• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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    • 专利摘要:
    Methods for Producing Certain 2- (Pyridin-3-yl) Thiazoles The present invention relates to the field of processes for producing certain 2- (pyridin-3-yl) thiazoles as intermediates for the synthesis of pesticidal activity thiazol amides.
    公开号:BR112014029957B1
    申请号:R112014029957-9
    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；Kim E. Arndt；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) THIAZOLES. CROSS REFERENCES TO RELATED APPLICATIONS [0001] This Order claims priority and benefit from Provisional Order No. 2 US 61 / 655,089, filed on June 4, 2012. The entire contents of that Provisional Order are incorporated into this document for reference in this Order.
    FIELD OF THE INVENTION [0002] 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 amides with pesticidal activity.08006000410 trc
    BACKGROUND OF THE INVENTION [0003] 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. World agricultural losses account for billions of U.S. dollars a year. Pests, such as termites, are also known to cause damage to all types of private and public structures that result in losses of billions of U.S. dollars a year. Pests also eat and adulterate stored food, resulting in losses of billions of U.S. dollars a year, as well as a shortage of food needed by people.
    [0004] Certain pests have or are developing resistance to pesticides in use today. 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.
    [0005] Document 2 WO 2010/129497 (the entire description of which is incorporated in this document) reveals certain
    2/15 pesticides. However, the processes for making such pesticides can be both costly and inefficient. Consequently, there is a need for efficient processes for forming such pesticides.
    DEFINITIONS [0006] The examples provided in the definitions are generally not exhaustive and should not be constructed in a way that limits the invention described in that 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.
    [0007] 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.
    [0008] alkenyloxy means an alkenyl which additionally consists of a single carbon-oxygen bond, for example, allyloxy, butenyloxy, pentenyloxy, hexenyloxy, heptenyloxy, octenyloxy, nonenyloxy and decenyloxy.
    [0009] alkoxy means an alkyl that additionally consists of a single carbon-oxygen bond, for example, methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, isobutoxy, tert-butoxy, pentoxy, 2methylbutoxy, 1,1 -dimethylpropoxy, hexoxy, heptoxy, octoxy, nonoxy and decoxy. [0010] alkyl means an acyclic, saturated, branched or unbranched substituent 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
    3/15 genius, for example, ethynyl, propargyl, butynyl, pentinyl, hexynyl, heptinyl, octinyl, noninyl and decinyl.
    [0012] alkynyloxy means an alkynyl that additionally consists of a simple 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, for example, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloeptenyl, cyclooctenyl, cyclodecenyl, norbornenyl, bicycles [2.2. 2] octenyl, tetrahydronaphthyl, hexahydronaphil and octahydronaphthyl.
    [0015] cycloalkenyloxy means a cycloalkenyl which additionally consists of a single carbon-oxygen bond, for example, cyclobutenyloxy, cyclopentenyloxy, cyclohexenyloxy, cycloheptenyloxy, cyclooctenyloxy, cyclodecenyloxy, norbornenyloxy and bicyclo [2.2.2] octenyloxy.
    [0016] cycloalkyl means a monocyclic or polycyclic, saturated substituent consisting of carbon and hydrogen, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, norbornyl, bicycle [2.2.2] octyl and decahydronafty.
    [0017] cycloalkoxy means a cycloalkyl which additionally consists of a simple carbon-oxygen bond, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloeptyloxy, cyclooctyloxy, cyclodecyloxy, norbornyloxy and bicyclo [2.2.2] octyloxy.
    [0018] cycloalkylalkyl means a saturated monocyclic or polycyclic substituent consisting of halocarbon and hydrogen, for example, 1-chlorocyclopropyl, 1-chlorocyclobutyl and 1-dichlorocyclopentyl. [0019] halo means fluoro, chloro, bromo and iodo.
    [0020] haloalkyl means an alkyl consisting of additional
    4/15 in one to the maximum possible number of identical or different halos, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 1fluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chloromethyl, trichloromethyl and 1,1,2,2 -tetrafluoroethyl.
