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    • 专利摘要:
    METHOD FOR PREPARING N- (4-CHLORINE-3- (TRIFLUOR METHYL) PHENYL) -N '- (4- (2- (N- (METHYL-D3) AMINO FORMIL) -4-PYRIDYLOXY) PHENYL) Urea, METHOD FOR PREPARING 4-CHLORINE-PYRIDIL-2- (N- (METHYL-D3)) CARBOXAMIDE, USE OF THE INTERMEDIATE AND COMPOUND OF (Omega) -DIPHYENIL UREA DEUTERATED P-TOLUINE SULPHONATE. Methods and processes for preparing and producing deuterated (Omega) -diphenyl urels are disclosed. In particular, a species of deuterated (Omega) -diphenyl urea compounds which can inhibit phosphokinase and the method of preparing N- (4-chloro-3- (methyl trifluorine) phenyl) -N '- (4- ( 2- (N-d3-methyl carbomoyl) -4-pyridinyloxy) phenyl) urea. Dittos composed of deuterated (Omega) -diphenyl urea can be used to treat or prevent tumors and related diseases.
    公开号:BR112012023525B1
    申请号:R112012023525-7
    申请日:2011-03-17
    公开日:2020-11-03
    发明作者:Weidong Feng；Xiaoyong Gao；Xiaojun Dai
    申请人:Suzhou Zelgen Biopharmaceutical Co., Ltd；
    IPC主号:
    专利说明:

    Field of invention
    [0001] This invention relates to the field of chemical synthesis, and particularly relates to methods and processes for the preparation and production of deuterated ω-diphenyl urea. History of the invention
    [0002] Ω-diphenyl urea derivatives are known compounds with c-RAF kinase inhibiting activity. For example, W02000 / 042012 has disclosed a class of diphenyl urea substituted with ω-carboxyl-aryl and its use to treat cancer and related diseases.
    [0003] Initially, ω-diphenyl urea compounds, such as Soranefib, were first discovered as the c-RAF kinase inhibitor. The other studies showed that they could also inhibit MEK and ERK signal transduction pathways and tyrosine kinase activities including vascular endothelial growth factor receptor-2 (VEGFR-2), vascular endothelial growth factor receptor-3 (VEGFR-3), and platelet-derived growth factor β receptor (PDGFR-β) (Curr Pharm Des 2002, 8, 2255- 2257). Therefore, they were called multicinase inhibitors that resulted in dual antitumor effects.
    [0004] Soranefib (trade name NEXAVAR), a new oral multicinase inhibitor, was developed by Bayer and Onyx. In December 2005, based on its excellent performance in phase III clinical trials for advanced renal cell carcinoma, Soranefib was approved by the FDA to treat advanced renal cell carcinoma, and was marketed in China in November 2006. However, Soranefib has several side effects, such as hypertension, weight loss, rash, etc.
    [0005] However, it is still necessary to develop new compounds with raf kinase inhibition activity or better pharmacodynamic properties and the process of preparing them. Summary of the invention
    [0006] The objective of the invention is to provide new compounds with raf kinase inhibiting activity and better pharmacodynamic properties and their uses.
    [0007] Another objective of the invention is to provide a series of methods to prepare ω-diphenyl urea and its intermediates, thereby satisfying the production guidelines in the pharmaceutical industry and improving operability and safety.
    [0008] In the first aspect, the invention provides a deuterated ω-diphenyl urea compound or the pharmaceutically acceptable salts thereof, said compound being N- (4-chloro-3- (methyl trifluorine) phenyl) -N ' - (4- (2- (N- (methyl-dj) amino formyl) - 4-pyridyloxy) phenyl) urea;
    In an embodiment, N in said compound is 14N.
    [0009] In the second aspect, the invention provides a method for preparing N- (4-chloro-3- (methyl trifluorine) phenyl) -N '- (4- (2- (N- (methyl-d3) amino formyl) -4-pyridyloxy) phenyl) urea,
    comprising: (a) in an inert solvent and in the presence of a base, reacting compound III with compound V to form said compound;
    where, X is Cl, Br, or I; or, comprising: (b) in an inert solvent, reacting compound IX with CD3NH2 or CD3NH2.HCI to form said compound;
    wherein, R is a normal or branched chain C 1 -C 6 alkyl group, or aryl group; or comprising (c) in an inert solvent, reacting 4-chloro-3-trifluoromethyl methyl phenyl (VIII) isocyanate with compound 5 to form said compound;
    or comprising: (d) in an inert solvent and in the presence of GDI and CH2C12A, react compound 5 with compound 6 to form said compound.

    [0010] In an embodiment, compound III is prepared as follows: (i) condensing 4-hydroxy aniline (I) with 4-chloro-3-trifluoro methyl aniline (II) to form compound III.

    [0011] In an embodiment, compound III is prepared as follows: (ii) reacting p-methoxy aniline (X) with 4-chloro-3-trifluor methyl aniline (II) or 4-chloro-3-trifluor isocyanate methyl phenyl (VIII) to form compound XI,
    and then, in an acidic or basic condition, demethylate compound XI to give compound III.
    [0012] In an embodiment, compound VII is prepared as follows: in the presence of a base, react compound VI and p-hydroxyl aniline to form compound VII:
    where, X is chlorine, bromine or iodine; R is a normal or branched-chain C 1 -C 6 alkyl group, or aryl group.
    [0013] In an incorporation, said base is selected from potassium terciobutoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, solid hydroxide or a combination thereof.
    [0014] In an incorporation, method (a) further comprises that the reaction is carried out in the presence of a catalyst, the catalyst being selected from Cul and proline; or Cul and picolinate.
    [0015] In an incorporation, the reaction temperature is 0 - 200 ° C. In the third aspect, the invention provides an intermediate of formula B, in which Y is halogen or
    where Y is halogen or

    [0016] In an embodiment, Y is Cl and the structure of formula B is
    In the fourth aspect, the invention provides a method for preparing 4-chloro-N- (methyl-d3) picolinamide, which comprises: (al) in a basic condition and in an inert solvent, reacting methyl 4-chloro picolinate with (methyl-dj) ) amine or salts thereof to form i-chloro-N-methyl-dj) picolinamide; or (a2) in an inert solvent, react 4-chloro-picolinoyl chloride with (methyl-da) amine to form 4-chloro-N- (methyl-d3) picolinamide.
    [0017] In an embodiment, said inert solvent includes tetrahydrofuran, ethanol, methanol, water, or a mixture thereof.
    [0018] In an incorporation, in steps (al) and (a2), the reaction temperature is from -10 ° C to the reflux temperature, preferably from -4 ° C to 60 ° C, and more preferably from 5- 50 ° C.
    [0019] In an incorporation, in steps (al) and (a2), the reaction time is 0.5-72 hours, preferably 1-64 hours, and more preferably 2-48 hours.
    [0020] In an incorporation, in step (al), said basic condition means that potassium carbonate, sodium carbonate, cesium carbonate, KOH, NaOH, or the combination thereof is present in the reagent system.
    [0021] In the fifth aspect, the invention provides a method for preparing 4- (4-amino phenoxy) -N- (methyl-d3) picolinamide, which comprises: in a basic condition and in an inert solvent, reacting 4-chloro-N- (methyl-da) picolinamide with 4-amino phenol to form 4- (4-amino phenoxy) -N- (methyl-da) picolinamide.

    [0022] In an incorporation, said basic condition means that KOH, NaOH, potassium carbonate, sodium carbonate, cesium carbonate, potassium terciobutoxide, sodium terciobutoxide or the combination thereof is present in the reagent system.
    [0023] In an embodiment, said solvent is selected from DMF, DMSO, N, N-dimethyl acetylamide, tetrahydrofuran, methyl pyrrolidin-2-one, 1,4-dioxane, or a mixture thereof.
    [0024] In an embodiment, the reaction temperature described above is from 0 ° C to 160 ° C, preferably it is 20 ° C to 120 ° C, and more preferably it is 30-100 ° C.
    [0025] The reaction time is 0.5-48 hours, preferably it is 1-36 hours, and more preferably it is 3-24 hours.
    [0026] In the fifth aspect, the invention provides for the use of said intermediates according to the third aspect of the invention to prepare ω-diphenyl deuterated urea or as the starting material for preparing ω-diphenyl deuterated urea.
    [0027] In an embodiment, said deuterated diphenyl urea includes 4 - (4 - (3- (4-chloro-3- (methyl trifluorine) phenyl) ureido) - phenoxy) -N- (methyl-d3) picolinamide. (CM4307); and 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -phenoxy) -N- (methyl-d3) picolinamide. (CM4307> TsOH).
