JPS6056936A - Production of optically active 2,2-dimethylcyclopropane carboxylic acid and its derivative - Google Patents

Abstract

PURPOSE:To provide the titled substance, by the chromatographic treatment of a diastereomer mixture of the optically active N-methylephedrin ester of 2,2- dimethylcyclopropanecarboxylic acid, or by the fractional crystallization of its hydrochloride followed by hydrolysis. CONSTITUTION:A diastereomer mixture of the compound of formula I is optically resolved by chromatography, or its hydrochloride is converted to uniform solution by heating at room temperature -80 deg.C in a solvent such as water, dilute hydrochloric acid salt, saline water, methanol, etc. The solution is cooled slowly to effect the fractional crystallization. The diastereomers separated by the above process are optionally hydrolyzed to obtain the compound of formula II(R is H or residue of optically active N-methylephedrin). USE:Intermediate of agricultural chemicals and pharmaceuticals.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid or its optically active N-methylephedrine ester.

More specifically, by chromatographically treating a diastereomer mixture of optically active N-methylephedrine ester of 2,2-dimethylcyclopropanecarboxylic acid represented by formula (1), or by fractionally crystallizing its hydrochloride. The diastereomers are separated into each diastereomer and further hydrolyzed if desired to form the compound of the general formula (2) [wherein, 几represents a hydrogen atom or an optically active R-methylephedrine residue]. ] The present invention relates to a method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid or its ester.

An object of the present invention is to provide a novel 2,2-dimethylcyclopropanecarboxylic acid visiting conductor and to efficiently obtain the carboxylic acid using the same.

2.2-Dimethylcyclopropanecarboxylic acid is an important compound as an agricultural and pharmaceutical intermediate. For example, esters of the carboxylic acid with alcohols such as substituted 2-cyclobentenon-4-ol or substituted furfuryl alcohol have low toxicity to humans and livestock, and are useful as fast-acting insecticides against pests. It is also used as a component of biodegrading enzyme inhibitors of di-β-lactam antibiotics called pyrethroid insecticides (Chemistry and Biology, Soil 1,204).
(1981)).

The use of optically active agents is often desirable for such applications.

The present invention provides a novel compound and a method for producing the same in order to advantageously produce such a useful optical isomer of 2,2-dimethylcyclopropanecarboxylic acid.

2, 2-dimethylcyclopropanecarboxylic acid is synthesized as a racemate, that is, a (±) form, in the usual synthesis method, so in order to obtain the desired optical isomer, an optically active organic base moiety is used to further synthesize the optically active base. It had to be split.

Conventionally, as a method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid, a method of optically resolving Q-2,2-dimethylcyclopropanecarboxylic acid has been known. Kaisho 55-510
28), 2) resolution with d- or l-α-phenethylamine (UK Patent No. 1,260,847).

However, the former method requires the use of quinine, which is extremely expensive as a resolving agent and whose supply is unstable, and the yield is also low. There is a problem that only Ti-t or L!-2,2-dimethylcyclopropanecarboxylic acid can be obtained with low optical purity of +65" and -72°, and both of these methods have optical purity. Highly pure d- or l! It cannot be said that this is an industrially advantageous method for obtaining -2,2-dimethylcyclopropanecarboxylic acid.

Under such circumstances, the present inventors discovered that optically active 2,2-dimethylcyclopropanecarboxylic acid can be efficiently produced from the novel compound represented by the above formula (1),
The present invention was completed after further various studies.

Tttb62.2-dimethylcyclopropanecarboxylic acid dz or a mixture of d and j in any proportion and d or j
Esters with -N-methylephedrine can be separated into diastereomers by chromatography or fractional crystallization as hydrochloride; It has been discovered that fractional crystallization of mer can be carried out very conveniently.

From the thus obtained N-methylephedrine ester of one of the optically active carboxylic acids, optically active 2,2-dimethylcyclopropanecarboxylic acid can be obtained in high purity by hydrolysis in a steric retention manner. Furthermore, since the carboxylic acid moiety of the remaining enantiomer ester can be racemized if desired, by repeating this process, it is possible to efficiently produce one optically active 2,2-dimethylcyclopropanecarboxylic acid. It has become.

