HK1209110B - Processes to produce certain 2-(pyridine-3-yl)thiazoles - Google Patents

Description

Process for preparing certain 2- (pyridin-3-yl) thiazoles

Cross Reference to Related Applications

This application claims priority from U.S. provisional patent application 61/655,089 filed on 6/4/2012. The entire contents of this provisional application are incorporated by reference into this application.

Technical Field

The invention disclosed herein relates to the field of technology for the preparation of certain 2- (pyridin-3-yl) thiazoles as intermediates in the synthesis of thiazole amide insecticides.

Background

Control of pest numbers is critical to modern agriculture, food storage and hygiene. There are over ten thousand pests that cause agricultural losses. Billions of dollars are lost to agriculture worldwide each year. Pests such as termites are also known to cause damage to all individuals and public structures, resulting in billions of dollars being lost each year. Pests also eat stored food and become adulterated with it, resulting in billions of dollars being lost each year, as well as depriving people of their food needs.

Some pests have developed or are developing resistance to currently used pesticides. Hundreds of pest species are resistant to one or more pesticides. There is thus a continuing need for new pesticides and methods of forming these pesticides.

WO 2010/129497 (the entire contents of which are incorporated herein) discloses certain insecticides. But the processes for preparing these insecticides can be expensive and ineffective. Thus, there is a need for methods of efficiently forming these pesticides.

Definition of

The examples given in the definitions are generally non-exhaustive and should not be construed as limiting the invention disclosed in this application. It is to be understood that the substituents should comply with the rules of chemical bonding and stereochemical compatibility constraints with respect to the particular molecule to which they are attached.

"alkenyl" means an acyclic, unsaturated (at least one carbon-carbon double bond), branched or unbranched substituent consisting of carbon and hydrogen, such as vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl.

"alkenyloxy" means an alkenyl group further containing a carbon-oxygen single bond, such as allyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, and decenyloxy.

"alkoxy" denotes an alkyl group further comprising a carbon-oxygen single bond, such as methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentyloxy, 2-methylbutyloxy, 1-dimethylpropoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy and decyloxy.

"alkyl" means an acyclic, saturated, branched or unbranched substituent consisting of carbon and hydrogen, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyloxy, 2-methylbutyl, 1-dimethylpropyl, hexyl, heptyl, octyl, nonyl and decyl.

"alkynyl" means an acyclic, unsaturated (at least one carbon-carbon triple bond and any double bond), branched or unbranched substituent consisting of carbon and hydrogen, such as ethynyl, propargyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl.

"alkynyloxy" denotes an alkynyl group further comprising a carbon-oxygen single bond, such as pentynyloxy, hexynyloxy, heptynyloxy, octynyloxy, nonynyloxy and decynyloxy.

"aryl" means a cyclic aromatic substituent consisting of carbon and hydrogen, such as phenyl, naphthyl, and biphenyl.

"cycloalkenyl" means a monocyclic or polycyclic, unsaturated (at least one carbon-carbon double bond) substituent consisting of carbon and hydrogen, such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl, norbornenyl, bicyclo [2.2.2] octenyl, tetrahydronaphthyl, hexahydronaphthyl and octahydronaphthyl.

"cycloalkenyloxy" denotes cycloalkenyl groups which also contain carbon-oxygen single bonds, such as cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy, cyclodecenyloxy, norbornenyloxy and bicyclo [2.2.2] octenyloxy.

"cycloalkyl" denotes a mono-or polycyclic, saturated substituent consisting of carbon and hydrogen, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbornyl, bicyclo [2.2.2] octyl and decahydronaphthyl.

"Cycloalkoxy" denotes cycloalkyl groups which also contain a carbon-oxygen single bond, such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, cyclodecyloxy, norbornyloxy and bicyclo [2.2.2] octyloxy.

"halocycloalkyl" means a saturated substituent consisting of carbon, halogen and hydrogen in a single or multiple ring, for example, 1-chlorocyclopropyl, 1-chlorocyclobutyl and 1-dichlorocyclopentyl.

"halogen" means fluorine, chlorine, bromine and iodine.

"haloalkyl" means alkyl groups which also contain one to the maximum possible number of identical or different halogens, for example fluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2,2, 2-trifluoroethyl, chloromethyl, trichloromethyl and 1,1,2, 2-tetrafluoroethyl.

