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    • 专利摘要:
    Methods for Producing Certain 2- (Pyridin-3-yl) Thiazoles The invention described herein relates to the field of processes for producing certain 2- (pyridin-3-yl) thiazoles as intermediates for the synthesis of thiazol amide pesticides.
    公开号:BR112014030091B1
    申请号:R112014030091-7
    申请日:2013-05-30
    公开日:2019-01-15
    发明作者:Ronald Ross；Carl Deamicis；Yuanming Zhu；Noormohamed M. Niyaz；Scott P. West；Gary Roth
    申请人:Dow Agrosciences Llc；
    IPC主号:
    专利说明:

    Invention Patent Descriptive Report for PROCESSES TO PRODUCE CERTAIN 2- (PYRIDINE-3-IL) THIAZOLS. CROSS REFERENCES TO RELATED REQUESTS [001] This claim claims priority for, and benefit from, United States Interim Order 61 / 655,086, filed on June 4, 2012. The full content of this provisional order is therefore incorporated by reference into its wholeness.
    FIELD OF DESCRIPTION [002] The invention described in this document is related to the field of processes for producing certain 2- (pyridine-3-yl) thiazoles as intermediates for the synthesis of thiazole amide pesticides. BACKGROUND TO THE DESCRIPTION [003] Pest population control is essential for modern agriculture, food storage, and hygiene. There are more than ten thousand species of pests that cause losses in agriculture. Agricultural losses around the world amount to billions of US dollars each year. Pests, such as termites, are also known to cause damage to all types of private and public structures, resulting in billions of US dollars in losses each year. Pests also eat and adulterate stored food, resulting in billions of US dollars in losses each year, as well as deprivation of food needed by people.
    [004] Certain pests have developed or are developing resistance to pesticides in current use. Hundreds of pest species are resistant to one or more pesticides. Consequently, there is an ongoing need for new pesticides and processes for forming such pesticides.
    [005] WO 2010/129497 (the full description of which is incorporated herein) discloses certain pesticides. However, the pro-
    2/24 production of such pesticides can be both costly and inefficient. Consequently, there is a need for processes for efficiently forming such pesticides.
    DEFINITIONS [006] The examples given in the definitions are generally not exhaustive, and should not be construed as limiting the invention described in this document. It is understood that a substituent must comply with the rules of chemical bonding and steric compatibility restrictions in relation to the particular molecule to which it is attached.
    [007] alkenyl means an acyclic substituent, unsaturated (at least one carbon-carbon double bond), branched or unbranched, consisting of carbon and hydrogen, for example, vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl and decenyl.
    [008] alkenyloxy means an alkenyl additionally consisting of a single carbon-oxygen bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy and decenyloxy.
    [009] alkoxy means an alkyl additionally consisting of a single carbon-oxygen bond, for example, methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentoxy, 2-methylbutoxy, 1,1- dimethylpropoxy, hexoxy, heptoxy, octoxy, nonoxy and decoxy. [0010] alkyl means an acyclic substituent, saturated, branched or unbranched, consisting of carbon and hydrogen, for example, methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, isobutyl, tert-butyl, pentyl, 2 -methylbutyl, 1,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl and decyl.
    [0011] alkynyl means an acyclic substituent, unsaturated (at least one carbon-carbon triple bond, and any double bonds), branched or unbranched, consisting of carbon and hydro
    3/24 genius, for example, ethynyl, propargyl, butynyl, pentinyl, hexynyl, heptinyl, octinyl, noninyl and decinyl.
    [0012] alkynyloxy means an alkynyl additionally consisting of a single carbon-oxygen bond, for example, pentynyloxy, hexynyloxy, heptinyloxy, octinyloxy, noninyloxy and decinyloxy.
    [0013] aryl means a cyclic, aromatic substituent consisting of hydrogen and carbon, for example, phenyl, naphthyl and biphenyl.
    [0014] cycloalkenyl means a monocyclic or polycyclic substituent, unsaturated (at least one carbon-carbon double bond) consisting of carbon and hydrogen, e.g. , cyclodecenyl, norbornenyl, bicycles [2.2.2] octenyl, tetrahydronaphthyl, hexahydronaphil and octahydronaphthyl.
    [0015] cycloalkenyloxy means a cycloalkenyl additionally consisting of a single carbon-oxygen bond, for example, cyclobutenyloxy, cyclopentenyloxy, cyclohexylhexenyloxy, cyclohexenyloxy, cyclooctenyloxy, cyclodecenyloxy, norbornenyloxy, and 2,2-cyclohexylenoxy.
    [0016] cycloalkyl means a monocyclic or polycyclic substituent, saturated, consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylhexyl, cyclohexylheptyl, cyclooctyl, cyclodecyl, norbornyl, bicycle [2.2. 2] octyl and decahydronaphthyl.
    [0017] cycloalkoxy means a cycloalkyl additionally consisting of a single carbon-oxygen bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexylhexyloxy, cyclohexyloxy, cyclooctyloxy, cyclodecyloxy, norbornyloxy and 2.2 bicycle]. octyloxy.
    [0018] cyclohaloalkyl means a monocyclic or polycyclic substituent, saturated, consisting of halo carbon, and hydrogen, for example, 1-chlorocyclopropyl, 1-chlorocyclobutyl and 1-dichlorocyclopentyl.
    4/24 [0019] halo means fluorine, chlorine, bromine and iodine.
    [0020] haloalkyl means an alkyl additionally consisting of, from one to the maximum possible number of halos, identical or different, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, trichloromethyl and 1,1,2,2-tetrafluoroethyl.
