JP2003064064A - Method for producing amidothiazole derivative ester compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for easily obtaining an amidethiazole derivative ester compound useful as an intermediate of a cephalosporin antibiotic with high purity. SOLUTION: An N-protected amino acid compound such as tert-butoxycarbonyl-L-alanine and 2
-(2-aminothiazol-4-yl) -2- (Z)-
By condensing with an aminothiazole derivative ester compound such as ethyl methoxyiminoacetate, 2- (2-tert-
Butoxycarbonyl-L-alanylaminothiazole-
In a method for producing an ester compound of an amide thiazole derivative such as ethyl 4-yl) -2- (Z) -methoxyiminoacetate, a dicarbonate compound such as di-tert-butyl dicarbonate and N-methylmorpholine are used as a condensing agent. And used in combination with the tertiary amine compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an amidothiazole derivative ester compound from an N-protected amino acid compound and an aminothiazole derivative ester compound.

[0002]

BACKGROUND OF THE INVENTION Aminothiazole derivatives are useful compounds as intermediates in the production of pharmaceuticals, and are important compounds used as side chains of antibiotics such as cephalosporins. For example, β-, such as 7-aminocephalosporanic acid
The basic skeleton of an antibiotic is made by binding an aminothiazole derivative to a lactam compound by an amidation reaction.

[0003] The cephalosporin antibiotics are generally attracting attention because they have a broad antibacterial spectrum and few side effects. However,
A cephalosporin derivative synthesized from an aminothiazole derivative and a β-lactam compound generally has a problem of poor gastrointestinal absorbability. Therefore, by reacting an intermediate obtained by protecting the amino group of an aminothiazole derivative with a compound such as an amino acid that is easily cleaved by an in vivo enzyme such as peptidase, and a β-lactam compound, the digestive tract A technique for obtaining a highly absorbable cephalosporin derivative (also referred to as a prodrug-type cephalosporin derivative) has been developed.

Such a prodrug type cephalosporin derivative is represented by the following formula (V)

[0005]

[Chemical 5]

A prodrug type cephalosporin derivative represented by the formula (wherein R ⁷ is a 1-alkanoyloxyalkyl group or a 1-alkoxycarbonyloxyalkyl group) is known and its gastrointestinal absorbability is known. The demand for the derivative is increasing more and more due to its good quality.

Therefore, the following formula (III), which is an important intermediate of the above prodrug-type cephalosporin derivative, is used.

[0008]

[Chemical 6]

{In the formula, R ¹ is a protecting group for an amino group,
R ² is a hydrogen atom, a saturated hydrocarbon group having 1 to 6 carbon atoms, an unsaturated hydrocarbon group having 2 to 10 carbon atoms, and R ³ is 1 carbon atom.
7-alkyl group, or an aralkyl group having a carbon number of 7 to 11, Y is of the formula = ^{N-R 4} or = ^{CH-R 5} (wherein, ^{R 4} is an alkyl group having 1 to 7 carbon atoms, , Or an aralkyloxy group having 7 to 19 carbon atoms, R ⁵ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, an aralkyl group having 7 to 19 carbon atoms, an alkyloxy group having 1 to 7 carbon atoms, or carbon. It is a divalent group represented by the formula 7 to 19 aralkyloxy group) or two hydrogen atoms bonded to a carbon atom by a single bond. }, It is important to produce an amidothiazole derivative ester compound represented by the above formula with high purity and high yield. The amide thiazole derivative ester compound is desired to have a high optical purity in view of its use.

As a method for synthesizing this amidothiazole derivative ester compound, an N-protected amino acid compound is
After reacting with N-hydroxysuccinimide in the presence of dicyclohexylcarbodiimide as a condensing agent to synthesize a succinimide derivative, it is further reacted with an aminothiazole derivative ester compound to isolate an amide thiazole derivative ester compound. .4% (calculated value based on the value described in the literature. Since the yield exceeds 100%, the isolated product at this time is considered to contain impurities.) Kaisho 58-1804
91), and an N-protected amino acid compound and an aminothiazole derivative ester compound in the presence of 4-dimethylaminopyridine, which is a water-soluble carbodiimide as a condensing agent, 1-ethyl-3- (3-dimethylaminopropyl). A method of reacting with carbodiimide hydrochloride to synthesize an amidothiazole derivative ester compound with an isolated yield of 67.5% (JP-A-3-204883), N-
A method of synthesizing an amidothiazole derivative ester compound by reacting a protected amino acid compound and an aminothiazole derivative ester compound with carbonyldiimidazole as a condensing agent (JP-A-2000-81083).
It has been known.

[0011]

However, in the method described in JP-A-58-180491, dicyclohexylcarbodiimide is prepared from N-tert-butoxycarbonyl-L-alanine and N-hydroxysuccinimide. When the succinimide compound is synthesized by using, a sparingly soluble urea compound is produced as a by-product, and therefore this is filtered and then 2- (2-aminothiazol-4-yl) -2-
It is necessary to react with methoxyiminoacetic acid methyl ester, and there is a problem that the process is complicated. In addition, the isolated yield was 112.4% (calculated value based on the value described in the literature).
Since the yield exceeds 100%, it is considered that the product isolated at this time contains impurities, and the isolation yield after the next step which proceeds quantitatively is 69.3. %, It is predicted that the true condensation yield was a low value of about 70%.

