimethyl ether; halogen solvents such as methylene chloride; hydrocarbon solvents such as toluene; DMF; And the like, preferably THF and 1,4-dioxane. The reaction temperature is in the range of -78 to 30C, preferably in the range of -30 to 10C. For example,
If the resulting salt precipitates after activation of the carboxyl group, it can be removed by filtration.

(2) Reaction of the active compound of the formula 3 with the compound of the formula 4 The compound of the formula 1 is produced by reacting the compound of the formula 4 with the compound of the formula 3 having a carboxyl group activated. Can be. The amount of the compound of formula 4 is, for example,
The compound may have a range of 1 to 5 equivalents, preferably 1 to 2 equivalents. As the reaction solvent, for example, the same solvent as the solvent used in the activation reaction of the carboxyl group can be used. The reaction temperature is, for example, in the range of -78 to 30 ° C, preferably -20 to 30 ° C.
A range of 0 ° C is mentioned.

(3) Preparation of the compound of formula 4 The compound of formula 4 can be prepared by treating the corresponding cyanoacetate with a base in an inert solvent. Preferred examples of the cyanoacetate include tertiary alkyl cyanoacetates, and particularly preferred are t-butyl cyanoacetate and the like. As the base, for example, lithium amide, sodium amide, potassium amide,
Metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium hydride, sodium hydride,
Metal hydrides such as potassium hydride, potassium carbonate, metal carbonates such as sodium carbonate, n-butyllithium, s-butyllithium, alkyllithiums such as t-butyllithium, n-butylmagnesium chloride, s-butylmagnesium chloride, Alkyl magnesium such as t-butylmagnesium chloride, etc., and alkoxy metals such as sodium methoxide, potassium methoxide, magnesium methoxide, magnesium ethoxide, etc.
Amines such as-(dimethylamino) pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.0] non-5-ene; And preferably lithium amide, sodium amide, sodium hydride, lithium hydride and the like. The amount of the base to be used is, for example, in the range of 1 to 2 equivalents, preferably 1.0 to 1.2 equivalents, based on cyanoacetate. As the reaction solvent,
For example, the same solvent as that used in the activation reaction of the carboxyl group can be used. The reaction temperature varies depending on the type of base used, but is usually in the range of -78 to 100 ° C. When an amide such as lithium amide or sodium amide is used as a base, the reaction temperature is 5
The temperature is preferably in the range of 0 to 80 ° C, and the reaction is preferably performed while introducing an inert gas such as a nitrogen gas or an argon gas into the reaction solution.

[0036]Method for producing isoxazole derivative of formula 8  The method for producing the isoxazole derivative of the formula 8 is described below.
And will be described in detail.

Embedded image [R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above. The compound of formula 6 prepared by the method described above is converted to a compound of formula 7: N
A cyanoamide derivative represented by C—N (R ⁸ ) R ⁹ ,
In the presence of a base or acid, in an inert solvent or without solvent,
By reacting at a reaction temperature of 20 to 130 ° C., formula 8
Can be produced. The amount of the cyanoamide derivative to be used is, for example, in the range of 1 to 20 equivalents, preferably 1.0 to 1.2 equivalents, relative to the compound of the formula 6. As the base, for example, lithium hydride, sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, lithium amide,
Sodium amide, potassium amide, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, n-butylmagnesium chloride, s-butylmagnesium chloride, t-butylmagnesium chloride, sodium methoxide,
Potassium methoxide, magnesium methoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, lithium t-butoxide, sodium t-butoxide, potassium t-butoxide and the like, preferably lithium hydride, sodium hydride, carbonate Examples include potassium, lithium amide, sodium amide, lithium t-butoxide, potassium t-butoxide and the like. When alkoxide is used as a base, the alkoxide can be prepared by allowing an appropriate base to act on an alcohol such as t-butanol in the reaction system. In this case, as the base to act, lithium hydride, sodium hydride, lithium amide, sodium amide, potassium amide and the like are preferable. When using amides such as lithium amide and sodium amide, the reaction temperature is 50
The reaction temperature is preferably in the range of -80 ° C, and the reaction is preferably performed while introducing an inert gas such as a nitrogen gas or an argon gas into the reaction solution. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Lewis acid, etc., preferably, hydrochloric acid, sulfuric acid, phosphoric acid, aluminum chloride, titanium trichloride, titanium tetrachloride, tin dichloride, boron trifluoride etherate And the like. The amount of the base or acid to be used is, for example, in the range of 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to the compound of the formula 6. Preferred solvents include, for example, DM
F, DMA, THF, toluene, acetonitrile, t-
Butanol, methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and the like. The isoxazole derivative of the formula 8 can be converted into a pharmaceutically acceptable salt, if necessary, by salification according to a conventional method.

The isoxazole derivative of the formula 8 or a pharmaceutically acceptable salt thereof can be used in an animal model of chronic inflammation (rat adjuvant arthritis, etc.) and an animal model of immune abnormality (mouse II
It shows a remarkable effect in test systems including, for example, type I allergic reaction) and experimental allergic encephalomyelitis mice (such as multiple sclerosis). Therefore, the isoxazole derivatives of the formula 8 and the like act not only on the obvious effect on chronic inflammation but also on the underlying immune abnormality, such as autoimmune diseases (eg, rheumatoid arthritis, systemic erythematous Lupus, systemic scleroderma, Sjogren's syndrome, Hashimoto's disease, myasthenia gravis, Basedow's disease, Addison's disease, juvenile diabetes (type I diabetes), autoimmune bloody diseases (eg, aplastic anemia, hemolytic Anemia, idiopathic thrombocytopenia, etc.), ulcerative colitis, chronic active hepatitis, glomerulonephritis, interstitial pulmonary fibrosis, multiple sclerosis, etc.) and inflammatory diseases (eg, osteoarthritis, gout) , Atopic dermatitis, psoriasis, etc.).

The isoxazole derivative of the formula 8 or a pharmaceutically acceptable salt thereof may be used orally or parenterally (for example, by intravenous, subcutaneous or intramuscular injection, topical, rectal) , Transdermal, or nasal). Forms for oral administration include, for example, tablets, capsules, pills, granules, powders, solutions, syrups and suspensions, and forms for parenteral administration include, for example, injection Aqueous or oily agents, ointments, creams, lotions,
Aerosols, suppositories, patches and the like can be mentioned. These preparations are prepared using a conventionally known technique, and can contain an acceptable usual carrier, excipient, binder, stabilizer and the like. When the composition is used in the form of an injection, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added. The dose and frequency of administration of the isoxazole derivative of the formula 8 or a pharmaceutically acceptable salt thereof vary depending on the condition, age, body weight, and dosage form. About 1 to 2000m per day
g, preferably 10 to 500 mg, can be administered once or in several divided doses.