    [0021] heterocyclyl means cyclic substituent that can be completely saturated, partially unsaturated, or completely unsaturated, where the cyclic structure contains at least one carbon and at least one heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen, for example, benzofuranyl , benzoylothiazolyl, benzoyloxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl cinolinyl, furanyl, indazolyl, indolyl, imidazolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyrazazolyl, oxazazolyl, pyrazazolyl, pyrazazolyl, oxazazolyl, pyrazazolyl, oxazazolyl, oxazazolyl 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 OF THE DESCRIPTION [0022] One embodiment of this invention is illustrated in Scheme One
    5/24
    Scheme One
    where [0023] (A) each R 1 is independently selected from H, F, Cl,
    Br, I, CN, NO 2j and substituted or unsubstituted (C 1 -C 6 ) alkyl, in which each substituted R 1 has one or more substituents independently selected from F, Cl, Br, I, CN, NO 2 , (Ci -C 6 ) alkyl, and (C r C 6 ) haloalkyl;
    [0024] (B) R 2 is selected from (C-C 6 ) substituted or unsubstituted alkyl, (C2-C 6 ) substituted or unsubstituted alkenyl, (C r C 6 ) substituted or unsubstituted alkoxy, (C2- C 6 ) substituted or unsubstituted alkenyloxy, substituted or unsubstituted (C 3 -C 10) cycloalkyl, substituted or unsubstituted (C 3 -C 2 ) cycloalkyl, (C 6 -C 2) substituted or unsubstituted aryl, (C 1 -C 6) alkyl ) (C6-C2o) substituted or unsubstituted aryl, and (C1-C2o) substituted or unsubstituted heterocyclyl, in which each substituted R 2 has one or more substituents independently selected from F, Cl, Br, I, CN, NO 2 , (C-C 6 ) alkyl, (C 2 C 6 ) alkenyl, (C-C 6 ) haloalkyl, (C2-C 6 ) haloalkenyl, (C r Cejhaloalkyloxy, (C2-C 6 ) haloalkenyloxy, (C 3 - Cio) cycloalkyl, (C 3 Cio) cycloalkenyl, (C 3 -Cio) halocycloalkyl, (C 3 -Cio) halocycloalkenyl, (C 6 -C2o) aryl, and (Ci-C2o) heterocyclyl;
    [0025] (C) R 3 is selected from H, (C 1 -C 6 ) substituted or unsubstituted alkyl
    6/24 substituted, (C 3 -Cio) substituted or unsubstituted cycloalkyl, (C r C 6 ) substituted or unsubstituted (C 3 -C 10 ) cycloalkyl, (C 6 C 20 ) substituted or unsubstituted aryl, and (C6-C6) alkyl (C6-C 2 o) substituted or unsubstituted aryl, in which each substituted R 3 has one or more substituents independently selected from F, Cl, Br, and I; and [0026] (D) R 4 is selected from H, (C 1 -C 6 ) substituted or unsubstituted alkyl, (C 3 -C 10) substituted or unsubstituted cycloalkyl, (C r C 6 ) (C 3 -C) alkyl 10 ) substituted or unsubstituted cycloalkyl, (C 6 C 20 ) substituted or unsubstituted aryl, (C 1 -C 6 ) alkyl (C 6 -C 2 ) aryl substituted or unsubstituted, (C 1 -C 6 ) alkyl (C 2 -C 6 ) alkenyl substituted or unsubstituted, and (C 1 -C 6 ) alkyl (C 2 -C 6 ) substituted or unsubstituted alkynyl, in which each said R 4 , which is substituted, has one or more substituents selected from F, Cl, Br , I, CN, NO 2 , (Ci-C 6 ) alkyl, (Ci-C 6 ) haloalkyl, (Ci-C 6 ) alkyloxy, (Ci-C 6 ) haloalkyloxy, (C 3 Cio) cycloalkyl, (C 3 -Cio) halocycloalkyl, (C6-C 20 ) aryl and (C1-C20) heterocyclyl.
    [0027] In another embodiment of this invention, each R 1 is independently selected from H, F, and Cl.
    [0028] In another embodiment of this invention, R 1 is H.
    [0029] In another embodiment of this invention, R 3 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) haloalkyl and (C 6 -C 20 ) aryl.
    [0030] In another embodiment of this invention, R 3 is selected from H, CF 3 , CH 2 F, CHF 2 , CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , and phenyl.
    [0031] In another embodiment of this invention, R 3 is selected from H and CH 3 .
    [0032] In another embodiment of this invention, R 4 is (C r C6) alkyl (C 3 -C 10) cyclohaloalkyl.
    [0033] In another embodiment of this invention, R 4 is selected from H, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkyl (C 6 -C 2 o) aryl, (C 1 -C 6 ) haloalkyl, (C r C6) (C 3 -C 10) alkyl cycloalkyl, (C 3 -C 10) cycloalkyl-0- (C 1 -C 6) alkyl, and (C 3 7/24
    Cyclohaloalkyl.
    [0034] In another embodiment of this invention, R 4 is selected from H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , cyclopropyl, (C 6 C 20 ) aryl, CH 2 -phenyl, CH 2 -phenyl-OCH 3 , CH 2 OCH 2 -phenyl, CH 2 CH 2 CH 3 , CH 2 CH 2 F, CH 2 CH 2 OCH 3j CH 2 cyclopropyl, and cyclopropyl-O-CH 2 CH 3 .
    [0035] In another embodiment of this invention, R 4 is selected from H, CH 3 , CH 2 CH 3 , CH (CH 3 ) 2 , CH 2 CH (CH 3 ) 2 , CH 2 CH 2 CH 3 . cyclopropyl, CH 2 cyclopropyl, and CH 2 CH = CH 2 , CH 2 C 2 CH.
    [0036] In another embodiment of this invention, molecules having a structure according to compound (III) are described as useful intermediates for the synthesis of thiazole amide pesticides.
    [0037] In general, SR 2 is a starting group in which R 2 is part of the starting group that does not substantially and adversely affect the desired reaction. It is desirable that R 2 is a group that beneficially affects the volatility of the by-product of the reaction.
    [0038] In step a, compounds (I) and (II) are reacted to produce compound (III). The reaction can be conducted at room temperature and under room pressure, but higher or lower temperatures and pressures can be used, if desired. 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, npropanol, ethanol, methanol, acetic acid, and water. Currently, methanol is preferred.