    [0028] It should be understood that in the present invention, any of the technical characteristics specifically described above and below (as in the Examples) can be combined with each other, thus constituting new or preferred technical solutions that are not described as a powder one in the specification. Description of the figures
    [0029] Figure 1 shows the drug concentration curves (ng / mL) in plasma after oral administration of 3 mg / kg of the control compound CM4306 in male SD rats;
    [0030] Figure 2 shows the drug concentration curves (ng / ml) in plasma after oral administration of 3 mg / kg of the CM4307 compound of the invention in male SD rats; and
    [0031] Figure 3 shows the curves of CM4306 and CM4307 inhibition efficacy in a xenograft model in nude mice inoculated with human liver cancer cells SMMC-7721. In this figure, "treatment" means that the treatment period was 14 days, followed by the observation period after administration is stopped. The five days before treatment was the period to prepare the animal models. Detailed description of the invention
    [0032] After studies, the inventors discovered, unexpectedly, that compared to the non-deuterated compound, ω-diphenyl urea and its pharmaceutically acceptable salts have better pharmacokinetic and / or pharmacodynamic properties. Therefore, they were much more appropriate as raf kinase inhibitors for preparing drugs to treat cancer and relevant diseases.
    [0033] In addition, the inventors have also discovered that diphenyl urea compounds can be quickly and efficiently prepared using the new intermediate of formula B,
    where Y is halogen or
    Based on this discovery, the inventors completed the present invention. Definitions
    [0034] When used herein, the term "halogen" refers to F, Cl, Br and I. Preferably, halogen is selected from F, Cl, and Br.
    [0035] When used herein, the term "alkyl" refers to a normal or branched chain alkyl group. Preferably, alkyl is C1-C4 alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terciobutyl, etc.
    [0036] When used here, the term "deuterated (o)" means that one or more hydrogen atoms (XH) in the compound or group are replaced by deuterium atoms (2H or D2). "Deuterado (a)" can be monosubstituted, bisubstituted, multisubstituted or totally substituted. The terms, "one or more replaced by deuterium" and "replaced by deuterium one or more times", can be used to allow for exchange and / or substitution.
    [0037] In an embodiment, the deuterium content in a position replaced by deuterium is at least greater than the natural abundance of deuterium (0.015%), preferably> 50%, more preferably> 75%, more preferably> 95%, more preferably> 97%, more preferably> 99%, more preferably> 99.5%.
    [0038] In an embodiment, the compound of formula (I) comprises at least one deuterium atom, preferably three deuterium atoms, and more preferably five deuterium atoms.
    [0039] When used herein, the term "compound CM4306" is 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) -phenoxy) -N-methyl picolinamide.
    [0040] When used herein, the term "compound CM4307" is 4- (4 - (3- (4-chloro-3- (methyl trifluorine) phenyl) ureido) -phenoxy) -N- (methyl-ds) picolinamide.
    [0041] When used herein, the term "TsOH" represents p-toluenesulfonic acid. Therefore, CM4307 * TsOH represents the CM4307 p-toluenesulfonate.
    [0042] ω-diphenyl urea replaced by deuterium
    [0043] According to the invention, the preferred compounds of ω-diphenyl urea substituted by deuterium have the formula (I):
    where X is N or N + -O “; R1 is halogen (such as F, Cl or Br), one or more C1-C4 alkyl groups substituted by deuterium or pre-deuterated; R is non-deuterated C1-C4 alkyl group, one or more C1-C4 alkyl groups substituted by deuterium or pre-deuterated, or C1-C4 alkyl partially or totally substituted by halogen; each of R3, R4, R5, R8, R9, R10, R11, R12, R13 or R14 is, independently, hydrogen, deuterium, or halogen (such as F, Cl or Br); R6 is hydrogen, deuterium or one or more C1-C4 alkyl groups substituted by deuterium or pre-deuterates; R7 hydrogen, deuterium or one or more C1-C4 alkyl groups substituted by deuterium or pre-deuterated; as long as at least one of R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13 or R14 is deuterated, ie deuterium.
    [0044] In an embodiment, the deuterium content in a position replaced by deuterium is at least greater than the natural abundance of deuterium (0.015%), preferably> 30%, more preferably> 50%, more preferably> 75%, or> 95 %, or> 99%.
    [0045] In an incorporation, except for H, all or almost all (> 99% by weight) of the elements (such as N, C, O, F, etc.) in the compound of formula (I) are naturally occurring elements with abundance maximum, such as 14N, 12C, 16O and 19F.
    [0046] In an embodiment, compounds of formula (I) contain at least one deuterium atom, preferably three deuterium atoms and more preferably five deuterium atoms.
    [0047] In an incorporation, R1 is halogen, and preferably chlorine.
    [0048] In an incorporation, R2 is trifluoro methyl (a).
    [0049] In an incorporation, R6 or R7 is independently selected from hydrogen, deuterium, deuterated methyl, or deuterated ethyl; preferably, monodeuterated methyl, bideuterated methyl, trideuterated methyl, monodeuterated ethyl, bideuterated ethyl, trideuterated ethyl, tetradeuterated ethyl, or pentadeuterated ethyl.
    [0050] In an incorporation, R or R is independently selected from hydrogen, deuterium, methyl or trideuterated methyl.
    [0051] In an incorporation, R3, R4 or R5 is independently selected from hydrogen or deuterium.
    [0052] In an incorporation, R, R9, R10 or R11 is independently selected from hydrogen or deuterium.
    [0053] In an incorporation, R12, R13 or R14 is independently selected from hydrogen or deuterium.
    [0054] In an embodiment, said compound is the preferred compound selected from the group consisting of the following compounds: N- (4-chloro-3- (methyl trifluorine) phenyl-N '- (4- (2- (N- (methyl -dβ) amino formyl) -4-pyridyloxy) phenyl) urea (or 4— (4— (3 - (4-chloro-3- (methyl trifluorine) phenyl) ureido) -phenoxy) -N- (methyl- d3) picolinamide));
    4- (4- (3- (4-chloro-3- (trifluoro methyl) phenyl) ureido) phenoxy) -2- (N- (methyl-d3) amino formyl) pyridine-1-oxide;
    Intermediaries
    [0055] When used herein, the term "the intermediate of the invention" is the compound of formula B:
    in which, Y is halogen or

    [0056] In an embodiment, except for H, all or almost all (> 99% by weight) of the elements (such as N, C, O, etc.) in the above compounds are naturally occurring elements with maximum abundance, such as 14N, 12C, and 16O. Active ingredients
    [0057] When used herein, the term "compound of the invention" refers to the compound of formula (I). This term also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compound of formula (I).
    [0058] When used herein, the term "pharmaceutically acceptable salts" refers to salts that are suitable for medicines and formed by the compound of the invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. A preferred salt is formed by the compound of the invention and an acid. The appropriate acid to form salt includes, but is not limited to, inorganic acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid; organic acid, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, methanesulfonic benzene acid , benzenesulfonic acid; and amino acid, such as aspartic acid, glutamic acid. Preparation
    [0059] The preparation methods for the compound (I) and the intermediate of formula (B) are described in detail below. However, these specific methods are not provided for the purpose of limiting the invention. The compounds of the invention can be prepared quickly by optionally combining any of the various methods described in the specification or the various methods known in the art, and such combination can be quickly performed by the person skilled in the art.
    [0060] The method for preparing non-deuterated ω-diphenyl urea and the physiologically compatible salts thereof used in the invention is known. Non-deuterated ω-diphenyl urea can be prepared in the same way using the corresponding deuterated compounds as starting materials. For example, compound (I) can be prepared according to the method described in W02000 / 042012, except that deuterated material is used in the reaction instead of non-deuterated material.
    [0061] In general, during preparation, each reaction is carried out in an inert solvent, at a temperature between room temperature and reflux temperature (such as 0-80 ° C, preferably 0-50 ° C). Generally, the reaction time is 0.1-6 hours, preferably 0.5-48 hours.
    [0062] Considering CM4307 as an example, an optimized preparation route is shown as follows:
    Layout 1
    [0063] As shown in Scheme 1, in the presence of N, N'-carbonyl diimidazole, phosgene or triphosgene, 4-amino phenol (Compound I) reacts with 3-trifluoro methyl-4-chloroaniline (Compound II) to give 1- (4-chloro-3- (trifluoro methyl) phenyl-3- (4-hydroxy phenyl) urea (Compound III) 2- (N- (methyl-d3)) carbamoyl pyridine (Compound V) is obtained by reacting methyl picolinate (Compound IV) with (methyl-d3) amine or (methyl-d3) amine hydrochloride directly, or in the presence of the base such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine and the like. In the presence of base (such as potassium terciobutoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide) and an optional catalyst (such as cuprous iodide and proline or cuprous iodide and picolinic acid), Compound III reacts with Compound V to form compound CM4307. The above reactions are performed in an inert solvent, t such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N, N-dimethyl formamide, dimethyl sulfoxide, etc., and at a temperature of 0-200 ° C.