[0039]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. Example 1 (S) -3- [1- (2-fluoro-biphenyl-4-)
Synthesis of yl) ethyl] -5-aminoisoxazole

Embedded image The vessel was purged with nitrogen, lithium amide (10.63 g),
After adding THF (550 mL), t-butyl cyanoacetate (65.36 g) was added thereto while stirring at room temperature. Then, while bubbling nitrogen through the reaction solution, 8
After stirring at 0 ° C. for 1.5 hours, the temperature was returned to room temperature and bubbling was completed (reaction solution 1). On the other hand, isopropyl chloroformate (42.87 mL) and TH
After adding F (200 mL), the mixture was cooled to -15 ° C. In addition, (S)-(+)-flurbiprofen (94.6)
% ee, 75.64 g), N-methylmorpholine (33.
97 mL) and a mixed solution of THF (200 mL) was added dropwise over 30 minutes. After the completion of the dropwise addition, the mixture was further stirred for 30 minutes (reaction solution 2). The N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the reaction solution 1 cooled to -15 ° C. After stirring for 30 minutes, water (3.0 L) was added. The resulting white crystals were filtered, washed with water (200 mL), and dried by heating under reduced pressure. As a result, white crystals of lithium (S) -1-t-butoxycarbonyl-1-cyano-3-methyl-3- (2-fluoro-biphenyl-4-yl) -1-propene-2-oleate were obtained. 54 g (HP
LC purity 90.5%, retention time 16.8 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. Prepared from 5M phosphoric acid solution) / acetonitrile = 1/3 ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (d, J = 6.0 Hz, 3
H), 1.37 (s, 9 H), 4.21 (m, 1 H), 7.15-7.21 (m, 2
H), 7.35-7.52 (m, 6 H). MS (EI) 282 (M ⁺ , 23%).

Next, lithium (S) -1-t-butoxycarbonyl-1-cyano-3-methyl-3- (2-fluoro-biphenyl-4-yl) -1-propene-2-oleate (60. 0g), isopropanol (500m
L), phosphate buffer (500 mL, pH 8.0, 0.1
M sodium dihydrogen phosphate solution and 0.1 M NaOH) and hydroxylamine hydrochloride (33.5 g) were mixed and stirred at 80 ° C. for 1 hour, and water (3.0 L) was added. This gives a light pink solid of (S) -3- (1-methyl-1- (2-fluoro-biphenyl-4-yl) -5-
Amino isoxazole was obtained (31.40 g, yield 6).
9.2%). The optical purity of this substance by HPLC was 93.4% ee. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (300 MHz , CDCl ₃ ) δ 1.61 (d, J = 7.1 Hz, 3
H), 4.08 (q, J = 7.1 Hz, 1 H), 4.55 (bs, 2 H), 4.8
9 (s, 1 H), 7.05-7.17 (m, 2 H), 7.31-7.44 (m, 4
H), 7.50-7.76 (m, 2 H). Melting point: 94-95 ° C. IR (KBr) 3451,3311,3169,2975,1634,1582,1485,1463,141
6,1269,1223,1130,1075,1011,975,917,874,834 cm ^-1 .

Example 2 (R) -3- (1-Methoxy-1-phenylmethyl)-
Synthesis of 5-aminoisoxazole

Embedded image The reaction vessel was purged with nitrogen and lithium amide (654 m
g) and THF (50 mL) were added thereto, and t-butyl cyanoacetate (3.86 mL) was added thereto while stirring at room temperature. Thereafter, the mixture was stirred at 70 ° C. for 40 minutes, and further stirred at 70 ° C. for 80 minutes while bubbling nitrogen through the reaction solution, and returned to room temperature to complete the bubbling (reaction solution 1). On the other hand, (R)-(-)-2-
Methoxy-2-phenylacetic acid (98% ee, manufactured by Aldrich Co., 3.0 g), THF (80 mL) and N-methylmorpholine (1.98 mL) were added, and the mixture was cooled to -15 ° C.
While stirring, add isopropyl chloroformate (2.05
mL) was added dropwise (reaction solution 2). After 30 minutes, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the ice-cooled reaction solution 1. After stirring for 30 minutes under ice-cooling, saturated saline (200 mL) was added, and ethyl acetate (150 mL × 3) was added.
Extracted. The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This allows lithium
(R) -1-t-butoxycarbonyl-1-cyano-3
6.78 g of a yellow mucus which was -methoxy-3-phenyl-1-propene-2-oleate was obtained (HPLC purity: 97.0%, retention time: 15.5 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 2/3

Next, lithium (R) -1-t-butoxycarbonyl-1-cyano-3-methoxy-3-phenyl-
1-propene-2-oleate (6.78 g), isopropanol (55 mL), 5 mM sodium dihydrogen phosphate solution (55 mL), hydroxylamine hydrochloride (3.7
6g) and stirred at 80 ° C. for 3 hours. After returning to room temperature, a sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2). This gives a yellow solid 3
-(1-Methoxy-1-phenylmethyl) -5-aminoisoxazole was obtained (2.64 g, two-stage yield 71.1.
6%, based on (R)-(-)-2-methoxy-2-phenylacetic acid). The optical purity of this substance by HPLC was 98.
It was 0% ee. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.42 (s, 3 H), 4.41 (br, 2
H), 5.05 (s, 1 H), 5.25 (s, 1 H), 7.27-7.44 (m, 5 H). Melting point: 64-65 ℃. MS (FAB +) 205 (M ⁺ +1, 29%) HRMS (FAB +) calcd for 205.0977, found 205.0963.

Example 3 (S) -3- [1- (6-methoxy-2-naphthyl) d
Synthesis of [tyl] -5-aminoisoxazole

Embedded image The reaction vessel was replaced with nitrogen, and lithium amide (748 m
g) and THF (40 mL) were added, and then, while stirring at room temperature, t-butyl cyanoacetate (4.59 g) was added thereto. After that, while bubbling nitrogen through the reaction solution, 70
After stirring at room temperature for 1 hour, the temperature was returned to room temperature and bubbling was completed (reaction solution 1). On the other hand, (S)
-(+)-2- (6-Methoxy-2-naphthyl) propionic acid (5.0 g), THF (20 mL) and N-methylmorpholine (2.38 mL) were added, and the mixture was heated to -15 ° C.
While stirring, add isopropyl chloroformate (3.01).
mL) was added dropwise (reaction solution 2). 2 hours after the end of dropping,
The N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the reaction solution 1 cooled to -15 ° C. After stirring for 1 hour, water (700 mL) was added. The resulting white crystals were filtered, washed with water (100 mL), and dried by heating under reduced pressure. Thereby, lithium (S) -1-t-butoxycarbonyl-1-
5.86 g of cyano-3-methyl-3- (6-methoxy-2-naphthyl) -1-propene-2-oleate was obtained as white crystals (HPLC purity 90.3%, retention time 32.3 minutes). ). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0 Prepared from 5M phosphoric acid solution) / acetonitrile = 1/2

Next, lithium (S) -1-tert-butoxycarbonyl-1-cyano-3-methyl-3- (6-methoxy-2-naphthyl) -1-propene-2-oleate (1.
0 g), DMF (20 mL), water (20 mL), 35% hydrochloric acid (0.5 mL), hydroxylamine hydrochloride (0.5 mL).
8g) and stirred at 80 ° C for 1 hour. After returning to room temperature, a saturated saline solution (200 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3). This makes the yellow liquid 3
-(1-Methyl-1- (6-methoxy-2-naphthyl)
Methyl) -5-aminoisoxazole was obtained (544m
g, yield 73.0%). The optical purity of this substance by HPLC was 99.3% ee. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (270 MHz, DMSO -d ₆ ) δ 1.55 (d, J = 7.2 Hz, 3
H), 3.85 (s, 3 H), 4.09 (q, J = 7.1Hz, 1H), 4.75
(s, 1H), 6.48 (s, 2 H), 7.13 (dd, J = 2.5 and8.9 H
z, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.38 (dd, J =
1.8 and 8.5 Hz, 1 H), 7.79-7.70 (m, 3 H). Melting point: 170-172 ° C IR (KBr) 3478, 3149, 2973, 1633, 1606, 1489, 1463,
1258, 1216, 1165, 1030, 856 cm ^-1 .MS (EI) 268 (M ⁺ , 67%).