    [0039] In step b, the compound (III) is cyclized using a dehydrating agent. Examples of such dehydrating agents include, but are not limited to, POCI 3 , H 2 SO 4 , SOCI 2 , P 2 O 5 , polyphosphoric acid, p-toluene sulfonic acid, and trifluoroacetic anhydride. The reaction can be conducted at room temperature and under room pressure, higher or lower temperatures and pressures can be used, if desired. It is currently preferred if a temperature higher than
    8/24 room temperature is preferably used up to and including the boiling point of the solution, for example, a temperature of about 60 ° to about 120 ° can be used. The reaction is conducted in a protic polar solvent. Currently, acetonitrile is preferred.
    [0040] An advantage of steps a and b over the technique is that compounds (III) and (IV) are generally produced as substantially pure solids that do not require additional purification procedures. Another advantage with these processes is that in compound (IV) - if R 3 is H, it can be halogenated. Consequently, at this point, R 3 additionally now includes F, Cl, Br, and I (see Scheme Two).
    Scheme Two
    [0041] In step c, any halogenating agent can be used, for example, 1-chloropyrrolidine-2,5-dione, / V-bromosuccinimide, and 1-chloromethyl-4-fluoro-1,4-diazoniabicycle [2.2. 2] octane bis (tetrafluoroborate). Polar solvents can be used, such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile, and dimethyl sulfoxide. Currently, dichloromethane is preferred. The reaction can be conducted at ambient temperature and pressure, but higher or lower temperatures and pressures can be used, if desired. Currently, temperatures of about 0Ό to about room temperature are preferred.
    [0042] In another embodiment of this invention, R 3 is preferably Cl.
    [0043] The compound (IV) or the compound (V) can be further reacted 9/24 to form certain pesticides described in WO 2010/129497 (the full description of which is incorporated herein by reference).
    EXAMPLES [0044] The examples are for the purpose of illustration, and are not to be construed as limiting the invention described in this document to only the embodiments described in these examples.
    [0045] Starting materials, reagents and solvents, which were obtained from commercial sources, were used without further purification. Anhydrous solvents were purchased as Sure / Seal ™ from Aldrich, and were used as received. Melting points were obtained on a Thomas Hoover Unimelt capillary melting point apparatus, or on an OptiMelt Automatic Melting Point System from Stanford Research Systems, and are uncorrected. Molecules are given their known names, named according to naming programs within ISIS Draw, ChemDraw or ACD Name Pro. If such programs are unable to name a molecule, the molecule is named using conventional naming rules. All NMRs are in ppm (δ), and were recorded at 300, 400, or 600 MHz, unless otherwise noted.
    Example 1: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A / -ethyl-2methyl-3- (methylthio) propanamide:
    Cl
    Step 1: Preparation of A / -ethyl-2- (pyridin-3-carbothioamido) acetamide:
    10/24
    [0046] To a 3 L dry round-bottom flask equipped with mechanical stirrer, nitrogen inlet, sequential three-stage mercaptan purifier (bleach, 30% sodium hydroxide, and saturated potassium hydroxide), thermometer, and funnel additionally, 2-amino-A / -ethylacetamide hydrochloride (SPECS, Catalog # AS787, 68.8 g, 500 mmol) and methanol (500 mL) were loaded. The reaction was cooled to 5 ° C, and triethylamine (50.6 g, 500 mmol) in methanol (50 ml) was added dropwise (note: slightly exothermic at 10 ° C). To this mixture was added methyl pyridine-3-carbodithiolate (85.0 g, 500 mmol) in methanol (100 ml) dropwise, and the resulting mixture stirred at 510 ° C for 2 hours. The reaction mixture was allowed to warm to 25 C, and stirred under nitrogen for 2 hours. The reaction mixture was cooled to 5 ° C, and water (1 L) was added to a solid precipitated from the solution. The solid was collected by vacuum filtration, washed with water (3 L), hexanes (500 mL), and dried with air for 16 hours to give / V-ethyl-
    2- (pyridin-3-carbothioamido) acetamide as a soft yellow solid (free of any mercaptan odor) which was dried in vacuo at 40 ° C for 6 hours. This gives a yellow solid (77.7 g, 70% yield): mp 143-145 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 9.02 (dd, J = 2.4, 0.7 Hz, 1H), 8.86 (s, 1H), 8.70 (dd, J = 4, 8, 1.6 Hz, 1H), 8.15 (ddd, J = 8.0, 2.4,
    1.7 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 6.05 (s, 1H), 4.43 (d, J = 4 , 5 Hz, 2H), 3.38 (dd, J = 13.0, 6.4 Hz, 2H), 1.20 (t, J = 7.3 Hz, 3H); 13 C-NMR (101 MHz, CDCI 3 ) δ 195.66, 166.90, 152.00, 147.20, 136.32, 134.96, 123.24, 49.45, 34.92, 14, 75; Analytical Calculation for C10H13N3OS: C, 53.79; H, 5.87; N, 18.82; S, 14.36, Found: C, 53.77: H, 5.79; N, 18.87; S, 14.52.