In the method described in the above-mentioned JP-A-3-204883, the isolation yield of the target amide thiazole derivative ester compound is as low as about 67.5%, and it is necessary to remove it during the reaction. However, there was a problem that a water-soluble urea compound was by-produced as a by-product that had to be finally removed.

Further, in the method described in JP 2001-81083 A, although the reaction yield is high, carbonyldiimidazole used as a condensing agent reacts rapidly with water to generate carbon dioxide. It was necessary to be careful in handling during use and storage.

Therefore, it has been desired to develop a method for producing an amide thiazole derivative ester compound represented by the above formula (III) in a high yield and a high purity by using a condensing agent which is easy to handle.

[0015]

SUMMARY OF THE INVENTION In view of such circumstances, the present inventors first examined the reaction mechanism of the above-mentioned conventional method. As a result, when a carbodiimide-based condensing agent such as dicyclohexylcarbodiimide or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was used, the acid anhydride of the N-protected amino acid compound was used as one of the reaction routes. It was found that the yield is low because the reaction route between the acid anhydride and the aminothiazole derivative ester compound is very slow.

Based on the above findings, various studies were conducted on a condensing agent which is easy to handle and which allows the reaction to proceed without passing through the above-mentioned low-reactivity acid anhydride.
The inventors have found that the use of a dicarbonate compound as a condensing agent in the presence of a tertiary amine compound allows the intended product to be obtained in a high yield, and completed the present invention.

That is, the present invention provides the following general formula (I)

[0018]

[Chemical 7]

(In the formula, R ¹ is a protecting group for an amino group,
R ² is a hydrogen atom, a saturated hydrocarbon group having 1 to 6 carbon atoms, or an unsaturated hydrocarbon group having 2 to 10 carbon atoms. ) And an N-protected amino acid compound represented by the following general formula (II)

[0020]

[Chemical 8]

[In the formula, R ³ is an alkyl group having 1 to 7 carbon atoms or an aralkyl group having 7 to 11 carbon atoms, and Y is the following formula: NR ⁴ or ═CH ⁵ R ⁵ (wherein , R ⁴ is an alkyloxy group having 1 to 7 carbon atoms or an aralkyloxy group having 7 to 19 carbon atoms, and R ⁵ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, or an aralkyl group having 7 to 19 carbon atoms. , An alkyloxy group having 1 to 7 carbon atoms, or an aralkyloxy group having 7 to 19 carbon atoms), or two hydrogen atoms bonded to a carbon atom by a single bond. } And an aminothiazole derivative ester compound represented by the following general formula (III)

[0022]

[Chemical 9]

[0023] (wherein, ^{R 1} and ^{R 2} are the same as R ¹ and ^{R 2} in each of the general formula (I), ^{R 3} and Y, R ³ and in each of the general formula (II) Y In the method for producing an amide thiazole derivative ester compound represented by the formula (1), wherein a dicarbonate compound and a tertiary amine compound are used in combination as a condensing agent. Is the way.

[0024]

BEST MODE FOR CARRYING OUT THE INVENTION In the production method of the present invention, an N-protected amino acid compound represented by the above general formula (I) (hereinafter, also simply referred to as “raw material N-protected amino acid”) and the above general formula (II). By condensing an aminothiazole derivative ester compound (hereinafter, also simply referred to as “raw material aminothiazole derivative ester”) represented by
In the production of the amidothiazole derivative ester compound represented by I), a dicarbonate compound, particularly the following general formula (IV), is used as a condensing agent.

[0025]

[Chemical 10]

(In the formula, R ⁶ is a saturated hydrocarbon group having 1 to 10 carbon atoms or an unsaturated hydrocarbon group having 2 to 10 carbon atoms.) A dicarbonate compound represented by a tertiary amine compound The greatest feature is that they are used in combination.

In the present invention, the condensing agent means a compound having an action of promoting a condensation reaction, and the compound itself reacts with a reaction reagent to form an active intermediate, as a matter of course.
The direct reaction reagent refers to a compound which, even if it does not react, causes the condensation reaction to effectively proceed as a result of some action.

The dicarbonate compound used in the present invention can be used without any limitation as long as it is a compound having a dicarbonate structure.

In particular, the dicarbonate compound represented by the general formula (IV) is preferably used as the dicarbonate compound. R in the general formula (IV) is
⁶ is a saturated hydrocarbon group having 1 to 10 carbon atoms, or 2 carbon atoms
10 to 10 unsaturated hydrocarbon groups. These groups may be linear or branched. Examples of the saturated hydrocarbon group having 1 to 10 carbon atoms include alkyl groups such as methyl group, ethyl group, isopropyl group, tert-butyl group and tert-amyl group.

