JPH06192179A - Dicarboxylic ester and its production - Google Patents

Abstract

PURPOSE:To efficiently obtain in high yield the subject compound useful for medicines or pesticides by reaction between each a specific acrylic ester and compound under basic conditions. CONSTITUTION:The objective compound of formula III can be obtained by reaction between (A) acrylic t-butyl ester of formula I and (B) a compound of formula II (R<1> is 1-6C alkyl except t-butyl; X is Cl, or Br) such as 2,2- dihalogenoacetate under basic conditions (e.g. in the presence of lithium hydroxide).

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a compound useful for producing a compound excellent as a medicine and an agricultural chemical and a process for producing the same.

[0002]

2. Description of the Related Art A quinolone derivative having a 1,2-cis-2-fluorocyclopropyl group shown in Chemical formula 13 as a substituent at the 1-position has both strong antibacterial activity and high safety, and is an excellent synthetic antibacterial drug. (Japanese Patent Laid-Open No. 2-231475)
See the official gazette. ).

[0003]

[Chemical 13] 1,2-cis-2-fluorocyclopropanecarboxylic acid was used to construct the 1,2-cis-2-fluorocyclopropyl group of this compound. The carboxylic acid ester for obtaining this was synthesized by the process shown in Chemical formula 14 using butadiene as a raw material (Bulletin of Faculty of Education, Wakayama University, 33, 33 (198
Four))).

[0004]

[Chemical 14]

[0005]

The synthetic method shown in Chemical Formula 14 involves using a trialkyltin hydride, such as tributyltin hydride. This trialkyl tin hydride is industrially difficult to use due to its toxicity and price.

As a result of earnest research, the present inventors have found that 1-halogeno
1,2-Cyclopropanedicarboxylic acid monoester (half ester) derivative is a very excellent compound as a synthetic intermediate for easily obtaining 1,2-cis-2-fluorocyclopropanecarboxylic acid derivative Furthermore, the inventors have found that a diester derivative of 1-halogeno-1,2-cyclopropanedicarboxylic acid is an excellent compound as a synthetic intermediate of the compound, which simply gives the above monoester derivative and completed the present invention. .

That is, the present invention provides formula I

[0008]

[Chemical 15] Or formula II

[0009]

[Chemical 16] (In the formula, R ¹ means an alkyl group having 1 to 6 carbon atoms which does not become a tertiary butyl group, X means a chlorine atom or a bromine atom, and ^t Bu means a tertiary butyl group. )).

The invention also provides the formula III

[0011]

[Chemical 17] (In the formula, R ² means an alkyl group having 1 to 6 carbon atoms,
X means a chlorine atom or a bromine atom. ) Or a salt thereof.

The invention further provides the formula IV

[0013]

Embedded image The compound represented by CH ₂ ═CH—COO ^t Bu IV and the formula V

[0014]

Embedded image X ₂ CHCOOR ¹ V (wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms which does not become a tertiary butyl group, and X represents a chlorine atom or a bromine atom). It relates to a process for preparing a compound of formula I, characterized in that the compound of formula is reacted under basic conditions.

The present invention also provides the formula VI

[0016]

Embedded image A compound represented by CH ₂ ═CH—COOR ¹ VI (in the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms which does not become a tertiary butyl group) and the compound represented by the formula VII.

[0017]

Embedded image A compound of the formula II, characterized in that the compound of the formula X ₂ CHCOO ^t Bu VII (X represents a chlorine atom or a bromine atom) is reacted under basic conditions. Regarding manufacturing method.

The present invention also relates to a process for preparing a compound of formula III, characterized in that one ester of the compound of formula I or formula II is selectively converted into a carboxyl group.

The present invention also provides methyl 2-tertiary butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate, ethyl 2-tertiary butoxycarbonyl-1-chloro-1-cyclopropanecarboxylate, 2- Chloro-2-
Methoxycarbonyl-1-cyclopropanecarboxylic acid or its salt, 2-chloro-2-ethoxycarbonyl-1-cyclopropanecarboxylic acid or its salt, tertiary butyl
1-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylate or 2-tertiary butoxycarbonyl-2-
It relates to chloro-1-cyclopropanecarboxylic acid or a salt thereof.