    11/24
    Step 2: Preparation of A / -ethyl-2-foiridin-3-yl) thiazol-5-amine:
    [0047] To a 1 L dry round-bottom flask equipped with mechanical stirrer, addition funnel and reflux condenser was charged A / -ethyl-2- (pyridine-3-carbothioamido) acetamide (50.0 g, 224 mmol ) and acetonitrile (400 ml). To this mixture was added phosphorus oxychloride (103 g, 672 mmol) dropwise, and the reaction stirred at room temperature for 20 minutes. The reaction mixture was heated to 55 C, and the course of the reaction was monitored by HPLC (YMC AQ column 5% acetonitrile (ACN) 95% water-0.05% trifluoroacetic acid (TFA) at 95% ACN 5% water with 0.05% TFA for 20 Min (1.0 ml / min). After 2 hours, the reaction was essentially complete. The reaction was cooled to 25 ° C, and the solvent removed by rotary evaporation to give a thick yellow syrup. The thick yellow syrup was carefully poured into a saturated aqueous solution of sodium bicarbonate (1.5 L) with rapid stirring. The pH of the resulting yellow solution was adjusted with solid to slightly basic sodium bicarbonate (pH = 8), and a yellow solid precipitated from the solution. Additional cold water (1 L) was added to the mixture, and stirred for an additional 20 minutes. The precipitate was collected by vacuum filtration, and rinsed with water (1 L) and hexanes (500 mL). The collected solid was dried in vacuo at 40 ° C for 16 hours to give / V-ethyl-2 (pyridin-3-yl) thiazol-5-amine as a yellow solid (36.7 g, 80%): mp 97- 98 C; 1 H NMR (400 MHz, CDCI 3 ) δ 8.98 (dd, J = 2.3, 0.8 Hz, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H) , 8.07 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.31 (ddd, J = 8.0, 4.8, 0.8 Hz, 2H), 6 , 98 (s, 1H), 3.96 (s, 1H), 3.24 (q, J =
    5.8 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, CDCI 3 ) δ 152.00, 149.21, 149.21, 146.61, 132.17, 130.44, 123.62, 121.84,
    12/24
    43.09, 14.80, Analytical Calculation for C10HHN3S: C, 58.51; H, 5.40; N,
    20.47, Found: C, 58.34: H, 5.40; N, 20.38; ESIMS m / z 205 ([M + H] + ).
    Step 3: Preparation of 4-chloro- / V-ethyl-2- (pyridin-3-yl) thiazol5-amine hydrochloride:
    Cl .HCI [0048] To a 500 mL dry round-bottom flask equipped with magnetic stirrer, thermometer, and nitrogen inlet, A / -ethyl-2- (pyridin-3-yl) thiazole-5-amine ( 5.1 g, 25 mmol), diethyl ether (200 ml) and dioxane (5 ml). The resulting suspension (not all dissolved solid) was cooled to 5 ° C, and / V-chlorosuccinamide (3.65 g, 27.3 mmol) was added portion by portion. After all the chlorinating agent was added, a brown solid precipitated out of the solution. The reaction mixture was stirred at 5 C for 60 minutes, then analyzed by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0, 05% TFA for 20 Min @ 1.0 ml / min). HPLC analysis showed no starting material and a larger product consistent with the desired chloride. The brown suspension was filtered through a pad of Celite®, and the pad of Celite® rinsed with diethyl ether (~ 20 mL). The filtrate was cooled to 5 ° C and acidified with stirring by adding 6.5 ml of 4M HCI in dioxane. A yellow solid formed immediately. The solid was collected by vacuum filtration, rinsed with diethyl ether, and dried in vacuo at 40 ° C for 2 hours. This gave 4-chloro-A / -ethyl-2- (pyridin-3-yl) thiazol-5-amine hydrochloride as a yellow solid (6.3 g, 92%): mp 180-182 ° C; 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.07 (d, J = 2.0 Hz, 1H), 8.70 (dd, J = 5.4,
    13/24
    1.3 Hz, 1 Η), 8.59 - 8.42 (m, 1 Η), 7.86 (dd, J = 8.2, 5.3 Hz, 1H), 5.27 (s, 5H ), 3.20 (q, J = 7.2 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-de) δ 148.10, 140.19, 138.58, 137.91, 137.01, 132.06, 127.30, 115.89, 43.43, 13, 87; Analytical Calculation for C10HHCI2N3S: C, 43.49; H, 4.01; Cl, 25.67; N, 15.21; S, 11.61, Found: C, 43.42: H, 4.01; Cl, 25.55; N, 14.99; S, 11.46.
    Step 4: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A / -ethyl-2methyl-3- (methylthio) propanamide:
    [0049] In a 1 L three-neck flask fitted with a J-KEM type T temperature probe, upper stirrer, reflux condenser, and nitrogen inlet, 4-chloroA / -ethyl-2- hydrochloride ( pyridin-3-yl) thiazol-5-amine (75.8 g, 274 mmol) and dichloromethane (500 ml). To the resulting green suspension was added pyridine (55 g, 695 mmol, 2.5 eq) (note: fumigation, with exotherm of 20 Ca at 26 ° C) portion by portion for one minute. The reaction returned in a dark green-black solution. To this solution was added A /, A / -dimethylpyridin-4amine (DMAP, 16.5 g, 135 mmol, 0.5 eq) (note: no change in the appearance or temperature of the reaction), followed by 2-methyl-3-methylthiopropanoil chloride (44.3 g, 290 mmol, 1.06 eq), which was added portion by portion for one minute. The exothermic reaction of 17 Ca 29 C during the addition of acid chloride. The reaction was heated to 35 C for 19 hours and then cooled to 25 C for 4 hours. HPLC analysis (YMC AQ column 5% acetonitrile (ACN) 95% water0.05% trifluoroacetic acid (TFA) to 95% ACN 5% water with 0.05% TFA for 20 Min @ 1, 0 ml / min) showed that the reaction was 95% complete. The black reaction mixture was transferred to a 2 L separating funnel, and dichloromethane (200 ml) and water (300 ml) were added. The phases were separated, and the aqueous layer (brown) was extracted with dichloromethane (100 ml), and the dichloromethane extracts combined. The combined dichloromethane extract was
    14/24 washed with brine (300 ml), dried over anhydrous sodium sulfate, filtered, and evaporated (40 ° C, 40 mmHg, 1 hour). This gave 99.4 g of a thick black oil. The thick black oil was dissolved in dichloromethane (100 mL), and vacuum added to the top of a 240 g solid charge cartridge containing 230 g of silica gel 60. The solid charge cartridge was attached to an ISCO companion XL, and the Purified material on a 1.5 kg Redisep silica pre-filled column using a mobile hexane: ethyl acetate phase (gradient: 20% ethyl acetate 5 min, 20% -90% ethyl acetate for 70 minutes ) with a flow rate of 400 mL / min. The desired compound eluted from the column between 30-50 minutes was collected in 500 ml bottles (fractions 2-16). Fractions 2-9 were pooled (note: fractions 8-9, which were clouded, filtered through paper), and evaporated by rotation (40 ° C, 40 mmHg, 2 hours). This gave 56.8 g of a dark yellow oil which was 98% pure by HPLC at 254 nm. Fractions 10-15 were filtered and combined and evaporated by rotation (40 ° C, 40 mmHg, 2 hours) to give a golden oil (27.51 g). The sample was analyzed by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA for 20 Min @ 1.0 ml / min) at 254 nm, and showed a purity of 88%, and contained 10% of thiazolamine starting material and 2% of an unknown faster-moving impurity. The golden oil (27.5 g, 88% pure) was dissolved in ether (50 ml), and a yellow solid precipitated after 1 minute. The mixture was stirred for 15 minutes at 25 ° C, then hexane (50 ml) was added, and the mixture stirred for another 15 minutes at 25 ° C. The solid was collected by vacuum filtration, and the yellow solid washed with ether / hexane (1: 1, 25 ml). This gave 19.23 g of A / - (4-chloro-2- (pyridin-3yl) thiazol-5-yl) -A / -ethyl-2-methyl-3- (methylthio) propanamide as a yellow solid. HPLC analysis showed that the purity was 97% at 254 nm.