Examples of the unsaturated hydrocarbon group having 2 to 10 carbon atoms include alkenyl groups such as allyl group, aryl groups such as phenyl group, and aralkyl groups such as benzyl group.

Specific examples of the dicarbonate compound that can be preferably used in the present invention include dimethyldicarbonate, diethyldicarbonate, diallyldicarbonate, diisopropyldicarbonate and di-tert-carbonate.
Examples thereof include butyl dicarbonate, di-tert-amyl dicarbonate, diphenyl dicarbonate, dibenzyl dicarbonate and the like.

Among these, diisopropyl dicarbonate, di-tert-butyl dicarbonate, and di-ter are particularly preferred because of their high degree of condensation conversion and easy handling.
t-amyl dicarbonate and the like can be particularly preferably used.

These dicarbonate compounds are
Those obtained as reagents and industrial raw materials can be used as they are, or can be used after purification such as recrystallization and distillation as necessary. The unobtainable dicarbonate compound can be synthesized as follows. That is, it can be synthesized by reacting a corresponding alkali metal alkoxide with carbon dioxide and then reacting with an aromatic sulfonyl chloride compound. Further, the synthesized dicarbonate compound can be used as it is or after purification such as distillation as necessary.

The amount of these dicarbonate compounds to be used is not particularly limited, but if it is too small, unreacted raw materials remain, and if it is too large, by-products in which the raw material aminothiazole derivative ester directly reacts with the dicarbonate compound are produced. In order to increase the amount, 1 mol of the raw material N-protected amino acid
It is preferably used in the range of 0.5 to 5 mol. Furthermore, considering that a highly pure target product is obtained, it is particularly preferable to use it in the range of 0.8 to 3 mol per mol of the raw material N-protected amino acid.

In the present invention, known tertiary amine compounds can be used as the tertiary amine compound used in combination with the above-mentioned dicarbonate compound. At this time, if a primary or secondary amine is used, a by-product that reacts with the raw material N-protected amino acid and the primary or secondary amine compound is produced, so that the usable amine is limited to the tertiary amine compound. Specific examples of the tertiary amine compound that can be used in the present invention include trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylmethylamine, diisopropylethylamine and the like, preferably having 3 to 25 carbon atoms. Aliphatic tertiary amine compound; N-methylpyrrolidine, N-methylpiperidine, N
-Ethylpiperidine, N-methylmorpholine, N-ethylmorpholine and the like, preferably a C5-C10 cyclic tertiary amine compound; pyridine, N, N-dimethylaminopyridine, N-methylpyrrole and the like are suitable. Has 5 to 1 carbon atoms
0 cyclic unsaturated hydrocarbon tertiary amine compound; N, N,
N ', N'-tetramethylethylenediamine, N, N,
N ', N'-tetraethylethylenediamine, N, N,
N ', N'-tetramethylethylenediamine, N, N,
N ', N'-tetramethyl-1,3-propylenediamine, N, N, N', N'-tetramethyl-1,3-butanediamine, N, N, N ', N'-tetramethyl-1 ，
Preferable examples of 4-butanediamine and the like include aliphatic tertiary diamine compounds having 6 to 10 carbon atoms.

Among them, in particular, aliphatic tertiary amine compounds such as trimethylamine, triethylamine, diisopropylmethylamine, diisopropylethylamine and the like; N-methylmorpholine, N-, due to their high degree of condensation conversion.
Cyclic tertiary amine compounds such as ethylmorpholine; or
Aliphatic tertiary diamine compounds such as N, N, N ′, N′-tetramethylethylenediamine are more preferably used. All of these tertiary amine compounds are available as reagents and industrial raw materials, and the obtained products can be used as they are, or can be used after purification such as recrystallization and distillation as necessary.

The amount of the tertiary amine compound used is not particularly limited, but if the amount is too small, the reaction rate of the condensation reaction will markedly decrease. Further, if the amount is too large, it is necessary to separately perform an operation of removing the amine compound, and a reaction product of the dicarbonate compound and the aminothiazole derivative ester compound is by-produced, so that it is 0. Further, in the range of 01 to 5.0 mol, 0.1
It is particularly preferable to use it in the range of ˜1.5 mol.

The N-protected amino acid compound used in the present invention can be used without any limitation as long as it is a compound in which the amino group of the amino acid is protected by an amino-protecting group.

That is, as the N-protected amino acid compound, the raw material N-protected amino acid represented by the general formula (I) can be used. R in the general formula (I) is
¹ is a protecting group for an amino group. The R ¹ is not particularly limited as long as it is an organic residue having a function of protecting an amino group, and specific examples of the group having such a function include a formyl group, an acetyl group and a chloroacetyl group. Group, acyl type protecting group such as acetoacetyl group; alkoxycarbonyl group such as isopropoxycarbonyl group, tert-butoxycarbonyl group; aralkyloxycarbonyl group such as benzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group; benzyl group And an aralkyl group such as a triphenylmethyl group.