"Heterocyclyl" means a cyclic substituent which may be fully saturated, partially unsaturated or fully unsaturated, wherein the cyclic structure contains at least one carbon and at least one heteroatom, wherein the heteroatom is nitrogen, sulfur or oxygen, such as benzofuranyl, benzisothiazolyl, benzisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl, cinnolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, 1,3, 4-oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, 1,2,3, 4-tetrazolyl, thiazolinyl, thiazolyl, thienyl, 1,2, 3-triazinyl, 1,2, 4-triazinyl, 1,3, 5-triazinyl, 1,2, 3-triazolyl, and 1,2, 4-triazolyl.

Detailed Description

In scheme one, embodiments of the present invention are illustrated

Wherein

(A)R¹Each independently selected from H, F, Cl, Br, I, CN, NO₂And substituted or unsubstituted (C)₁-C₆) Alkyl, wherein each substituted R¹Having one or more substituents independently selected from the group consisting of: F. cl, Br, I, CN, NO₂、(C₁-C₆) Alkyl, and (C)₁-C₆) A haloalkyl group;

(B)R²selected from substituted or unsubstituted (C)₁-C₆) Alkyl, substituted or unsubstituted (C)₂-C₆) Alkenyl, substituted or unsubstituted (C)₁-C₆) Alkoxy, substituted or unsubstituted (C)₂-C₆) Alkenyloxy, substituted or unsubstituted (C)₃-C₁₀) Cycloalkyl, substituted or unsubstituted (C)₃-C₁₀) Cycloalkenyl, substituted or unsubstituted (C)₆-C₂₀) Aryl, substituted or unsubstituted (C)₁-C₆) Alkyl) (C₆-C₂₀) Aryl, and substituted or unsubstituted (C)₁-C₂₀) Heterocyclyl, wherein each substituted R²Having one or more substituents independently selected from the group consisting of: F. cl, Br, I, CN, NO₂、(C₁-C₆) Alkyl, (C)₂-C₆) Alkenyl, (C)₁-C₆) Haloalkyl, (C)₂-C₆) Haloalkenyl, (C)₁-C₆) Haloalkyloxy, (C)₂-C₆) Haloalkenyloxy, (C)₃-C₁₀) Cycloalkyl group, (C)₃-C₁₀) Cycloalkenyl group, (C)₃-C₁₀) Halocycloalkyl, (C)₃-C₁₀) Halocycloalkenyl group, (C)₆-C₂₀) Aryl, and (C)₁-C₂₀) A heterocyclic group;

(C)R³selected from H, substituted or unsubstituted (C)₁-C₆) Alkyl, substituted or unsubstituted (C)₃-C₁₀) Cycloalkyl, substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₃-C₁₀) Cycloalkyl, substituted or unsubstituted (C)₆-C₂₀) Aryl, and substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₆-C₂₀) Aryl radical, each of whichSubstituted R³Having one or more substituents independently selected from the group consisting of: F. cl, Br, and I; and

(D)R⁴selected from H, substituted or unsubstituted (C)₁-C₆) Alkyl, substituted or unsubstituted (C)₃-C₁₀) Cycloalkyl, substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₃-C₁₀) Cycloalkyl, substituted or unsubstituted (C)₆-C₂₀) Aryl, substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₆-C₂₀) Aryl, substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkenyl, and substituted or unsubstituted (C)₁-C₆) Alkyl radical (C)₂-C₆) Alkynyl, wherein each of said R⁴When substituted, one or more substituents selected from the group consisting of: F. cl, Br, I, CN, NO₂、(C₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkyloxy, (C)₁-C₆) Haloalkyloxy, (C)₃-C₁₀) Cycloalkyl group, (C)₃-C₁₀) Halocycloalkyl, (C)₆-C₂₀) Aryl, and (C)₁-C₂₀) A heterocyclic group.

In another embodiment of the invention, R¹Each independently selected from H, F, and Cl.

In another embodiment of the invention, R¹Is H.

In another embodiment of the invention, R³Selected from H, (C)₁-C₆) Alkyl, (C)₁-C₆) Haloalkyl, and (C)₆-C₂₀) And (4) an aryl group.

In another embodiment of the invention, R³Selected from H, CF₃、CH₂F、CHF₂、CH₃、CH₂CH₃、CH(CH₃)₂And phenyl.