    56.8 g of sample (golden oil, 98% pure) was dissolved in
    15/24 ether (100 mL), and after 1 minute, a light bronze solid precipitated. The mixture was stirred for 15 minutes at 25 ° C, and hexane (100 ml) was added. The mixture was stirred for an additional 15 minutes. The solid was collected by vacuum filtration, and washed with ether / hexane (1: 1, 2 x 50 mL). This gave 49.67 g of light yellow solid. HPLC analysis (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0.05% TFA for 20 Min @ 1.0 ml / min) at 254 nm, it showed a purity of> 99%. The mother liquors from both recrystallization were combined and evaporated by rotation (40 ° C, 40 mmHg, 1 hour). This gave 11.27 g of a dark yellow oil. The oil was redissolved in ether (40 ml), and stirred for 30 minutes during which time a dark yellow precipitate formed. Hexane (50 mL) was added, and the mixture stirred for 15 minutes. The dark solid was collected by vacuum filtration, and washed with ether / hexane (1: 1, 2 x 20 mL). This gave 5.0 g of a brown solid which was evaluated to> 99% pure by HPLC at 254 nm. The recrystallized samples were all combined and mixed manually to give A / - (4-chloro-2- (pyridin-3-yl) thiazol-5yl) -A / -ethyl-2-methyl-3- (methylthio) propanamide as a yellow solid (75 g, 85%): mp 80-81 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 9.12 (d, J = 1.9 Hz, 1H), 8.72 (dd, J = 4.8, 1.4 Hz, 1H), 8.22 (ddd, J = 8.0, 2.2, 1.8 Hz, 1H), 7.43 (ddd, J = 8.0, 4.8, 0.6 Hz, 1H), 4.03 - 3 , 80 (m, 1H), 3.80 3.59 (m, 1H), 2.97 - 2.68 (m, 2H), 2.60 - 2.39 (m, 1H), 2.03 ( s, 3H),
    I, 30-1.16 (m, 6H); 13 C NMR (101 MHz, DMSO-cfe) δ 175.66, 162.63, 151.89, 147.14, 138.19, 133.49 133.23, 128.58, 123.90, 44.81 , 38.94, 37.93, 18.16, 16.83, 12.90; Analytical Calculation for Ci 5 H 18 CIN 3 OS2: C, 50.62; H, 5.10; N, 11.81; S, 18.02, Found: C, 50.49: H, 5.21; N,
    II, 77; S, 17.99.
    Example 2: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A / cyclopropyl-3- (methylthio) propanamide:
    16/24, ci
    N,
    Step 1: Preparation of 2-amino- / V-cyclopropylacetamide hydrochloride:
    HCl [0050] To a solution of 3H- [1,2,3] triazolo [4,5-ò] pyridin-3-ol (7.77 g, 57.1 mmol), 2- (tert-butoxycarbonylamino) acid acetic (10 g, 57.1 mmol), cyclopropanamine (3.91 g, 68.5 mmol) and DMAP (8.37 g, 68.5 mmol) in DMF (28 mL), A / 1- ( (ethylimino) methylene) -A / 3, A / 3dimethylpropane-1,3-diamine hydrogen chloride salt, and the mixture stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate, washed with aqueous 0.1 N HCl, aqueous NaHCO 3 and brine, dried over MgSO 4 , filtered and concentrated in vacuo to give tert-butyl 2- (cyclopropylamino) -2-oxoethylcarbamate (8 , 90 g, 41.5 mmol, 72.8%) as a pale yellow oil: 1 H NMR (400 MHz, CDCl3) δ 6.18 (s, 1H), 3.74 (d, J = 5.9 Hz, 2H), 2.71 (m, 1H), 1.45 (s, 9H); 0.840.7 (m, 2H), 0.56-0.43 (m, 2H); EIMS m / z 214 ([M] + ). To a solution of tert-butyl 2- (cyclopropylamino) -2-oxoethylcarbamate (8.5 g, 39.7 mmol) in dioxane (20 mL), was added HCl (100 mmol, 25 mL in 4 M dioxane), and the mixture stirred at 10Ό for 3 h. The mixture was diluted with hexanes and filtered under vacuum to give 2-amino-A / -cyclopropylacetamide, HCl salt as a white solid (5.2 g, 83%): mp 139-142 ° C; 1 H NMR (400 MHz, DMSO-d6) δ 8.66 (bs, 1H), 8.19 (bs, 3H), 3.46 (s, 2H), 2.73-2.60 (m, 1H ), 0.71-0.60 (m, 2H), 0.48-0.36 (m, 2H).