Among these, particularly from the viewpoint of the effect of suppressing racemization during the condensation reaction, an isopropoxycarbonyl group, t
It is preferable to use an alkoxycarbonyl group such as an ert-butoxycarbonyl group; or an aralkyloxycarbonyl group such as a benzyloxycarbonyl group or a 9-fluorenylmethoxycarbonyl group. Further, it is most preferable to use a tert-butoxycarbonyl group because of the ease of deprotection.

R ² in the general formula (I) is a hydrogen atom, a saturated hydrocarbon group having 1 to 6 carbon atoms, or 2 to 2 carbon atoms.
10 unsaturated hydrocarbon groups. These groups may be linear or branched. Examples of suitable saturated hydrocarbon groups having 1 to 6 carbon atoms include alkyl groups such as methyl group, ethyl group, isopropyl group, 2-methylpropyl group and 1-methylpropyl group.

Examples of the unsaturated hydrocarbon group having 2 to 10 carbon atoms include aryl groups such as phenyl group and naphthyl group; aralkyl groups such as benzyl group, phenethyl group and 1-phenylethyl group.

Of these, a methyl group is particularly preferable as R ² since it has good absorbability and biodegradability when finally converted into a prodrug type cephalosporin derivative.

Specific examples of the raw material N-protected amino acid which can be used in the present invention include N-acetylglycine,
Acyl amino acid compounds such as N-acetylalanine, N-acetylvaline, N-acetylleucine, N-acetylphenylglycine, N-acetylphenylalanine; t
ert-butoxycarbonylglycine, tert-butoxycarbonylalanine, tert-butoxycarbonylvaline, tert-butoxycarbonylleucine, t
ert-butoxycarbonylphenylglycine, ter
Alkoxycarbonyl amino acid compounds such as t-butoxycarbonylphenylalanine; N-benzyloxycarbonylglycine, N-benzyloxycarbonylalanine, N-benzyloxycarbonylvaline, N-benzyloxycarbonylleucine, N-benzyloxycarbonylphenylalanine, N- ( 9-fluorenylmethoxycarbonyl) glycine, N- (9-fluorenylmethoxycarbonyl) alanine, N- (9-fluorenylmethoxycarbonyl) valine, N- (9-fluorenylmethoxycarbonyl) leucine, N Aralkyloxycarbonyl amino acid compounds such as-(9-fluorenylmethoxycarbonyl) phenylalanine; N-benzylglycine, N-benzylalanine, N-benzylvaline, N
-Benzylleucine, N-benzylphenylglycine,
N-benzylphenylalanine, N-triphenylmethylglycine, N-triphenylmethylalanine, N-triphenylmethylvaline, N-triphenylmethylleucine, N-triphenylmethylalanine, N-triphenylmethylphenylglycine, N- Examples thereof include aralkyl amino acid compounds such as triphenylmethylphenylalanine.

Among these, tert-butoxycarbonylalanine, tert-butoxycarbonylvaline and ter are particularly preferred because of their high ability to suppress racemization during the condensation reaction.
Alkoxycarbonyl amino acid compounds such as t-butoxycarbonylleucine, tert-butoxycarbonylphenylglycine, tert-butoxycarbonylphenylalanine; or N-benzyloxycarbonylalanine, N-benzyloxycarbonylvaline, N-benzyloxycarbonylleucine, N-benzyl Oxycarbonylphenylglycine, N-benzyloxycarbonylphenylalanine, N- (9-fluorenylmethoxycarbonyl) glycine, N- (9-fluorenylmethoxycarbonyl) alanine, N- (9-fluorenylmethoxycarbonyl) valine , N- (9-fluorenylmethoxycarbonyl) leucine, N- (9-fluorenylmethoxycarbonyl) phenylalanine, etc. It is preferable to use Roh acid compound. Furthermore, because of the ease of protection / deprotection reactions, tert
-Butoxycarbonylalanine, tert-butoxycarbonylvaline, tert-butoxycarbonylleucine, tert-butoxycarbonylphenylglycine,
t such as tert-butoxycarbonylphenylalanine
It is particularly preferable to use an ert-butoxycarbonyl amino acid compound.

These starting N-protected amino acids are available as reagents or industrial starting materials, but if they are not available, they can be synthesized. That is, it can be easily synthesized by reacting the corresponding amino acid with a protecting agent in the presence of a base.

Among these raw material N-protected amino acids are:
Some have asymmetric carbon. In the present invention, N-protected amino acid compounds of either L-configuration or D-configuration can be used,
The L-form is preferably used from the viewpoint of the pharmacological activity of the final product. The amidoaminothiazole derivative ester compound represented by the general formula (III) can be obtained even when an N-protected amino acid having an optical purity of 95% ee or less is used. In this case, the L-form, In order to obtain an amidoaminothiazole derivative ester compound which is a mixture of D-forms and has a high optical purity, optical resolution, purification of a chiral column and the like are required, and therefore, from the viewpoint of easy operation,
It is preferable to use an N-protected amino acid having an optical purity of 95% ee or higher.

