KR850000470B1 - Process for preparing azetidine derivatives - Google Patents

Abstract

Azetidines I [X = CH2, CHR, CR2(R = halo, alkyl, alkoxy); Y = CHR, CR2, CH CO2H; Z = CH2, CHR, CR2, CH CO2H were prepd. Thus, 4-methyl- 2-tetrahydrofuranone was brominated and treated with PhCH2OH to give BrCH2CHMeCHBrCo2H, which was treated with Ph2CHNH2 followed by hydrogenolysis, to give 3-methyl-2-carboxyazetidine derivatives. At 1000 ppm azetidine derivs. gave 69% inhibition of grain set in wheat.

Description

Method for preparing azetidine derivative

The present invention relates to a male anther infertility method of plants and F ₁ hybrid seeds made by this method, compositions and compounds used in this method, and methods for producing the same. In order to obtain F ₁ hybrid seeds, which have several advantages over non-hybrid seeds, breeders must carefully warn selected mother plants for other pollination. In the case of plants such as small grain plants, having positive flowers usually produces self-pollination. For these plants, F ₁ hybrid seeds are obtained by removing male anther from each flower by hand, and this method takes a lot of time. It takes a lot of skill and requires a high level of skill. In order to obtain the same result, various researches have been conducted on the treatment with chemicals.

In the method according to the present invention, a method of sterilizing male anther of a plant, that is, an azetidine derivative such as an acid or a salt or ester thereof, an amide, an alkylamide, a hydrazide or an alkyl hydrazide, of general formula (I) is applied to the plant. To add.

In the above formula, X is CH ₂ , CHR or CR ₂ , Y is CHR, CR ₂ or CHCO ₂ H, Z is CH ₂ , CHR, CR ₂ or CHCO ₂ H R is an aralkyl group or aryl group, cycloalkyl group, alkenyl group or alkyl group optionally substituted with one or more of the same or different substituents such as a halogen atom, an alkyl group or an alkoxy group, and only one of Y and Z is CHCO _It represents a 2H group. Each R is an alkenyl or alkyl group having up to 6 carbon atoms, in particular up to 4, a cycloalkyl group having 3-6 carbon atoms, or a benzyl group substituted with 1-2 identical or different substituents such as chlorine, fluorine or bromine atoms Or an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. In particular, each R is a methyl or ethyl group or a phenyl group substituted at 1-2 substitution temperatures of fluorine and chlorine atoms with methyl and methoxy groups. X is CH ₂ , Y is CHR or CHCO ₂ H, Z is CH ₂ or CHCO ₂ H and one of Y and Z is CHCO ₂ H.

Azetidine derivatives are, for example, free acids of general formula I, their alkali metal salts or hydrohalides, amides or hydrazides with C (1-4) alkyl, in particular amides or hydrazides, alkyls having 1-2 methyl groups Or alkyl esters or alkenyl esters or alkyl esters having 10 carbon atoms in the alkenyl group, in particular up to 7, or hydrohalides of such amide hydrazides or esters.

The azetidine derivative is preferably a free acid of Formula I, an alkali metal salt or hydrohalide thereof, a C (1-10) alkyl ester thereof or a hydrohalide of this hydrazide or ester.

Particularly suitable azetidine derivatives are 3-carboxy azetidine and 2-carboxy-3-methyl azetidine.

Azetidine derivatives exist in isomeric form according to the meaning of X, Y and Z. For example, 2-carboxy-3-methylazetidine exists as geometric isomers depending on the relative positions of the carboxy and methyl groups, and moreover as optical isomers for each of these geometric isomers. As is usual in processes involving biological strains, some isomers are much more active in the methods of the present invention than other isomers.

According to the method of the present invention, male infertility can be caused without affecting female fertility. The method applies to cereal plants such as corn and sorghum, especially small grain plants such as wheat and barley, when the plant is in the stage between late powdering and discharge.