The method of the present invention will be explained in detail below.

Oka, the symbol d-1/- used here represents the optical isomerism of the acid or alcohol constituting the ester, and does not represent the optical isomerism of the ester.

The carboxylic acid derivative represented by the formula (1) is produced, for example, as follows. That is, N-methylephedrine ester of 2,2-dimethylcyclopropanecarboxylic acid can be synthesized by reacting the acid halide or acid anhydride of the carboxylic acid with l or dN-methylephedrine.

The carboxylic acid halide comprises the carboxylic acid and thionyl chloride,
By reacting sulfuryl chloride, oxalyl chloride, phosgene or phosphorus chloride, etc., acid chloride is produced.
Alternatively, it can be obtained as acid bromide by reacting phosphorus bromide, thionyl bromide, etc.

Further, the carboxylic acid anhydride can be obtained by reacting the carboxylic acid with acetic anhydride, acetyl chloride, or the like. The acid halogenating agent or dehydrating agent used here is used in an amount of 1^4 mol based on the carboxylic acid anhydride as the raw material.
It can be carried out at a temperature of °C. The solvent at this time is saturated hydrocarbons such as pentane, hexane, heptane, etc.
Those that do not participate in the reaction can be used, such as aromatic hydrocarbons such as benzene and halogenated hydrocarbons such as dichloromethane.

As for 2.2-dimethylcyclopropanecarboxylic acid, a mixture of dj-form, d-form, or 1-form in any proportion can be used.

The resulting acid halide or acid anhydride is reacted with d or/-N-methylephedrine at a temperature of -20°C to 0°C to synthesize a diastereomeric ester. As the solvent, the same solvents as mentioned above, ie, those that do not participate in the reaction, such as saturated hydrocarbons, aromatic hydrocarbons, and halogenated hydrocarbons, can be used. If necessary, an organic base such as pyridine or triethylamine is used as a deoxidizing agent. In this case, when the acid anhydride synthesized from the racemic form of the carboxylic acid is esterified by reacting with optically active N-methylephedrine, one of the diastereomers is preferentially obtained.

The optically active N-methylephedrine used in esterification can be used in either the d-form or the d-form, and the optical purity of the carboxylic acid and its derivatives obtained after resolution is influenced by its optical purity.

The basic diastereomer ester mixture obtained by esterification can be optically resolved as it is by chromatography, etc., but fractional crystallization can be conveniently performed by forming the mineral acid salt, especially the hydrochloride. Become.

In this case, generally, from the salt of J-N-methylephedrine ester, a diastereomeric salt of d-carboxylic acid crystallizes, and from the salt of d-N-methylephedrine ester, one diastereomeric salt of carboxylic acid crystallizes. Stereomer salts crystallize. In other words, each mother liquor will yield a diastereomer of its opposite carboxylic acid.

Examples of solvents used in fractional crystallization include water, diluted hydrochloric acid, saline, alcohols such as methanol, ethanol, and isopropanol, and mixed solvents thereof. Using these solvents, a mixture of diastereomeric salts is heated to a carrier temperature to 80° C. to form a homogeneous solution, and then slowly cooled to precipitate crystals. At this time, seed crystals may be used or natural crystallization may be used. Care must be taken as increasing the heating temperature for dissolution will cause hydrolysis of the ester. The lower limit of the cooling temperature varies depending on the type of solvent used and the conditions, but it is usually -20° C. or higher from the viewpoint of practical operability, and if possible, it is desirable to select conditions so that crystals can be sufficiently precipitated at around room temperature. If necessary, the obtained crystals can be purified by repeated recrystallization. The salt thus obtained can be converted into the free 111 base by a conventional method, if desired.

The optically active carboxylic acid ester or salt thereof obtained as described above is hydrolyzed under basic or acidic conditions as desired, and the d-2,2-
3 carboxylic acid or l-2 in dimethylcyclopropane E
, 2-dimethylcyclopropane gives true carboxylic acid.