Another starting material compound used in the present invention is an aminothiazole derivative ester compound,
The starting amino body represented by the general formula (II) can be used. R ³ in the general formula (II) is an alkyl group having 1 to 7 carbon atoms or an aralkyl group having 7 to 11 carbon atoms. The alkyl group having 1 to 7 carbon atoms may be linear or branched, and as these alkyl groups,
Examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group. Examples of the aralkyl group having 7 to 11 carbon atoms include benzyl group and naphthylmethyl group.

Of these, a methyl group or an ethyl group is particularly preferable as R ³ because the operation involved in the subsequent hydrolysis is easy.

Y in the general formula (II) is a divalent group represented by the following formula: NR ⁴ or ═CHR ⁵ , or a single bond to a carbon atom to which Y is bonded. Two hydrogen atoms.

In the above formula, R ⁴ is an alkyloxy group having 1 to 7 carbon atoms or an aralkyloxy group having 7 to 19 carbon atoms. The alkyloxy group having 1 to 7 carbon atoms may be linear or branched, and specific examples thereof include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, n-butyloxy group, sec-butyloxy group. Base,
A tert-butyloxy group etc. are illustrated. Examples of the aralkyloxy group having 7 to 19 carbon atoms include benzyloxy group and triphenylmethyloxy group.

R ⁵ in the above formula is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, an aralkyl group having 7 to 19 carbon atoms,
An alkyloxy group having 1 to 7 carbon atoms or 7 to 19 carbon atoms
Is an aralkyloxy group. Examples of the alkyl group having 1 to 7 carbon atoms are the same as those in R ³ .
Examples of the unsubstituted aralkyl group having 7 to 19 carbon atoms include benzyl group and triphenylmethyl group. Also,
Examples of the alkyloxy group having 1 to 7 carbon atoms and the aralkyloxy group having 7 to 19 carbon atoms are the same as those in R ⁴ .

Further, Y is a single bond and is bonded to a carbon atom. 2
One of the cases is a hydrogen atom, -C in the general formula (II) (= Y) - group represented by the, -CH ₂ - underlying.

Specific examples of the raw material aminothiazole derivative ester that can be used in the present invention include 2- (2
-Aminothiazol-4-yl) methyl acetate, 2- (2
-Aminothiazol-4-yl) ethyl acetate, 2- (2
-Aminothiazol-4-yl) -2-methoxyiminoacetate methyl, 2- (2-aminothiazol-4-yl)
2-Methoxyiminoacetic acid ethyl, 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid ter
t-butyl, 2- (2-aminothiazol-4-yl)
Benzyl-2-methoxyiminoacetate, methyl 2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetate, ethyl 2- (2-aminothiazol-4-yl) -2-ethoxyiminoacetate, 2- (2-Aminothiazol-4-yl) -2-ethoxyiminoacetate benzyl, 2-
Ethyl (2-aminothiazol-4-yl) -2-benzyloxyiminoacetate, 2- (2-aminothiazol-
4-yl) -2-triphenyloxyiminoacetate ethyl, 2- (2-aminothiazol-4-yl) -2-triphenyloxyiminoacetate benzyl, 2- (2-aminothiazol-4-yl) -2 -Ethyl propenoate, 2
Ethyl-(2-aminothiazol-4-yl) -2-butenoate, 2- (2-aminothiazol-4-yl) -2
-Ethyl pentenoate etc. can be mentioned.

Among these, 2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid methyl ester, 2- (2-aminothiazole-) is used because of the high effect of the prodrug type cephalosporin derivative. 4-yl) -2-methoxyiminoacetic acid ethyl ester and the like are particularly preferably used.

These starting aminothiazole derivative esters are available as reagents or industrial starting materials, but if they are not available, they can be synthesized as follows. That is, the alkoxyiminoacetic acid compounds are the corresponding 2- (2-aminothiazol-4-yl) -2-
It can be synthesized by reacting an ester compound of hydroxyiminoacetic acid with an alkyl halide or an aralkyl halide, and alkenoic acid compounds are reacted with an aldehyde corresponding to an ester compound of 4-chloroacetoacetic acid to form 4-chloro-2-alkylidene. After obtaining an acetoacetic acid ester compound, it can be easily synthesized by reacting with thiourea.

The raw material aminothiazole derivative ester may have isomers of E form and Z form. In the present invention, both E form and Z form can be used, but the final product The Z form is preferably used from the viewpoint of pharmacological activity.

The amount of the raw material aminothiazole derivative ester used is not particularly limited, but if it is too small, unreacted raw material N-protected amino acid remains, and if it is too large, the raw material aminothiazole derivative ester is unreacted. Since it remains, it is 0.5 for 1 mol of the raw material N-protected amino acid.
It is preferably used in the range of ˜5 mol. Furthermore, from the viewpoint of obtaining a high-purity amidothiazole derivative ester compound, it is particularly preferable to use it in the range of 0.8 to 2 mol per mol of the starting N-protected amino acid.