Example 4 (S) -3- (1- (Nt-butoxycarbonyl) a
(Mino-2-phenylethyl) -5-aminoisoxazo
Synthesis

Embedded image Replace the reaction vessel with nitrogen and add lithium amide (777 m
g) and THF (50 mL) were added, and then, while stirring at room temperature, t-butyl cyanoacetate (4.78 g) was added thereto. After that, while bubbling nitrogen through the reaction solution, 70
The mixture was stirred for 2 hours at room temperature and returned to room temperature to complete bubbling (reaction solution 1). On the other hand, N-
(Nt-butoxycarbonyl) -L-phenylalanine
(5.0 g), THF (25 mL) and N-methylmorpholine (2.38 mL) were added, and the mixture was cooled to -15 ° C. While stirring, add isopropyl chloroformate (2.61 mL)
(25 mL) was added dropwise (reaction solution 2). After the addition, the mixture was stirred for 1 hour, and N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere.
This filtrate was added dropwise to the reaction solution 1 cooled to -15 ° C.
After stirring for 1 hour, water (800 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 4). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Thereby, lithium (S) -1-t-butoxycarbonyl-1-cyano-3- (Nt-butoxycarbonyl)
7.11 g of amorphous crystals as amino-3-phenyl-1-butene-2-oleate were obtained (HPLC purity: 92.7%, retention time: 11.8 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0 Prepared from 5M phosphoric acid solution) / acetonitrile = 1/2

Next, lithium (S) -1-t-butoxycarbonyl-1-cyano-3- (Nt-butoxycarbonyl) amino-3-phenyl-1-butene-2-oleate (7.0 g), Isopropanol (70 mL), phosphate buffer (70 mL, pH 8.0, prepared from 0.1 M aqueous sodium dihydrogen phosphate and 0.1 M aqueous sodium hydroxide), hydroxylamine hydrochloride (3.69 g)
And stirred at 80 ° C. for 2 hours. After returning to room temperature, water (800 mL) was added. The resulting white crystals were filtered, washed with water (300 mL), and dried by heating under reduced pressure. Thus, white crystals of (S) -3- (1- (Nt-butoxycarbonyl) amino-1-phenylmethyl) -5-
Amino isoxazole was obtained (3.35 g, yield 62.
0%). The optical purity of this substance by HPLC was 9
It was 9.4% ee. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 1.29 (s, 9 H), 2.85-3.
02 (m, 2 H), 4.58-4.71 (m, 1 H), 4.95 (s, 1 H), 6.5
5 (s, 2 H), 7.16-7.32 (m, 5 H). MS (EI) 303 (M ⁺ , 2%) Melting point: 155-158 ° C.

Example 5 (R) -3- (1 (R)-(Nt-butoxycarboni)
L) amino-2-phenylethyl) -5-aminoiso
Synthesis of Sasol

Embedded image The reaction vessel was replaced with nitrogen, and lithium amide (777 m
g) and THF (50 mL) were added, and then, while stirring at room temperature, t-butyl cyanoacetate (4.78 g) was added thereto. After that, while bubbling nitrogen through the reaction solution, 70
After stirring at 1.5 ° C. for 1.5 hours, the mixture was returned to room temperature and bubbling was completed (reaction solution 1). On the other hand, in another reaction vessel purged with nitrogen,
-(T-butoxycarbonyl) -D-phenylalanine
(5.0 g), THF (25 mL) and N-methylmorpholine (2.07 mL) were added, and the temperature was adjusted to -15 ° C. While stirring, add isopropyl chloroformate (2.61 mL)
(25 mL) was added dropwise (reaction solution 2). After completion of the dropwise addition, the mixture was stirred for 1.5 hours, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was cooled to -15 ° C.
Was dropped. After stirring for 2 hours, water (500 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thereby, lithium (R) -1-tert-butoxycarbonyl-1-cyano-3- (Nt-butoxycarbonyl) amino-3-phenyl-1-butene-2
7.29 g of amorphous crystals as oleate were obtained (HPLC purity 89.43%, retention time 22.3).
Minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 2/3

Next, lithium (R) -1-tert-butoxycarbonyl-1-cyano-3- (Nt-butoxycarbonyl) amino-3-phenyl-1-butene-2-oleate (7.0 g) , Isopropanol (70 mL), phosphate buffer (70 mL, pH 8.0, prepared from 0.1 M aqueous sodium dihydrogen phosphate and 0.1 M aqueous sodium hydroxide), hydroxylamine hydrochloride (3.69)
g) were mixed and stirred at 80 ° C. for 2 hours. After returning to room temperature, water (800 mL) was added. The resulting white crystals were filtered, washed with water (300 mL), and dried by heating under reduced pressure.
Thus, white crystals of (R) -3- (1- (Nt-butoxycarbonyl) amino-1-phenylmethyl) -5 were obtained.
-Aminisoxazole was obtained (3.21 g, yield 6).
0.0%). The optical purity of this substance by HPLC was 99.7% ee. HPLC conditions Column: OD-R (Daicel) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 1.29 (s, 9H), 2.85-3.
02 (m, 2 H), 4.58-4.71 (m, 1H), 4.95 (s, 1 H), 6.55
(s, 2H), 7.16-7.32 (m, 5H). Melting point: 158-161 ° C. MS (EI): 303 (M ⁺ , 4%).

Example 6 3- (1-methoxy-1-phenylmethyl) -5-amido
Synthesis of Neuoxoxazole

Embedded image The reaction vessel was purged with nitrogen and lithium amide (1.04
g) and THF (50 mL) were added, and while stirring at room temperature, t-butyl cyanoacetate (6.37 g) was added thereto. After that, while bubbling nitrogen through the reaction solution, 70
After stirring at 1.5 ° C. for 1.5 hours, the mixture was returned to room temperature and bubbling was completed (reaction solution 1). On the other hand, 2
-Methoxy-2-phenylacetic acid (5.0 g), THF
(25 mL) and N-methylmorpholine (3.64 mL) were added, and the temperature was adjusted to -15 ° C. With stirring, isopropyl chloroformate (4.18 mL) was added dropwise thereto (reaction solution 2). After completion of the dropwise addition, the mixture was stirred for 1 hour, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the reaction solution 1 cooled to -15 ° C. After stirring for 2 hours, water (500 mL) was added, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Thereby, lithium 1-t-butoxycarbonyl-
5.59 g of 1-cyano-3-methoxy-3-phenyl-1-propene-2-oleate as a white solid was obtained (HPLC purity: 83.9%, retention time: 11.0 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 1/2

Next, lithium 1-t-butoxycarbonyl-
1-cyano-3-methoxy-3-phenyl-1-propene-2-oleate (1.30 g), isopropanol (15 mL), 5 mM sodium dihydrogen phosphate solution (1
5 mL), hydroxylamine hydrochloride (0.917 g)
And stirred at 80 ° C. for 1 hour. After returning to room temperature, water (200 mL) was added and ethyl acetate (80 mL) was added.
× 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate / hexane = 1).
/ 3). Thereby, yellow oily 3- (1)
-Methoxy-1-phenylmethyl) -5-aminoisoxazole was obtained (0.682 g, yield 76.0%). ¹ H NMR (270 MHz, DMSO-d ₆ ) δ 3.27 (s, 3 H), 4.79
(s, 1 H), 5.16 (s, 1 H), 6.62 (s, 2 H), 7.27-7.37 (m,
5 H). MS (EI) 204 (M ⁺ , 10%). HRMS (EI) calcd for 204.0899, found 204.0903.