The compound represented by the formula I (hereinafter abbreviated as compound I. The compounds with other numbers are also abbreviated similarly) will be described. Compound I is a dicarboxylic acid diester derivative in which one ester of halogenocyclopropane dicarboxylic acid is a tertiary butyl ester. The ester group that is not a tertiary butyl ester is
It is attached to the carbon atom of cyclopropane to which the halogen atom is attached. The ester may be an alkyl ester containing an alkyl group having 1 to 6 carbon atoms, which is not a tertiary butyl ester.

Compound II is a halogenocyclopropane dicarboxylic acid diester derivative in which one ester is a tertiary butyl ester as in Compound I. However, in compound II, the ester bonded to the carbon atom to which the halogen atom is bonded is a tertiary butyl ester. The other ester may be an alkyl ester containing an alkyl group having 1 to 6 carbon atoms, which is not a tertiary butyl ester.

Each of the ester groups of 2 in the compound I or compound II may be present on the same side of the plane formed by the cyclopropane ring or on different sides.

In compound I or compound II, a halogen atom is bonded to the carbon atom to which one of the ester groups is bonded. Examples of the halogen atom include a chlorine atom and a bromine atom, but a chlorine atom is preferable.

One of the ester groups of compound I and compound II is a tertiary butyl ester group (tertiary butoxycarbonyl group). The tertiary butyl ester is easily converted into a carboxyl group by an acid treatment, but has a property of being less likely to be cleaved by alkali hydrolysis than other alkyl esters. Therefore, in compound I and compound II, only one ester can be selectively converted to a carboxyl group by selecting the processing conditions. The compound I and the compound II have the property of being easily converted into a monoester (half ester) of cyclopropanedicarboxylic acid.

That is, the compound I or compound II of the present invention
The required property is that under certain conditions, only one ester is converted to a carboxyl group, and the other ester is difficult to be converted to a carboxyl group under that condition, making it easy to convert to a cyclopropanedicarboxylic acid monoester. A cyclopropanedicarboxylic acid diester derivative that can be converted to (a carbon atom to which one ester is bonded is also bonded to a halogen atom at the same time. It is expected that the properties of the esters will be different, and if they are used, it is possible that one of them can be selectively converted into a carboxyl group even if they are the same ester. Is more convenient).

From this point of view, the compound suitable as the compound I or the compound II is specifically a reactive ester which is easily converted into a carboxyl group by acid treatment, or a carboxyl group by catalytic reduction. One ester is selected from a reactive ester that is easily converted to a carboxyl group by alkali hydrolysis, or a reactive ester that is easily converted to a carboxyl group by a metal and an acid. It can be said that the other ester may be a dicarboxylic acid diester derivative in which a reactive ester that is not easily converted into a carboxyl group under the conversion condition of the ester into a carboxyl group is combined.

Examples of the ester easily converted to a carboxyl group by an acid include tetrahydropyranyl ester, methoxyethoxymethyl ester, methylthiomethyl ester, verdyloxymethyl ester, diphenylmethyl ester, tertiary butyl ester, 4-methoxy ester. Examples thereof include benzyl ester and 2,4,6-trimethylbenzyl ester.

Examples of the ester converted into a carboxyl group by catalytic reduction include benzyloxymethyl ester, phenacyl ester, diphenylmethyl ester and benzyl ester.

Furthermore, examples of the ester converted into a carboxyl group by treatment with a metal such as zinc and an acid such as acetic acid include phenacyl ester and 2,2,2-trichloroethyl ester.

Therefore, as another embodiment of the dicarboxylic acid diester derivative of the present invention, diesters in which the above ester is one ester and the other is a methyl or ethyl ester can be exemplified.