In the production method of the present invention, it is preferable to use a solvent in the reaction in order to easily control the reaction conditions and carry out the reaction uniformly and in a short time. Specific examples of the solvent that can be used in the present invention include n-pentane and n-
Saturated hydrocarbons such as hexane, n-heptane, cyclopentane, cyclohexane; unsaturated hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride; diethyl ether, diisopropyl Ethers such as ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane; ethyl acetate, methyl acetate, n-acetate
Propyl, isopropyl acetate, n-butyl acetate, t-acetate
esters such as ert-butyl; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; carbonates such as dimethyl carbonate and diethyl carbonate; nitriles such as acetonitrile and propionitrile; N, N-dimethylformamide, N, N Examples thereof include amides such as dimethylacetamide; sulfoxides such as dimethyl sulfoxide; alcohols such as tert-butyl alcohol.

Among these solvents, unsaturated hydrocarbons, halogenated hydrocarbons, ethers, esters, ketones, or carbonates are preferably used because of their high condensation yield. Further, it is particularly preferable to use a solvent having a relative dielectric constant of 20 or less, such as toluene, diethyl ether, diisoproyl ether, chloroform, ethyl acetate, or tetrahydrofuran, from the viewpoint of preventing racemization from occurring during the reaction. is there.

The amount of these solvents used is not particularly limited, but from the viewpoint of easiness of reaction control and economical efficiency, it is 50 to 50 parts by weight with respect to 100 parts by weight of the raw material N-protected amino acid.
It is preferably used in an amount of 10,000 parts by weight, particularly 100 to 1000 parts by weight.

The operating procedure in the production method of the present invention is not particularly limited as long as a dicarbonate compound as a condensing agent is used in combination with a tertiary amine compound.
Regarding the method of adding each reaction reagent, even if all the components are added at the same time, the raw material N-protected amino acid compound, the tertiary amine compound and the dicarbonate compound are first added to react the dicarbonate compound with the raw material N-protected amino acid compound. After this, the raw material amidothiazole derivative ester compound may be added.

In this method, the method of mixing the raw material N-protected amino acid, the tertiary amine compound and the dicarbonate compound and, if necessary, the solvent is not particularly limited, and is appropriately mixed at a freezing point of the reaction system to 100 ° C. do it. Next, the reaction temperature at which the raw material aminothiazole derivative ester is added to carry out the condensation reaction is usually from the freezing point of the reaction system to 100 ° C. or less. From a viewpoint, −30 ° C.
It is preferable to carry out at 80 ° C or lower. At this time, it is preferable to carry out stirring in order to make the reaction temperature uniform.

The reaction time of the condensation reaction in the above method may be appropriately determined according to the reaction temperature, the type of solvent, etc., but usually 0.1 to 48 hours is sufficient.

Each reaction in the above methods can be carried out under normal pressure, under pressure, or under reduced pressure. Further, although these reactions can be carried out in the open to the atmosphere, in order to prevent the decomposition reaction from advancing due to moisture in the atmosphere, in a device equipped with a drying tube such as calcium chloride, nitrogen, helium, or argon. It is preferable to carry out under an inert gas atmosphere such as.

By carrying out the reaction as described above, an amidothiazole derivative ester having a structure corresponding to the structures of the starting N-protected amino acid and the starting aminothiazole derivative ester used, that is, represented by the above general formula (III) An amidothiazole derivative ester is obtained.

The obtained amidothiazole derivative ester can be isolated by separating and purifying as required. For example, when an organic solvent that is incompatible with water is used as the reaction solvent, after the reaction is complete, the reaction solution is washed with an aqueous acid solution, water, etc., and then the solvent is dried and separated and purified by recrystallization or column chromatography. Can be done by

Further, the obtained reaction solution may be used as a starting material for a reaction according to various purposes without being isolated after being left as a mixture or after being appropriately treated.

[0069]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 A reaction vessel equipped with a stirring blade, a thermometer, a nitrogen blowing port, and a dropping funnel was charged with N-tert-butoxycarbonyl-L.
-Alanine 1.89 g (10 mmol, 100% ee)
Was dissolved in 10 ml of methylene chloride. 2-in this solution
Ethyl (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetate 2.29 g (5 mmol), N
After adding 0.51 g (5 mmol) of methyl morpholine, 2.18 g (10 mmol) of di-tert-butyl dicarbonate was added dropwise at 20 ° C. over 10 minutes.
After the dropping was completed, the reaction was carried out at the same temperature for 24 hours.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), 2- (2
The yield of ethyl N-tert-butoxycarbonyl-L-alanylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetate (hereinafter abbreviated as BAAE) is 8.
It was 5.6%. 2- (2-tert-) which is a by-product
Butoxycarbonylaminothiazol-4-yl) -2
-(Z) -methoxyiminoacetic acid ester (hereinafter Boc
Abbreviated as body. ) Was produced by 0.7%. Further, when analysis was performed using an optical separation column, the optical purity of the target product was 99% ee. The D-form in N-tert-butoxycarbonyl-L-alanine used at this time was not detected.