Example 7 3- (1- (6-methoxy-2-naphthyl) ethyl)-
Synthesis of 5-aminoisoxazole

Embedded image The reaction vessel was replaced with nitrogen, and lithium amide (748 m
g) and THF (40 mL) were added, and then, while stirring at room temperature, t-butyl cyanoacetate (4.59 g) was added thereto. After that, while bubbling nitrogen through the reaction solution, 70
After stirring at 1.5 ° C. for 1.5 hours, the mixture was returned to room temperature and bubbling was completed (reaction solution 1). On the other hand, 2
-(6-Methoxy-2-naphthyl) propionic acid (5.0
g), THF (20 mL), N-methylmorpholine (2.
(3 mL), and then cooled to -15 ° C. While stirring, isopropyl chloroformate (3.0 mL) was added dropwise thereto.
(Reaction solution 2). 1.5 hours after completion of the dropwise addition, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the reaction solution 1 cooled to -15 ° C. After stirring for 3 hours, water (1.0 L) was added. The resulting white crystals were filtered, washed with water, and dried by heating under reduced pressure. This gives lithium 1-tert-butoxycarbonyl-1-cyano-3-methyl-3- (6-methoxy-2
5.70 g of -naphthyl) -1-propene-2-oleate as white crystals were obtained (HPLC purity: 88.4%,
Retention time 5.59 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 2/3

Next, lithium 1-t-butoxycarbonyl-
1-cyano-3-methyl-3- (6-methoxy-2-naphthyl) -1-propene-2-oleate (1.0 g);
DMF (20 mL), water (20 mL), 35% hydrochloric acid (0.
5mL) and hydroxylamine hydrochloride (0.58g) were mixed and stirred at 80 ° C for 1.5 hours. After returning to room temperature, saturated saline (200 mL) was added, and ethyl acetate (8 mL) was added.
0 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (ethyl acetate / hexane).
= 1/3). Thereby, yellow liquid 3- (1)
-Methyl-1- (6-methoxy-2-naphthyl) methyl) -5-aminoisoxazole was obtained (0.560
g, yield 75.0%). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 1/1 ¹ H NMR (270 MHz) , DMSO-d ₆ ) δ 1.55 (d, J = 7.2 H
z, 3 H), 3.85 (s, 3 H), 4.09 (q, J = 7.1 Hz, 1 H),
4.75 (s, 1 H), 6.48 (s, 2 H), 7.13 (dd, J = 2.5 an
d 8.9 Hz, 1 H), 7.27 (d, J = 2.5 Hz, 1 H), 7.38 (d
d, J = 1.8 and 8.5Hz, 1 H), 7.79-7.70 (m, 3 H). Melting point: 150-151 ℃.

Example 8 3- (3-chlorophenyl) -5-aminoisoxazo
Synthesis

Embedded image The reaction vessel was purged with nitrogen, and sodium hydride (1.92 g,
60% paraffin oil) and THF (100 mL), and then cooled with ice.
(6.83 mL) was added dropwise. After the completion of dropping, 30
The mixture was stirred for 1 minute (reaction solution 1). On the other hand, metachlorobenzoic acid (5.0 g), THF
(110 mL), N-methylmorpholine (3.51 m
After the addition of L), the temperature was lowered to -15 ° C. While stirring, isopropyl chloroformate (3.64 mL) was added dropwise thereto (reaction solution 2). After 30 minutes, N-methylmorpholine hydrochloride was removed from reaction solution 2 by filtration under a nitrogen atmosphere,
This filtrate was added dropwise to the reaction solution 1 cooled with ice. After completion of the dropwise addition, the mixture was stirred for 30 minutes under ice-cooling, and then saturated saline (200
mL) and extracted with ethyl acetate (150 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This allows sodium 2-t-
Butoxycarbonyl-1- (3-chlorophenyl) -2
As a result, 13.0 g of a yellow mucus which was a cyanoethenolate was obtained (HPLC purity: 98.8%, retention time: 29 minutes). HPLC conditions Column: ODSA-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 2/3

Next, sodium 2-t-butoxycarbonyl-1- (3-chlorophenyl) -2-cyanoethenolate (13.0 g), isopropanol (100 mL),
pH 8.0 phosphate buffer solution (100 mL, prepared from 0.1 M sodium dihydrogen phosphate solution and 0.1 M sodium hydroxide solution), hydroxylamine hydrochloride (6.66)
g) were mixed and stirred at 80 ° C. for 2 hours. After returning to room temperature, a sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2). This gave 3- (3-chlorophenyl) -5-aminoisoxazole as a white solid (4.27 g, two-step yield 68.7%, based on metachlorobenzoic acid). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.54 (br, 2H), 5.43 (s, 1
H), 7.33-7.41 (m, 2H), 7.62 (m, 1H), 7.72 (m, 1H). Melting point: 108-109.5 ° C IR (KBr) 3456, 1644, 1488, 968, 730 cm ^-1 . ) 195 (M ⁺ +1, 100%). HRMS (FAB +) calcd for 195.0325, found 195.0327.

Example 9 3- (4-chlorophenoxymethyl) -5-aminoisox
Synthesis of Sasol

Embedded image The reaction vessel was replaced with nitrogen, and sodium hydride (1.46) was added.
g, 60% paraffin oil) and THF (60 mL) were added, and the mixture was cooled with ice, and t-butyl cyanoacetate (5.22 mL) was added dropwise thereto with stirring. After dropping, add 3
The mixture was stirred for 0 minutes (reaction solution 1). Meanwhile, 4-chlorophenoxyacetic acid (5.0 g) was placed in another reaction vessel purged with nitrogen.
THF (150 mL), triethylamine (3.42 m
After adding L), the temperature was lowered to -15 ° C. With stirring, isopropyl chloroformate (2.78 mL) was added dropwise thereto (reaction solution 2). After 30 minutes, triethylamine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the ice-cooled reaction solution 1. After completion of the dropwise addition, the mixture was stirred for 30 minutes under ice-cooling, then saturated brine (200 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Thus, sodium 1-tert-butoxycarbonyl-3- (4-chlorophenoxy) -1-cyano-
The yellow mucus, 1-propene-2-oleate, was 10.1
7 g (HPLC purity 92.5%, retention time 1
5.3 minutes). HPLC conditions Column: ODSA-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0.5 M (Prepared from phosphoric acid solution) / acetonitrile = 2/3

Next, sodium 1-t-butoxycarbonyl-3- (4-chlorophenoxy) -1-cyano-1-propene-2-oleate (10.17 g), isopropanol (85 mL), pH 8.0 phosphorus Acid buffer solution (85
mL, 0.1 M sodium dihydrogen phosphate solution and 0.1 M
Sodium hydroxide solution) and hydroxylamine hydrochloride (5.08 g) were mixed and stirred at 80 ° C. for 2 hours. After returning to room temperature, a sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2). This gives 3- (4-chlorophenoxymethyl) as a white solid.
This gave -5-aminoisoxazole (1.71 g, two-step yield 31.2%, based on 4-chlorophenoxyacetic acid). ¹ H NMR (300 MHz, CDCl ₃ ) δ 4.49 (br, 2 H), 4.98 (s,
2H), 5.23 (s, 1H), 6.88-6.93 (m, 2H), 7.21-7.26
(m, 3H). Melting point: 91.5-93.0 ° C. IR (KBr) 3442,1638,1492,1244,829 cm ^-1 . MS (FAB +) 225 (M ⁺ +1, 100%). HRMS (FAB +) calcd for 225.0431, 225.0463.