Further, a diester derivative having a combination of an alkyl ester and an allyl ester can be exemplified.

Further, for example, a diester derivative having the characteristics required for the compound of the present invention can be obtained by selecting and combining two kinds which are not the same from the above-mentioned three kinds of different reactive esters. For example, a combination of tertiary butyl ester and 2,2,2-trichloroethyl ester, a combination of benzyl ester and tertiary butyl ester, and the like.

As the combination of esters having the characteristics required by the present invention, the combination of a tertiary butyl ester and a methyl or ethyl ester is the simplest.

The compound I can be obtained by reacting the tertiary butyl acrylate of formula IV with the 2,2-dihalogenoacetic acid ester derivative of formula V under basic conditions. .

The compound II is obtained by reacting the acrylic ester derivative represented by the formula VI and the 2,2-dihalogenoacetic acid tert-butyl ester derivative represented by the formula VII under basic conditions. You can

Each reaction to obtain compound I or compound II is usually carried out in a solvent, but a solvent may not be used. The solvent is not particularly limited as long as it is inert to the reaction. Examples of the solvent that can be used include aliphatic hydrocarbons such as pentane and hexane, aromatic hydrocarbons such as benzene, toluene and xylene, diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and ethers such as dioxane. Examples thereof include N, N-dimethylformamide, N, N-dimethylacetamide, N-alkylamides such as N-methyl-2-pyrrolidone, dimethyl sulfoxide, sulfoxides such as sulfolane, and the like. Also alcohols can be used.

Each reaction to obtain compound I or compound II may be carried out under basic conditions, that is,
The reaction may be carried out in the presence of a base or in the presence of a base and a phase transfer catalyst.

As the base, both an inorganic base and an organic base can be used. An example of an inorganic base is lithium,
Examples thereof include alkali metal hydroxides such as sodium and potassium, hydrogen carbonates and carbonates.
Further, a metal hydride such as sodium hydride or calcium hydride can also be used.

Further, tertiary butoxy potassium or sodium, alkoxides such as methoxides and ethoxides, and N-benzyltrimethylammonium hydroxide can also be used.

The amount of the base used is compound IV or compound VI.
1 to 2 times the equivalent may be used, but it is usually the equivalent.

Compound IV or compound VI may be reacted in an equivalent amount with respect to compound V or compound VII, respectively, but a small excess amount may be used.

The reaction temperature may range from about 10 ° C. to about 150 ° C. below zero, but it will also vary depending on the reaction conditions. For example, N, N-
When sodium hydride is used as a base in dimethylformamide, it is usually performed at about 0 ° C to about 50 ° C. When using carbonates as bases in N, N-dimethylformamide, the reaction is usually performed at room temperature to about 100 ° C.

Each reaction for obtaining compound I or compound II may be carried out in the presence of a base and a phase transfer catalyst.

As the phase transfer catalyst, a quaternary ammonium type or phosphonium type catalyst can be used.
In addition, crown ethers and tertiary amines (particularly higher aliphatic tertiary amines) may be used. Examples of quaternary ammonium type catalysts include tetra-n-butylammonium bromide, tetra-n-butylammonium hydrogen sulfate and tri-n-
Examples thereof include octylmethylammonium chloride, tri-n-octylmethylammonium bromide, triethylbenzylammonium chloride and triethylbenzylammonium bromide. Examples of the phosphonium type compound include tetraphenylphosphonium chloride, tetraphosphonium bromide, tetra n-butylphosphonium chloride, tetra n-butylphosphonium bromide, triphenylmethylphosphonium bromide, tri n-octylphosphonium bromide and the like.

The amount of the phase transfer catalyst used may be about 1% to 30% by weight with respect to the compound IV or compound VI.
Usually, about 5% is used.

When carrying out the reaction by a two-phase reaction, the base used is generally an aqueous solution of an inorganic salt such as a hydroxide of an alkali metal atom. An aqueous solution of sodium oxide may be used. The concentration of the aqueous base solution is usually about 3N. The amount of the aqueous base solution used is usually about 5 times the volume of compound IV or compound VI (volume / weight ratio. For example, compound IV, 1 g
To 5 ml. ) Is good. When carrying out the reaction by a two-phase reaction, a solvent that is not miscible with water is usually selected.