    [0021] heterocyclyl means a cyclic substituent that can be totally saturated, partially unsaturated or totally 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, pyroazolyl, oxazazolyl, pyrazazolyl, pyrazazolyl, pyrazazolyl, pyrazazolyl, pyrazazole , 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 INVENTION [0022] One embodiment of this invention is illustrated in the schematic one s
    Layout 1
    alkyl (Ci-Ca)
    (i)
    5/15
    where [0023] (A) each R 1 is independently selected from H, F,
    Cl, Br, I, CN, NO 2 and substituted or unsubstituted (C 1 -C 6 ) alkyl, where each substituted R 1 has one or more substituents independently selected from F, Cl, Br, I, CN, NO 2 , alkyl (C 1 -C 6 ) and haloalkyl (CrCe);
    [0024] (B) R 2 is selected from alkyl (Ci-C6) substituted or unsubstituted alkenyl (C 2 -C 6) substituted or unsubstituted, alcóxiíCrCe) substituted or unsubstituted alkenyloxy (C2-C6 ) substituted or unsubstituted, cycloalkyl (C3-Cio) substituted or unsubstituted, cycloalkenyl (C3-C 10 ) substituted or unsubstituted, aryl (C 6 -C 20 ) substituted or unsubstituted, alkyl (C-C 6 ) aryl -C6-C 2 o) substituted or unsubstituted and substituted or unsubstituted heterocyclyl), where each substituted R 2 has one or more substituents independently selected from F, Cl, Br, I, CN, NO 2 , alkyl (Ci -C 6 ), alkenyl (C 2 -C 6 ), haloalkyl (CrCe), haloalkenyl (C 2 -C 6 ), haloalkyloxy (CrC 6 ), haloalkenyloxy (C 2 -C 6 , cycloalkyl (C 3 -Cio, cycloalkenyl (C 3- C10), halocycloalkyl (C 3 -C 10 ), halocycloalkenyl (C 3 -C 10 ), aryl (C 6 -C 20 ) and heterocyclyl (C 1 -C 2 o);
    [0025] (C) R 3 is selected from H, substituted or unsubstituted alkyl, (C 3 -Cio) cycloalkyl, substituted or unsubstituted, substituted or unsubstituted (C-C 6 ) cycloalkyl (C 3 -Cio) alkyl , aryl (C 2 -C 6) substituted or unsubstituted alkyl and (C 1 -C 6) aryl (C 6 -C 2 o) substituted or unsubstituted, wherein each R 3 is substituted one or more substi6 / 15 tuentes independently selected from F, Cl, Br and I; and [0026] (D) R 4 is selected from substituted or unsubstituted H, substituted or unsubstituted (C3-C10) cycloalkyl (C3-CK) cycloalkyl (CC-CK)) substituted or unsubstituted, aryl (C 6 C 2) o) substituted or unsubstituted, alkyl (Ci-C6) aryl (C6-C2o) substituted or unsubstituted, alkyl (Ci-C6) alkynyl (C2-C6) substituted or unsubstituted alkyl and (C 1 -C 6 ) substituted or unsubstituted (C 2 -C 6 ) alkynyl, in which each said R 4 , which is substituted, has one or more substituents selected from F, Cl, Br, I, CN, NO 2 , alkyl (CrCe), haloalkyl ( Ci-C 6) alkyloxy (Ci-C6), haloalkyloxy (Ci-C6), cycloalkyl (C3-C10) halocicloalquila (C 3 -C 10) aryl (C 6 -C 2 o) θ heterocyclyl (C 1 -C 2 o) · [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, alkyl (CrCe), haloalkyl (CrCe) and aryl (C 6 -C 2 o) · [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 alkyl (C 1 -C 10 ) cycloalkyl (C 3 -C 10).
    [0033] In another embodiment of this invention, R 4 is selected from H, alkyl (C 1 -C 6 ), alkyl (C 1 -C 6) aryl (C 6 -C 2), haloalkyl (C 1 -C 6 ), alkyl C 1 -C 6 cycloalkyl CK)), C ^ OJ-cicloalquilaíCa-alquilaíCrCe) and cicloaloalquila (C 3 -Cio).
    [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, aryl (C 6 C 20 ), 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 3 , CH 2 , cyclopropyl and cyclopropyl-O-CH 2 CH3.
    7/15 [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 ChCH.
    [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 amides with pesticidal activity.
    [0037] In general, SR 2 is a leaving group, where R 2 is part of the leaving 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 a1, compounds (I) and (11a) are reacted to produce compound (11b). The reaction can be conducted at room temperature and under room pressure, however, higher or lower temperatures and pressures can be used, if desired. Compounds (11a) and (11b) can be in the form of a salt or free base. The reaction is conducted in the presence of a base, such as triethylamine, when the compound (11a) is a salt. The reaction is conducted in a protic polar 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.