The proper dosage of the active compound is 0.05-2 kg / ha, in particular 0.25-1 kg / ha. According to the method according to the present invention, F ₁ hybrid seeds are produced, that is, the plants treated by the method according to the present invention are subjected to other pollination as secondary plants of different strains.

Azetidine derivatives are prepared in a pollen inhibiting composition and used appropriately in the process according to the invention. Therefore, according to the present invention, a pollen inhibiting composition is made of a compound prepared by adding a suitable carrier to the general formula (I) or salts thereof and esters, amides, alkylamides, hydrazides or alkylhydrazides.

Most azetidine derivatives are new. The present invention therefore relates to a novel azetidine derivative of an acid or a salt thereof and esters, amides, alkylamides, hydrazides or alkyl hydrazides of the formula (I) as defined above wherein Y is CHC ₂ H ₅ or CHCO ₂ H and X should be CHR or CR ₂ ). Suitable new azetidine derivatives are 3-methyl-2-carboxazetidine.

The method for producing a novel compound according to the present invention is any one of the following two methods.

(A) Y is CH.CO by removing the protecting group if necessary after hydrolysis or dialcoholization of the corresponding cyano compound in which the 1-nitrogen atom in the ring is substituted with A, a protecting group removed from the azetidine ring. To prepare azetidine derivatives of ₂ H, or ( _b ) in the presence of amines ANH ₂ , where A has the same meaning as described above, where General Hal is a chlorine atom or a bromine atom and X and Y Compound having a meaning assigned to an azetidine derivative)

Cyclization or general formula III (where Hal, X and Y have the same meanings as above)

Z is a CH.CO ₂ H group to prepare an azetidine derivative wherein Z is a CH · CO ₂ H group by cyclizing the ester of the compound of the compound of the azetidine ring, and any of the azetidine derivatives prepared by the method (A) or (B). In one case, when different azetidine derivatives are required, the prepared derivatives are converted to the desired derivatives.

The method (a) can be carried out by carrying out a known method of converting a cyano group to a carboxyl group or a derivative thereof. For example, hydrolysis can be carried out by treating an acidic or alkaline liquid with a cyano compound under gentle conditions to produce an azetidine derivative in the form of a free acid or salt thereof. Alcoholysis can be carried out by refluxing a cyano compound in alcohol in the presence of dry hydrogen chloride to produce an azetidine derivative in the form of an ester or hydrochloride thereof.

If protecting group A is present, it can be removed in a suitable way. Particularly useful protecting groups A are benzyl groups, in particular α-phenyl benzyl groups, which can be removed from the azetidine ring by reaction with a catalyst such as palladium hydroxide or palladium deposited on charcoal and gaseous hydrogen under suitable conditions.

Such cyano compounds are prepared by reacting a corresponding hydroxy compound with methylsulfonyl chloride to form a 3-methyl sulfonylazetidine homologue which is then treated with an alkali metal cyanide, such as sodium cyanide. The 3-hydroxy compound is prepared by reacting a halo epoxide with a primary amine. In the method of (b), when the compound of the general formula (II) is cyclized with barium hydroxide, the free acid of the general formula (II) is used to form a barium salt of azetidine 2-carboxylic acid.

However, the method of (b) can cyclize the ester of the compound of general formula (III) in the presence of an amine, which is easily accomplished by refluxing both reactants together in a polar solvent such as acetonitrile. The amine is preferably a benzyl amine or an α-phenyl benzylamine since the benzyl or α-phenyl benzyl group is easily removed from the azetidine ring by the hydrogenation reaction described above in the method (a).

The compound of general formula (II) may be prepared by a modification of Gabriel phthalimide synthesis. Using bromine and red, the compound of general formula (IV)

Halogenation produces a compound of formula (V) and treatment with hydrohalide acid to release the required hydrohalogenated amine from the compound.

Compounds of general formula (III) are lactones and halogens of general formula (VI), especially bromine

The resulting product is prepared by reacting with alcohol in the presence of an acidic catalyst. A suitable example according to the present invention is to use benzyl alcohol as the alcohol. Therefore, the compound of the general formula (VII) may be prepared by reacting the benzyl ester of the compound of the formula (III) with benzylamine or α-phenylbenzylamine.