    Step 2: Preparation of A / -cyclopropyl-2- (pyridine-3carbothioamido) acetamide:
    17/24
    [0051] To a solution of methyl pyridine-3-carbodithioate (2.97 g, 17.52 mmol) in methanol (10 mL) was added to the solution of 2-amino / V-cyclopropylacetamide (2 g, 17.52 mmol) (HCI salt), and triethylamine (3.55 g, 35.0 mmol). The mixture was stirred at room temperature for 1 hour and then diluted with ethyl acetate, and washed with saturated aqueous NaHCO 3 , brine, dried over MgSO 4 , filtered, and concentrated in vacuo to give A / -cyclopropyl-2 - (pyridine-3carbothioamido) acetamide as a yellow solid (3.60 g, 83%): mp 152-153 Ό; 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.91 (ddd, J = 7.0, 2.3, 0.7 Hz, 1H), 8.76 - 8.56 (m, 1H), 8.10 (m, 2H), 7.57 - 7.32 (m, 1H), 4.26 (m, 2H), 2.73 - 2.57 (m, 1H), 0.77 - 0.61 (m, 2H), 0.50 0.29 (m, 2H); ESIMS (m / z) 234 ([MH]).
    Step 3: Preparation of A / -cyclopropyl-2- (pyridin-3-yl) thiazol-5-amine:
    [0052] A / -Cyclopropyl-2- (pyridine-3-carbothioamido) acetamide (1.00 g, 4.25 mmol) was dissolved in acetonitrile (5 mL) in a dry flask, and phosphoryloxy trichloride (3.26 g, 21.25 mmol) was added dropwise. The mixture was heated to 100Ό and stirred for 1 hour. The mixture was cooled to room temperature, and the yellow solid filtered under vacuum. This solid was washed with acetonitrile and dried in vacuo to give 0.36 g of A / -cyclopropyl-2- (pyridin-3-yl) thiazol-5-amine HCI salt (LCMS and 1 H-NMR indicated 100% of purity). The filtrate was diluted with ethyl acetate and carefully basified with saturated aqueous NaHCO 3 . The organic phase was separated and washed with brine, dried over Mg
    18/24
    SO 4 , and concentrated in vacuo to give A / -cyclopropyl-2- (pyridin-3-yl) thiazol5-amine as a brown oil (0.45 g, 3.47 mmol, 82%): 1 H NMR (400 MHz, CDCI 3 ) δ 9.10 (d, J = 2.1 Hz, 1H), 8.68 (dd, J = 5.5, 1.2 Hz, 1H), 8.63-8.58 ( m, 1H), 7.89 (dd, J = 8.1, 5.4 Hz, 1H), 7.07 (d, J = 7.8, 1H), 2.57 (dt, J = 10.0 , 3.3 Hz, 1H), 0.85-0.68 (m, 2H), 0.57-0.45 (m, 2H); ESIMS (m / z) 216 ([MH]).
    Step 4: Preparation of 4-chloro-A / -cyclopropyl-2- (pyridin-3-yl) thiazol-5amine:
    [0053] To a solution of A / -cyclopropyl-2- (pyridin-3-yl) thiazol-5-amine (1.00 g, 4.60 mmol) in acetonitrile (2 mL), 1 chloropyrrolidine-2 was added, 5-dione (645 mg, 4.83 mmol), and the mixture stirred at 0Ό for 1 h. The mixture was filtered, and the filtrate was treated with excess HCl (4M in dioxane), to give 4-chloro-A / -cyclopropyl-2- (pyridin-3yl) thiazol-5-amine as a brown solid: mp 56-60 ° C.
    Step 5: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) - / Vcyclopropyl-3- (methylthio) propanamide:
    [0054] To a solution of 4-chloro-A / -cyclopropyl-2- (pyridin-3-yl) thiazol5-amine HCl salt (288 mg, 1 mmol) and DMAP (305 mg, 2,500 mmol) in CH 2 CICH 2 CI (1 mL), 3- (methylthio) propanoyl chloride (166 mg, 1,200 mmol) was added, and the mixture stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate, mixed with aqueous NaHCO 3 (10 ml). The organic phase was separated, rinsed with brine (2x), dried over MgSO 4 , and concentrated in vacuo, to give a yellow gum. This gum was purified by reverse phase column chromatography (C-18, CH 3 CN / H 2 O), to give / V- (4-chloro-2 (pyridin-3-yl) thiazol-5-yl) -A / -cyclopropyl-3- (methylthio) propanamide (82 mg,
    19/24
    22%) as a brown gum: 1 H NMR (400 MHz, CDCI 3 ) δ 9.10 (s, 0.6H), 9.02 (s, 0.4H), 8.71 (s, 6H), 8.61 (d, J = 3.4 Hz, 0.4H), 8.21 (d, J = 7.6 Hz, 1H), 8.19-8.10 (m, 1H), 7.41 (d, J = 5.6, 0.6H), 7.35 (dd, J = 8.3, 4.5 Hz, 0.4H), 3.16 (bs, 1H), 2.91 (s , 3H), 2.88 - 2.72 (m, 2H), 2.11 (m, 2H), 0.85 (m, 4H); ESIMS (m / z) 354.56 ([M + H] + ).