When a phase transfer catalyst is used, the reaction can be carried out without being a two-phase reaction. In this case, the catalyst may be selected from the above-mentioned phase transfer catalysts and used, and the usage amount thereof may be the same as above. Further, as the base, in addition to the above-mentioned hydroxide of alkali metal atom, carbonate or hydrogen carbonate of alkali metal or alkaline earth metal can be used. For example, lithium carbonate, potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like. The amount of the base used may be about 1 to 5 times equivalent, but preferably about 1.2 times equivalent. As the solvent, an amide-based solvent may be usually used, and examples thereof include dimethylacetamide, dimethylformamide, and N-methylpyrrolidone.

The actual operation of the reaction may be carried out according to the reaction of a commonly known phase transfer catalyst. That is, the starting compound is mixed with the reaction solvent, the phase transfer catalyst and the base are added thereto, and the reaction is carried out at a suitable temperature with sufficient stirring.

The compounds I and II can be easily converted into cyclopropanedicarboxylic acid monoesters. Examples of such conditions include acid treatment, catalytic reduction treatment, alkali hydrolysis, treatment with a metal and an acid, and the like. These conditions may be selectively used based on the difference in reactivity between the ester that converts into a carboxyl group and the ester that does not convert into a carboxyl group.

As the acid that can be used in the acid treatment, both organic acids and inorganic acids can be used. Examples of organic acids include methanesulfonic acid, sulfonic acids such as paratoluenesulfonic acid, and trifluoroacetic acid. Examples of the inorganic acid include hydrochloric acid and sulfuric acid. Compound I or compound II together with these acids may be heated in a suitable solvent, if necessary. The solvent may be a water-containing solvent. If the acid can also serve as the solvent, the solvent need not be used.

The treatment by catalytic reduction may be carried out in the presence of a metal catalyst in a hydrogen gas atmosphere. For example, a Raney nickel catalyst or a palladium-carbon catalyst may be used. Alkaline hydrolysis may be carried out at room temperature or under heating in a solvent miscible with an aqueous solution of an inorganic salt such as a hydroxide of an alkali metal atom. A typical example of the treatment with a metal and an acid is a reaction of treating with zinc in acetic acid.

Compound III is a half ester of a dicarboxylic acid in which the carboxyl group on the carbon atom to which the halogen atom is bonded is an ester. The ester may be an alkyl ester including tertiary butyl ester.

In the compound III, the ester and the carboxyl group may be present on the same side of the plane formed by the cyclopropane ring, or may be present on different sides.

In compound III, a halogen atom is simultaneously bonded to the carbon atom to which the ester is bonded.
Examples of the halogen atom include a chlorine atom and a bromine atom, but a chlorine atom is preferable.

The compound III may be an inorganic salt or an organic salt. Examples of the inorganic salt include salts with alkali metal atoms or alkaline earth metal atoms such as lithium, sodium, potassium, magnesium, calcium and barium. Examples of the organic salt include trialkylamines, N-alkyl cyclic amines such as N-methylpiperidine, and saturated, partially saturated or aromatic compounds such as N-methylmorpholine and 4-dimethylaminopyridine. Heterocyclic compounds and salts with aromatic compounds such as dialkylanilines can be mentioned.

Compound III or a salt thereof may be anhydrous, but may be hydrate or solvate.

When this compound III is treated with gaseous fluorine gas, decarboxylation of the carboxyl group and fluorination of the carbon atom to which the carboxyl group is bound simultaneously proceed to give 2-fluoro-1-halogenocyclopropanecarboxylic acid. The acid ester can be easily obtained.

