HK1141013B - Process for the preparation of certain substituted sulfilimines - Google Patents

Description

Process for preparing certain substituted sulfilimines

Cross reference to related applications

This non-provisional application claims priority from provisional application 60/903,471 filed on 26/2/2007.

Technical Field

The present invention relates to a process for the preparation of certain substituted sulfilimines.

Background

Substituted sulfilimines are useful intermediates for the preparation of certain novel insecticidal sulfoximines (sulfoximines), see, for example, U.S. patent application publication 2005/0228027, in which cyano-substituted sulfilimines are prepared by reacting the corresponding sulfide with cyanamide in the presence of iodobenzene diacetate (iodobenzenediacetate). It may be beneficial to obtain sulfilimines efficiently and in high yields from the corresponding sulfides without the use of iodobenzene diacetate, since iodobenzene diacetate presents waste disposal problems in addition to its cost.

Disclosure of Invention

In the present invention, iodobenzene diacetate is replaced by hypochlorite. In addition to low cost, hypochlorite eliminates the serious waste problems associated with iodobenzene diacetate. Thus, the present invention relates to a process for the preparation of certain substituted sulfilimines of the general formula (I),

wherein

Het represents:

x represents halogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₂-C₄Haloalkenyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, CN, NO₂、SO_mR⁶Wherein m is an integer of 0-2, COOR⁴Or CONR⁴R⁵；

Y represents hydrogen, halogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₂-C₄Haloalkenyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, CN, NO₂、SO_mR¹Wherein m is an integer of 0-2, COOR⁴、CONR⁴R⁵Aryl or heteroaryl;

n is an integer of 0 to 3;

l represents a single bond; or L represents-CH (CH)₂)_P-, in this case R¹S and L together represent a 4, 5 or 6 membered ring and p is an integer from 1 to 3; or L represents-CH (CH)₂OCH₂) -, in this case R¹S and L together represent a six-membered ring; or L represents-CH-, in which case L, R²Together with the common carbon to which they are attached represent a 4, 5 or 6 membered ring containing up to but not more than 1 heteroatom;

R¹is represented by C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Alkenyl radical, C₃-C₆Alkynyl, C₃-C₆Haloalkenyl, arylalkyl, heteroarylalkyl, or when R is¹R represents a 4, 5 or 6 membered ring when S and L together¹represents-CH₂-；

R²And R³Independently represent hydrogen, halogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₂-C₄Alkenyl radical, C₂-C₄Alkynyl, C₂-C₄Haloalkenyl, C₁-C₄Alkoxy radical, C₁-C₄Haloalkoxy, CN, SO_mR⁶Wherein m is an integer of 0-2, COOR⁴、CONR⁴R⁵Arylalkyl, heteroarylalkyl, or R²And R³Form a 3-6 membered ring with the common carbon to which they are attached;

R⁴and R⁵Independently represent hydrogen, C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Alkenyl radical, C₃-C₆Alkynyl, C₃-C₆Haloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; and

R⁶is represented by C₁-C₄Alkyl radical, C₁-C₄Haloalkyl, C₃-C₆Alkenyl radical, C₃-C₆Alkynyl, C₃-C₆Haloalkenyl, arylalkyl or heteroarylalkyl;

the process comprises contacting a sulfide of formula (II) with a cyanamide and hypochlorite solution at a temperature of from about-40 ℃ to about 30 ℃ in a suitable organic solvent that is substantially inert to the reaction conditions,

wherein R is¹、R²、R³L, Het and n are as defined above.