    [0064] Considering CM4307 as an example, another preferred method is shown below:

    [0065] As shown in Scheme 2, amine (Compound VII) is obtained by reacting picolinate (Compound VI) with 4-amino phenol (Compound I) in the presence of base (such as potassium terciobutoxide, sodium hydride potassium, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide) and an optional catalyst (such as cuprous and proline iodine or cuprous iodide and picolinic acid). Urea is obtained (Compound or by reacting Compound VII with Compound II in the presence of N, N'-carbonyl diimidazole, phosgene or triphosgene, or with l-chloro-4-isocyanate-2- (methyl trifluorine) benzene (Compound VIII): Compound CM4307 is obtained by reacting Compound IX with (methyl-ds) amine or (methyl-da) amine hydrochloride directly, or in the presence of the base (such as sodium carbonate, potassium carbonate, sodium hydroxide , triethylamine, pyridine and the like). The above reactions are carried out in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N, N-dimethyl formamide, dimethyl sulfoxide, etc., and in a temperature of 0-200 ° C.
    [0066] Considering CM4307 as an example, another preferred method is shown below:

    Layout 3
    [0067] As shown in Scheme 3, urea (Compound XI) is obtained by reacting 4-methyloxy phenylamine (Compound X) with Compound II in the presence of N, N'-carbonyl diimidazole, phosgene or triphosgene, or with l -chloro-4-isocyanate-2- (methyl trifluorine) benzene (Compound VIII). 1- (4-chloro-3- (methyl trifluorine) phenyl-3- (4-hydroxy phenyl) urea (Compound III) is obtained using any of the demethylation methods known in the art. Compound CM4307 is obtained by reacting the Compound III with Compound V using the same method described in Scheme 1, or any methods known in the art The above reactions are carried out in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N, N-dimethyl formamide, dimethyl sulfoxide, etc., and at a temperature of 0-200 ° C.
    [0068] Considering CM4307 as an example, another particularly preferred method is shown below:
    Layout 4
    [0069] Deuterium can be introduced using deuterated methylamine.
    [0070] Deuterated methylamine or its hydrochloride can be prepared through the following reactions. Deuterated nitromethane is obtained by reacting nitromethane with deuterium water in the presence of base (such as sodium hydride, potassium hydride, deuterated potassium hydroxide, deute sodium hydroxide, potassium carbonate, and the like) or phase transfer catalyst . If necessary, the above experiment can be repeated to produce high purity deuterated nitromethane. Deuterated nitromethane is reduced in the presence of powdered zinc, powdered magnesium, iron, nickel and the like to form deuterated methylamine or its hydrochloride.
    In addition, deuterated methylamine or its hydrochloride can be obtained through the following reactions.

    [0071] Key intermediate 3 can be synthesized from deuterated methanol (CD3OD) through the following reactions.
    In Example 1, the detailed preparation procedure is described.
    [0072] The main advantages of the present invention include: (1) The compounds of the present invention have excellent phosphokinase inhibiting activities such as raf kinases; (2) Various types of high purity deuterated diphenyl urea can be prepared conveniently and very efficiently using the intermediate of formula B of the invention; (3) The reaction conditions are more moderate and the operation is safer.
    [0073] Additionally, the present invention will be illustrated below with reference to specific examples. It should be understood that these examples are only illustrative of the invention, but do not limit the scope of the invention. Experimental methods without mentioning any specific conditions described in the following examples are generally carried out under conventional conditions, or according to the manufacturer's instructions. Unless otherwise indicated, parts and percentages by weight are calculated. Example 1: Preparation of N- (4-chloro-3- (methyl trifluorine) phenyl) - N '- (4- (2 - (N- (methyl-cb) amino formyl) -4-pyridyloxy) phenyl) urea ( Compound CM4307).
    [0074] Synthetic route:
    Layout 5 1. Preparation of 4-chloro-N- (methyl-d5) picolinamide (3)
    [0075] In a 250 mL single-necked round-bottom flask equipped with a residual gas treatment device, thionyl chloride (60 mL) was added. Anhydrous DMF (2 mL) was added slowly and dropwise while maintaining the temperature at 40-50 ° C during the addition. After the addition, the mixture was stirred for 10 min, and then nicotinic acid (20 g, 162.6 mmol) was added in portions over a 20 min period. The color of the solution gradually changed from green to light purple. The reaction mixture was heated to 72 ° C, and refluxed for 16 hours with stirring. A large amount of solid precipitate formed. The mixture was cooled to room temperature, diluted with toluene (100 ml) and concentrated to almost dryness. The residue was diluted with toluene and concentrated to dryness. The residue was filtered and washed with toluene to give 4-chlorine picolinyl chloride as a light yellow solid. The solid was slowly added in a saturated solution of (methyl-d3) amine in tetrahydrofuran in an ice bath. The mixture was kept below 5 ° C and stirred for 5 hours. Then, the mixture was concentrated and ethyl acetate was added to give a white solid precipitate. The mixture was filtered, and the filtrate was washed with saturated brine, dried over sodium sulfate and concentrated to give 4-chloro-N- (methyl-dj) picolinamide (3) (20, 68 g, 73% yield) like a light yellow solid.
    [0076] XH NMR (CDCl3, 300 MHz): 8.37 (d, 1H), 8.13 (s, 1H), 7.96 (br, 1H), 7.37 (d, 1H). 2. Preparation of 4- (4-amino phenoxy) -N- (methyl-ds) picolinamide (5)
    [0077] 4-Amino phenol (9.54 g, 0.087 mol) and potassium terciobutoxide (10.3 g, 0.092 mol) in dry DMF (100 ml) were added successively. The color of the solution became dark brown. After stirring at room temperature for 2 hours, 4-chloro-N- (methyl-d3) picolinamide (3) (13.68 g, 0.079 mol) and anhydrous potassium carbonate (6.5 g) were added to the reaction mixture. , 0.0467 mol), then heated to 80 ° C and stirred overnight. TLC detection showed that the reaction was over. The reaction mixture was cooled to room temperature, and poured into a mixture of ethyl acetate solution (150 ml) and saturated brine (150 ml). The mixture was stirred and then rested for separation into layers. The aqueous phase was extracted with ethyl acetate (3 x 100 ml). The extracted layers were combined, washed with saturated brine (3 x 100 mL) before drying over anhydrous sodium sulfate, and concentrated to provide 4- (4-amino phenoxy) -N- (methyl-dj) picolinamide (5) ( 18.00 g, 92% yield) as a light yellow solid.
    [0078] NMR (CDC13, 300 MHz): 8.32 (d, 1H), 7.99 (br, 1H), 7.66 (s, 1H), 6.91-6.85 (m, 3H) , 6.69 (m, 2H), 3.70 (br, s, 2H). 3. Preparation of N- (4-chloro-3- (methyl trifluorine) phenyl) -N '- (4- (2- (N- (methyl-ds) amino formyl) -4-pyridyloxy) phenyl) urea (CM4307 )
    [0079] 4-chloro-3-trifluoro methyl phenylamine (15.39 g, 78, 69 mmol) and N, N'-carbonyl diimidazole (13.55 g, 83.6 mmol) in methylene chloride ( 120 mL). After stirring at room temperature for 16 hours, a solution of 4- (4-amino phenoxy) -N- (methyl-d3) picolinamide (18 g, 73 mmol) in methylene chloride (180 g) was slowly added dropwise. ml) and the mixture was stirred at room temperature for another 18 hours. Detection by TLC showed that the reaction was complete. The mixture was concentrated to approximately 100 ml by removing part of the methylene chloride through a rotary evaporator and resting for several hours at room temperature. A large amount of white solid precipitated. The solid was filtered and washed with plenty of methylene chloride. The filtrate was concentrated by removing some solvent, and again some solid precipitated. Two parts of the solid were combined and washed with enough methylene chloride to provide N- (4-chloro-3- (methyl trifluorine) phenyl) -N '- (4- (2- (N- (methyl-da) amino formyl) -4-pyridyloxy) phenyl) urea (CM4307, 20.04 g, 58% yield) as a white powder (pure product).
    [0080] NMR (CD3OD, 300 MHz): 8.48 (d, 1H), 8.00 (d, 1H), 7.55 (m, 5H), 7.12 (d, 1H), 7.08 (s, 2H), ESI-HRMS m / z: C2IHI3D3C1F3N4O3, Calculated: 467.11. Found: 490.07 (M + Na) +.
    [0081] In addition, Compound CM4307 was dissolved in methylene chloride which reacted with peroxybenzoic acid to produce the corresponding oxidized derivative: 4- (4- (3- (4-chloro-3- (trifluor methyl) phenyl) ureido ) phenoxy) -2- (N- (methyl-d3) amino formyl) pyridine-1-oxide.
    Example 2: Preparation of 4-chloro-N- (methyl-d3) picolinamide (3).