The base used when hydrolyzing under basic conditions is a base that is commonly used when hydrolyzing carboxylic acid esters such as caustic soda and caustic potash, and the amount thereof is 1 to 4 per mole of ester. It is a mole. The reaction temperature is about 50° C. and the reaction is carried out under reflux conditions. The reaction time is related to the reaction conditions, but usually 0.6 hours to 10 hours is sufficient. As the solvent, in addition to water, a mixed medium of water and an organic solvent such as methanol or ethanol may be used, and a surfactant may also be used.

After the reaction, the optically active N-methylephedrine was collected, and the aqueous layer was acidified and extracted, and the fluorine retained its vitality.
Carfonic acid can be obtained with 2-dimethylcycloprono.

Furthermore, it is possible to obtain a corresponding optically active carbonic acid derivative from the mother liquor containing the N-methylefedrin ester of the carboxylic acid that was not crystallized in the above-mentioned fractional crystallization process. ! There's no point in that. If desired, only the carboxylic acid moiety can be selectively racemized by the following method after the acid is neutralized and eliminated using Alsica 9 batches.

That is, by treating the N-methylephedrine ester of the carboxylic acid with an alkali metal or its hydride, a dispersion thereof, or an alkali metal alconate, the carboxylic acid moiety can be efficiently removed without side reactions. Can only be racemized. To explain further, the racemization method is based on lithium,
The carboxylic acid ester is converted to shrimp using an alkali metal such as sodium or potassium, or an alloy of two or more alkali metals such as sodium-potassium as a catalyst. In this case, a method for producing a so-called alkali metal dispersion in which the alkali metal is made into fine particles in a medium is known.
By using as a dispersion medium an alkali metal dispersed in toluene, xylene, petrolatum, naphthalene, anthracene, mineral oil, etc., or supported on a porous carrier such as alumina, silica gel, activated carbon, etc. The reaction proceeds more smoothly. Furthermore, in the method of the present invention, an alkali metal hydride such as lithium hydride, sodium hydride, potassium hydride, etc. can be used as a catalyst. The alkali metal hydride can be used in any form, but it can be more effective if it is used in the form of fine powder. Although alkali metal hydrides dispersed in mineral oil have been put to practical use, the reaction can be carried out satisfactorily without removing such dispersants.

Examples of alkali metal alcoholides include sodium methylate, sodium ethylate, and potassium te.
rt-butilade et al.

The amount of catalyst required varies depending on the optical isomer ratio of the raw materials and the reaction conditions, but it is preferably in the ester to be treated.
- to 100 5 .

A solvent is not particularly required, but if used, a solvent that does not inhibit the racemization reaction is selected. Such solvents include saturated hydrocarbons, aromatic hydrocarbons, and ethers. A mixed solvent of these can also be used.

This reaction can be carried out regardless of external pressure, and the reaction proceeds under either normal pressure or increased pressure. In order to exclude moisture from the reaction system, the reaction is preferably carried out under an inert gas atmosphere such as nitrogen or argon.The reaction temperature is usually 20°C to 200°C, preferably 50°C.
-170°C.

Although the reaction time varies depending on the reaction conditions such as the amount of catalyst and heating temperature, the objective can usually be achieved within several minutes to several tens of hours. The racemic ester of the carboxylic acid thus obtained can be subjected to the above-described separation purification to obtain the desired optically active 2,2-dimethylcyclobrobancarboxylic acid derivative.

As detailed above, the method of the present invention provides an extremely advantageous industrial method for producing 2,2-dimethylcyclopropanecarboxylic acid and its derivatives.

Next, the present invention will be explained in detail by way of examples.