In another embodiment of the invention, R³Is selected from H and CH₃。

In another embodiment of the invention, R⁴Is (C)₁-C₆) Alkyl radical (C)₃-C₁₀) A cyclic haloalkyl group.

In another embodiment of the invention, R⁴Selected from H, (C)₁-C₆) Alkyl, (C)₁-C₆) Alkyl radical (C)₆-C₂₀) Aryl group, (C)₁-C₆) Haloalkyl, (C)₁-C₆) Alkyl radical (C)₃-C₁₀) Cycloalkyl group, (C)₃-C₁₀) cycloalkyl-O- (C)₁-C₆) Alkyl, and (C)₃-C₁₀) A cyclic haloalkyl group.

In another embodiment of the invention, R⁴Selected from H, CH₃、CH₂CH₃、CH(CH₃)₂、CH₂CH(CH₃)₂Cyclopropyl group, (C)₆-C₂₀) Aryl radical, CH₂-phenyl, CH₂-phenyl-OCH₃、CH₂OCH₂-phenyl, CH₂CH₂CH₃、CH₂CH₂F、CH₂CH₂OCH₃、CH₂Cyclopropyl, and cyclopropyl-O-CH₂CH₃。

In another embodiment of the invention, R⁴Selected from H, CH₃、CH₂CH₃、CH(CH₃)₂、CH₂CH(CH₃)₂、CH₂CH₂CH_3,Cyclopropyl, CH₂Cyclopropyl, and CH₂CH＝CH₂、CH₂C≡CH。

In another embodiment of the present invention, as an intermediate useful in the synthesis of the thiazole amide insecticides, a molecule having the structure of compound (III) is disclosed.

Generally speaking, S-R²Is a leaving group, wherein R²Is a leaving group moiety that does not significantly and adversely affect the desired reaction. Expectation of R²Are groups that favorably affect the volatility of the sulfur-containing by-products of the reaction.

In step a1, compounds (I) and (IIa) are reacted to give compound (IIb). The reaction can be carried out at ambient temperature and pressure, but higher or lower temperatures and pressures can be used if desired. The compounds (IIa) and (IIb) may be in the form of salts or free bases. When compound (IIa) is a salt, the reaction is carried out in the presence of a base (e.g. triethylamine). The reaction is carried out in a polar protic solvent. Examples of such solvents include, but are not limited to, formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, and water. Currently, methanol is preferred.

In step a2, compound (IIb) is reacted with compound (IIc) to yield compound (III). The reaction may be carried out at ambient temperature and pressure, but higher or lower temperatures and pressures, for example temperatures of from 50 ℃ to 70 ℃, may be used if desired. The reaction is carried out in a polar solvent, such as an ether or alcohol. Examples of such solvents include, but are not limited to, dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide, n-butanol, isopropanol, n-propanol, ethanol, and methanol. Currently, methanol is preferred. An excess molar ratio of compound (IIc) to (IIb) may also be used, for example about 25:1(IIc) to (IIb), but a molar ratio of about 3:1 to 20:1 may be used, preferably a molar ratio of about 10:1 to 15: 1.

In step b, compound (III) is cyclized using a dehydrating agent. Examples of such dehydrating agents include, but are not limited to, POCl₃、H₂SO₄、SOCl₂、P₂O₅Polyphosphoric acid, p-toluenesulfonic acid, and trifluoroacetic anhydride. The reaction can be carried out at ambient temperature and pressure, but higher or lower temperatures and pressures can be used if desired. At present, it is preferred to use a temperature above ambient temperature, and preferably up to and including the boiling point of the solution, e.g. one may useA temperature of about 60 ℃ to about 120 ℃. The reaction is carried out in a polar protic solvent. Currently, acetonitrile is preferred.

The advantage of these processes is that in the compounds (IV) -if R³Is H, which may be halogenated. Thus, at this time, R³Also included are F, Cl, Br, and I (see scheme II below).

In step c, any halogenating agent may be used, for example, 1-chloropyrrolidine-2, 5-dione, N-bromosuccinimide and 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate)). Polar solvents such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethylsulfoxide can be used. Currently, dichloromethane is preferred. The reaction can be carried out at room temperature and pressure, but higher or lower temperatures and pressures can be used if desired. Currently, temperatures from about 0 ℃ to about ambient temperature are preferred.