The process is well suited for the preparation of sulfilimines of the following classes:

(1) a compound of formula (I) wherein Het is (6-substituted) pyridin-3-yl, and wherein X is halo or C₁-C₂Haloalkyl, and Y is hydrogen;

(2) a compound of formula (I) wherein R²And R³As defined above, R¹Is methyl, n is 1, and L is a single bond, the compound having the structure:

(3) a compound of formula (I) wherein n is 1, R¹S and L together form a standard 4, 5 or 6 membered ring, in which case L is-CH (CH)₂)_P-, and p is an integer from 1 to 3, and R¹is-CH₂-, the compound has the following structure:

(4) a compound of formula (I) wherein n is 0, R¹S and L together form a standard 4, 5 or 6 membered ring, in which case L is-CH (CH)₂)_p-, and p is an integer from 1 to 3, and R¹is-CH₂-, the compound has the following structure:

Detailed Description

Throughout this application, all temperatures are in degrees Celsius and all percentages are by weight unless otherwise indicated.

The terms "alkyl", "alkenyl" and "alkynyl" as well as derivative terms such as "alkoxy", "acyl", "alkylthio", "arylalkyl", "heteroarylalkyl" and "alkylsulfonyl" as used herein include within their scope straight chain, branched chain and cyclic moieties. Typical alkyl groups are therefore methyl, ethyl, 1-methylethyl, propyl, 1-dimethylethyl and cyclopropyl. Unless otherwise indicated, each group may be unsubstituted or substituted with one or more substituents selected from, but not limited to: halogen, hydroxy, alkoxy, alkylthio, C₁-C₆Acyl radical (C)₁-C₆acyl), formyl, cyano, aryloxy or aryl, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy (strain energy). The terms "haloalkyl" and "haloalkenyl" include alkyl and alkenyl groups substituted with one to the maximum possible number of halogen atoms, including all combinations of halogens. The term "halogen" or "halo" includes fluorine, chlorine, bromine and iodine, preferably fluorine. The terms "alkenyl" and "alkynyl" are intended to include one or more unsaturated bonds.

The term "aryl" refers to phenyl, indanyl (indanyl) or naphthyl. The term "heteroaryl" refers to a 5 or 6 membered aromatic ring containing one or more heteroatoms (i.e., N, O or S); these heteroaromatic rings may be fused with other aromatic systems. The aryl or heteroaryl substituents may be unsubstituted or substituted with one or more substituents selected fromSubstituent group substitution: halogen, hydroxy, nitro, cyano, aryloxy, formyl, C₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-C₆Alkoxy, halo C₁-C₆Alkyl, halo C₁-C₆Alkoxy radical, C₁-C₆Acyl radical, C₁-C₆Alkylthio radical, C₁-C₆Alkylsulfinyl radical, C₁-C₆Alkylsulfonyl, aryl, C₁-C₆Alkyl C (O) O-, C₁-C₆Alkyl C (O) NH-, -C (O) OH, C₁-C₆Alkyl OC (O) -, -C (O) NH₂、C₁-C₆Alkyl NHC (O) -or (C)₁-C₆Alkyl radical)₂Nc (o) -, provided that the substituents are sterically compatible and satisfy the rules of chemical bonding and strain energy.

The sulfide starting material of formula II or a method for its preparation is disclosed in U.S. patent application publication No. 2005/0228027. Sulfide (II) can be prepared in different ways, which are illustrated in schemes A, B, C, D, E, F and G.

In scheme A, formula (A)₁) Wherein L is a single bond, n is 1, R³H, and R¹、R²And Het is as defined above) may be prepared from the halide of formula (D) by nucleophilic substitution with a sodium salt of an alkyl thiol.

Scheme A

In scheme B, formula (A)₂) Wherein L is a single bond, n is 3, R³H, and R¹、R²And Het is as defined above) may be prepared from the chloride of formula (E) as follows: reacting the chloride of formula (E) with 2-monosubstituted methyl malonate in presence of base such as potassium tert-butoxide to obtain2, 2-disubstituted malonates, hydrolyzed under basic conditions to form diacids, decarboxylating the diacids by heating to give monoacids, reducing the monoacids with borane-tetrahydrofuran complex to give alcohols, tosylating the alcohols with tosyl chloride (tossylchloride) in the presence of a base such as pyridine to give tosylates (tosilates), which are then replaced with the sodium salt of the desired thiol.