In the above formula, A ¹ is a benzyl group or an α-phenylbenzyl group. Subsequent catalytic hydrogenation leads to cleavage of the benzyl ester group and NA ¹ group to form the free acid of formula (I).

The carrier in the composition according to the present invention may be a material which is easy to apply to plants or that can be added and blended with active ingredients easily for storage, transportation or handling. Such carriers may be solids or liquids and are usually gaseous, but may be compressed and liquid, and may be used as long as the carriers are commonly used in compounding agricultural compositions.

Suitable solid carriers include natural and synthetic clays and silicates, such as natural silica (e.g. diatomaceous earth) magnesium silicate (e.g. talc), aluminum silicate magnesium (e.g. attapulgite, vermiculite) and aluminum silicate (e.g. : Kaolinite, Montmorillonite, Mica), Calcium Carbonate, Calcium Sulphate, Synthetic Silicon Oxide, Synthetic Calcium Silicate, Synthetic Aluminum Silicate (e.g. Carbon, Sulfur), Natural and Synthetic Resins (e.g. Coumarone Resin, Polyvinyl Chloride, Styrene) Polymers, styrene copolymers), solid polychlorophenols, bitumen, waxes (biswax, paraffin waxes, chlorinated inorganic waxes), solid fertilizers (superphosphates) and the like.

Suitable liquid carriers include water, alcohols (e.g. isopropane, glycols), ketones (e.g. acetone, methylethylketone, methylisobutylketone, cyclohexanone), ethers, aromatic or aliphatic hydrocarbons (e.g. benzene, toluene , Xylene), petroleum fractions (eg kerosene, light oil), chlorinated hydrocarbons (eg carbon tetrachloride, perchloroethylene, trichloroethane).

Mixtures of different liquids are also sometimes used.

The agricultural composition is blended, concentrated and transported, and diluted in use. Carriers, which are surfactants, are convenient for thinning when used in small amounts. Thus at least one carrier used in the composition according to the invention is a surfactant. For example, the composition may contain at least two carriers, at least one of which is a surfactant. Surfactants can be used as emulsifiers, dispersants or wetting agents, which use nonionic or ionic ones.

Suitable surfactants include condensation products of amines, fatty acids or aliphatic amines with at least 12 carbon atoms in the sodium or calcium salt molecules of polyacrylic acid and lignin sulfonic acid with ethylene or propylene oxide, glycerol, sorbitan, sucrose or pentaeryte Fatty acid esters of itol, condensates of these with ethylene oxide or propylene oxide, alkyl phenols or fatty alcohols such as p-octylphenol or p-octylcresol, condensation products of ethylene oxide or propylene oxide, sulfates of these condensation products Or lead sulfonates, alkalis of sulfonic acid esters or sulfuric acid esters having at least 10 carbon atoms in the molecule, or salts of alkaline earth metals, in particular sodium salts (e.g. sodium lauryl sulfate, sodium sulfate secondary sodium, sodium salts of sulfonated copper oil) And sulfates of alkylaryls such as sodium sulfonate and dodecylbenzene sodium ), A copolymer of ethylene oxide and polymers of ethylene oxide and propylene oxide of the.

와 완용성 개질제, 결합제 안정제 같은 첨가제 0-10wt.%를 함유하는 것이 보통이다.The composition according to the present invention can be formulated with such things as hydrating agents, powders, granules, solutions, emulsifiable concentrates, emulsions, suspension concentrates and aerosols. In the hydrating agent, 25,50 and 75 wt.% Of the active ingredient are added, and in addition to the solid inert carrier, 3-10 wt.% Dispersant and 0-10 wt.% Stabilizer or other additives such as penetrant or tackifier are added as necessary. The powder is usually formulated as a powder concentrate with a composition similar to that of the hydrating agent but without the addition of a dispersant and usually added to the solid carrier to dilute in situ so that it contains 1 / 2-10 wt.% Of the active ingredient. Granules are usually made with a particle size of 10-100BS mesh (1.676-0.152 mm) and are prepared by agglomeration method or impregnation method. Generally active ingredients in granules

And additives such as soluble modifiers and binder stabilizers 0 to 10 wt.%.