In another embodiment of the invention, R³Preferably Cl.

Compound (IV) or compound (V) may be further reacted to form certain pesticides disclosed in WO 2010/129497, the entire contents of which are incorporated herein by reference.

Examples

The examples are for illustrative purposes and should not be construed as limiting the invention disclosed in this application to only the embodiments disclosed in these examples.

Commercial starting materials, reagents and solvents were used without further purification. Without waterSolvent from Aldrich as Sure/Seal^TMPurchased and used as received. Melting points were obtained by Thomas Hoover Unimelt capillary Melting Point apparatus or Optimelt Automated Melting Point System in Stanford Research Systems and are uncorrected. The molecules are given their known names, which are named according to the naming program in ISIS Draw, chemddraw or acdiname Pro. If the program is unable to name a molecule, the molecule is named using conventional naming rules. All NMR's are given in ppm () and are recorded at 300, 400 or 600MHz unless otherwise stated.

Example 1 preparation of N-Ethyl-2- (pyridine-3-carbothioic acid amide):

step 1 preparation of methyl 2-pyridine-3-carbothioamide acetate:

to a dry 50ml round bottom flask equipped with a magnetic stirrer, nitrogen inlet, bleach scrubber, thermometer, and addition funnel was added picoline-3-dithiocarboxylic acid ester (2.0g,11.82mmol), methyl 2-aminoacetate hydrochloride (1.48 g; 11.82mmol), and 20ml methanol. Triethylamine (1.20g,11.82mmol) in methanol (5mls) was added dropwise. The mixture was stirred at ambient temperature for 16 hours. The reaction mixture was poured into 200ml of water and the aqueous mixture was extracted with 3x50ml ethyl acetate. The combined organic extracts were washed with water and brine, anhydrous MgSO₄Dried, filtered and concentrated on a rotary evaporator under reduced pressure. The crude product was then dissolved in dichloromethane and chromatographed on silica gel (80g ISCO cartridge) with a gradient of 100% hexane to 100% ethyl acetate over 20 minutes. The pure fractions were combined and the solvent was evaporated in vacuo to give the title compoundIt was a viscous yellow oil (1.6g, 64%):¹H NMR(400MHz,CDCl₃)8.96(dd,J＝2.4,0.8Hz,1H),8.68(dd,J＝4.8,1.7Hz,1H),8.47(bs,1H),8.16(ddd,J＝8.0,2.4,1.7Hz,1H),7.35(ddd,J＝8.0,4.8,0.9Hz,1H),4.59(d,J＝4.7Hz,2H),3.86(s,3H)；ESIMS m/z 209.17([M-H]^-).

step 2, preparing N-ethyl-2- (pyridine-3-thiocarboxamide) acetamide:

to a cooled (-40 ℃ C.) solution of methyl 2- (pyridine-3-thiocarboxamide) acetate (2.5g,11.89mmol) in 20ml methanol in a 45ml Parr reactor was added ethylamine (6.6g,146.00 mmol). The Parr reactor was closed and heated to 60 ℃ for 5 hours. To this solution 5g of silica gel was added and the reaction was evaporated to dryness. The sample was chromatographed on ISCO using a gradient of ethyl acetate and dichloromethane followed by 100% ethyl acetate. The solvent was removed in vacuo to give the title compound as a yellow solid (1.8 g; 68%); mp 136-138 ℃;¹H NMR(400MHz,d₆-DMSO)10.62(s,1H),8.94(dd,J＝2.4,0.7Hz,1H),8.68(ddd,J＝13.4,4.8,1.7Hz,1H),8.15-7.94(m,2H),7.49(tdd,J＝8.0,4.8,0.8Hz,1H),4.34(s,2H),3.21-3.03(m,2H),1.03(t,J＝7.2Hz,3H)；¹³CNMR(101MHz,DMSO-d₆)195.74(s),166.34(s),151.87(s),151.29(s),148.66(s),147.70(s),136.20(s),135.02(d,J＝18.7Hz),123.37(s),123.00(s),48.79(s),40.13(s),39.93(s),39.72(s),39.51(s),39.30(s),39.09(s),38.88(s),33.51(s),14.71(s)。