[0058]

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

Example 1. Methyl 2-tertiary butoxyl
Bonyl-1-chloro-1-cyclopropanecarboxylate
(Compound I; R ¹ = Me, X = Cl) 60% Sodium hydride (80 g ) was suspended in N, N-dimethylformamide (1000 ml), and 352 ml of acrylic acid tert-butyl ester was cooled in 30 minutes. Dropped. Then, 207 ml of dichloroacetic acid methyl ester was added dropwise over 1.5 hours while maintaining the temperature of the reaction solution at 10 ° C. After completion of the dropping, the temperature of the reaction solution was maintained at 10 to 20 ° C. and stirring was continued for 2 hours. Concentrated hydrochloric acid was added to the reaction solution until it became neutral, and further water was added. The reaction solution was extracted with ethyl acetate, the organic layer was separated and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 384 g of the title compound as a colorless oily substance.

Boiling point: 96-105 ° C./1.0 mmHg ¹ H-NMR (CDCl ₃ ) δ: 1.44, 1.49 (9H, each s), 1.61 (3/5
H, dd, J = 6.8, 9.8 Hz), 1.88 (1H, d, J = 8.8 Hz),
2.10 (2 / 5H, dd, J = 6.3, 7.8 Hz), 2.37 (2 / 5H, dd, J =
7.8, 9.8 Hz), 2.60 (3 / 5H, dd, J = 8.8, 8.8 Hz), 3.7
8 and 3.81 (3H, each s).

Example 2. 2-Chloro-2-methoxycarboni
Ru-1-cyclopropanecarboxylic acid (compound III; R ² = Me,
X = Cl) 158 g of the compound obtained in Example 1 was added to 350 ml of dichloromethane.
Dissolve in, add 160 ml of trifluoroacetic acid and add at room temperature for 6
Stir for hours. The reaction solution was concentrated under reduced pressure, and n-hexane was added to the residue. The resulting crystals were collected and washed with n-hexane,
116 g of the title compound were obtained as colorless crystals.

Melting point: 77.7-79.1 ° C. ¹ H-NMR (CDCl ₃ ) δ: 1.76 (2 / 5H, dd, J = 6.8, 9.8 Hz),
1.95 (3 / 5H, dd, J = 6.3, 7.8 Hz), 2.01 (3 / 5H, dd, J =
5.8, 9.4 Hz), 2.20 (2 / 5H, dd, J = 6.8, 7.8 Hz), 2.4
7 (2 / 5H, dd, J = 7.8, 9.8 Hz), 2.72 (3 / 5H, dd, J =
7.8, 9.3 Hz), 3.79 and 3.83 (3H, each s).

Example 3. Ethyl 2-tertiary butoxyl
Bonyl-1-chloro-1-cyclopropanecarboxylate
(Compound I; R ¹ = Et, X = Cl) 60% Sodium hydride (80 g ) was suspended in N, N-dimethylformamide (1000 ml), and 352 ml of acrylic acid tert-butyl ester was cooled in 30 minutes. Dropped. Then, 314 g of dichloroacetic acid ethyl ester was added dropwise over 1.2 hours while maintaining the temperature of the reaction solution at 10 ° C or lower. After completion of dropping, the temperature of the reaction solution was kept at 10 ° C or lower and stirring was continued for 5 hours. 1N Hydrochloric acid was added to the reaction solution until it became neutral, and water was further added. The reaction solution was extracted with ethyl acetate, and the organic layer was separated and washed with saturated brine. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give the title compound (379 g) as a colorless oil.

Boiling point: 103-106 ° C./0.3 mmHg ¹ H-NMR (CDCl ₃ ) δ: 1.30, 1.32 (3H, each t, J = 7 Hz),
1.44 and 1.49 (9H, each s), 1.60 (2 / 3H, dd, J = 6.3,
9.8 Hz), 1.87 (1H, d, J = 8.8 Hz), 2.09 (1 / 3H, dd, J
= 6.3, 7.8 Hz), 2.35 (1 / 3H, dd, J = 6.3, 7.8 Hz),
2.59 (2 / 3H, dd, J = 8.8, 8.8 Hz), 4.22-4.27 (2H,
m).