    Example 3: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A /, 2-
    Step 1: Preparation of / V-methyl-2- (pyridine-3-carbothioamido) acetamide:
    [0055] A round-bottomed flask of three 5-liter necks was fitted with a nitrogen inlet over a drip funnel, a mechanical stirrer, and a reflux condenser. One tube from the top of the condenser was exhausted using a 1 liter impact flask and then a sprinkler tube in another 5 liter three-neck stirred flask filled with 2.5 liters of 12% bleach. The discharge from the bleach bottle was exhausted through an alligator trap with about 250 mL of 12% bleach solution. The reactor was charged with 2-amino-A / -methylacetamide (160 g, 1.81 mol) and acetonitrile (3 L), to give a cloudy solution. The drip funnel was loaded with methyl pyridine-3-carbodithioate (307 g, 1.81 mol) and acetonitrile (200 ml). The addition of the dithioate takes about 20 min, and the reaction was flushed with a good stream of nitrogen. A slight exotherm was noted after the addition (about 3 ° C). After
    20/24 the addition was completed, the drip funnel was rinsed with 550 ml of acetonitrile to bring the total volume of acetonitrile to 3750 ml. After stirring for about 10 min, the red solution precipitated to give a solid similar to cottage cheese that would not stir. The drip hopper was replaced with a 1/4 inch vertical tube to bubble nitrogen into the reactor. The reactor was heated slowly to about 45-50 ° C to form a reddish solution and then allowed to cool back slowly to room temperature, and crystallized to a yellowish needle-like solid that easily agitated. The needles were collected by vacuum filtration and washed with 100 ml of acetonitrile. The solid was dried under vacuum at 40 ° for 16 h to give A / -methyl-2- (pyridine-3-carbothioamido) acetamide (268.6 g, 71%) as a light yellow solid: mp 135-137 ° C; 1 H NMR (400 MHz, DMSO-de) δ 10.65 (s, 1H), 8.95 (dd, J = 2.4, 0.7 Hz, 1H), 8.67 (dd, J = 4 , 8, 1.6 Hz, 1H), 8.14 (ddd, J = 8.0, 2.3, 1.7 Hz, 1H), 7.95 (d, J = 4.3 Hz, 1H) , 7.48 (ddd, J = 7.9, 4.8, 0.7 Hz, 1H), 4.34 (s, 2H), 2.62 (d, J = 4.6 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 194.98, 165.77, 150.37, 146.40, 135.25, 134.04, 121.51, 47.66, 24.41; Analytical Calculation, for C9HHN3OS: C, 51.65; H, 5.30; N, 20.08; S, 15.32, Found:
    C, 51.47: H, 5.30; N, 20.01; S, 15.53.
    Step 2: Preparation of A / -methyl-2- (pyridin-3-yl) thiazol-5-amine:
    [0056] To a 2 L dry round-bottom flask equipped with mechanical stirrer, addition funnel, and reflux condenser, A / -methyl-2- (pyridine-3-carbothioamido) acetamide (100 g, 478 mmol ) and acetonitrile (1 L). To this mixture, phosphorus oxychloride (256 g, 1672 mmol) was added portion by portion for 10 minutes. The reaction mixture was stirred at room temperature for 10 minutes for
    21/24 whose time a slight exotherm occurred at 22 Ca 34 ° C (Note: some solid remained undissolved in the reaction mixture, and the mixture becomes thick, but still stirred reasonably well). The reaction mixture was heated to 85 ° C (reflux gently). After 3 hours, all of the solid had dissolved, forming a dark amber solution. The analysis of an aliquot by TLC (70% ethyl acetate: 30% hexanes) after 4 hours, indicated that the reaction was essentially complete. The reaction mixture was allowed to cool to 25 ° C, and the solvent was removed by rotary evaporation. The residue was dissolved in water, and treated with solid to slightly basic sodium bicarbonate (pH ~ 8) with continuous stirring (Note: No attempt was made to control the temperature, and the flask was slightly heated to the touch). A brown precipitate started to form after a few minutes. The mixture was continued to stir at 25 ° C for 16 hours. The brown solid was collected by vacuum filtration and washed with water. This gave a tanned solid wet cake (91 g), which was then dried in vacuo at 40 ° C at a constant weight. This gave A / -methyl-2- (pyridin-3-yl) thiazol-5amine as a sand colored solid (68.5 g, 75%): mp 140-141 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 8.98 (dd, J = 2.3, 0.7 Hz, 1H), 8.53 (dd, J = 4.8, 1.6 Hz, 1H) , 8.07 (ddd, J = 8.0, 2.2, 1.7 Hz, 1H), 7.40 - 7.21 (m, 1H), 6.96 (s, 1H), 4.18 (s, 1H), 2.96 (s, 3H); 13 C NMR (101 MHz, Chloroform) δ 153.23, 149.15, 146.54, 132.23, 130.47, 123.65, 121.20, 34.48; Analytical Calculation for C9H9N3S: C, 56.52; H, 4.74; N, 21.97; S, 16.77, Found: C, 56.31: H, 4.74; N, 21.81; S, 16.96.
    Step 3: Preparation of 4-chloro- / V-methyl-2- (pyridin-3-yl) thiazol-5-amine:
    Cl [0057] To a 500 ml dry round-bottom flask equipped
    22/24 with magnetic stirrer, thermometer, and nitrogen inlet, A / -methyl-2- (pyridin-3-yl) thiazol-5-amine (0.528 g, 2.76 mmol) and dichloromethane (50 mL) were loaded . The resulting solution was cooled to 5 ° C, followed by the portion-by-portion addition of the solid / V-chlorosuccinamide. After all the chlorinating agent was added, a dark brown solution formed. The solution was stirred at 5 C for 20 minutes, then an aliquot was analyzed by HPLC (YMC AQ column 5% ACN 95% water-0.05% TFA to 95% ACN 5% water with 0, 05% TFA over 20 Min @ 1.0 ml / min). HPLC analysis did not show agitation of the starting material and a larger product. The reaction mixture was poured into a separatory funnel containing dichloromethane (50 ml) and washed with water (2x10 ml), followed by saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to give a powdered brown solid (0.51 g). The solid was purified in an ISCO Combiflash Rf (80 g silica gel cartridge, mobile phase A = hexane, B = ethyl acetate, gradient 0% B to 100% B for 20 minutes). The fractions were collected in 25 mL test tubes. The tubes containing the desired material were combined and rotary evaporated to provide 4-chloro-A / -methyl-2- (pyridin-3-yl) thiazol-5-amine as a canary yellow solid (0.32 g, 51% ); 1 H NMR (400 MHz, CDCl3) δ 8.97 (dd, J = 2.3, 0.7 Hz, 1H), 8.54 (dd, J = 4.8, 1.6 Hz, 1H), 8.07 (ddd, J = 8.0, 2.3, 1.6 Hz, 1H), 7.45 - 7.14 (m, 1H), 4.07 (dd, J = 40.5, 38 , 0 Hz, 1H), 3.03 (d, J = 5.3 Hz, 3H); 13 C NMR (101 MHz, CDCl 3) δ 149.55, 146.03, 145.60, 145.28, 131.73, 129.71, 123.64, 117.37, 35.75; Analytical Calculation for C 9 H 8 CIN 3 S: C, 49.89; H, 3.57; N, 18.62; S, 14.21, Found: C, 48.03: H, 3.64; N, 18.42; S, 14.23.