EXAMPLE 2 preparation of N- (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -N, 2-dimethyl-3- (methylthio) propionyl Amine:

step 1 preparation of N-methyl-2- (pyridin-3-yl) thiazol-5-amine:

a dry 2L round bottom flask equipped with a mechanical stirrer, addition funnel and reflux condenser was charged with N-methyl-2- (pyridine-3-thiocarboxamide) acetamide (100g,478mmol) and acetonitrile (1L). To this mixture was added phosphorus oxychloride (256g,1672mmol) in portions over 10 minutes. The reaction mixture was stirred at ambient temperature for 10 minutes during which a slight exotherm from 22 ℃ to 34 ℃ occurred. The reaction mixture was heated to 85 ℃ (mild reflux). After 3 hours, all solids had dissolved, forming a dark amber solution. After 4 hours an aliquot was analyzed by TLC (70% ethyl acetate: 30% hexane) indicating that the reaction was essentially complete. The reaction mixture was allowed to cool to 25 ℃ and the solvent was removed by rotary evaporation. The residue was dissolved in water with continuous stirring and treated with sodium bicarbonate solid until slightly basic (pH 8). After a few minutes a brown precipitate began to form. The mixture was stirred continuously at 25 ℃ for 16 hours. The brown solid was collected by vacuum filtration and washed with water. This gave a brown solid wet cake (91g) which was then dried under vacuum at 40 ℃ to constant weight. This gave N-methyl-2- (pyridin-3-yl) thiazol-5-amine as a colored sand-like solid (68.5g, 75% yield); mp140-141 ℃;¹H NMR(400MHz,CDCl₃)8.98(dd,J＝2.3,0.7Hz,1H),8.53(dd,J＝4.8,1.6Hz,1H),8.07(ddd,J＝8.0,2.2,1.7Hz,1H),7.40–7.21(m,1H),6.96(s,1H),4.18(s,1H),2.96(s,3H)；¹³C NMR(101MHz,CDCl₃)153.23,149.15,146.54,132.23,130.47,123.65,121.20, 34.48; to C₉H₉N₃C, 56.52; h, 4.74; n, 21.97; s,16.77, actually measuring C,56.31: H, 4.74; n, 21.81; and S, 16.96.

Step 2 preparation of 4-chloro-N-methyl-2- (pyridin-3-yl) thiazol-5-amine:

equipped with a magnetic stirrer, a thermometer, anda dry 100mL round bottom flask with nitrogen inlet was charged with N-methyl-2- (pyridin-3-yl) thiazol-5-amine (0.528g,2.76mmol) and dichloromethane (50 mL). The resulting solution was cooled to 5 ℃ and solid N-chlorosuccinamide (0.312g,2.76mmol) was added in portions. After all chlorinating agent was added, a dark brown solution was formed. The solution was stirred at 5 ℃ for 20 min, then aliquots were analyzed by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water and 0.05% TFA over 20 min @1.0 ml/min). HPLC analysis showed no starting material and showed one major product. The reaction mixture was poured into a separatory funnel containing dichloromethane (50mL) and washed with water (2 × 10mL) followed by saturated aqueous sodium chloride (10 mL). Dried over anhydrous magnesium sulfate, filtered and the organic phase rotary evaporated to give a brown solid (0.51g) as a powder. The solid was purified on an ISCO Combiflash Rf (silica gel 80g cartridge, mobile phase a ═ hexane, B ═ ethyl acetate, gradient 0% B to 100% B over 20 minutes). The tubes containing the desired material were combined and rotary evaporated to give 4-chloro-N-methyl-2- (pyridin-3-yl) thiazol-5-amine as a pale yellow solid (0.32g, 51% yield);¹H NMR(400MHz,CDCl₃)8.97(dd,J＝2.3,0.7Hz,1H),8.54(dd,J＝4.8,1.6Hz,1H),8.07(ddd,J＝8.0,2.3,1.6Hz,1H),7.45–7.14(m,1H),4.07(dd,J＝40.5,38.0Hz,1H),3.03(d,J＝5.3Hz,3H)；¹³C NMR(101MHz,CDCl₃)149.55,146.03,145.60,145.28,131.73,129.71,123.64,117.37, 35.75; to C₉H₈ClN₃S, C,49.89 of analysis and calculation; h, 3.57; n, 18.62; s,14.21, actually measuring C,48.03: H, 3.64; n, 18.42; s, 14.23.