Reference Example 1 In a 100-ml flask, 20.01 dJ-2,2-dimethylcyclopropanecarboxylic acid and 20.01 11-hexane were added.
f/-dimethylfor, Muami 1:0.1? Add 70
Heat to ℃ and add thionyl chloride from the dropping funnel without stirring.
A combined solution of 1.85'- and n-hexane 20.05' was added dropwise. After stirring at the same temperature for 8 hours, the reaction solution was distilled off under reduced pressure, and the residual solution was distilled to give a bp of 58-60°C.
7408 sokute 22. IP dl-2,2-dimethylcyclopropanecarboxylic acid chloride (stilled).

5.9F of z-N-methylephedrine and 25% of methylene chloride in a 100tRt flask. 4.4 tons of liquid and 5 tons of methylene chloride were added to the top of the dropping funnel while stirring under ice-cooling. A slurry mixture was added dropwise. After stirring at the same temperature for 1 hour, the mixture was kept at room temperature overnight.

After the reaction, a 1.5-sodium hydroxide aqueous solution was added to the reaction solution, extracted and separated twice, and the organic layer was washed with water and concentrated.
．． A residual liquid of 9SL was obtained.

When the residual liquid is distilled, bp t t 5-121℃10.
8.7t of dJ-2,2-dimethylcyclopropanecarboxylic acid/-N-methylephedrine ester was obtained in 4 HP.

This one has an optical rotation [α]δ'-48.7° (C=1.0
ethanol), and the infrared absorption spectrum and nuclear magnetic resonance spectrum were as follows.

Infrared absorption spectrum (liquid film law countries) 1720
．． 1600.1265.1160'■-Nuclear magnetic resonance spectrum (dJ-2,2-dimethylcyclopropanecarboxylic acid-1-N-methylephedrine ester, 90 M
Hz.

0 DOIs) (,1f13.

δ(PPm) Number of hydrogens Scutt Coupling constant Assignment 2.
91HmO-s 1.6 1ft m C-1 1,218H,y2 s 0-a511%1.17 8
Hs C-s or + 1.07 8Hd Js-7=6.8tlz C-71
,068H72g (3-s Nu is 61O,852Lim
O-3 Reference example 2 d! ! -2+2-dimethylcyclopropanecarboxylic acid chloride 4.4? and d-,N-methylephedrine5.
9? dj'- of 8.81 by reacting in the same manner as in Reference Example 1.
2,2-dimethylcyclopro,pancarboxylic acid-dN
-Methyl ephedrine ester was obtained.

This one has an optical rotation [α]Δ'+48.4° (c=l, Q
ethanol], and the infrared absorption spectrum (liquid film method) was consistent with Reference Example 1.

In addition, nuclear magnetic resonance spectrum ('H-NMR).

9OMHz% cpcza) was consistent with Reference Example 1 except for the assignment of optical isomers.

Example 1 d/-2,2-dimethylcyclopropanecarboxylic acid-1-N-methylephedrine ester obtained in Reference Example 14.
After adding 5.911 liters of 10% hydrochloric acid to 4P and stirring at 60°C, the mixture was gradually cooled and kept at 20°C, and the precipitated crystals were harvested. When I dried this thing, it was 2.0? Met.

A portion of the sample was converted into a free basic diastereomer ester, and the optical isomer ratio was analyzed using gas chromatography, resulting in 6 esters: 1! Body (contains 222-dimethylcyclopropanecarboxylic acid moiety. The same applies hereinafter) =
The ratio was 97.5:2.5, and when the liquid was analyzed in the same manner, it was found that the 21 d-isomers were 18.6:81.4. When this crystal was recrystallized from water, 6 bodies: j body = 99.
9:0. Crystals with an optical isomer ratio of 1 were obtained.

The melting point of this product was mp 240-242°C (decomposed), and the optical rotation was H[a]7' + 18.8° (C=1.08, water).

Example 2 1.5% aqueous sodium hydroxide solution was added to 1.4v of d-2,2-dimethylcyclopropanecarboxylic acid-/-N-methylephedrine ester hydrochloride obtained in Example 1 to make it basic and chloride. Methylene was added for extraction, and the 1° filter layer was washed with water, dried with anhydrous sodium sulfate, and concentrated.
A residual liquid of 251' was obtained. When this product is distilled on a Kugelrohr, taO~185℃10. Is it parrot? 1.2t
d-2,2-dimethylcyclopropanecarboxylic acid-/
-N-methylephedrine ester was obtained as a distillate. This also 3 (7) + 7) Optical rotation j, t Ca11D-14,62°
(near), and the infrared absorption spectrum matched that of Reference Example 1.