    (a) In a solution of phthalimide (14.7 g, 0.1 mol), deuterated methanol (3.78 g, 0.105 mol, 1.05 equivalents) and triphenyl phosphine (28.8 g, 0.11 mol, 1 , 1 equivalents) in anhydrous tetrahydrofuran a solution of DEAD (1.1 equivalents) in tetrahydrofuran was added dropwise in an ice bath. After the addition, the mixture was stirred for 1 hour at room temperature. The mixture was purified by column chromatography, and the solvent was removed from the mixture and then, the residue was dissolved in an appropriate amount and cooled in the refrigerator to precipitate the solid. The mixture was filtered and the filtrate was concentrated on a rotary evaporator, and then the residue was purified by flash column chromatography to yield the pure 2- (N- (methyl-d )) -Isoindol-1,3-dione product (14.8 g, 90% yield). (b) 2- (N- (methyl-d )) -isoindol-1,3-dione (12.5 g, 0.077 mol) was dissolved in hydrochloric acid (6N, 50 mL) and the mixture was subjected to reflux for 24-30 hours in a sealed tube. The reaction mixture was cooled to room temperature and then cooled below 0 ° C in a refrigerator to precipitate the solid. The solid was filtered and washed with cold deionized water. The filtrate was collected and concentrated on a rotary evaporator to remove water and dried to produce (methyl-d3) amine hydrochloride. DCM (100 mL) was added to the (methyl-ds) amine hydrochloride and then 4-chloro picolinate hydrochloride (6.52 g, 0.038 mol, 0.5 equivalent) and sodium carbonate (12.2 g) were added , 0.12 mol, 1.5 equivalents). The reaction flask was sealed and placed in a refrigerator for one day. TLC detection showed that the reaction was over. The reaction mixture was washed with water, dried, concentrated and purified by column chromatography to produce 4-chloro-N- (methyl-c / 3) picolinamide (compound (3), 5.67 g, 86% yield). The structural characteristic was the same as that of Example 1. Example 3: Preparation of compound CM4307
    1. Preparation of 1-chloro-4-isocyanate-2- (methyl trifluorine) benzene A4
    [0082] With a residual gas absorption device, triphosgene (167 g, 0.56 mol, 0.5 equivalent) was dissolved in chloroform (500 mL). A solution of N-methyl morpholine (11.4 g, 0.11 mol, 0.1 equivalent) in chloroform (100 ml) was added dropwise to the above mixture at 5 ° C. After addition, a solution of 4-chloro-3- (trifluoro methyl) aniline (220 g, 1.13 mol, 1.0 equivalent) in chloroform (700 ml) was added dropwise at 10 ° C. The mixture was heated to 50 ° C and stirred for 5 hours, and then heated to 60-65 ° C and refluxed for 5 hours. The solvent was removed at atmospheric pressure. the residue was vacuum distilled (oil temperature 110-120 ° C, vacuum 200 Pa) and the fractions were collected at 95-100 ° C to give the title compound (200 g, 98.7% purity, 84% yield) as a colorless liquid. 2. Preparation of 4-chloro-N- (methyl-dj) picolinamide (intermediate A2) Method 1:
    [0083] In a three-neck flask with tetrahydrofuran (250 mL), methyl 4-chloro picolinate (50 g, 0.29 mol, 1 equivalent), (methyl-d3) amine hydrochloride (31 g, 0.44 mol, 1.5 equivalents) and anhydrous potassium carbonate (400 mesh, 80 g, 0.58 mol, 2 equivalents). After stirring the mixture for 20 hours at room temperature, water (250 ml) and methyl terciobutyl ether (150 ml) were added. After stirring, the organic layer was separated. The aqueous layer was extracted with methyl terciobutyl ether (100 ml). The organic layers were combined, dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to give the title compound (48 g, 99% purity, 96% yield) as a light yellow liquid.
    [0084] XH NMR (DMSO-d &, 400 MHz): Õ7.64 (dd, J = 2Hz, 5.2Hz, 1H), 7.97 (d, J = 1.6Hz, 1H), 8.54 ( d, J = 5.2 Hz, 1H), 8.74 (br, 1H).
    [0085] MS (ESI, m / z) calculated for C7H4D3C1N2O: 173; found: 174 [M + H] +. Method 2:
    [0086] Methyl 4-chloro picolinate (130 g, 0.76 mol, 1 equivalent) was dissolved in anhydrous ethanol (1.3 L). (Methyl-d3) amine hydrochloride (80 g, 1.13 mol, 1.5 equivalents) and anhydrous potassium carbonate (313 g, 2.67 mol, 3 equivalents) were added to the mixture with stirring. The mixture was stirred at room temperature for 50 hours. The mixture was filtered and washed with ethanol (2 x 260 ml), the solvent was removed from the filtrate under reduced pressure, ethyl acetate (400 ml) was added and the resulting mixture was washed with saturated brine (2 x 250 ml) ). The aqueous layer was extracted with ethyl acetate (2 x 100 ml). The organic layers were combined, dried over anhydrous sodium sulfate, and filtered. The solvent was removed from the filtrate under reduced pressure to give the title compound (109 g, 98% purity, 83% yield) as a light yellow liquid.
    [0087] NMR (DMSO-d &, 400 MHz): δ7.64 (dd, J = 2Hz, 5.2Hz, 1H), 7.97 (d, J = 1, 6Hz, 1H), 8.54 (d , J = 5.2 Hz, 1H), 8.7 4 (br, 1H).
    [0088] MS (ESI, m / z) calculated for C7H4D3C1N2O: 173; found: 174 [M + H] +. 3. Preparation of 1- (4-chloro-3-trifluoro methyl phenyl) -3- (4-hydroxy phenyl) urea A5 Method 1:
    [0089] 4-Amino phenol (5 g, 45.82 mmol, 1 equivalent) was dissolved in dichloromethane (40 ml) at room temperature. A solution of 1-chloro-4-isocyanate-2- (methyl trifluorine) benzene (10.7 g, 48.11 mmol, 1.05 equivalents) in dichloromethane (40 mL) was added dropwise. The mixture was stirred at room temperature for 16 hours. The mixture was filtered and washed with dichloromethane (2 x 10 ml) to give the title compound (14.2 g, 97% purity, 94% yield) as a light brown solid.
    [0090] NMR (DMSO-d6, 400 MHz): δ6.70 (dd, J = 2Hz, 6.8Hz, 1H), 7.22 (dd, J = 2Hz, 6.4Hz, 1H), 7.58 -7.24 (m, 1H), 8.10 (d, J = 2Hz, 1H), 8.50 (br, 1H), 9.04 (br, 1H), 9.14 (br, 1H).
    [0091] MS (ESI, m / z) calculated for C14H10CIF3N2O2: 330; found: 331 [M + H] +. Method 2

    [0092] 1-Chloro-4-isocyanate-2- (methyl trifluorine) benzene (5.15 g, 26 mmol, 1.05 equivalent) was dissolved in dichloromethane (30 mL). A solution of p-methoxy aniline (3.07 g, 25 mmol, 1 equivalent) in dichloromethane (20 mL) was added dropwise and the mixture was stirred at room temperature for 20 hours. The mixture was filtered and washed with dichloromethane (2x5 ml). The solid was dissolved in ethyl acetate (50 ml), and the resulting solution was washed with dilute hydrochloric acid (1 N, 10 ml) and saturated brine (20 ml). The organic phase was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give 1- (4-chloro-3-trifluoromethyl) -3- (4-methoxy phenyl) urea A6 (4.5 g , 52% yield) as a white solid.
    [0093] XH NMR (DMSO-dg, 400 MHz): δ3.73 (s, 3H), 6.86-6.90 (m, 2H), 7.35-7.39 (m, 2H), 7 , 59-7.65 (m, 2H), 8, 11 (d, J = 2Hz, 1H), 8.65 (br, 1H), 9.09 (br, 1H).
    [0094] MS (ESI, m / z) calculated for C15H12CIF3N2O2: 344; found: 345 [M + H] +.
    [0095] 1- (4-chloro-3-trifluoro methyl phenyl) -3- (4-methoxy phenyl) urea A6 (344 mg, 1 mmol, 1 equivalent) was dissolved in acetic acid (4 mL). Hydrobromic acid (40%, 1 mL) was added and the mixture was refluxed for 5 hours. The mixture was cooled to room temperature and ice / water (10 ml) was added. The mixture was extracted with ethyl acetate (20 ml). The organic phase was washed with saturated sodium bicarbonate (10 ml), dried over anhydrous sodium sulfate. The solvent was removed from the organic phase under reduced pressure to give the title compound (140 mg, 90% purity, 42% yield) as a light yellow solid.
    [0096] 1H NMR (DMSO-de, 400 MHz): 56, 70 (dd, J = 2Hz, 6.8Hz, 1H), 7.22 (dd, J = 2Hz, 6, 4Hz, 1H), 7, 58-7.24 (m, 1H), 8, 10 (d, J = 2Hz, 1H), 8.50 (br, 1H), 9.04 (br, 1H), 9, 14 (br, 1H) .