    Step 4: Preparation of A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) - / V, 2-dimethyl-
    3- (methylthio) propanamide:
    [0058] To a 500 ml dry round-bottom flask equipped
    23/24 with magnetic stirrer, thermometer, and nitrogen inlet, 4-chloro-A / -methyl-2- (pyridin-3-yl) thiazol-5-amine (22 g, 97 mmol), and dichloromethane ( 250 mL). The suspension was stirred at room temperature, while pyridine (8.48 g, 107 mmol) and DMAP (1.20 g, 9.75 mmol) were added. To this suspension was added 2-methyl-3 (methylthio) propanoyl chloride (17.8 g, 117 mmol) for 5 minutes. During the addition of all the solids being in the solution, the reaction was exothermic at 20 Ca 30 C. The reaction was stirred at room 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 with 0.05% TFA for 20 Min @ 1.0 ml / min), which showed complete conversion of all starting material. The reaction mixture was diluted with dichloromethane, and water was then added. The mixture was poured into a separating funnel with dichloromethane and water, and the layers separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to provide 33.6 g of a dark oil. The oil was purified in an ISCO Combiflash Rf (330 g of silica gel cartridge, mobile phase A = hexane, B = ethyl acetate, gradient 0% B to 100% B for 20 minutes). The fractions were collected in 25 mL test tubes. The tubes containing the desired product were combined and the solvent removed by rotary evaporation. This provided 22.8 g of a thick yellow liquid in 68.4% isolated yield. The total sample was crystallized, and hexane (200 ml) was added to give a slurry. The slurry was filtered under vacuum, and the solid allowed to air dry. This gave A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A /, 2-dimethyl-3 (methylthio) propanamide as a non-white blank; mp 75-80 ° C; 1 H NMR (400 MHz, CDCI 3 ) δ 9.12 (d, J = 1.4 Hz, 1H), 8.73 (d, J = 3.8 Hz, 1H), 8.34 - 8.09 (m, 1H), 7.43 (dd, J = 7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06 - 2.70 (m, 2H), 2, 49 (d, J = 7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J =
    24/24
    6.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-cfe) δ 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; Analytical Calculation, for Ci 4 H 16 CIN 3 OS2: C, 49.18; H, 4.72; N, 12.29; S, 18.76, Found: C, 49.04: H, 4.68; N, 12.29; S, 18.68.
    权利要求:
    Claims (7)
    [1]
    1. Process, characterized by the fact that it comprises:
    Scheme One (I) compound (I) with compound (II) to produce compound (III), said reaction being conducted in a protic polar solvent under ambient pressure; followed by (ii) cyclization of the compound (III) using a dehydrating agent to produce the compound (IV), the said cyclization being conducted at ambient pressure and temperatures from 60 ° C to 120 ° C;
    said dehydrating agent being selected from the group consisting of POCL 3 , H 2 SO 4 , SOCI 2 , P 2 O 5 , polyphosphoric acid, p-toluene sulfonic acid, tetra-fluoro-acetic anhydride, or a mixture thereof ;
    where (A) each R 1 is H;
    (B) R 2 is (C r C 6 ) alkyl;
    (C) R 3 is H or (Cf-Cejalquila; and (D) R 4 is H, (C- | -C 6 ) alkyl or cyclopropyl.
    [2]
    2. Process according to claim 1, characterized by the fact that said protic polar solvent is acid
    Petition 870160008370, dc 03/09/2016, p. 4/8
    2/2 formic, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water, or a mixture thereof.
    [3]
    3. Process according to claim 1, characterized by the fact that said protic polar solvent is methanol.
    [4]
    4. Process according to claim 1, characterized by the fact that it further comprises halogenating said R 3 of compound (IV) to F, Cl, Br, or I, in a polar solvent, at a temperature of 0 ° C at room temperature.
    [5]
    5. Process according to claim 4, characterized by the fact that said halogenation is carried out in a solvent selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethyl sulfoxide.
    [6]
    6. Process according to claim 5, characterized by the fact that said polar solvent is dichloromethane.
    [7]
    Process according to any one of claims 4 to 6, characterized by the fact that R 3 is Cl.
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    法律状态:
    2018-03-06| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-03-13| B06F| Objections, documents and/or translations needed after an examination request according art. 34 industrial property law|
    2018-03-20| B06I| Technical and formal requirements: publication cancelled|Free format text: ANULADA A PUBLICACAO CODIGO 6.6.1 NA RPI NO 2462 DE 13/03/2018 POR TER SIDO INDEVIDA. |
    2018-11-06| B09A| Decision: intention to grant|
    2019-01-02| B15K| Others concerning applications: alteration of classification|Free format text: A CLASSIFICACAO ANTERIOR ERA: C07D 417/04 Ipc: A01N 43/78 (1980.01), C07D 417/04 (1974.07) |
    2019-01-15| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 30/05/2013, OBSERVADAS AS CONDICOES LEGAIS. |
    优先权:
    申请号 | 申请日 | 专利标题
    US201261655086P| true| 2012-06-04|2012-06-04|
    US61/655,086|2012-06-04|
    PCT/US2013/043208|WO2013184476A2|2012-06-04|2013-05-30|Processes to produce certain 2-thiazoles|
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