The nuclear magnetic resonance spectrum is shown below.

d-2,2-dimethylcyclopropanecarboxylic acid-/-
N-methylephedrine ester'H-N M R (9
0MHz, CDCl! 3) δ (ppm) Number of hydrogen Scut Coupling constant Assignment 7.27 5Hs (3-s(
(3sHs) 5.95 In d +4-s=4.6H
z 0-a2.86 1Hm J 5-7=6,8 C
=s2.81 611 s 0-s l, 17 8Hs 0-s l, 07 8Hd +7-s=6.8 0-71.06
9n s C-5 O,852Hm +3-Btrans)=B0gHz(
3-3Ja-31 = 4.9Hz d-2,2-dimethylcycloprobanca, IL, 4(
nitric acid/-N-methylephedrine ester a δ (ppm) Scatting Attribution 171.9sO-1 140,6s 0-t2 128.1 d O,-1a, ta127.4 d
C-15 126,1d 1j-ta, 17 75, Od C-7 619d (3-8 41,4q 0-1o, 1t 27, 1 d, q C-2i 0-a or has28.
8s c-a 22,1 L C-4 18,8q C-9 or 5 or 6 9.6QO-s or 6 or 9 Example 8 Flasking of 50- d-2,2- obtained in Example 2 Dimethylcyclopropanecarboxylic acid 1-N-methylephedrine ester 1. l? To the mixture was added aqueous sodium hydroxide solution 1.2), and the mixture was stirred under reflux for 2 hours.

After the reaction, the solvent was distilled off under reduced pressure, water was added to the residual solution, chloride was added, and neutral substances were extracted with methylene. The aqueous layer was acidified with hydrochloric acid, extracted with methylene chloride, and the organic layer was washed with water and dried by adding anhydrous sodium sulfate. After removing the sodium sulfate, the solvent was distilled off under reduced pressure to obtain a residual liquid (0.5). When this material is distilled using a Ku Φ gel roll, it becomes 140-150'C/20
A distillate of may 0.459- was obtained. This substance was determined by gas chromatography and infrared absorption spectrum.
It was confirmed that it was -2,2-dimethylcyclopropanecarboxylic acid, and its optical isomer ratio was d/J:99.
510.5, optical rotation [α) 75 + 181.2° (0-
2,064, EtoH), flj81.4854 T::.

The neutral extract was washed with water and concentrated to obtain colorless crystals of 0.7 SL. This product was confirmed to be /-N-methylephedrine by gas chromatography and infrared absorption spectrum.

Example 4 A 20% aqueous sodium hydroxide solution obtained in Example 1 was added to the mixture to pH 11 or higher, and the mixture was extracted three times with toluene. The organic layer was washed with saturated brine and dried by adding anhydrous sodium sulfate.

After removing the sodium sulfate, the solvent was distilled off under reduced pressure to leave a residual liquid of 2.7 mm. I got it. This substance consists of 18.6 d-isomers and 81.4-j-isomers by gas chromatography.
It was confirmed that it was rich 2 + 2-cy/tylcyclopropanecarboxylic acid/-N-methylephedrine ester.

In a 25 m flask in a nitrogen stream, add 2.5 ml of the above residual solution, 0.0 ml of potassium and 0.0 ml of butyralate. IP was added and stirred for 1 hour in a 120°C oil bath. After the reaction, toluene was added, washed with water, and concentrated to obtain a 2.4 P residual liquid. When the residual liquid is distilled, it has a pH of 5 to 121°C, 10.4 Fuji H? So 2.859-
A distillate was obtained.

This one was found by Cass chromatography to have 4 bodies, 48.5
It was confirmed that the product was dj-2,2-dimethylcyclopropanecarboxylic acid 1-N-methylephedrine ester consisting of 51.5 units.