Example 4. 2-Chloro-2-ethoxycarbonyl
Ru-1-cyclopropanecarboxylic acid (compound III; R ² = Et,
X = Cl) 379 g of the compound obtained in Example 3 and 235 m of trifluoroacetic acid
l was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to obtain 288 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ ) δ: 1.28 and 1.33 (3H, eac
ht, J = 7 Hz), 1.76 (1 / 3H, dd, J = 7.8, 9.8 Hz), 1.9
7, 1.99 (4 / 3H, each dd, J = 7.8, 5.8 Hz), 2.19 (1 / 3H,
dd, J = 6.3, 7.8 Hz), 2.47 (1 / 3H, dd, J = 7.4, 9.8
Hz), 2.71 (2 / 3H, dd, J = 7.8, 9.3 Hz), 4.23-4.28
(2H, m).

Example 5. 2-Chloro-2-methoxycarboni
Ru-1-cyclopropanecarboxylic acid (compound III; R ² = Me,
X = Cl) 1830 ml of acetic acid and hydrochloric acid were added to 394 g of the compound obtained in Example 1.
170 ml was added and it stirred at 45 degreeC for 3 hours. The reaction solution was concentrated under reduced pressure, and n-hexane was added to the residue. The formed crystals were collected and washed with n-hexane to give the title compound as a colorless crystal.
got g. Melting point: 77.7-79.1 ° C

Example 6. Methyl 2-tertiary butoxyl
Bonyl-1-bromo-1-cyclopropanecarboxylate
(Compound I; R ¹ = Me, X = Br) 38 ml of tert-butyl acrylate and 20.12 g of methyl dibromoacetate were added to N, N-dimethylformamide.
Dissolve in 100 ml and cool with ice to 60% sodium hydride 3.8
g was suspended in 100 ml of N, N-dimethylformamide and added little by little. After adding sodium hydride, the mixture was further stirred for 1 hour. Pour the reaction mixture into 150 ml of ice water and add ether 1
It was extracted 3 times with 50 ml. The ether layer is saturated saline solution 200 m
The extract was washed 3 times with l, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 19 g of the title compound as a brown oily substance.

¹ H-NMR (CDCl ₃ ) δ: 1.44, 1.50 (9H, each
s), 1.61 (1 / 3H, dd, J = 6.8, 9.3 Hz), 1.85 (1 / 3H, d
d, J = 5.9, 8.3 Hz), 1.91 (1 / 3H, dd, J = 5.9, 9.3 H
z), 2.08 (2 / 3H, dd, J = 7.8, 7.8 Hz), 2.36 (2 / 3H, dd,
J = 7.8, 9.3 Hz), 2.52 (1 / 3H, dd, J = 8.3, 9.3 Hz),
3.76 and 3.80 (3H, each s).

Example 7. 2-Bromo-2-methoxycarboni
Ru-1-cyclopropanecarboxylic acid (compound III; R ² = Me,
(X = Br) 4 g of the compound obtained in Example 6 was dissolved in 40 ml of dichloromethane, 11.2 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (3.0 g) as a brown oil.

¹ H-NMR (CDCl ₃ ) δ: 1.77 (2 / 3H, dd, J = 9.
8, 6.8 Hz), 1.92 (1 / 3H, dd, J = 6.3, 7.8 Hz), 2.04 (1
/ 3H, dd, J = 9.8, 5.9 Hz), 2.18 (2 / 3H, dd, J = 7.8,
7.8 Hz), 2.46 (2 / 3H, dd, J = 7.3, 9.8 Hz), 2.64 (1/3
H, dd, J = 9.8, 7.8 Hz), 3.77 and 3.81 (3H, each s).