    [0039] In step a2, compounds (llb) and (llc) are reacted to produce compound (III). The reaction can be conducted at room temperature and under ambient pressure, however, higher or lower temperatures and pressures can be used, if desired, such as temperatures from about 500 to about 700. The reaction is conducted in a polar solvent, such as an ether or an 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 me
    8/15 tanol. Currently, methanol is preferred. It is also useful to use an excess molar amount of the compound (llc) and (Ilb), such as about 25: 1 (llc) :( llb), however, the molar ratios of about 3: 1 to about 20 : 1 can be used and preferably molar ratios from 10: 1 to 15: 1 are used.
    [0040] 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 , P2O5, polyphosphoric acid, p-toluene sulfonic acid and trifluoroacetic anhydride. The reaction can be conducted at room temperature and under room pressure, however, higher or lower temperatures and pressures can be used, if desired. Currently, it is preferred that a temperature higher than 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 carried out in a polar aprotic solvent. Currently, acetonitrile is preferred.
    [0041] An advantage of these processes is the fact that in compound (IV) - if R 3 is Η, it can be halogenated. Consequently, at this point, R 3 now additionally includes F, Cl, Br and I (see Scheme Two).
    [0042] 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-diazoniabicyclo [2.2.2] octane bis (tetrafluoroborate). Polar solvents can be used, such as
    9/15 such as dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethyl sulfoxide. Currently, dichloromethane is preferred. The reaction can be conducted at room temperature and pressure, however, higher or lower temperatures and pressures can be used, if desired. Currently, temperatures from about 0Ό to about room temperature are preferred.
    [0043] In another embodiment of this invention, R 3 is preferably Cl.
    [0044] Compound (IV) or compound (V) can be further reacted to form certain pesticides disclosed in document 2 WO 2010/129497 (the entire description of which is incorporated by reference in this document).
    EXAMPLES [0045] The examples are for the purpose of illustration and should not be constructed in such a way as to limit the invention described in that document to only the modalities disclosed in those examples.
    [0046] The starting materials, reagents and solvents that 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 device or an OptiMelt Automated Melting Point System, available from Stanford Research Systems and are uncorrected. The molecules are given their known names, named according to the nomenclature 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 except where otherwise stated.
    10/15
    Example 1: Preparation of N - ethyl-2- (pyridin-3-carbothioamido) acetamide: S
    H
    Step 1: Preparation of methyl 2-pyridine-3-carbothioamidoacetate: s
    [0047] In a dry 50 ml round-bottom flask equipped with a magnetic stirrer, nitrogen inlet, bleaching purifier, thermometer and addition funnel, methyl pyridine-3carbodithioate (2.0 g, 11.82 mmoles) was loaded, methyl 2-aminoacetate hydrochloride (1.48 g; 11.82 mmol) and 20 ml of methanol. Triethylamine (1.20 g, 11.82 mmoles) in methanol (5 ml) was added by dropping. The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 200 ml of water and the aqueous mixture was extracted with 3 x 50 ml of ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure on a rotary evaporator. The crude product was then dissolved in dichloromethane and subjected to silica gel chromatography (80 g ISCO cartridge) with a gradient of 100% hexanes to 100% ethyl acetate over 20 minutes. The pure fractions were combined and then the solvent evaporated in vacuo to provide the title compound as a thick yellow oil (1.6 g, 64%): 1 H NMR (400 MHz, CDCI 3 ) δ 8.96 ( dd, J = 2.4, 0.8 Hz, 1H), 8.68 (dd, J = 4.8, 1.7 Hz, 1H), 8.47 (bs, 1H), 8.16 (ddd , J = 8.0, 2.4, 1.7 Hz, 1H), 7.35 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 4.59
    11/15 (d, J = 4.7 Hz, 2H), 3.86 (s, 3H); ESIMS m / z 209.17 ([M-H] ’).