Scheme B

In scheme C, formula (A)₃) Wherein L is a single bond, n is 2, R³H, and R¹、R²And Het is as defined above), may be prepared from a nitrile of formula (F) as follows: deprotonation of the nitrile of formula (F) with a strong base and alkylation with an alkyl iodide gives an α -alkylated nitrile, hydrolysis of the α -alkylated nitrile in the presence of a strong acid such as HCl gives an acid, reduction of the acid with a borane-tetrahydrofuran complex gives an alcohol, tosylation of the alcohol with tosyl chloride in the presence of a base such as pyridine gives a tosylate, which is then replaced with the sodium salt of the desired thiol.

Scheme C

In scheme D, formula (A)₄) (iii) sulfide of (wherein n is 0, R)¹is-CH₂-, L is-CH (CH)₂)_P-, where p is 2 or 3, and R¹S and L together form a 5 or 6 membered ring, and Het is as described above), may be prepared from tetrahydrothiophene (p ═ 2) or thiahexacyclic (p ═ 3) (G). The cyclic sulfide starting material is chlorinated with N-chlorosuccinimide in benzene, followed by certain lithiated heterocycles or Grignard reagents (Grignard reages)nt) to give the desired sulfide (A) in a satisfactory yield₄)。

Scheme D

Obtaining the formula (A)₄) A more efficient scheme for cyclic sulfides of (a) is illustrated in scheme E, wherein Het is 6-substituted pyridin-3-yl, and Z is as defined above. Accordingly, thiourea is added to a substituted chloromethylpyridine, hydrolyzed, and alkylated with the appropriate bromochloroalkane (p ═ 1, 2, or 3) under aqueous base conditions to give the sulfide (H). Subsequent cyclization of (H) in a polar aprotic solvent such as THF (tetrahydrofuran) in the presence of a base such as potassium tert-butoxide affords the cyclic sulfide (A)₄)。

Scheme E

Certain of the formula (A)₁) Wherein Het is substituted pyridin-3-yl, Z is as defined above, and R¹、R²＝CH₃) Alternatively prepared by the method set forth in scheme F. Correspondingly, the appropriate enone is coupled with dimethylaminoacrylonitrile and then cyclized with ammonium acetate in DMF to give the corresponding 6-substituted pyridine-3-carbonitrile. It is treated with methylmagnesium bromide, reduced with sodium borohydride, chlorinated with thionyl chloride and then nucleophilic substituted with the sodium salt of an alkylthiol to give the desired sulfide (A)₁)。

Scheme F

A variation of scheme F is illustrated in scheme G, wherein an enamine is coupled to a substituted enone, followed by ammonium acetate at CH₃Cyclization in CN gives the desired sulfide (A)₁) The enamines are formed by the addition of amines, such as pyrrolidines, to Michael adducts (Michael adducts) of certain sulfides with appropriately substituted α, β -unsaturated aldehydes, where R is¹、R²、R³And Z is as defined above.

Scheme G

The cyanamide can be used as a solid or an aqueous solution. It is generally preferred to use a 50 wt% aqueous solution of cyanamide. A stoichiometric amount of cyanamide is required, but it is generally convenient to employ about 0.9 to about 1.1 molar equivalents of cyanamide based on the amount of sulfide.

Hypochlorite solution refers to an aqueous solution of a metallic salt of hypochlorous acid (metallic salt). The metallic salt may be an alkali metal salt of main Group I (Group I) or an alkaline earth metal salt of main Group II (Group II). Preferred hypochlorites are sodium hypochlorite or calcium hypochlorite. The aqueous hypochlorite solution typically contains from about 2% to about 12% hypochlorite, most preferably from about 5% to about 6% hypochlorite. It is generally most appropriate to use commercially available Clorox^TMA bleaching agent comprising from about 5 wt% to about 6 wt% aqueous sodium hypochlorite. A stoichiometric amount of hypochlorite is required but it is generally convenient to employ from about 0.95 to about 1.2 molar equivalents of hypochlorite based on the amount of sulphide.