In addition to the solvent, the emulsion concentrate may contain 0-20% w / v of cosolvent, active ingredient 10-50% w / v, emulsifier 2-20% w / v and other additives such as stabilizers, penetrants and corrosion inhibitors, if necessary. do. Suspension concentrates are usually formulated as a stable, non-settling, flowable product, typically 10-75 wt.% Dispersant 0.5-15 wt.% Active ingredient, 0.1-10 wt.% Suspending agent such as protective colloids, thixotropes, Add 0-10 wt.% Of other additives such as corrosion inhibitors, stabilizers, penetrants and tackifiers and water or organic liquids, where the active ingredient is insoluble. Other organic solids or inorganic salts are dissolved and used as anti-sedimentation or antifreeze agents for water.

Liquid dispersions and emulsions, such as a composition obtained by diluting the hydrating agent or the concentrate with water according to the present invention, also belong to the scope of the present invention. The emulsion can be made water-in-oil or oil-in-water and may have a viscosity like mayonnaise.

In the composition according to the invention, other components may also be added, i.e., other compounds which impart pesticidal, herbicidal or bactericidal properties.

The present invention is described in detail according to the embodiment.

Example 1

3-Methyl-2-carboxazetidine Preparation

(A): 4-Methyl tetrahydrofuran-2-one (6.5 g, 0.065 mol) and (0.4 g) were stirred together and heated to 100-115 degreeC. The mixture was treated with bromine (30 g, 0.18 mol) until hydrogen bromide was released, then cooled to 0-5 ° C. and benzyl alcohol (36 g, 0.3 mol) was added. The mixture was saturated with dry hydrogen chloride and left for 24 hours. Diethyl ether (100 ml) was added and the mixture was poured into a 3% solution of sodium bicarbonate with ice and extracted several times with diethyl ether. The ether extract was dried over magnesium sulfate and then evaporated. The resulting pale yellow oil was vacuum distilled. All liquids having a boiling point of 122 ° C. at 0.6 mm Hg were removed.

NMR analysis of the residue (15 g) confirmed that it was 1,3-dibromo-2-methylbutanoic acid benzyl ester and the yield was 66%.

Assay C H Br

Calcd for C ₁₂ H ₄ Br ₂ O ₂ 41.1 4.0 45.7

Anal 44.1 4.5 44.6

(B): dibromo ester (15.0g, 0.043mol), α-phenylbenzylamine (27.8g, 0.13mol) and acetonitrile (250ml) obtained by (A) for 24 hours at reflux, filtered and evaporated After drying with dry and diethyl ether (200 ml), the mixture was filtered again. The grayish solid obtained by passing dry hydrogen chloride through the ether solution for 5 minutes was collected, suspended in chloroform (300 ml) and treated with a slight excess of triethylamine (20 ml). The resulting clear solution was evaporated to dryness and extracted with diethyl ether.

10 g of oil obtained by evaporating the resulting ether solution was passed through a silica column using a mixture having a mixture ratio of ethyl acetate and petroleum ether (boiling point 60-80 ° C.) of 1.5: 8.5 as an eluent. The rapidly effluent component was evaporated to yield oil and solidified by standing. This solid was recrystallized in ethanol to obtain 2.2 g of benzyl ester (melting point 101-102 ° C.) of 1-diphenylmethyl-2-carboxy-3-methylazetidine.