    [0097] MS (ESI, m / z) calculated for C14H10CIF3N2O2: 330; found: 331 [M + H] +.
    [0098] 4. Preparation of 4- (4- (3- (4-chloro-3- (trifluor methyl) phenyl] ureido) -phenoxy) -N- (methyl-dj) picolinamide (CM4307)
    [0099] 1- (4-chloro-3-trifluoro methyl phenyl) -3- (4-hydroxy phenyl) urea A5 (4 g, 12.10 mmol, 1 equivalent) was dissolved in N, N-dimethyl formamide ( 20 mL). Potassium terciobutoxide (4.6 g, 41.13 mmol, 3.4 equivalents) was added in portions. Then, the mixture was stirred for 3 hours, and 4-chloro-N- (methyl-dj) picolinamide (2.3 g, 13.31 mmol, 1.1 equivalents) and potassium carbonate (0.8) were added g, 6.05 mmol, 0.5 equivalent). The mixture was heated to 80 ° C and stirred for 1.5 hours. The mixture was cooled to room temperature and ethyl acetate (200 ml) was added, and filtered to remove the inorganic salts. The filtrate was washed with concentrated brine (3 x 50 ml) and the organic layer was separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed under reduced pressure to give a solid followed by the addition of acetonitrile (15 ml). The resulting mixture was refluxed for 2 hours, cooled to room temperature, and filtered to give CM4307 (3.4 g, 96% purity, 60% yield) as a light yellow solid.
    [0100] NMR (DMSO-d6, 400 MHz): 57.15 (dd, J = 2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d , J = 2.4Hz, 1H), 7.59- 7.69 (m, 4H), 8.13 (d, J = 2.4Hz, 1H), 8.51 (d, J = 6Hz, 1H) , 8.75 (br, 1H), 8.90 (br, 1H), 9.22 (br, 1H).
    [0101] MS (ESI, m / z) calculated for C21H13D3CIF3N4O3: 467; found: 468 [M + H] +. Example 4:
    [0102] Preparation of CM4307
    1. Preparation of 4-chloro-N- (methyl-d3) picolinamide (Intermediate A2).
    [0103] Under nitrogen, tetrahydrofuran (10.86 kg) was added in a reactor (30 kg). After starting the mixer, (N- (methyl-d3)) amine hydrochloride (1.50 kg, 21.26 mol, 1.5 equivalents), methyl 4-chloro picolinate (2.43 kg, 14.16 mol, 1 equivalent) and anhydrous potassium carbonate (3.92 kg, 28.36 mol, 2 equivalents). The reaction was carried out at 33 ° C for 15 h, and then pure water (12.20 kg) was added. The reaction mixture was extracted with methyl terciobutyl ether (2 x 3.70 kg). The organic phases were combined, dried over anhydrous sodium sulfate (0.50 kg), stirred for 1 hour and filtered. The solvents were removed in vacuo (<-0.09 MPa) at (40 ± 2) ° C with a water bath to give the title compound (2.41 kg, 99.0% purity, 98% yield) like a light yellow oil.
    [0104] XH NMR (DMSO-cU, 400 MHz): Õ7.64 (dd, J = 2Hz, 5.2Hz, 1H), 7.97 (d, J = 1.6Hz, 1H), 8.54 ( d, J = 5.2 Hz, 1H), 8.74 (br, 1H).
    [0105] MS (ESI, m / z) calculated for C7H4D3C1N2O: 173, found: 174 [M + H] +. 2. Preparation of 4- (4-amino phenoxy) -N- (methyl-d3) picolinamide (Intermediate A3) Method 1:
    [0106] Under nitrogen, dimethyl sulfoxide (2.75 kg) was added in a reactor (20 L). After starting the mixer, 4-chloro-N- (methyl-d3) picolinamide (2.41 kg, 13.88 mol, 1 equivalent), 4-amino phenol (1.62 kg, 14.84 mol) were successively added , 1.08 equivalents) and potassium terciobutoxide (1.66 kg, 14.79 mol, 1.1 equivalents). After the reactor temperature stabilized, the internal temperature was increased to 80 ° C and stirred for 4 hours. After lowering the internal temperature to 40 ° C, isopropanol (7.90 kg) was added to dilute the reaction mixture with stirring. The reactor was washed with isopropanol, and the resulting mixture was transferred to a reactor (30 L). Under nitrogen, hydrochloric acid (5.81 kg) was added dropwise. After the addition, the mixture was stirred, filtered by centrifugation, and washed with pure water. The solid was transferred to a reactor (50 L) and completely dissolved in water (21.00 kg) with stirring. Under nitrogen, a solution of potassium carbonate (2.5 kg of potassium carbonate dissolved in 7 L of pure water) was added dropwise to the above reactor (50 L) for about 1.5 hours. The mixture was discharged and centrifuged, and the product was washed with pure water and vacuum dried for 24 hours to give the title compound (2.72 kg, 99.9% purity, 78% yield) as a light brown crystal. .
    [0107] NMR (DMSO-CZ6, 400 MHz): δ5.19 (br, 2H), 6.66-6, 68 (m, 2H), 6, 86-6, 88 (m, 2H), 7, 07 (dd, J = 2.8Hz, 5.6Hz, 1H), 7.36 (d, J = 2.8Hz, 1H), 8.45 (d, J = 5.6Hz, 1H), 8.72 (br, 1H).
    [0108] MS (ESI, m / z) calculated for CI3HI0D3N3O2C1: 246; found: 247 [M + H] +. Method 2:

    [0109] 4-Chloro-N- (methyl-d3) picolinamide (4.3 g, 24.77 mmol, 1 equivalent) was dissolved in tetrahydrofuran (20 mL) at room temperature. Tetrabutyl ammonium hydrogen sulfate (1.68 g, 4.95 mmol, 0.2 equivalent) and sodium hydroxide (1.35 g, 33.69 mmol, 1.36) were added with stirring at room temperature equivalent). A solution of sodium hydroxide in water (45%, sodium hydroxide (1.32 g) in water (1.6 ml)) was added slowly and dropwise. The mixture was heated to 67 ° C and stirred for 20 hours. The mixture was cooled to below 20 ° C, and concentrated hydrochloric acid (37%, 10 mL) was added at a rate maintaining the reaction temperature below 25 ° C. The mixture was stirred for 1 hour, filtered and washed with tetrahydrofuran (20 ml). The resulting solid was dissolved in water (60 ml). The mixture was cooled to 10-20 ° C and a sodium hydroxide solution (22.5%, 2.6 mL) was slowly added dropwise until the pH reached a value of 3-3.5 . A sodium hydroxide solution (22.5%, 3.4 mL) was added continuously until the pH reached a value of 7-8 and a light yellow solid precipitated. During the addition, the temperature of the mixture was maintained below 20 ° C. The mixture was filtered and the solid was washed with water (2 x 12 ml). The solid was vacuum dried to give 4- (4-amino phenoxy) -N- (methyl-ds) picolinamide (5.01 g, 99% purity, 82% yield) as a light yellow solid.
    [0110] XH NMR (DMSO-d &, 400 MHz): δ5.19 (br, 2H), 6.66- 6.68 (m, 2H), 6, 86-6.88 (m, 2H), 7 , 07 (dd, J = 2.8 Hz, 5.6 Hz, 1H), 7.36 (d, J = 2.8 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 8, 72 (br, 1H).
    [0111] MS (ESI, m / z) calculated for C13H10D3N3O2CI: 246; found: 247 [M + H] +. 3. Preparation of 4- (4- (3- (4-chloro-3- (methyl trifluorine) phenyl] ureido) -phenoxy) -N- (methyl-dj) picolinamide (CM4307).
    [0112] Under nitrogen, dichloromethane (17.30 kg) and dimethyl sulfoxide (2.92 kg) were added in a dry reactor (50 L). The mixture was stirred at room temperature, and 4- (4-amino phenoxy) -N- (methyl-ds) picolinamide (2.65 kg, 10.76 mol) was added. 1-Chloro-4-isocyanate-2- (methyl trifluorine) benzene (2.50 kg, 11.26 mol, 1.05 equivalents) was dissolved in dichloromethane (7.00 kg). The solution of 1-chloro-4-isocyanate-2- (trifluoromethyl) benzene in dichloromethane was added dropwise to the reactor. The reaction was carried out for 10 min at room temperature. The reaction mixture was cooled to (3 ± 2) ° C with an ice / brine bath. Pure water (10.60 kg) was added dropwise to the reactor keeping the temperature at (3 ± 2) ° C. After the addition, the mixture was stirred for 30 min, and then discharged and centrifuged. The product was washed with dichloromethane (7.00 kg). The resulting product was vacuum dried for 24 h to give an ivory-colored powder (4.8 kg, 99.8% purity, 95.4% yield).