Metabisulfites (such as sodium metabisulfite or potassium metabisulfite) may be used to quench any excess hypochlorite. The preferred salt selected is the sodium salt. The number of equivalents of metabisulfite may be from about 1.0 to about 5.0 relative to the stoichiometric amount of hypochlorite. The preferred range of equivalents is from about 2.0 to about 4.0 equivalents of metabisulfite per equivalent of hypochlorite remaining.

The process of the invention is carried out in a suitable organic solvent which is substantially inert to the strong oxidation conditions of the reaction. Particularly suitable organic solvents are aliphatic hydrocarbons such as petroleum ether, oxidation-resistant aliphatic alcohols such as tert-butanol, halogenated aliphatic hydrocarbons and halogenated aromatic hydrocarbons such as dichloromethane, chloroform, 1, 2-dichloroethane and dichlorobenzene, and aliphatic and aromatic nitriles such as acetonitrile and benzonitrile. Halogenated aliphatic hydrocarbons and aliphatic nitriles are preferred. It is generally convenient to carry out the oxidation in a biphasic solvent system comprising, for example, a mixture of a halogenated aliphatic hydrocarbon such as methylene chloride and water. Organic solvents that can facilitate partitioning of the desired sulfilimine are also desirable, with acetonitrile being particularly preferred.

The reaction temperature may range from about-40 ℃ to about 30 ℃. The preferred range is from about-10 ℃ to about 10 ℃, with about-5 ℃ to about 0 ℃ being most preferred.

The reaction is conveniently carried out in a two-step sequence. For example, hypochlorite may be added to a cold solution of cyanamide in a substantially inert solvent, followed by a brief post-addition of sulfide. Alternatively, the cyanamide and the sulfide may be mixed together in a substantially inert solvent, and the hypochlorite then added directly to the cold mixture. After the hypochlorite addition, the reaction mixture is stirred at 0 ℃ for 15 minutes to 2 hours, usually 30 minutes. A small amount of aqueous metabisulphite solution is generally added to destroy excess oxidizing agent by using starch-I₂Test paper tests. At this time, the aqueous phase is separated from the organosulfur imine phase. The organic solution of sulfilimine can be used directly for subsequent oxidation to give the insecticidal sulfoximine, or the sulfilimine can be isolated and purified by conventional techniques.

The following examples are set forth to illustrate the invention.

Examples

Comparative example using iodobenzene diacetate: (1- {6- [ trifluoromethyl ]]Pyridin-3-yl } ethyl (Methyl) -lambda⁴Preparation of sulfoximines

221g (1.0mol) of 3- [1- (methylthio) ethyl]A mixture of-6- (trifluoromethyl) pyridine and 42g (1.0mol) cyanamide in 1200mL acetonitrile was cooled to below 10 ℃. To this solution was added 322g (1.0mol) iodobenzene diacetate in one portion. The reaction mixture was stirred at below 10 ℃ for 10 minutes, then the ice bath was removed. The reaction mixture was allowed to warm slowly to room temperature over 1.5 hours and then exothermed from 22 ℃ to 30 ℃ over an additional 0.5 hour. The reaction mixture was slowly brought to room temperature and 800mL of water were then added. Excess oxidant was destroyed by adding about 20mL of aqueous sodium metabisulfite solution. To the mixture was added 800mL of hexane, and the mixture was stirred for 5 minutes and then separated. The bottom aqueous layer was returned to the flask, and 400mL of water and 400mL of hexane were added. The mixture was stirred for 5 minutes and separated. The aqueous layer was returned to the round bottom flask again and then extracted a third time with 400mL of hexane. The aqueous layer was concentrated in vacuo until a cloudy biphasic mixture was obtained. The mixture was extracted twice with dichloromethane (700mL, 300mL), the organics combined and then MgSO₄Dry overnight. After filtration, LC analysis indicated a solution of two thioimine isomers in dichloromethane (1560g) in a 28: 64 (area) ratio.