Assay C H N

Calcd for C ₂₅ H ₂₅ NO ₂ 80.8 6.8 3.8

Found 80.2 6.8 3.6

(C): The mixture obtained by suspending the cyclic ester (2.0 g, 0.0054 mol) obtained in (B) in ethanol (500 ml) and methanol (20 ml) and adding a catalyst of 0.5% palladium / charcoal (0.5 g) Hydrogenation was carried out for 15 minutes in a parrapparatus under hydrogen pressure of -4 absolute atmospheric pressure. The mixture was filtered, evaporated, diethyl ether was added, the liquid phase was extracted several times, and evaporated to dryness to obtain 0.5 g of a white solid which was recrystallized from ethanol to give 2-carboxy-3-methylazetidine [melting point 200-201 ° C. (decomposition). ] Was obtained at a yield of 83%.

Assay C H N

Calcd for C ₅ H ₉ NO ₂ 52.17 7.8 12.17

Found 51.2 8.2 11.9

NMR analysis showed that this compound was a mixture in which the mixing ratio of geometric isomers was 9: 1.

Example 2

3-Carboxyzetidine Preparation

(A): A solution of 1-diphenylmethyl-3-cyano azetidine (15 g, 0.06 mol) and 2-methoxyethanol (150 mol) and potassium hydroxide (13 g, 0.2 mol) and water (10 ml) Added to. This mixture was refluxed and poured into ice water (1500 ml) during 15 hours reflux. The mixture was acidified with dilute hydrochloric acid to pH 1.5 and extracted with dichloromethane. Solid sodium bicarbonate was added and the liquid phase was adjusted to pH 5 and stirred.

1-diphenylmethyl-3-carboxazetidine was separated from the solution into a very fine white solid in about 30 minutes, collected, washed with water and air dried to obtain 13 g, which was 81%. Melting point was 190-191 ° C. (decomposition).

Assay C H N

Calcd for C ₁₇ H ₁₇ NO ₂ 76.4 6.4 5.2

Found 75.4 6.4 5.1

(B) 6 g of palladium hydroxide hydroxide suspended in methanol (300 ml) and deposited on charcoal in N-substituted acids (10 g, 0.037 mol) obtained in (A) [Tetrahedro Letters (1967), page 1663. Prepared by the method].

대기압(절대압)의 수소압에서 파르장치중에서 3시간 수소화 반응시켰다. 1시간후에 수소 흡수를 갑자기 중지시켰다. 용액을 여과하고 감압하에서 거의 증발 건조시켰다. 액상의 잔류물을 디클로로메탄으로 수차 추출한 후 증발건고시켰다. 생성된 백색의 고체잔류물을 에탄올에서 재결정하여 융점이 169-170℃(분해)인 광휘가 있는 판상의 수화된 3-카르복시아제티딘 2.6g을 얻었다.About this mixture

Hydrogenation was carried out in a Parr apparatus at atmospheric pressure (absolute pressure) for 3 hours. After 1 hour hydrogen absorption was abruptly stopped. The solution was filtered and evaporated to dryness under reduced pressure. The liquid residue was extracted several times with dichloromethane and evaporated to dryness. The resulting white solid residue was recrystallized in ethanol to give 2.6 g of plate-shaped hydrated 3-carboxazetidine having a brightness of 169-170 ° C (decomposition).

Assay C H N

Calcd for C _{4 H 7 NO 2 · H 2 O} 40.3 7.5 11.7

Found 40.3 6.7 11.6

Evaporation of the recrystallization solvent gave an additional 1.2 g of crystals having a melting point of 235-270 ° C. (decomposition), which consisted of 3-carboxazetidine anhydride and the NMR analysis was identical to the hydrated acid.

The yield of step (b) was 95%.

Example 3

3-ethyl-2-carboxy azetidine preparation

(A) Bromine (21 g, 0.132 mol) was added to the stirred mixture of 4-ethyl-γ-butyrolactone (15 g, 0.132 mol) and red (0.3 g) at 120 ° C. Bromine was added just below the surface of the reaction mixture and hydrogen bromide was released at the end of bromine addition. The reaction mixture was cooled and benzyl alcohol (40 ml) was added to saturate the resulting solution with dry hydrogen chloride gas at room temperature. The resulting mixture was left for 24 hours.