    Step 2: Preparation of N - ethyl-2- (pyridin-3-carbothioamido) acetamide: [0048] To a cooled (-400) solution of methyl 2- (pyridine-3carbothioamido) acetate (2.5 g, 11, 89 mmoles) in 20 ml of methanol in a 45 ml Parr reactor, ethylamine (6.6 g, 146.00 mmoles) was added. The Parr reactor was sealed and heated to 600 for 5 hours. To this solution was added 5 g of silica gel and the mixture evaporated to dryness. The sample was subjected to chromatography at ISCO using a gradient of ethyl acetate and dichloromethane, followed by 100% ethyl acetate. The solvent was removed in vacuo to provide the title compound as a yellow solid (1.8 g; 68%); mp 136 to 1380; 1 H NMR (400 MHz, de-DMSO) δ 10.62 (s, 1H), 8.94 (dd, J = 2.4, 0.7 Hz, 1H), 8.68 (ddd, J = 13.4, 4.8, 1.7 Hz, 1H), 8.15 to 7.94 (m, 2H), 7.49 (tdd, J = 8.0, 4.8, 0.8 Hz, 1H), 4.34 (s, 2H), 3.21 and 3.03 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 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 = 18.7 Hz), 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, 2dimethyl-3- (methylthio) propanamide:
    Cl
    Step 1: Preparation of N-methyl-2- (pyridin-3-yl) thiazol-5-amine:
    12/15 [0049] In a dry 2 L round-bottom flask equipped with a mechanical stirrer, addition funnel and reflux condenser, A / -methyl-2- (pyridine-3-carbothioamido) acetamide (100 g, 478 mmoles) and acetonitrile (1 I). To this mixture was added phosphorus oxychloride (256 g, 1,672 mmoles) in portions over 10 minutes. The reaction mixture was stirred at room temperature for 10 minutes during which time a slight exotherm of 22 “C to 34Ό occurred. The reaction mixture was heated to 85Ό (mild reflux). After 3 hours, all the solid was 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 removed by rotary evaporation. The residue was dissolved in water and treated with solid sodium bicarbonate until it became slightly basic (pH ~ 8) with continuous stirring. 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 generated a solid yellow-brown moist cake (91 g) which was then dried in vacuo at 40Ό at a constant weight. This generated A / -methyl-2- (pyridin-3-yl) thiazol-5-amine as a sand-colored solid (68.5 g, 75% yield); mp 140 to 141 "C; 1 H NMR (400 MHz, CDCI3) 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 to 7.21 (m, 1H), 6.96 (s, 1H), 4.18 (s, 1H), 2.96 (s, 3H); 13 C NMR (101 MHz, CDCl 3) δ 153.23, 149.15, 146.54, 132.23, 130.47, 123.65, 121.20, 34.48; Anal. Calculated for C 9 H 9 N 3 S: 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.
    13/15
    Step 2: Preparation of 4-chloro-N-methyl-2- (pyridin-3-yl) thiazol-5-amine:
    Cl [0050] In a dry 100 ml round-bottom flask equipped with a magnetic stirrer, thermometer and nitrogen inlet / / / -methyl-2- (pyridin-3-yl) thiazol-5-amine (0.528 g , 2.76 mmoles) and dichloromethane (50 ml). The resulting solution was cooled to 5 * C, followed by the partial addition of solid A / -chlorosuccinimide (0.312 g, 2.76 mmoles). After all the chlorinating agent was added, a dark brown solution was formed. The solution was stirred at 5Ό for 20 minutes, then analyzed an aliquot by HPLC (YMC AQ column ACN 5% water 95% TFA 0.05% to ACN 95% water 5% with TFA 0.05% for 20 min. in 1.0 ml / min.). HPLC analysis did not show any starting material and a main product. The reaction mixture was poured into a separating funnel containing dichloromethane (50 ml) and washed with water (2x10 ml) after the saturated aqueous sodium chloride solution (10 ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and rotary evaporated to generate a powdered brown solid (0.51 g). The solid was purified in an ISCO Combiflash Rf (silica gel 80 g 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 provide 4-chloro- / V-methyl-2- (pyridin-3-yl) thiazol-5-amine as a canary yellow solid (0.32 g, yield of 51%); 1 H NMR (400 MHz, CDCI 3 ) 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, CDCI3) δ 149.55, 146.03, 145.60, 145.28, 131.73, 129.71,
    14/15
    123.64, 117.37, 35.75; Anal. Calculated 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 3: Preparation of N- (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -N, 2-dimethyl3- (methylthio) propanamide:
    [0051] In a dry 500 ml round-bottom flask equipped with a magnetic stirrer, thermometer and nitrogen inlet, 4-chloro-A / -methyl-2- (pyridin-3-yl) thiazol-5-amine ( 22 g, 97 mmoles) and dichloromethane (250 ml). The suspension was stirred at room temperature while pyridine (8.48 g, 107 mmoles) and DMAP (1.20 g, 9.75 mmoles) were added. To these suspensions was added 2-methyl-3- (methylthio) propanoyl chloride (17.8 g, 117 mmol) over 5 minutes. During the addition all solids penetrated the solution and the reaction was exothermic from 20Ό to 30Ό. The reaction was stirred at room temperature for 16 h. The mixture was checked by HPLC (YMC AQ column ACN 5% water 95% TFA 0.05% to ACN 95% water 5% with TFA 0.05% for 20 min. At 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 over 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 with 68.4% isolated yield. The entire sample crystallized and hexane (200 ml) was added to generate a slurry. THE
    15/15 slurry was vacuum filtered and the solid allowed to air dry. This generated A / - (4-chloro-2- (pyridin-3-yl) thiazol-5-yl) -A /, 2-dimethyl-3- (methylthio) propanamide as an off-white solid; mp 75 to 80Ό; 1 H NMR (400 MHz, CDCI3) δ 9.12 (d, J = 1.4 Hz, 1H), 8.73 (d, J = 3.8 Hz, 1H), 8.34 to 8.09 (m, 1H), 7.43 (dd, J = 7.9, 4.9 Hz, 1H), 3.30 (s, 3H), 3.06 to 2.70 (m, 2H), 2, 49 (d, J = 7.4 Hz, 1H), 2.04 (s, 3H), 1.21 (d, J = 6.4 Hz, 3H); 13 C NMR (101 MHz, DMSO-d6) 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; Anal. Calculated for C 14 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 (11)
    [1]
    1. Process, characterized by the fact that it comprises:
    Scheme 1 (i) reaction of the compound (I) with the compound (11a) to produce the compound (llb), said reaction being conducted at ambient temperature and pressure, and in a protic polar solvent; followed by (ii) reaction of the compound (llb) with the compound (llc) to produce the compound (III), the said reaction being conducted at ambient temperature and pressure, and in a polar protic solvent; followed by (iii) cyclization of the compound (III) using a dehydrating agent to produce the compound (IV), the said reaction being
    Petition 870160008350, of 03/09/2016, p. 4/9
    [2]
    2/3 conducted at ambient temperature and pressure, and in a polar protic solvent;
    where (A) R 1 is H;
    (B) R 2 is (C 1 -C 6 ) alkyl;
    (C) R 3 is H; and (D) R 4 is (C 1 -C 6 ) alkyl.
    2. Process according to claim 1, characterized by the fact that, in step “a1”, said protic polar solvent is formic acid, n-butanol, isopropanol, n-propanol, ethanol, methanol, acetic acid, water , or a mixture of them.
    [3]
    3. Process, according to claim 1, characterized by the fact that, in step "aΤ ', said protic polar solvent is methanol.
    [4]
    4. Process, according to claim 1, characterized by the fact that, in step “b”, the compound (III) is cyclized using a dehydrating agent selected from POCI 3 , H 2 SO 4 , SOCI 2 , P 2 5 , polyphosphoric acid, p-toluene sulfonic acid, trifluoroacetic anhydride, or a mixture thereof.
    [5]
    5. Process, according to claim 1, characterized by the fact that step “b” is conducted at a temperature of 6 (rCa 120Ό.
    [6]
    6. Process according to claim 1, characterized by the fact that, in step “b”, said protic polar solvent is acetonitrile.
    [7]
    7. Process according to claim 1, characterized by the fact that it further comprises halogenating said R 3 to F, Cl, Br or I.
    [8]
    8. Process according to claim 7, characterized by the fact that said halogenation is conducted in a solvent
    Petition 870160008350, of 03/09/2016, p. 5/9
    3/3 selected from dichloromethane, tetrahydrofuran, ethyl acetate, acetone, dimethylformamide, acetonitrile and dimethyl sulfoxide.
    [9]
    9. Process according to claim 8, characterized by the fact that said solvent is dichloromethane.
    [10]
    Process according to any one of claims 7 to 9, characterized in that said halogenation is carried out at a temperature of OO at room temperature.
    [11]
    11. Process according to any of claims 7 to 9, 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
    US201261655089P| true| 2012-06-04|2012-06-04|
    US61/655,089|2012-06-04|
    PCT/US2013/043260|WO2013184480A2|2012-06-04|2013-05-30|Processes to produce certain 2-thiazoles|
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