Isomer a:

a portion of the above thioimine solution (40mL) was concentrated in vacuo and then exposed to high vacuum to give a thick orange/amber oil. The oil was dissolved in 10mL EtOAc and then 10mL hexane was added. To the cloudy mixture was added 1mL EtOAc to again give a clear solution. The flask was scraped with a glass rod to initiate crystallization. The mixture was cooled in a refrigerator for 1 hour, filtered, then exposed to high vacuum and dried to give 1.2g of white powder, mp 115-117 ℃, with the first eluting isomer > 99% (area) LC;¹H NMR(CDCl₃)：δ8.72(d，J＝2Hz，1H)，8.04(dd，J＝2Hz，8Hz，1H)，7.81(d，J＝8Hz，1H)，4.41(q，J＝7Hz，1H)，2.62(s，3H)，1.90(d，J＝7Hz，3H)。

isomer B:

the filtrate was concentrated in vacuo to give a thick amber oil (15: 67 area ratio of the two isomers by LC). The oil was flash chromatographed on silica gel (5% EtOH/CHCl)₃Elution) and purification. Some small amount of colored material is discarded first. The major thioimine isomer (second eluted isomer by LC detection) was then collected, concentrated in vacuo, and then dried by exposure to high vacuum to give 3.2g of a thick amber oil. The oil was slurried and then treated with 20mL Et₂Scraping, cooling in a refrigerator, filtering, and then exposing to high vacuum for drying to obtain 2.48g of white powder, mp 78-80 ℃, the isomer eluted for the second time is more than 99% (area) LC is more than 99%;¹H NMR(CDCl₃)：δ8.74(d，J＝2Hz，1H)，7.95(dd，J＝2Hz，8Hz，1H)，7.81(d，J＝8Hz，1H)，4.45(q，J＝7Hz，1H)，2.65(s，3H)，1.92(d，J＝7Hz，3H)。

example 1(1- {6- [ trifluoromethyl ]]Pyridin-3-yl } ethyl) (methyl) -lambda⁴Preparation of sulfoximines

22.1g (0.1mol) of 3- [1- (methylthio) ethyl]A solution of-6- (trifluoromethyl) pyridine and 5.04g (0.12mol) cyanamide in 150mL acetonitrile was cooled to-5 ℃. To this solution, 150g of NaOCl in water (0.115mol, Clorox) was added dropwise over a period of 15 minutes^TM5.7% wt). The reaction mixture was stirred at-5 ℃ for 45 minutes and then warmed to 5 ℃. To the mixture was added 5mL of a 25% aqueous solution of sodium metabisulfite, and the biphasic mixture was allowed to settle. To the organic phase was added 5.7mL (0.1mol) of glacial acetic acid, and the solution was concentrated in vacuo to give an oil. Mixing the oil with waterThe mixture was dissolved in 70mL of CH₂Cl₂In (1), the mixture was washed with 50mL of water. The aqueous layer was washed with 30mL CH₂Cl₂And then extracting. The organics were combined and then MgSO₄And (5) drying. After filtration, the dichloromethane solution was analyzed by LC and contained 42: 52 (area) ratio of isomers A and B above.

Example 2: (1- {6- [ trifluoromethyl ]]Pyridin-3-yl } ethyl) (methyl) -lambda⁴Preparation of sulfoximines

110.6g (0.475mol, 95% determination) of 3- [1- (methylthio) ethyl]A solution of-6- (trifluoromethyl) pyridine and 25.2g (0.6mol) cyanamide in 600mL acetonitrile was cooled to-5 ℃. To this solution was added 750g of NaOCl in water (0.575mol, Clorox) dropwise over 45 minutes^TM5.7% wt) while keeping the temperature below 0 ℃. The reaction mixture was stirred at-1 ℃ for 30 minutes. To the mixture was added a solution of 9.5g (0.05mol) of sodium metabisulfite in 25mL of water, and then the biphasic mixture was allowed to settle. The aqueous phase is re-extracted 2 times with 50mL acetonitrile. The organics were combined and the acetonitrile/sulfilimine solution was used directly for subsequent oxidation. LC analysis showed a 40: 54 (area) ratio of the two isomers.