Examples 2 to 4 The same operation as in Example 1 was carried out except that the compounds shown in Table 1 were used as the dicarbonate compound. The results are shown in Table 1.
In addition, the adduct in the table means a dicarbonate compound and 2-
Represents a reaction product with ethyl (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetate.

[0073]

[Table 1]

Examples 5 to 6 The same operations as in Example 1 were carried out except that the compounds shown in Table 2 were used as the tertiary amine compound. The results are shown in Table 1. The Boc form in the table is a by-product 2- (2-ter).
t-butoxycarbonylaminothiazol-4-yl)
2- (Z) -methoxyiminoacetic acid ester is shown.

[0075]

[Table 2]

Examples 7 to 12 The compounds shown in Table 3 as N-protected amino acid compounds (all 1
The same operation as in Example 1 was carried out except that 00% ee) was used. The results are shown in Table 3.

[0077]

[Table 3]

Examples 13 to 18 The same operation as in Example 1 was carried out except that the compounds shown in Table 4 were used as the aminothiazole derivative ester compound. The results are shown in Table 4. In addition, the Boc body in the table means di-ter
2 shows a reaction product of t-butyl dicarbonate and an aminothiazole derivative ester compound.

[0079]

[Table 4]

Example 19 A reaction vessel equipped with a stirring blade, a thermometer, a nitrogen blowing port, and a dropping funnel was charged with N-tert-butoxycarbonyl-L.
-Alanine 1.89 g (10 mmol, 100% ee)
And 0.51 g (5 mmol) of N-methylmorpholine were dissolved in 10 ml of methylene chloride. Di-tert-butyl dicarbonate 2.1 was added to the solution at 20 ° C.
After 8 g (10 mmol) was added dropwise over 10 minutes, the mixture was reacted at the same temperature for 24 hours. After that, add 20 ℃ to this reaction solution.
And 2- (2-aminothiazol-4-yl) -2-
2.29 g (5 mmol) of ethyl (Z) -methoxyiminoacetate was reacted at the same temperature for 23 hours.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), it was found that BAAE
The yield was 83.4%. By-product 2- (2-
tert-Butoxycarbonylaminothiazole-4-
0.5% of (yl) -2- (Z) -methoxyiminoacetic acid ester was formed. Further, when analysis was performed using an optical separation column, the optical purity of the target product was 99% ee. The D-form in N-tert-butoxycarbonyl-L-alanine used at this time was not detected.

Examples 20 to 23 The same operation as in Example 1 was carried out except that the compounds shown in Table 5 were used as the reaction solvent. The results are shown in Table 5.

[0083]

[Table 5]

Examples 24 to 26 The same operations as in Example 1 were carried out except that the amounts of the tertiary amine compound used were those shown in Table 6. The results are shown in Table 6.

[0085]

[Table 6]

Comparative Example 1 A reaction vessel equipped with a stirring blade, a thermometer, a nitrogen blowing port, and a dropping funnel was charged with N-tert-butoxycarbonyl-L.
-Alanine 9.46 g (50 mmol, 100% e)
e), after adding 50 ml of methylene chloride and dissolving, 5
Cooled to ° C. To this solution, 11.46 g (50 mmol) of ethyl 2- (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetate and 0.61 g (5 mmol) of N, N′-dimethylaminopyridine were added. After adding and stirring uniformly, dicyclohexylcarbodiimide was added. After reacting at 5 ℃ for 0.5 hours, 20 minutes at 20 ℃
The temperature was raised to, and the reaction was performed at the same temperature for 23 hours.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), it was found that BAAE
The yield was 67.0%. By-product N-tert-
Butoxycarbonyl-L-alanine anhydride 32.5%
Was being generated.

Comparative Example 2 To a 100 ml round-bottomed flask, 3.60 g (10 mmol) of N-tert-butoxycarbonyl-L-alanine anhydride was added and dissolved in 20 ml of methylene chloride. 2- (2-aminothiazol-4-yl) -2 was added to this solution.
Ethyl-(Z) -methoxyiminoacetate 2.29 g (10
Mmol), N, N'-dimethylaminopyridine 0.1
2 g (1 mmol) was added and reacted at 25 ° C. for 4 days.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), it was found that BAAE
Was only 4.3%, and it was confirmed that the reactivity between the acid anhydride of the N-protected amino acid compound and the aminothiazole derivative ester compound was low.

From the results of Comparative Examples 1 and 2, when a carbodiimide type condensing agent was used, N-
It can be seen that there is a reaction route via the acid anhydride of the protected amino acid compound and the reaction between the acid anhydride and the aminothiazole derivative ester compound is extremely slow, resulting in a low yield.