Example 8. Ethyl 2-tertiary butoxyl
Bonyl-1-chloro-1-cyclopropanecarboxylate
(Compound I; R ¹ = Et, X = Cl) Acrylic acid tertiary butyl ester 70.3 ml and dichloroacetic acid ethyl ester 62.8 g are dissolved in N, N-dimethylformamide 200 ml, and potassium carbonate 55.3 g is added thereto. The mixture was stirred at 100 ° C. for 20 hours. 200 ml of ethyl acetate was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Ethyl acetate (300 ml) was added to the residue, and the mixture was washed with 200 ml of water twice and further washed with 1N hydrochloric acid. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was distilled under reduced pressure to give a colorless oil with a boiling point of 106-115 ° C / 3mmHg.
9.3 mg was obtained.

Example 9. 2-tertiary butoxycarbonyl
-1-Chloro-1-cyclopropanecarboxylic acid methyl ester
(Compound I; R ¹ = Me, X = Cl) Acrylic acid tertiary butyl ester 70.3 ml and dichloroacetic acid methyl ester 41.4 ml were dissolved in N, N-dimethylformamide 200 ml, and potassium carbonate 55.3 g and triethylbenzyl were dissolved. 5.0 g of ammonium chloride was added, and the mixture was stirred at room temperature for 20 hours, at 50 ° C. for 2 hours, and further at room temperature for 30 hours. Then, it heated at 50 degreeC, 11.0 g of potassium carbonate was added, and it stirred at the same temperature for 16 hours. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was distilled under reduced pressure to obtain 73.04 g of the title compound as a colorless oily substance. Boiling point: 98-102 ℃ / 3mm
Hg

Example 10. Dichloroacetic acid tertiary butyl ester
Diethyl ether ester dichloroacetyl chloride 227 g 1
A solution prepared by dissolving 137 g of tertiary butanol and 146.2 g of pyridine in 850 ml of diethyl ether was added dropwise under ice cooling, and the mixture was stirred at room temperature for 4 hours.

To the reaction solution was added 1N hydrochloric acid (500 ml) and the mixture was stirred for 30 minutes. After separating the organic layer, the organic layer was washed with 1N hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and water, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, 271 g of the title compound was obtained as an oil.

¹ H-NMR (90 MHz, CDCl ₃ ) δ: 1.53 (9 H, s),
5.85 (1H, s).

Example 11. 1-chloro-2-methoxycarbo
Nyl-1-cyclopropanecarboxylic acid tertiary butyl ester
(Compound II; R ¹ = Me, X = Cl) Dichloroacetic acid tert-butyl ester 55.5 g and methyl acrylate 25.8 g dimethylformamide 160 ml
Was dissolved in water, and 49.8 g of potassium carbonate and 3.41 g of triethylbenzylammonium chloride were added thereto at 50 ° C., and the mixture was stirred at the same temperature for 24 hours.

320 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with water, 1N hydrochloric acid and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was distilled under reduced pressure to give the title compound as an oil (56.6 g). This was analyzed by gas chromatography and was found to be a mixture of cis and trans isomers in a ratio of 2.6: 1 (here, both ester residues in the cis isomer are the same with respect to the plane of cyclopropane). I mean what is on the side.).

¹ H-NMR (90 MHz, CDCl ₃ ) cis δ: 1.50 (9H, s), 1.90 (2H, d, J = 7.2 Hz), 2.
66 (1H, t, J = 7.2 Hz), 3.80 (3H, s). Transformer body δ: 1.48 (9H, s), 1.56-2.44 (3H, m), 3.7
3 (3H, s). Boiling point: 99-102 ℃ / 1 mmHg (mixture of cis and trans)

Example 12. 2-tertiary butoxycarbonyl
-2-Chloro-1-cyclopropanecarboxylic acid (Compound II
I; R ² = ^t Bu, X = Cl) 1-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid tert-butyl ester 46.9 g in methanol 3
Dissolve in 00 ml, 16% aqueous sodium hydroxide solution (w / v)
60 ml was added at 0 ° C., and the mixture was stirred at the same temperature for 1 hour and further at room temperature for 2 hours.