Example 10 3- (3-phenylpropyl) -5-aminoisoxazo
Synthesis

Embedded image The reactor was purged with nitrogen, and sodium hydride (1.83 g,
60% paraffin oil) and THF (50 mL), and then cooled with ice.
(6.51 mL) was added dropwise. After completion of the dropwise addition, the mixture was stirred at an ice temperature for 10 minutes, and further stirred at room temperature for 30 minutes (reaction solution 1). On the other hand, 4-phenylbutyric acid (5.0 g), THF (100 mL), and N-methylmorpholine (3.38 mL) were placed in another reaction vessel purged with nitrogen, and then cooled to -15 ° C. While stirring, isopropyl chloroformate (3.
47 mL) was added dropwise (reaction solution 2). After 30 minutes, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was added dropwise to the ice-cooled reaction solution 1. After completion of the dropwise addition, the mixture was stirred for 30 minutes under ice-cooling, and saturated saline (200 mL) was added.
50 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This gave 13.84 g of a yellow viscous liquid which was sodium 1-t-butoxycarbonyl-1-cyano-5-phenyl-1-pentene-2-oleate (HPLC purity 99.3).
%, Retention time 35.6 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0. (Prepared from 5M phosphoric acid solution) / acetonitrile = 2/3

Next, sodium 1-tert-butoxycarbonyl-1-cyano-5-phenyl-1-pentene-2-oleate (13.84 g) and isopropanol (110 m
L), pH 8.0 phosphate buffer solution (110 mL, 0.1 mL).
A 1 M sodium dihydrogen phosphate solution and a 0.1 M sodium hydroxide solution) and hydroxylamine hydrochloride (3.65 g) were mixed and stirred at 80 ° C for 2 hours.
After returning to room temperature, a sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2). This gave 3- (3-phenylpropyl) -5-aminoisoxazole as a white solid (4.47 g, two-step yield 72.6%, 4%).
-Based on phenylbutyric acid). ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.95 (tt, J = 7.6 and 7.7
Hz, 2 H), 2.56 (t, J = 7.6 Hz, 2 H), 2.68 (t, J =
7.7 Hz, 2 H), 4.36 (br, 2 H), 7.15-7.21 (m, 3 H), 7.26
-7.31 (m, 2 H) mp:... 73.0-73.5 ℃ IR ( KBr) 3455,1635,1494,1458 cm -1 MS (FAB +) 203 (M + + 1,100%) HRMS (FAB +) calcd for 203.1184, found 203.1206.

Example 11 3- (4-Fluorophenyl) methyl-5-aminoisoxa
Synthesis of sol

Embedded image The reaction vessel was replaced with nitrogen, and lithium amide (1.18
g) and THF (100 mL) were added, and while stirring at room temperature, t-butyl cyanoacetate (6.95 mL) was added thereto. Thereafter, the mixture was stirred at 70 ° C. for 30 minutes, and further stirred at 70 ° C. for 80 minutes while bubbling nitrogen through the reaction system, and returned to room temperature to complete bubbling (reaction solution 1). On the other hand, 4-fluorophenylacetic acid (5.0 g), THF (100 mL), and N-methylmorpholine (3.56 mL) were charged into another reaction vessel purged with nitrogen, and then cooled to -15 ° C. While stirring, isopropyl chloroformate (3.
69 mL) was added dropwise (reaction solution 2). After 30 minutes, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration under a nitrogen atmosphere, and the filtrate was dropped into the ice-cooled reaction solution 1. After dropping, the mixture was stirred for 30 minutes under ice cooling,
Saturated saline (200 mL) was added, and ethyl acetate (150 m
L × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Thereby, lithium 1-t-butoxycarbonyl-1-cyano-3-
11.81 g of a yellow mucus, which was (4-fluorophenyl) methyl-1-propene-2-oleate, was obtained (HPL
C purity 98.1%, retention time 20.1 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: pH 2.5 phosphate buffer solution (5 mM sodium dihydrogen phosphate solution and 0 Prepared from 0.5M phosphoric acid solution) / acetonitrile = 2/3

Next, lithium 1-t-butoxycarbonyl-1-cyano-3- (4-fluorophenyl) methyl-1
-Propylene-2-oleate (11.81 g), isopropanol (100 mL), 5 mM sodium dihydrogen phosphate solution (100 mL), and hydroxylamine hydrochloride (6.76 g) were mixed and stirred at 80 ° C for 3 hours. After returning to room temperature, a sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/2). This gave 3- (4-fluorophenyl) methyl-5-aminoisoxazole as a white solid (3.38 g, two-step yield 54.
0%, based on 4-fluorophenylacetic acid). _{^{1 H NMR (CDCl 3) δ}} 3.82 (s, 2 H), 4.70 (br, 2 H), 4.88
(s, 1 H), 6.95-7.03 (m, 2H), 7.19-7.26 (m, 2 H). Melting point: 73.5-74.0 ° C IR (KBr) 3455,1652,1511,1228,1002 cm ^-1 .MS (FAB +) 193 (M ⁺⁺ 1, 100%). HRMS (FAB +) calcd for 193.0777, found 193.0793.

Example 12 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
Synthesis of no-morpholin-4-yl-methyl) -amine

Embedded image The reaction vessel was replaced with nitrogen, and lithium amide (17.2 m
g) and acetonitrile (1.5 mL) were added thereto, and the mixture was stirred at room temperature while stirring.
(1-Methyl-1- (2-fluoro-biphenyl-4-
Yl))-5-aminoisoxazole (optical purity 91%
ee, 141 mg) and cyanomorpholine (67 m
g) was added and stirred at 70 ° C. for 4 hours. After returning to room temperature, the reaction solution was poured into stirring water (10 mL). The resulting pale yellow crystals were collected by filtration, washed with water (5 mL), and dried by heating under reduced pressure. As a result, 151 mg of the target amine was obtained.
(HPLC purity 78%, optical purity 90% ee,
Retention time 7.8 minutes). HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 2/3 ¹ H NMR (CDCl ₃ ) δ 1.66 (d, 3H, J = 7.1Hz), 3.45-3.55
(m, 4H), 3.65-3.75 (m, 4H), 4.15 (q, 1H, J = 7.1Hz),
5.25 (s, 1H), 5.38 (br-s, 2H), 7.05-7.17 (m, 2H), 7.33
-7.54 (m, 6H). Melting point: 114-115 ℃

Example 13 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine phosphoric acid
Salt synthesis