Step 3 preparation of N- (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -N, 2-dimethyl-3- (methylthio) propionyl Amine:

to a dry 500mL round bottom flask equipped with a magnetic stirrer, thermometer, and nitrogen inlet was added 4-chloro-N-methyl-2- (pyridin-3-yl) thiazol-5-amine (22g,97mmol) and dichloromethane (250 mL). The suspension was stirred at room temperature while adding pyridine (8.48g,107mmol) and DMAP (1.20g,9.75 mmol). To this suspension was added 2-methyl-3- (methylthio) propionyl chloride (17.8g,117mmol) over 5 minutes. During the addition processAll solids went into solution and the reaction exothermed from 20 ℃ to 30 ℃. The reaction was stirred at ambient temperature for 16 h. The mixture was checked by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water and 0.05% TFA over 20 min @1.0ml/min), which showed that all starting materials were completely converted. The reaction mixture was diluted with dichloromethane and then water was added. The mixture was poured into a separatory funnel containing dichloromethane and water, and layer separation occurred. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and rotary evaporated to give 33.6g of a dark oil. The oil was purified on an ISCO Combiflash Rf (330g silica gel cartridge, mobile phase a ═ hexane, B ═ ethyl acetate, gradient 0% B to 100% B, over 20). Fractions were collected into 25mL assay tubes. The tubes containing the desired material were combined and the solvent removed by rotary evaporation. This gave 22.8g of a viscous yellow liquid, isolated in 68.4% yield. The entire sample was crystallized and hexane (200mL) was added to give a slurry. The slurry was vacuum filtered and the solid allowed to air dry. This gave N- (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -N, 2-dimethyl-3- (methylthio) propionamide as an off-white solid; mp 75-80 ℃;¹H NMR(400MHz,CDCl₃)9.12(d,J＝1.4Hz,1H),8.73(d,J＝3.8Hz,1H),8.34–8.09(m,1H),7.43(dd,J＝7.9,4.9Hz,1H),3.30(s,3H),3.06–2.70(m,2H),2.49(d,J＝7.4Hz,1H),2.04(s,3H),1.21(d,J＝6.4Hz,3H)；¹³CNMR(101MHz,DMSO-d₆)175.22,162.37,151.91,146.53,136.46,134.64,133.35,127.98,124.27,37.47,36.71,36.47,17.56,15.44 pairs of C₁₄H₁₆ClN₃OS₂C, 49.18; h, 4.72; n, 12.29; s,18.76, actually measuring C,49.04, H, 4.68; n, 12.29; and S, 18.68.

Claims (10)

1. A method comprising

Scheme one

(i) Reacting compound (I) with compound (IIa) to produce compound (IIb), wherein the reaction is carried out at ambient temperature and ambient pressure and in a polar protic solvent; followed by

(ii) Reacting compound (IIb) with compound (IIc) to produce compound (III), wherein the reaction is carried out at ambient temperature and ambient pressure and in a polar solvent; followed by

(iii) Cyclizing compound (III) using a dehydrating agent to produce compound (IV), wherein the reaction is carried out at ambient temperature and pressure and in a polar protic solvent;

wherein

(A)R¹Is H;

(B)R²is (C)₁-C₆) An alkyl group;

(C)R³is H; and

(D)R⁴is (C)₁-C₆) An alkyl group.

2. The process of claim 1, wherein step a1 is performed in formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water, or a mixture thereof.

3. The process of claim 1 wherein step a1 is carried out in methanol.

4. The process according to claim 1, wherein the cyclisation of the compound (III) of step b is carried out using a dehydrating agent selected from POCl₃、H₂SO₄、SOCl₂、P₂O₅Polyphosphoric acid, p-toluenesulfonic acid, trifluoroacetic anhydride, and mixtures thereof.

5. The process of claim 1, wherein step b is performed in acetonitrile.

6. The method of claim 1, wherein the method further comprises subjecting the R to³Halogenation is F, Cl, Br or I.

7. The process of claim 6 wherein the halogenation is carried out in a solvent selected from the group consisting of dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethylsulfoxide.

8. The process of claim 7, wherein the solvent is dichloromethane.

9. The process of any one of claims 6, 7 and 8, wherein the halogenation is carried out at a temperature of from 0 ℃ to ambient temperature.

10. The method of any one of claims 6, 7 and 8, wherein R is³Halogenation to Cl.