Comparative Example 3 A reaction vessel equipped with a stirring blade, a thermometer, a nitrogen blowing port, and a dropping funnel was charged with N-tert-butoxycarbonyl-L.
-Alanine 9.46 g (50 mmol, 100% ee)
Was dissolved in 50 ml of methylene chloride. To this solution was added 3.56 g (50 mmol) of pyrrolidine, 2-
After adding 11.46 g (50 mmol) of ethyl (2-aminothiazol-4-yl) -2-methoxyiminoacetate, di-tert-butyl dicarbonate 1 was added at 20 ° C.
0.91 g (50 mmol) was added dropwise over 10 minutes.
After the dropping was completed, the reaction was carried out at the same temperature for 24 hours.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), 2- (2
The yield of ethyl N-tert-butoxycarbonyl-L-alanylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetate (hereinafter abbreviated as BAAE) is 1.
It remained at 2.6%, and 64.8% of N-tert-butoxycarbonyl-pyrrolidine was detected.

As shown in Comparative Example 3, even when the dicarbonate compound was used, when the primary or secondary amine compound was used instead of the tertiary amine compound, the raw material amino acid reacted with the primary or secondary amine compound. By-products are produced as by-products, and the yield is reduced.

Comparative Example 4 N-tert-butoxycarbonyl-L was placed in a reaction vessel equipped with a stirring blade, a thermometer, a nitrogen blowing port, and a dropping funnel.
-Alanine 1.89 g (10 mmol, 100% ee)
Was dissolved in 10 ml of methylene chloride. 2-in this solution
After adding 2.29 g (5 mmol) of ethyl (2-aminothiazol-4-yl) -2- (Z) -methoxyiminoacetate, at 20 ° C., 2.18 g (10 mmol of di-tert-butyl dicarbonate). ) Was added dropwise over 10 minutes. After the dropping was completed, the reaction was carried out at the same temperature for 24 hours.

When this reaction solution was analyzed by high performance liquid chromatography (hereinafter abbreviated as HPLC), 2- (2
The yield of ethyl N-tert-butoxycarbonyl-L-alanylaminothiazol-4-yl) -2- (Z) -methoxyiminoacetate (hereinafter abbreviated as BAAE) was 1.
It remained at 50%.

As shown in Comparative Example 4, when not used in combination with the tertiary amine compound, the raw material aminothiazole derivative ester hardly reacts because of low reactivity. Therefore, when a dicarbonate compound is used as a condensing agent, the presence of a tertiary amine compound is essential.

[0097]

According to the production method of the present invention, an amidothiazole derivative ester compound, which is an important intermediate of a prodrug tapuicephalosporin derivative, is obtained in high yield from a raw material N-protected amino acid and a raw material aminothiazole derivative ester. Obtainable. Further, in the present invention, the amide thiazole derivative ester compound obtained can maintain a high optical purity of the raw material aminothiazole derivative ester used as a raw material, and manufacture of a pharmaceutical intermediate having greatly different drug efficacy depending on the type of optical isomer. It can be said that this is an excellent manufacturing method.

Claims (4)

[Claims] 1. The following general formula (I): (In the formula, R ¹ is a protecting group for an amino group, and R ² is a hydrogen atom, a saturated hydrocarbon group having 1 to 6 carbon atoms, or an unsaturated hydrocarbon group having 2 to 10 carbon atoms.) -A protected amino acid compound and the following general formula (II): {In the formula, R ³ is an alkyl group having 1 to 7 carbon atoms or an aralkyl group having 7 to 11 carbon atoms, and Y is the following formula: = N-R ⁴ or = CH-R ⁵ (in the formula, R ⁴ Is an alkyloxy group having 1 to 7 carbon atoms or an aralkyloxy group having 7 to 19 carbon atoms, and R ⁵ is a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, an aralkyl group having 7 to 19 carbon atoms, or a carbon number. A divalent group represented by 1 to 7 alkyloxy groups or aralkyloxy groups having 7 to 19 carbon atoms, or two hydrogen atoms bonded to carbon atoms with a single bond. } And the aminothiazole derivative ester compound represented by the following formula are condensed using a condensing agent to give a compound represented by the following general formula (III): (Wherein, ^{R 1} and ^{R 2} are the same as R ¹ and ^{R 2} in each of the general formula (I), ^{R 3} and Y are synonymous with R ³ and Y in each of the general formula (II) In the method for producing an amidothiazole derivative ester compound represented by the formula (1), a dicarbonate compound and a tertiary amine compound are used in combination as a condensing agent. 2. The dicarbonate compound has the following general formula (IV): (In the formula, R ⁶ is a saturated hydrocarbon group having 1 to 10 carbon atoms or an unsaturated hydrocarbon group having 2 to 10 carbon atoms.) An amidothiazole derivative ester according to claim 1. Method for producing compound. 3. The method for producing an amide thiazole derivative ester compound according to claim 1, wherein R ¹ in the general formulas (I) and (III) is a tert-butoxycarbonyl group. 4. The optical purity of the N-protected amino acid compound represented by the general formula (I) is 95% ee or higher, and the optical purity of the amidoamidothiazole derivative ester compound represented by the general formula (III) is 95%. % Ee or more, The manufacturing method of the amido thiazole derivative ester compound in any one of Claims 1-3.