Embedded image The reaction vessel was purged with nitrogen, and isopropyl alcohol (19
After adding 85% phosphoric acid (4.3) with stirring.
8 g) was added to prepare a phosphoric acid solution. On the other hand, another reaction vessel was purged with nitrogen, and (S)-({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl ) -Amine (HPLC purity 91.8%, optical purity 99)
% Ee, 15.0 g) and isopropyl alcohol (190 mL) were added, and the temperature was raised to 50 ° C. with stirring to completely dissolve the crystals. The solution was filtered while hot, the container and the residue were washed with isopropyl alcohol (19 mL), and the filtrate was stirred at 70 ° C. for 10 minutes. After the seed crystals (0.02 g) of the target phosphate were added, the phosphoric acid solution prepared above was immediately added dropwise at 70 ° C. over 5 minutes. After confirming the precipitation of crystals, the slurry solution was stirred at 70 ° C. for 1 hour, cooled to 0 ° C. over 3 hours, and further cooled at 0 ° C. for 1 hour.
Stirred for hours. The crystals were collected by filtration, the container and the residue were washed with cold isopropyl alcohol (19 mL), and then dried by heating under reduced pressure. As a result, 18.0 g of white crystals as the target phosphate were obtained (HPLC purity: 97.8%, retention time: 9.5 minutes). HPLC conditions Column: ODS A-212 (Sumipax (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 2/3 The optical purity was 99%. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: 5 mM aqueous sodium dihydrogen phosphate / acetonitrile = 2/3 ¹ H NMR (CDCl ₃ ) δ 1.54 (d, 3H, J = 7.3Hz), 3.40-3.43
(m, 4H), 3.55-3.58 (m, 4H), 4.11 (q, 1H, J = 7.3Hz),
5.42 (s, 1H), 6.46 (br-s, 2H), 7.21-7.26 (m, 2H), 7.38
-7.53 (m, 6H) .IR (neat) 3381,2973,2361,1682,1618,1552,1484,1456,14
11,1274,1113 cm ^-1 . Melting point: 141-143 ℃

Example 14 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine phosphoric acid
Salt synthesis

Embedded image After the reaction vessel was replaced with nitrogen and lithium amide (8.3 g) and THF (140 g) were added, the mixture was heated to 68 ° C. with stirring, and t-butyl cyanoacetate (56 g) was added dropwise over 1 hour. After that, nitrogen is flowed into the gas phase of the reaction vessel,
After removing the generated ammonia gas, it was cooled to -15 ° C (reaction solution 1). On the other hand, isopropyl chloroformate (22 g) and THF (94
g) and cooled to -15 ° C. (S)-(+)
-Flurbiprofen (40 g, 98.9% ee) and N
A solution of -methylmorpholine (19 g) in THF (94 g) was added dropwise over 1 hour, and the mixture was stirred for 30 minutes (reaction solution 2). Under a nitrogen atmosphere, N-methylmorpholine hydrochloride was removed from the reaction solution 2 by filtration.
(40 g). The filtrate and the washing solution are combined, and -1
It was added dropwise to the reaction solution 1 cooled to 5 ° C over 1 hour. 2
After a period of time, water (660 g) was added dropwise over 30 minutes, and then seed crystals (40 mg) of the target lithium salt were inoculated and stirred at room temperature for 30 minutes. Then heptane (310 g) was added to 3
The mixture was added dropwise over 0 minutes and stirred at room temperature for 3 hours. The precipitated crystals were filtered, washed with water (200 g),
Drying under reduced pressure for a desired time: lithium salt: lithium
(S) -1-t-butoxycarbonyl-1-cyano-3
-Methyl-3- (2-fluoro-biphenyl-4-yl) -1-propene-2-oleate 50.7 g (yield 8
3%). ¹ H NMR (CDCl ₃ ) δ 1.31 (d, 3H, J = 6.8 Hz), 1.37 (s, 9
H), 4.21 (q, 1H, J = 6.8Hz), 7.15-7.22 (m, 2H), 7.35-
7.52 (m, 6H).

Next, water (240
g), 36% hydrochloric acid (6.9 g) and hydroxylamine hydrochloride (23 g), followed by a solution of the lithium salt (41.1 g) obtained above in DMF (250 g),
The mixture was heated and stirred at 0 ° C. for 5 hours. Thereafter, the mixture was cooled to room temperature and extracted twice with toluene (210 g each).
Washed once with brine (210 g) and twice with water (210 g each). The obtained toluene solution was concentrated under reduced pressure at an internal temperature of 40 ° C. or lower to remove water. Desired (S) -3- (1-methyl-1- (2-fluoro-biphenyl-4-yl))
29.2 g of 5-aminoisoxazole (94% yield,
99.5% ee) is not isolated as crystals, 8.64%
Obtained as a toluene solution. A solution was prepared by adding toluene to a toluene solution of 5-aminoisoxazole (10.85 g) obtained above to make the content 7.5%, and cyanomorpholine (4.31 g) was added thereto (reaction solution). 3). Toluene (14.1 g) and lithium amide (1.76 g) were placed in a reaction vessel purged with nitrogen, and heated and stirred at 70 ° C. To this, t-butanol (21.70 g) was added dropwise over 30 minutes. Then, the temperature was raised to 80 ° C., nitrogen was flowed into the gas phase of the reaction vessel to remove generated ammonia gas, and then cooled to room temperature. The reaction solution 3 was added dropwise over 30 minutes, and the mixture was stirred at 27 ° C. for 8 hours. Thereafter, 5% saline (43.5 g) was added to carry out liquid separation.
7.9 g), and concentrated under reduced pressure at an internal temperature of 40 ° C. or lower to remove water, and isopropyl alcohol (16.3 g) was used.
g) and the desired (S)-({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine 11.52 g (76% yield) of 12.8%
Obtained as a toluene-isopropyl alcohol solution.

A toluene-isopropyl alcohol solution of the above-obtained 5-aminoisoxazole derivative (11.52 g) was placed in a reaction vessel purged with nitrogen, and toluene (73) was added.
g) was added and heated at 50 ° C. (S)-
Seed crystals (10 mg) of ({3- [1- (2-fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine phosphate were added. Then, 85% phosphoric acid (4.71)
g) in isopropyl alcohol (13.11 g) was added dropwise over 30 minutes. After incubating at 50 ° C for 1 hour,
It was cooled to 0 ° C over time and kept at 0 ° C for 1 hour. The precipitated crystals were filtered, washed with a cold solution of toluene (21.0 g) and isopropyl alcohol (5.2 g), and again toluene (10.5 g) and isopropyl alcohol (2.
6 g), and then dried under reduced pressure (30 ° C., 10 ° C.).
Time) and 11.93 g of the final desired phosphate (yield 83).
%, 99.3% ee). _{^{1 H NMR (CDCl 3) δ}} 1.54 (d, 3H, J = 7.3Hz), 3.40-3.43
(m, 4H), 3.55-3.58 (m, 4H), 4.11 (q, 1H, J = 7.3Hz),
5.42 (s, 1H), 6.46 (br-s, 2H), 7.21-7.26 (m, 2H), 7.38
-7.53 (m, 6H) .IR (neat) 3381,2973,2361,1682,1618,1552,1484,1456,14
11,1274,1113 cm ^-1 . Melting point: 141-143 ℃

Example 15 (S)-({3- [1- (2-fluoro-biphenyl-)
4-yl) -ethyl] -isoxazol-5-ylimi
No-morpholin-4-yl-methyl) -amine phosphoric acid
Salt purification

Embedded image The 5-aminoisoxazole derivative was purified by the following method. That is, (S)-
({3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine phosphate3.
0 g (98.4% ee), toluene (30 g) and water (15 g) were added, heated to 40 ° C., and kept warm for 30 minutes. A 5% aqueous sodium carbonate solution was added to the mixture to adjust the pH to 7, and 4
Stirred at 0 ° C. for 30 minutes. After separating at 40 ° C., the oil layer was washed with water (15 g), concentrated under reduced pressure to remove water, isopropyl alcohol (0.75 g) was added at room temperature, and (S)-(｛3- [1- (2-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-methyl) -amine in toluene-isopropyl alcohol (15.75)
g) was obtained (reaction solution 1). Hexane (45 g) and isopropyl alcohol (3.
0 g), heated to 50 ° C., and 10% of the reaction solution 1 was added dropwise over 10 minutes. Next, a free seed crystal (15m
After inoculating g), the remaining reaction solution 1 was added dropwise over 50 minutes and kept at 50 ° C. for 1 hour. Then, it cooled to 0 degreeC over 2 hours, and stirred at 0 degreeC for 1 hour. The precipitated crystals were hexane (5.4 g) and isopropyl alcohol (0.
6g), and dried under reduced pressure (30 ° C., 10 hours) to obtain 2.13 g (yield: 88.6%, 99.5% ee) of the desired 5-aminoisoxazole derivative in a free form. White crystals were obtained. ¹ H NMR (CDCl ₃ ) δ 1.66 (d, 3H, J = 7.1Hz), 3.45-3.55
(m, 4H), 3.65-3.75 (m, 4H), 4.15 (q, 1H, J = 7.1Hz),
5.25 (s, 1H), 5.38 (br-s, 2H), 7.05-7.17 (m, 2H), 7.33
-7.54 (m, 6H). Melting point: 114-115 ℃