The solvent was distilled off under reduced pressure and the resulting residue was treated with water 3
00 ml was added and washed with methylene chloride. Concentrated hydrochloric acid was added to the aqueous layer to adjust the pH to 1, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 41 g of the title compound as a semi-crystalline substance. As a result of analysis by HPLC, this was a mixture having a ratio of cis isomer to trans isomer of 2.6: 1. The semi-crystalline substance was washed with hexane to obtain a cis-form as white crystals.

¹ H-NMR (90 MHz, CDCl ₃ ) cis δ: 1.50 (9H, s), 1.90 (2H, d, J = 7.2 Hz), 2.
66 (1H, t, J = 7.2 Hz), 9.05 (1H, br-s). Transformer body δ: 1.46 (9H, s), 1.60-2.44 (3H, m), 9.5
0 (1H, br-s). Melting point: 127-130 ℃ (cis form)

Example 13 Cis-2-tertiary butoxyl
Bonyl-2-chloro-1-cyclopropanecarboxylic acid potassium
Salt 1-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid tertiary butyl ester 205.8 g in methanol 1
Dissolved in 300 ml, 26% aqueous sodium hydroxide solution (w / v)
220 ml was added so that the reaction temperature did not exceed 30 ° C., and then the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the obtained residue was washed with acetic acid ester, and the solid matter was collected by filtration. The collected solid matter was dried under reduced pressure to obtain 48.5 g of the title compound as white crystals.

¹ H-NMR (90 MHz, D ₂ O; DOH contained in heavy water
The proton peak of is set to 4.80 ppm. ) Δ: 1.52 (9
H, s), 1.60-2.00 (2H, m), 2.66 (1H, t, J = 7.2 H
z). Melting point: 193-196 ° C (decomposition)

Front Page Continuation (72) Inventor Koji Sato 1-16-13 Kita Kasai, Edogawa-ku, Tokyo Daiichi Pharmaceutical Co., Ltd. Tokyo Research and Development Center

Claims (11)

[Claims] 1. Formula I Or Formula II (Wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms which does not become a tertiary butyl group, and X represents a chlorine atom or a bromine atom). 2. Formula III: (In the formula, R ² means an alkyl group having 1 to 6 carbon atoms,
X means a chlorine atom or a bromine atom. ) Or a salt thereof 3. A compound represented by the formula IV: CH ₂ ═CH—COO ^t Bu IV and a compound of the formula V: X ₂ CHCOOR ¹ V (wherein R ¹ is a tertiary butyl group) Which means an alkyl group having 1 to 6 carbon atoms, and X represents a chlorine atom or a bromine atom.), A compound represented by the formula I ] (Wherein R ¹ and X are the same as defined above) 4. A compound represented by the formula VI: CH ₂ ═CH—COOR ¹ VI (wherein R ¹ represents an alkyl group having 1 to 6 carbon atoms which does not become a tertiary butyl group). And a compound represented by the formula V: X ₂ CHCOO ^t Bu VII (X represents a chlorine atom or a bromine atom) under a basic condition. Chemical 9] (Wherein R ¹ and X are the same as defined above) 5. Formula I Or Formula II (In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms that does not become a tertiary butyl group, and X represents a chlorine atom or a bromine atom.) Formula characterized by selectively converting to a carboxyl group
III [Chemical 12] (In the formula, R ² means an alkyl group having 1 to 6 carbon atoms,
X means a chlorine atom or a bromine atom. ) The manufacturing method of the compound represented by 6. Methyl 2-tertiary butoxycarbonyl-1
-Chloro-1-cyclopropanecarboxylate 7. Ethyl 2-tertiary butoxycarbonyl-1
-Chloro-1-cyclopropanecarboxylate 8. 2-Chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid or a salt thereof 9. 2-Chloro-2-ethoxycarbonyl-1-cyclopropanecarboxylic acid or a salt thereof 10. Tertiary butyl 1-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylate 11. 2-Tertiary butoxycarbonyl-2-chloro-1-cyclopropanecarboxylic acid or a salt thereof