    [0113] XH NMR (DMSO-d6, 400 MHz): Õ7.15 (dd, J = 2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 ( d, J = 2.4Hz, 1H), 7.59- 7.69 (m, 4H), 8.13 (d, J = 2.4Hz, 1H), 8.51 (d, J = 6Hz, 1H ), 8.75 (br, 1H), 8.90 (br, 1H), 9.22 (br, 1H).
    [0114] MS (ESI, m / z) calculated for C21H13D3CIF3N4O3: 467; found: 468 [M + H] +. Example 5:
    [0115] Preparation of 4- (4- (3- (4-chloro-3- (trifluoro-methyl) phenyl] ureido) -phenoxy) -N- (methyl-ds) picolinamide p-toluenesulfonate (CM4307 »TsOH).
    [0116] A reactor (100 L) was loaded with anhydrous ethanol (45.00 kg). After turning the mixer on, 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl] ureido) phenoxy) - N- (methyl-ds) picolinamide (4.50 kg, 9 , 62 mol, 1 equivalent) and p-toluenesulfonic acid monohydrate (0.66 kg, 3.47 mol, 0.36 equivalent) The mixture was heated to 78 ° C and refluxed until the solid completely dissolved.
    [0117] P-Toluenesulfonic acid monohydrate (1.61 kg, 8.46 mol) in anhydrous ethanol (4.50 kg) was added and the mixture was heated to 70 ° C until the solid dissolved. The resulting solution was added to the reactor (100 L). The mixture was cooled to 0-2 ° C and maintained for 30 min. The mixture was discharged and filtered by centrifugation. The solid was washed with anhydrous ethanol (13.50 kg), dried in vacuo for 24 h to give the title compound (5.75 kg, 99.3% purity, 93.4% yield) as a white solid the color of ivory.
    [0118] XH NMR (DMSO-d &, 400 MHz): δ2.30 (s, 3H), 7.15 (d, J = 8.8Hz, 2H), 7.20 (d, J = 8.8Hz, 2H), 7.23 (dd, J = 2.8Hz, 6Hz, 1H), 7.52 (d, J = 8Hz, 2H), 7.55 (d, J = 2.8Hz, 1H), 7, 63 (d, J = 8.8Hz, 3H), 7.68 (dd, J = 2.4Hz, 9.2Hz, 1H), 8, 03 (br, 1H), 8, 14 (d, J = 2 , 4Hz, 1H), 8, 56 (d, J = 6Hz, 1H), 8, 91 (br, 1H), 9.17 (br, 1H), 9.36 (br, 1H).
    [0119] 13C NMR (DMSO-d6, 400 MHz): δ21, l, 26.1, 111.7, 115.2, 117.0, 120.7 (2C), 121.6 (2C), 121, 9, 122.8, 123.2, 124, 6, 125, 6 (2C), 127.2, 129.0 (2C), 132.3, 138.8, 139, 5, 139, 9, 144, 1, 146, 6, 147.2, 152.8, 159, 9, 170.7 ppm.
    [0120] Liquid chromatography condition: Agilent 1000 Series; chromatographic column SYNERGI 4 | 1 POLAR-RP 80A, 250 X 4.6 mm, 4 µm; column temperature: 25 ° C; detection wavelength: 210 nm UV; mobile phase: A: 10 mmol / L ammonium dihydrogen phosphate, B: methanol; injection volume 10 | 1L; flow rate: 0.8 mL / min; operating time: 70 min; gradient: 50% of mobile phase B from 0 to 15 min, the mobile phase B being increased to 75% from 15 to 32 min, then 75% of mobile phase B eluting for 23 min from 32 to 55 min; retention time: 4.95 min (p-toluenesulfonic acid); 47.11 min (CM4307). Example 6:
    [0121] Preparation of Compound CM4307
    1. Preparation of 4-chloro terciobutyl picolinate A7
    [0122] 4-chloro picolinic acid (10.5 g, 66, 64 mmol) was suspended in thionyl chloride (40 ml), and the mixture was heated to 80 ° C and refluxed. N, N-N-dimethyl formamide (0.2 mL) was added dropwise and the mixture was refluxed for 2 hours. Excess thionyl chloride for light yellow acyl chloride was removed under reduced pressure, followed by the addition of dichloromethane (60 ml). The resulting solution was added in a mixed solution of terciobutanol (25 ml), pyridine (20 ml) and dichloromethane (80 ml) at -40 ° C. The reaction mixture was heated to 50 ° C and stirred for 16 hours. The solvents were removed under reduced pressure and ethyl acetate (150 ml) was added. The resulting mixture was washed with saturated brine (2 x 50 ml) and sodium hydroxide solution (IN, 2 x 50 ml), and separated. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dried under vacuum to give the title compound (11.1 g, 95% purity, 78% yield) as a light yellow solid.
    [0123] NMR (DMSO-d &, 400 MHz): δl, 56 (s, 9H), 7.80 (dd, J = 2.4Hz, 5.2Hz, 1H), 8, 02 (d, J = 2Hz , 1H), 8.69 (d, J = 5.2 Hz, 1H).
    [0124] MS (ESI, m / z) calculated for CI0HI2C1NO2: 213; found: 158 [M-But + H] +. 2. Preparation of terciobutyl 4- (4-amino phenoxy) picolinate A8
    [0125] At room temperature p-amino phenol (0.51 g, 4.70 mmol, 1 equivalent) was dissolved in N, N-dimethyl formamide (10 ml). In the resulting solution, potassium terciobutoxide (0.53 g, 4.70 mmol, 1 equivalent) was added in portions and the resulting mixture was stirred for 0.5 h. Terciobutyl 4-chloro picolinate (1 g, 4.70 mmol, 1 equivalent) and potassium carbonate (45 mg, 0.33 mmol, 0.07 equivalent) were added, and the mixture was heated to 80 ° C and stirred for 2 hours. The mixture was cooled to room temperature and ethyl acetate (50 ml) was added. The mixture was filtered to remove undissolved material and the filtrate was washed with saturated brine (2 x 20 ml). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove the solvent. The residue was purified by column chromatography (dichloromethane: ethyl acetate = 30: 1) to give the title compound (805 mg, 96% purity, 60% yield).
    [0126] XH NMR (DMSO-de ;, 400 MHz): δl, 52 (s, 9H), 5.21 (br, 2H), 6, 64 (d, J = 8.8Hz, 2H), 6, 87 (d, J = 8Hz, 2H), 7.35 (dd, J = 2.4Hz, 5.6Hz, 1H), 8, 50 (d, J = 6Hz, 1H).
    [0127] MS (ESI, m / z) calculated for C10H12CINO2: 286; found: 231 [M-But + H] +. 3. Preparation of terciobutyl 4- (4- (3- (4-chloro-3- (methyl trifluorine) phenyl) ureido) phenoxy) picolinate A9.
    [0128] At room temperature, l-chloro-4-isocyanate-2- (methyl trifluorine) benzene (656 mg, 2.96 mmol, 1.05 equivalents) was dissolved in dichloromethane (5 mL). In the resulting solution, a solution of terciobutyl 4- (4-amino phenoxy) picolinate (805 mg, 2.81 mmol, 1 equivalent) and dichloromethane (5 mL) was slowly added dropwise. The mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the resulting solid was purified by column chromatography (dichloromethane: ethanol = 30: 1) to give the title compound (1.4 g, 95% pure, 85% yield) as a white solid.
    [0129] 1H NMR (DMSO-d &, 400 MHz): δl, 53 (s, 9H), 7, 13 (dd, J = 2.4Hz, 5.2Hz, 1H), 7, 18 (d, J = 8.8Hz, 2H), 7.41 (d, J = 2.4Hz, 1H), 7.59-7, 66 (m, 4H), 8, 13 (d, J = 1.6Hz, 1H), 8.55 (d, J = 5.6 Hz, 1H), 9.06 (br, 1H), 9.27 (br, 1H).
    [0130] MS (ESI, m / z) calculated for C24H2IC1F3N3O4: 507; found: 508 [M + H] +. 4. Preparation of 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) picolinic acid AIO.
    [0131] At room temperature, 4— (4— (3— (4— chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) terciobutyl picolinate (1.4 g, 2.76 mmol) was dissolved in dichloromethane (20 mL). In the resulting solution, trifluoroacetic acid (20 ml) and triethyl silane (0.5 ml) were added. The resulting mixture was heated to 50 ° C and stirred for 16 hours. The solvent was removed under reduced pressure, and water (50 ml) and ethyl acetate (70 ml) were added. The resulting mixture was separated and the organic phase was removed. The aqueous layer was filtered and the solid was washed with water (2 x 30 ml). The solid was vacuum dried to give the title compound (1.1 g, 97% purity, 90% yield) as a light green solid.