Example 3: (1- {6- [ trifluoromethyl ]]Pyridin-3-yl } ethyl) (methyl) -oxy-lambda⁴Preparation of sulfoximines

100mL of acetonitrile, 200mL of water, and 160g (0.45mol) of 40% NaMnO₄The mixture of aqueous solutions (Aldrich) was cooled to 15 ℃. To a solution of sulfilimine (about 0.475mol, from example 2) in about 700mL of acetonitrile was added 26mL (0.45mol) of glacial acetic acid. The sulfimide solution was added to the permanganate mixture with rapid stirring over a 50 minute period. Therein, theDuring which the ice bath temperature was lowered or raised to maintain the reaction temperature around 19 ℃. The reaction mixture was allowed to continue for 45 minutes. The mixture was cooled to 12 ℃ and a solution of 171g (0.9mol) of sodium metabisulphite in 300mL of water was added over 15 minutes with rapid stirring. The mixture was stirred at room temperature for 30 minutes, and then filtered. The off-white solid was rinsed with 50mL acetonitrile. The two-phase mixture was transferred to a 2L separatory funnel and the aqueous layer was discarded. The organic layer was concentrated in vacuo to about 50% wt product. The mixture was poured onto 300mL of rapidly stirred water in an ice bath. The mixture was cooled under stirring for 1h and filtered to give 147.6g of a white solid. The product was air dried in a fume hood (hood) to give 116.5g of product, which was then further dried in a vacuum oven at 35 ℃ to give 116.5g (88% wt) of a white powder. LC analysis showed a 43: 52 (area) ratio of the two isomers and 95% area purity.

Example 4: preparation of N-cyano-S- [1- (6-trifluoromethyl-pyridin-3-yl) ethyl ] -S-methylthioimine

Acetonitrile (50mL), cyanamide (1.14 g, 27.1mmol) and 3- [1- (methylthio) ethyl ] -6- (trifluoromethyl) pyridine (5.00 g, 22.6mmol, 99 +% assay) were mixed in a 100mL 3-neck round bottom flask equipped with a thermowell/K-thermocouple (thermowell/K-thermocouple), a stopper, a nitrogen oil bubbler (nitrogen oil bubbler) and a magnetic stir bar. The stirred solution was cooled to about-5 ℃ with an acetone/ice bath. 55.96 g of a 6.0 wt% aqueous solution of calcium hypochlorite (3.36 g of calcium hypochlorite, 23.5mmol, 65% available chlorine) were added dropwise to the solution over 44 minutes. Some undissolved solids were present in the calcium hypochlorite solution and were also added. The temperature was kept below 0 ℃ during the addition. The light yellow reaction mixture was stirred at about 0 ℃ for 65 minutes. To the yellow reaction mixture was added 0.53g (2.8mmol) of sodium metabisulfite in solid form in portions to destroy any remaining oxidizing agent. White flocs were present in the reaction mixture. The entire reaction mixture was vacuum filtered through a medium sintered glass filter funnel to remove white flocs. The filtrate was transferred to a separatory funnel and the phases were allowed to settle. The phases were separated and the aqueous phase re-extracted with acetonitrile (10mL and 15 mL). Sodium chloride (10.01 grams) was added to the aqueous phase at the second extraction to facilitate phase disruption. The organics were combined and the acetonitrile/sulfilimine solution was used directly for subsequent oxidation. LC analysis showed two sulfur imine isomers at a 1.00: 1.08 area ratio and showed 80 area% sulfur imine and 13 area% sulfoxide (two isomers).