[0067] In a reaction vessel purged with nitrogen, the free product (2.13 g) obtained above and isopropyl alcohol (21.0 g) were added.
g) was added thereto, and the mixture was heated and stirred at 50 ° C., filtered while hot, and the residue was washed with isopropyl alcohol (2.1 g).
Subsequently, at 50 ° C, phosphate: (S)-(｛3- [1- (2
-Fluoro-biphenyl-4-yl) -ethyl] -isoxazol-5-ylimino} -morpholin-4-yl-
Methyl) -amine phosphate (2 mg) was inoculated, and a solution of 85% phosphoric acid (0.64 g) and isopropyl alcohol (2.13 g) was added dropwise over 30 minutes.
C. for 1 hour, cooled to 0 ° C. over 2 hours,
Incubated at ℃ for 1 hour. The precipitated crystals were collected by filtration, washed with isopropyl alcohol (2.13 g), and dried under reduced pressure (30 ° C., 10 hours) to obtain 2.60 g of the desired phosphate.
(98% yield, 99.5% ee). ¹ H NMR (CDCl ₃ ) δ 1.54 (d, 3H, J = 7.3 Hz), 3.40-3.43
(m, 4H), 3.55-3.58 (m, 4H), 4.11 (q, 1H, J = 7.3Hz),
5.42 (s, 1H), 6.46 (br-s, 2H), 7.21-7.26 (m, 2H), 7.38
-7.53 (m, 6H) .IR (neat) 3381, 2973, 2361, 1682, 1618, 1552, 1484,
1456, 1411, 1274, 1113 cm ^-1 . Melting point: 141-143 ℃

Further, (S)-({3- [1- (2-fluoro
-Biphenyl-4-yl) -ethyl] -isoxazole
-5-ylimino} -morpholin-4-yl-methyl)
-By treating the amine with various acids, each of the following
A seed salt was obtained. Example 16:Hydrochloride  Melting point: 134-136 ℃¹ H NMR (CDCl_Three) δ 1.64 (d, 3H, J = 7.3Hz), 3.45-3.60
(m, 4H), 3.60-3.80 (m, 4H), 4.15 (q, 1H, J = 7.3Hz),
5.69 (s, 1H), 7.02-7.12 (m, 2H), 7.32-7.52 (m, 6H),
8.44 (br-s, 2H). [Α]_D ²²= + 14.4 ° (c: 1.00, CHCl
₃Example 17:Methanesulfonate  Melting point: 162-165 ℃¹ H NMR (CDCl_Three) δ 1.66 (d, 3H, J = 7.3Hz), 2.72 (s, 3
H), 3.46-3.51 (m, 4H), 3.71-3.78 (m, 4H), 4.17 (q, 1
H, J = 7.1Hz), 5.59 (s, 1H), 7.02-7.12 (m, 2H), 7.33-
7.46 (m, 4H), 7.50-7.53 (m, 2H), 8.62 (br-s, 2H), 11.
13 (br-s, 1H). IR (neat) cm^-1 2972, 1668, 1634, 1548, 1484, 144
6, 1418, 1198, 1116, 1062, 1010, 768, 699. [α]_D ²²= + 12.0 ° (c: 0.80, CHCl
₃Example 18:Benzene sulfonate ¹ H NMR (CDCl_Three) δ 1.59 (d, 3H, J = 7.1Hz), 3.50 (m, 4
H), 3.66 (m, 4H), 4.26 (q, 1H, J = 7.1Hz), 5.98 (s, 1H),
 7.25-7.59 (m, 13H). IR (neat) cm^-1 3135, 1679, 1630, 1552, 1484, 144
5, 1418. [α]_D ²⁰= + 16.8 ° (c: 0.51, MeO
H) Example 19:Sulfate ¹ H NMR (CDCl_Three) δ 1.53 (d, 3H, J = 6.8Hz), 3.30-3.80
(m, 8H), 4.05-4.10 (m, 1H), 5.72 (s, 1H), 6.97-7.05
(m, 2H), 7.28-7.44 (m, 6H), 7.95 (br-s, 1H). [α]_D ²²= + 20.2 ° (c: 1.00, THF) Example 20:D-camphor-sulfonate  Melting point: 167-168 ℃¹ H NMR (CDCl_Three) δ 0.76 (s, 3H), 0.95 (s, 3H), 1.24-1.
32 (m, 1H), 1.54-1.65 (m, 1H), 1.66 (d, 3H, J = 7.1Hz),
 1.79 (d, 1H, J = 18.1Hz), 1.82-1.91 (m, 1H), 1.96-2.0
0 (m, 1H), 2.21-2.30 (m, 1H), 2.35-2.47 (m, 1H), 2.75
(d, 1H, J = 14.6Hz), 3.26 (d, 1H, J = 14.7Hz), 3.48-3.5
2 (m, 4H), 3.73-3.76 (m, 4H), 4.17 (q, 1H, J = 7.1Hz),
5.66 (s, 1H), 7.04-7.14 (m, 2H), 7.33-7.52 (m, 6H),
8.53 (br-s, 2H), 11.11 (br-s, 1H).

Comparative Example 1

Embedded image Under a nitrogen atmosphere, sodium amide (222 mg) was added to methyl t-butyl ether (3.0 mL), and the mixture was cooled to -10 ° C. (R) -2
A solution of-(2-fluoro-biphenyl-4-yl) -propionic acid ethyl ester (82% ee, 559 mg), acetonitrile (0.267 mL) and methyl t-butyl ether (3.0 mL) was added dropwise. ,
Stir for 1.5 hours. The reaction mixture was diluted with 1N hydrochloric acid (40 m
L) and extracted with ethyl acetate (20 mL × 2).
The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 4-crystal by recrystallization (hexane / chloroform)
(2-Fluoro-biphenyl-4-yl) -4-methyl-3-oxo-pentanitrile was obtained (453 mg, yield 83%). The optical purity of this substance by HPLC was 0.0
% Ee. HPLC conditions Column: OD-R (Daicel (registered trademark)) Detection wavelength (UV): 254 nm Flow rate: 1.0 mL / min Mobile phase: water / acetonitrile = 1/1

Formulation Example 1Tablet manufacturing  After mixing the ingredients, granulating if necessary,
Thus, a tablet can be produced. Amount (mg / tablet) Isoxazole derivative of Example 13 20 Lactose 70 Maize starch 17 Low-substituted hydroxypropylcellulose 8 Hydroxypropylcellulose 4 Magnesium stearate 1 Total 120 mg