    [0132] XH NMR (DMSO-d &, 400 MHz): 57.21-7.25 (m, 2H), 7.33 (dd, J = 2.8Hz, 6Hz, 1H), 7.57 (d, J = 2.8Hz, 1H), 7.60- 7.67 (m, 4H), 8, 12 (d, J = 2.4Hz, 2H), 8, 64 (d, J = 6Hz, 1H), 9.84 (br, 1H), 10.17 (br, 1H),.
    [0133] MS (ESI, m / z) calculated for C2oHi2ClF4N304: 451; found: 450 [M-H] -. 5. Preparation of 4- (4- (3- (4-chloro-3- (methyl trifluorine) phenyl) ureido) phenoxy) -N- (methyl-d3) picolinamide CM4307. Method 1:
    [0134] At room temperature, 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) picolinic acid (0.5 g, 1.11 mmol, 1 equivalent) was dissolved ) in N, N-dimethyl formamide (5 ml). (N- (methyl-ds)) amine hydrochloride (0.15 g, 2.22 mmol, 2 equivalents), 2- (7-aza-1H-benzotriazol-l-yl) hydrochloride were added to the resulting solution ) -N, N, N'N'-tetramethyl uronium (HATU, 0.84 g, 2.22 mmol, 2 equivalents) and N, N-diisopropyl ethylamine (DIEA, 0.86 g, 6.66 mmol, 3 equivalent). At room temperature, the resulting mixture was stirred for 16 hours. To the above reaction mixture water (20 ml) was added. The resulting mixture was stirred for 0.5 h and then filtered to give a yellowish white solid. The solid was dissolved in ethyl acetate (50 ml) and the resulting mixture was washed with saturated brine (3 x 10 ml) and then separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to give CM4307 (0.42 g, 97% purity, 81% yield) as an ivory-colored solid.
    [0135] NMR (DMS0-d6, 400 MHz): 57, 15 (dd, J = 2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 (d , J = 2.4Hz, 1H), 7.59- 7.69 (m, 4H), 8.13 (d, J = 2.4Hz, 1H), 8.51 (d, J = 6Hz, 1H) , 8.75 (br, 1H), 8.90 (br, 1H), 9.22 (br, 1H).
    [0136] MS (ESI, m / z) calculated for C21H13D3CIF3N4O3: 467; found: 468 [M + H] +. Method 2:

    [0137] 4- (4- (3- (4-chloro-3- (trifluoromethyl) phenyl) ureido) phenoxy) picolinic acid (0.5 g, 1.11 mmol) was suspended in methanol (10 mL) . At room temperature, concentrated sulfuric acid (2 mL) was added, and the resulting mixture was refluxed for 3 hours. Under reduced pressure, the solvent was removed, and the residue was purified by column chromatography (dichloromethane: methanol = 10: 1) to give 4- (4- (3- (4-chloro-3- (trifluor methyl) phenyl) ureido) phenoxy) All methyl picolinate (0.46 g, 95% purity, 90% yield) as a white solid.
    [0138] TH NMR (DMSO-d6, 400 MHz): δ3.85 (s, 3H), 7.18- 7.21 (m, 3H), 7.43 (d, (dd, J = 2.4Hz , 1H), 7.59-7.66 (m, 4H), 8.13 (d, J = 2.4Hz, 1H), 8.59 (d, J = 6Hz, 1H), 9.06 (br , 1H), 9.27 (br, 1H),.
    [0139] MS (ESI, m / z) calculated for C21H15CIF3N3O4: 465; found: 466 [M + H] +.
    [0140] 4- (4- (3- (4 — chlorine — 3— (methyl trifluorine) phenyl) ureido) phenoxy) methyl picolinate (300 mg, 0.65 mmol, 1 equivalent) was added in a three bottlenecks containing tetrahydrofuran (10 mL) with stirring. To the resulting mixture, (N- (methyl-dj)) amine hydrochloride (91 mg, 1.3 mmol, 2 equivalents) and anhydrous potassium carbonate (400 mesh, 179 mg, 1.3 mmol, 2 equivalents) were added . After stirring the mixture at room temperature for 20 hours, water (5 ml) and methyl terciobutyl ether (15 ml) were added. The mixture was stirred and the organic phase was separated. The aqueous layer was extracted with methyl terciobutyl ether (10 ml), and the organic layers were combined, dried with anhydrous sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure to give CM4307 (261 mg, 96% purity, 86% yield) as an ivory-colored solid.
    [0141] XH NMR (DMSO-di, 400 MHz): 57, 15 (dd, J = 2.8Hz, 5.6Hz, 1H), 7.17-7.19 (m, 2H), 7.40 ( d, J = 2.4Hz, 1H), 7.59- 7.69 (m, 4H), 8.13 (d, J = 2.4Hz, 1H), 8.51 (d, J = 6Hz, 1H ), 8.75 (br, 1H), 8.90 (br, 1H), 9.22 (br, 1H).
    [0142] MS (ESI, m / z) calculated for C2iHi3D3ClF3N4O3: 467; found: 468 [M + H] +. Example 7: Pharmacokinetic evaluation of deuterated diphenyl urea compounds in rats.
    [0143] Eight male Sprague-Dawley rats, 7-8 weeks old and with a body weight of about 210g, were divided into two groups, 4 in each group (rat #: control group was 13-16; experimental group was 9-12). The rats received an oral dose of 3 mg / kg of (a) non-deuterated compound N- (4-chloro-3- (methyl trifluorine) phenyl) -N '- (4- (2- (N-methyl-amino) formyl) -4-pyridyloxy) phenyl) urea (control compound CM4306) or (b) N- (4-chloro-3- (methyl trifluor) phenyl) - N '- (4- (2- (N— (methyl -dj) -amino formyl) -4-pyridyloxy) phenyl) urea (Compound CM4307 of the invention) prepared in Example 1. The pharmacokinetic differences of CM4306 and CM4307 were compared.
    [0144] The rats were fed the standard diet, given water and chlorodiazepoxide. Chlorodiazepoxide was stopped on the last night before the experiment, and given again two hours after administration of the compound. The rats fasted for 16 hours before the test. The compound was dissolved 30% PEG 400. The time to collect orbital blood was 0, 083, 0, 25, 0, 5, 1, 2, 4, 6, 8 and 24 hours after administration of the compound.
    [0145] The rats were briefly anesthetized by inhaling ether. A 300 µl orbital blood sample was collected in tubes containing 30 µl of 1% heparin saline. The tubes were dried overnight at 60 ° C before using them. After blood samples were collected sequentially, the rats were anesthetized with ether and sacrificed.
    [0146] After collecting the samples, the tubes were gently inverted at least five times to mix the contents sufficiently, and placed on ice. The blood samples were centrifuged at 4 ° C at 5000 rpm for 5 minutes to separate the serum and red blood cells. With a pipette, 100 µl of serum was removed into a clean plastic centrifuge tube, and the tube was labeled with a label containing the compound name and time point. Serum was stored at - 80 ° C prior to LC-MS analysis.
    [0147] Figures 1-2 show the results. The results showed that, compared to CM4306, the half-life (Ii / 2) of CM4307 was longer [(11.3 ± 2.1) h for CM4307 and (8.6 ± 1.4) h for CM4306, respectively, the area under the curve (AUCQ-∞) of CM4307 was significantly greater [(11255 ± 2472) ng.h / mL for CM4307 and (7328 ± 336) ng.h / mL for CM4306, respectively], and the clearance apparent value of CM4307 was lower [(275 ± 52) mL / h / kg for CM4307 and (410 ± 18.7) mL / h / kg for CM4306, respectively].
    [0148] The above results showed that the compound of the present invention had better pharmacokinetic properties in the animal and therefore had better therapeutic and pharmacodynamic effects.
    [0149] Furthermore, the metabolism for the compound of the present invention in the body has been changed through deuteration. In particular, hydroxylation of phenyl has become more difficult, which has led to the reduction of the first pass effect. In such cases, the dose can be changed, long-acting preparations can be formed, and applicability can be improved using long-acting preparations.
    [0150] In addition, pharmacokinetics have also changed through deuteration. Since another hydrate film forms completely in deuterated compounds, the distribution of deuterated compounds in organisms is significantly different from that of non-deuterated compounds. Example 8: Pharmacodynamic evaluation of CM4307 to inhibit growth of SMMC-7721 human hepatocellular carcinoma tumor in a hairless rat xenograft model.
    [0151] Seventy hairless rats n / nu Balb / c, 6 weeks old, females, were purchased from the Experimental Animal Resource Center (Shanghai B&K Universal Group Limited).
    [0152] SMMC-7721 cells were commercially obtainable from Shanghai Institutes for Biological Science, CAS (Shanghai, China).