Example 5: preparation of N-cyano-S- [1- (6-trifluoromethyl-pyridin-3-yl) ethyl ] -S-methylsulfoxime

Acetonitrile (5mL), water (10mL) and 7.63 g (21.5mmol) of 40% NaMnO₄Aqueous solutions (Aldrich) were mixed in a 100mL 3-neck round bottom flask equipped with a magnetic stir bar, a pressure equalizing addition funnel, a thermowell K-thermocouple, a nitrogen oil bubbler, and a stopper. A solution of sulfilimine (about 22.6mmol) in about 70mL acetonitrile was filtered through a cone of Whatman filter paper to remove a small amount of white floc. To the filtrate was added 1.23mL (21.5mmol) of glacial acetic acid. The resulting solution was loaded into a dropping funnel. The sodium permanganate solution was cooled to about 13 ℃. The sulfilimine solution was added to the permanganate mixture with rapid stirring over a period of 60 minutes. The temperature range during the addition was 13 to 18 ℃. The reaction mixture was allowed to continue for 45 minutes. The dark mixture was cooled to about 12 ℃ and then a solution of 7.75 g (40.8mmol) of sodium metabisulfite in 12mL of water was added over 7 minutes with rapid stirring. The maximum reaction temperature occurring during the addition was about 16 ℃. At the end of the addition the reaction mixture was still dark but gradually lightened to give an off-white floc. A small amount of dark dry skin (rind) remained on the sidewall of the flask at this time, but dissipated as stirring continued. Under stirringThe mixture was allowed to warm to room temperature over 105 minutes. The entire mixture was vacuum filtered through a coarse sintered glass filter funnel. The brown wet cake was rinsed with acetonitrile (10 mL). The combined filtrates were transferred to a separatory funnel and the phases were allowed to settle. The clear colorless lower phase (43.0 g) was removed. The upper organic phase (56.1 g) was concentrated to a mass of 22.0 g at a pressure of 70 to 80mm Hg and a temperature of 20 to 25 ℃. The resulting two-phase mixture was poured into 44.5 g of cold (< 5 ℃) water with thorough stirring. A white slurry was formed and stirred at < 5 ℃ for about one hour. The solid was collected by vacuum filtration on a coarse sintered glass filter funnel and the white solid was rinsed with 10mL of cold water. The product, 5.24 grams of wet filter cake, was air dried overnight in a fume hood to yield 4.01 grams (65%) of the desired sulfoximine. LC analysis showed a 1.04: 1.00 (area) ratio of the two isomers and an area purity of 94% with the major impurity being sulfone (3.5% area).

Claims (7)

1. A process for preparing a sulfilimine of formula (I),

wherein

Het represents:

x represents halogen, C₁-C₄Alkyl or C₁-C₄A haloalkyl group;

y represents hydrogen;

n is an integer of 0 to 3;

l represents a single bond;

R¹is represented by C₁-C₄An alkyl group;

R²and R³Independently represent hydrogen or C₁-C₄An alkyl group;

said process comprising contacting a sulphide of formula (II) with a solution of cyanamide and hypochlorite at a temperature of-40 ℃ to 30 ℃ in a suitable organic solvent which is substantially inert to the reaction conditions,

wherein R is¹、R²、R³L, Het and n are as defined above.

2. The method of claim 1, wherein Het is (6-substituted) pyridin-3-yl, and wherein X is halo or C₁-C₂Haloalkyl, and Y is hydrogen.

3. The method of claim 1, wherein the sulfilimine has the structure:

wherein

Het、R²And R³As defined in claim 1, R¹Is methyl, n is 1, and L is a single bond.

4. The method of claim 1, wherein the temperature is from-10 ℃ to 10 ℃.

5. The method of claim 1, wherein the hypochlorite solution is an aqueous solution containing 5% to 6% sodium hypochlorite.

6. The process of claim 1, wherein the organic solvent is an aliphatic nitrile or a halogenated aliphatic hydrocarbon.

7. The process of claim 1, wherein the process is carried out in a biphasic solvent system comprising a mixture of a halogenated aliphatic hydrocarbon and water.