Formulation Example 2Tablet manufacturing  After mixing the ingredients, granulating if necessary,
Thus, a tablet can be produced. Amount (mg / tablet) Isoxazole derivative of Example 13 20 D-mannitol 60 Calcium hydrogen phosphate 25 Carmellose calcium 8 Hydroxypropyl methylcellulose 4 Talc 3 Total 120 mg

Formulation Example 3Manufacture of capsules  After mixing each component and granulating if necessary
By filling, a capsule can be produced. Amount (mg / capsule) Isoxazole derivative of Example 13 20 Lactose 150 Maize starch 40 Low-substituted hydroxypropylcellulose 8 Magnesium stearate 2 Total 220 mg

Formulation Example 4Manufacture of capsules  After mixing each component and granulating if necessary
By filling, a capsule can be produced. Amount (mg / capsule) Isoxazole derivative of Example 13 20 D-mannitol 123.5 Carmellose calcium 5 Magnesium stearate 1.5 Total 150 mg

Formulation Example 5Manufacture of powder  By mixing each component and granulating as necessary, powder
Can be manufactured. Amount (mg / 1 g) Isoxazole derivative of Example 13 40 Lactose 750 Maize starch 200 Magnesium stearate 10 Total 1000 mg

Formulation Example 6Manufacture of powder  By mixing each component and granulating as necessary, powder
Can be manufactured. Amount (mg / 1g) Isoxazole derivative of Example 13 40 D-mannitol 700 Corn starch 200 Magnesium stearate 10 Total 1000 mg

[0076]

According to the present invention, it is possible to provide a method for producing a 5-aminoisoxazole derivative with less side reaction. Further, a method for producing an optically active 5-aminoisoxazole derivative from a carboxylic acid derivative having an asymmetric carbon by suppressing steric isomerization can be provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/535 A61K 31/535 A61P 37/00 A61P 37/00 (72) Inventor Kazunori Shimano Konohana-ku, Osaka-shi 3-1-98 Kasuganaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Shogo Nakatani 3-1-198 Kasuganaka Nakanohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Shinichiro Okada Osaka-shi Within Sumitomo Pharmaceutical Co., Ltd. 3-1-198 Kasuganaka, Konohana-ku (72) Inventor Masashi Nakatsuka 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd.

Claims (17)

[Claims] [Claim 1] Formula: By reacting a hydroxylamine salt with a compound represented by the formula: A method for producing a 5-aminoisoxazole derivative represented by the formula: [In the formula, R represents an organic group. R ¹ represents a carboxyl-protecting group. M ⁺ represents a cation. ] 2. An activator of a carboxyl group having the formula: Activating the carboxyl group of the compound represented by the formula: By reacting a compound represented by the formula: By reacting a hydroxylamine salt with a compound represented by the formula: A method for producing a 5-aminoisoxazole derivative represented by the formula: [Wherein, R, R ¹ and M ⁺ have the same meaning as in claim 1]. ] (3) R is a compound represented by the formula: [R ² , R ³ and R ⁴ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, or an optionally substituted Alkenyl group, optionally substituted alkynyl group, optionally substituted aryl group, optionally substituted heterocyclic group, optionally substituted alkoxy group, optionally substituted cycloalkoxy group, optionally substituted An aryloxy group, an optionally substituted heterocyclic oxy group,
—SR ⁵ (R ⁵ is a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl Represents an optionally substituted aryl group, an optionally substituted acyl group, or an optionally substituted alkoxycarbonyl group) or an optionally substituted amino group. Also, R ² , R ³ and R ⁴
And any two of these may be bonded together to form, together with the carbon atom, an optionally substituted hydrocarbon ring or an optionally substituted heterocyclic ring. The production method according to claim 1 or 2, wherein 4. R is a compound of the formula: [R ³ and R ⁴ have the same meanings as in claim 3. The production method according to claim 1 or 2, wherein 5. The method according to claim 1, wherein R ¹ is a tertiary alkyl group.
5. The production method according to any one of the above items 4. 6. The method according to claim 1, wherein R ¹ is a t-butyl group.
The production method according to any one of the above. 7. The method according to claim 1, wherein M ⁺ is an alkali metal ion, an alkaline earth metal ion or an ammonium ion. 8. The production method according to claim 1, wherein M ⁺ is a lithium ion or a sodium ion. 9. The method according to claim 2, wherein the activator of the carboxyl group is alkyl chloroformate, pivaloyl chloride or 1,1-carbonyldiimidazole. 10. The formula: embedded image A compound represented by the formula: Wherein R ¹ and M ⁺ are
Is synonymous with R ² , R ³ and R ⁴ have the same meanings as in claim 3. ] 11. The compound according to claim 10, wherein R ² is a hydrogen atom. 12. The method according to claim 10, wherein R ¹ is a tertiary alkyl group.
Or the compound according to 11. 13. The compound according to claim 10, wherein R ¹ is a t-butyl group. 14. The compound according to claim 10, wherein M ⁺ is an alkali metal ion, an alkaline earth metal ion or an ammonium ion. 15. The compound according to claim 10, wherein M ⁺ is a lithium ion or a sodium ion. 16. The formula: embedded imageIs reacted with a hydroxylamine salt.
And the formula:A 5-aminoisoxazole derivative represented by
And the formula: NC-N (R ⁸) R⁹The compound represented by
By reacting and, if necessary, further salifying, the formula:Or an isoxazole derivative represented by the formula:
Method for producing a salt. [Wherein, R¹And M⁺Is the claim
Synonymous with the meaning in 1. R⁶Is 2-fluoro-
Biphenyl-4-yl, 3-benzoylphenyl, 2 '
-Fluoro-biphenyl-4-yl or biphenyl-
Represents 4-yl. R⁷Is hydrogen atom, methyl group, methoxy
Represents an ethoxy group or an ethoxy group. R⁸And R⁹Is the following
(A), (b) or (c). (A) independently a hydrogen atom or an alkyl having 1 to 3 carbon atoms
Represents a group. (B) one represents a hydrogen atom and the other is-(CH₂)_n−
CO₂R¹⁰(N represents an integer of 1 to 3. R¹⁰Is carbon
Represents an alkyl group of Formulas 1 to 3. ),-(CH₂)_m-O
R¹¹(M represents 2 or 3. R¹¹Is a hydrogen atom,
An alkyl group having 1 to 3 carbon atoms, 2-hydroxyethyl or
Represents 3-hydroxypropyl. ) Or-(C
H₂)_m−N (R¹²) R¹³(M is as defined above.
You. R¹²And R¹³Is independently a hydrogen atom or charcoal
Represents an alkyl group having a prime number of 1 to 3, or R¹²and
R¹³Together with the nitrogen atom, pyrrolidine,
Peridine, morpholine or N-methylpiperazine (this
In these, pyrrolidine, piperidine, morpholine and
And N-methylpiperazine are one or two methyl
It may be replaced. ). ). (C) Together with the nitrogen atom, pyrrolidine, pipet
Lysine, morpholine or N-methylpiperazine (this
Use pyrrolidine, piperidine, morpholine and
And N-methylpiperazine are substituted with one or two methyls.
It may be exchanged. ). ] 17. R ⁷ is a hydrogen atom or a methyl group,
—N (R ⁸ ) R ⁹ is morpholino, 4-methyl-piperazinyl, 1,1-dioxo- [1,4] thiazinan-4
-Yl, dimethylamino, diethylamino, methylamino, ethylamino, hydroxyamino, 2-hydroxyethylamino, 2-morpholinoethylamino, 2-methoxyethylamino or 2- (2-hydroxyethyl)
17. The production method according to claim 16, which is -ethylamino.