Example 5 dj-2,2-dimethylcyclopropanecarboxylic acid-dN-methylephedrine ester obtained in Reference Example 28.
10.6 tons of 10% hydrochloric acid water was added to 0P and treated in the same manner as in Example 1 to obtain 8.5? A dry cake was obtained. The optical isomer ratio of this is 1 body = d body = 97.0:8.0,
When the furnace liquid was analyzed in the same manner, 1 body = d body = 21.
It was 0 near 9.0. Similarly, when recrystallized from water, the optical isomer ratio of 1 body = d body = 100:0 is j-2,2.
-Dimethylcyclopropanecarboxylic acid-dN-methylephedrine ester hydrochloride crystals were obtained.

The optical rotation of this object is [α)I, -18,58° (c=
1.02, Wednesday).

Example 6 I! obtained in Example 5! -2,2-Dimethylcyclopropanecarboxylic acid-dN-methylephedrine ester hydrochloride (2.81 g) was treated in the same manner as in Example 2 to obtain 2.6 P of concentrated residual liquid.

When this substance is distilled, the boiling point is 91-102℃10, l
m, Ef to obtain 2.4P j-2,2-dimethylcyclopropanecarphonic acid-d-N-methylephedrine ester as a distillate 1:, this also (7) 0) The optical rotation is [α ] n + 14-48° (near, and the infrared absorption spectrum was -e with Reference Example 1.Nuclear magnetic resonance spectrum ("[1-NMR.

g g MBz , CDCLS ) c Consistent with Example 2.

Example 5 I! obtained in Example 6 was placed in a 50-ml flask. -2゜2-dimethylcyclopropanecarbon[-dN-methylephedrine ester 2.21 methanol 2.1', 20!
Example 8 Adding 2.89FF of sodium hydroxide aqueous solution
It was treated in the same manner as above to obtain a concentrated residual liquid of 0.9y-. Distill this in a Ku [F] gel roll and get 185~b Parrot HP 0.9? A distillate was obtained.

This one is based on Cass chromatography and infrared absorption spectrum! -2,2-dimethylcyclopropanecarboxylic acid was confirmed, and its optical isomer ratio was d/
l! = 0/100 and the optical rotation [α] is also 7-181.2
° (0=1.995, EtoH), n261.487
It was 0.

In addition, the neutral extract was treated in the same manner as in Example 8. Colorless crystals were obtained. This product was confirmed to be dN-methylephedrine by gas chromatography and infrared absorption spectrum.

Claims (3)

[Claims] By chromatographically treating the diastereomer mixture of optically active N-methylephedrine ester of 2,2-dimethylcyclopropanecarboxylic acid represented by the formula (1), or by fractionally crystallizing its hydrochloride, each diastereomer [In the formula, 1. ] Optical activity 2.2-
Process for producing dimethylcyclopropanecarboxylic acid or its ester. (2) The method according to claim 1, wherein the method for separating the diastereomer mixture into each diastereomer is a method of fractional crystallization of the hydrochloride. (3) A diastereomeric mixture of optically active N-methylephedrine ester of 2,2-dimethylcyclopropanecarboxylic acid represented by the formula is fractionated and crystallized as a hydrochloride, and one diastereomeric hydrochloride is separated by fractionation. Then, the remaining diastereomeric hydrochloride is neutralized to form a basic ester, and the carboxylic acid moiety of the basic ester is further neutralized with ξ and a base selected from alkali metal alcoholades, alkali metals, or alkali metal hydrides. The obtained diastereomer mixture of optically active N-methylephedrine ester of 2,2-dimethylcyclopropanecarboxylic acid is separated into each diastereomer by fractional crystallization treatment again as a hydrochloride, and if desired, further A general formula characterized by hydrolysis [wherein R represents a hydrogen atom or an optically active N-methylephedrine residue]. ] A method for producing optically active 2,2-dimethylcyclopropanecarboxylic acid or its ester shown by