The mixture was partitioned between ether and sodium hydrogen carbonate solution, the ether layer was separated and dried over magnesium sulfate. The dried solution was distilled off to obtain benzyl ester of 2-bromo-3-bromo methyl pentanoic acid (boiling point of 149 ° C./0.7 mmHg) in a yield of 43%.

Assay C H N

Calcd for C ₁₃ H ₁₀ Br ₂ O ₂ 42.9 4.4 44.0

Anal 43.5 4.5 43.3

(B): Dibromoester (19.5g, 0.054mol) and benzhydrylamine (29g, 0.16mol) obtained in (A) were added to acetonitrile and refluxed for 48 hours. The resulting mixture was cooled and filtered in the absence of insoluble amine salts and the filtrate was evaporated to dryness. The residue was partially purified on a column of silica gel and petroleum ether / ethyl acetate, used as eluent as a complex mixture of products. The primary effluent was collected and evaporated to yield benzyl ester (NMR analysis 65%) of 1-diphenylmethyl-2-carboxy-3-ethylazetidine as the main component in the crude residual mixture (8 g).

(C): Mixture of crude ester (8g) obtained from (B) with ethanol (100ml) and 5% palladium charcoal catalyst (10g) for 10 hours at room temperature and hydrogen pressure of 3-4 atmospheric pressure (absolute pressure) in a Parr apparatus. Hydrogenation was carried out. The resulting mixture was filtered, evaporated to dryness and partitioned between methyl chloride and water. The liquid phase was separated and evaporated and poured into a Dowex 8-50 × (H) resin column. The amino acids can be separated by eluting the washed column with 2M ammonia solution. The washed product was evaporated to give a white solid which was recrystallized from ethanol to obtain 3-ethyl-2-carboxazetidine, which is an isomer mixture [1α: 3β].

Assay C H N

Calcd for C ₆ H ₁₁ NO ₂ 55.8 8.5 10.85

Found 55.8 8.8 10.7

Evaporation of the recrystallized solvent further gave 3-ethyl-2-carboxazetidine with a different isomer composition [2α: 3β].

Assay C H N

Found 55.8 8.9 10.7

Example 4

Proof of Pollen Inhibition

The sicco varieties, spring wheat, were bred in 13 cm jars containing cultured soils in october in glass greenhouses. By supplementing the light using high pressure mercury lamp, the length was kept constant for 16 hours, and the temperature was maintained at about 20 ° C.

The test compound was prepared as a solution using 0.1% of nonidet p 40 (trademark) as the wetting agent and adding 1% of acetone to improve solubility. The formulation was diluted to 1000 ppm with water and sprayed onto the plants. The plants were treated at the growth stage by the time the second node of the plant was detected. During the emergence stage before flowering, five spikes from the corneal jars were placed in cellophane bags to prevent other pollination.

At the maturity stage, the ear bags were collected from the bag and the deletion rate was recorded and compared with that of no treatment. The results are shown in the following table.

[table]

As can be seen from the table, these compounds have a significantly reduced deletion rate compared to untreated, which clearly demonstrates that the compound has the ability to infer wheat mackerel.

Claims (1)

The corresponding cyano compounds of the general formula or derivatives thereof are subjected to hydrolysis or dialcohol degradation followed by removal of the protecting groups,

Next, a method for preparing an azetidine derivative of general formula (I).

In the above expression X is CH ₂ , CHR or CR ₂ , Y is CHCO ₂ H, Z is CH ₂ , CHR or CR ₂ , and R is optionally substituted on the aryl nucleus with one or more of the same or different substituents of a halogen atom, an alkyl group or an alkoxy group It is a substituted aralkyl group or an aryl group, a cycloalkyl group, an alkenyl group or an alkyl group, and the 1-nitrogen atom in the ring of the cyano compound mentioned above can be substituted by the protecting group removable from an azetidine ring.