    [0153] The establishment of a xenograft model in hairless mice with a tumor: SMMC-7721 cells were grown in a period of logarithmic growth. After counting the number of cells, the cells were suspended in 1 x PBS, and the number of cells in suspension was adjusted to 1.5 x 107 / ml. Tumor cells were inoculated under the right axillary skin of hairless rats with a 1 ml, 3 x 106 / 0.2 ml / rat syringe. In total, seventy hairless mice were inoculated. O
    [0154] When the tumor size reached 30-130 mm, 58 rats were randomly divided into different groups. The difference in the mean value of tumor volume in each group was less than 10%, and the drugs began to be administered.
    [0155] The test doses for each group are listed in the following table.

    [0156] Animal body weight and tumor size were tested twice during the test. Each day clinical symptoms were recorded. At the end of the administration, the tumor size was photographed. One rat was sacrificed in each group and the tumor tissue was removed and fixed in 4% paraformaldehyde. The observation continued after administration, and when the average tumor size was greater than 2000 mm3, or the dying state appeared, the animals were sacrificed, macroscopic anatomy was performed, and the tumor tissue was removed and fixed in paraformaldehyde at 4 %.
    [0157] The formula for calculating the tumor volume (TV) is: TV = a x b2 / 2, in which a, b independently represent the length and width of the tumor. The formula for calculating the relative tumor volume (RTV) is: RTV = Vt / Vo, where Vo is the tumor volume volume at the start of administration, and Vt is the tumor weight when measured. The index to assess antitumor activity is the relative rate of tumor growth T / C (%), and the formula is: T / C (%) = (TRRV / CRTV) X 100%, in which, TRTV is RTV of the treatment group, and CRTV is the RTV of the negative control groups.
    [0158] Efficacy assessment standard: it is effective if the relative T / C tumor increment rate (%) is <40% and p <0.05 by statistical analysis.
    [0159] Figure 3 shows the results. CM4306 and CM4307 were administered intragastrically every day for 2 weeks at doses of 10, 30, 100 mg / kg, respectively, and both compounds showed the dose-dependent effect of tumor growth inhibition. At the end of the administration, CM4306 T / C% was 56.9%, 40.6% and 32.2%, respectively. T / C% of CM4307 was 53.6%, 40.8% and 19.6%. T / C% for 100 mg / kg dose groups was <40%, and the tumor volume was significantly different (p <0.01) from the control group, indicating the significant effect in inhibiting tumor growth.
    [0160] Compared with CM4306, tumor growth inhibitory efficacy at a dosage of 100 mg / kg of CM3407 was stronger (T / C% for CM4307 and CM4306 is 19.6% and 32.2%, respectively, in 15 days), there was a significant difference in tumor volume between groups (p <0.01). Compared with CM4306, the absolute value of tumor inhibition rate for CM4307 increased by more than 10%, the relative value increment about 60% (32.2% / 19.6% -1 = 64%), and CM4307 showed most significant effect in inhibiting tumor growth.
    [0161] Furthermore, during the experiment, no other relevant toxic effects of the drug were observed. Example 9: Pharmaceutical compositions Compound CM4307 (Example 1) = 20 g Starch = 140 g Microcrystalline cellulose = 60 g.
    [0162] By routine methods, these substances were mixed evenly, and loaded into ordinary gelatin capsules, thus forming 1000 capsules.
    [0163] All of the literature mentioned in the present patent application is incorporated by reference, as if each were incorporated herein individually. Additionally, it should be understood after reading the above teachings, that many variations and modifications can be made by the person skilled in the art, and these equivalents are also within the limits of the scope defined by the attached claims.
    权利要求:
    Claims (3)
    [0001]
    1. Method for preparing N- (4-chloro-3- (trifluoro methyl) phenyl) -N '- (4- (2- (N- (methyl-d3) amino formyl) -4-pyridyloxy) phenyl) urea,
    [0002]
    2. Method according to claim 1, characterized in that compound 5 is prepared as follows: reacting compound 3 with compound 4 to form compound 5:
    [0003]
    3. Use of the intermediate, as defined in claim 2, characterized by the fact that it is to prepare deuterated w-diphenyl urea, with deuterated w-diphenyl urea being 4- (4- (3- (4-chloro-3) ptoluenesulfonate - (methyl trifluorine) phenyl) ureido) -phenoxy) -N- (methyl-d3) picolinamide, and CM4307 is prepared using the method: in an inert solvent, react the 4-chloro-3-3-trifluoromethyl phenyl isocyanate (VIII) with compound 5 to form said compound, the inert solvent being the mixed solvent of dimethyl sulfoxide and dichloromethane: CM4307 (IX)
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    同族专利:
    公开号 | 公开日
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    WO2011113368A1|2011-09-22|
    EP3330254A2|2018-06-06|
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    JP2013522244A|2013-06-13|
    BR112012023525A2|2016-07-26|
    CA2793594C|2015-10-13|
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    US8618306B2|2013-12-31|
    CN102190616B|2015-07-29|
    US20130060044A1|2013-03-07|
    US9078933B2|2015-07-14|
    EP3330254A3|2018-08-22|
    EP2562159A4|2013-11-20|
    CN102803220A|2012-11-28|
    JP5752315B2|2015-07-22|
    CN102844303B|2015-02-04|
    US20140088311A1|2014-03-27|
    CN102190616A|2011-09-21|
    US9072796B2|2015-07-07|
    CN103936669A|2014-07-23|
    JP2013522243A|2013-06-13|
    EP2548868A4|2015-07-08|
    JP5671558B2|2015-02-18|
    RU2012143523A|2014-04-27|
    US8759531B2|2014-06-24|
    JP2015091845A|2015-05-14|
    JP5676656B2|2015-02-25|
    KR101459401B1|2014-11-07|
    WO2011113367A1|2011-09-22|
    US20140128612A1|2014-05-08|
    EP2548868A1|2013-01-23|
    WO2011113366A1|2011-09-22|
    US8669369B2|2014-03-11|
    RU2527037C2|2014-08-27|
    CN102803222B|2015-02-04|
    KR20130008050A|2013-01-21|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    EP1140840B1|1999-01-13|2006-03-22|Bayer Pharmaceuticals Corp.|-g-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors|
    US6846832B2|2002-08-07|2005-01-25|Hoffman-La Roche Inc.|2,3-dihydro-isoindol-1-one derivatives|
    JP4777887B2|2003-07-23|2011-09-21|バイエル、ファーマシューテイカルズ、コーポレイション|Fluoro-substituted omegacarboxyaryl diphenylureas for the treatment and prevention of diseases and conditions|
    US8124782B2|2004-09-29|2012-02-28|Bayer Pharma Aktiengesellschaft|Process for the preparation of 4-{4-[phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide|
    WO2008089389A2|2007-01-19|2008-07-24|Bayer Healthcare Llc|Treatment of cancers with acquired resistance to kit inhibitors|
    CA2675979A1|2007-01-19|2008-07-24|Bayer Healthcare Llc|Treatment of cancers having resistance to chemotherapeutic agents|
    US20080234332A1|2007-03-20|2008-09-25|Xiong Cai|Raf kinase inhibitors containing a zinc binding moiety|
    WO2009034308A2|2007-09-10|2009-03-19|Cipla Limited|Process for the preparation of a raf kinase inhibitor and intermediates for use in the process|
    US20090069388A1|2007-09-11|2009-03-12|Protia, Llc|Deuterium-enriched sorafenib|
    WO2009054004A2|2007-10-22|2009-04-30|Natco Pharma Limited|Process for the preparation of sorafenib|
    WO2010019701A2|2008-08-14|2010-02-18|Concert Pharmaceuticals, Inc.|Diaryl urea derivatives|
    CN101676266B|2008-09-19|2011-10-26|苏州泽璟生物制药有限公司|Deuterium-substituted omega-diphenylurea and its derivatives, as well as pharmaceutical composition containing the same|
    US8410082B2|2009-05-22|2013-04-02|Concert Pharmaceuticals, Inc.|Fluorinated diaryl urea derivatives|
    US20120077851A1|2009-06-09|2012-03-29|Medolution Limited|Urea Derivatives as Kinase Inhibitors|
    CN102190616B|2010-03-18|2015-07-29|苏州泽璟生物制药有限公司|A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production|
    EP2548859B1|2010-03-18|2015-03-04|Suzhou Zelgen Biopharmaceutical Co., Ltd.|Preparation methods of methyl-d3-amine and salts thereof|CN102190616B|2010-03-18|2015-07-29|苏州泽璟生物制药有限公司|A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production|
    CN103387536B|2012-05-10|2016-06-29|苏州泽璟生物制药有限公司|Fluorine-containing deuterated ω-diphenyl urea or the polymorph of its salt|
    CN103570613B|2012-07-18|2016-06-15|苏州泽璟生物制药有限公司|The polymorphic form of deuterated ω-diphenyl urea or its salt|
    WO2015035531A1|2013-09-12|2015-03-19|杭州普晒医药科技有限公司|Crystal form of regorafenib salt and preparation method and application thereof|
    CN114014804A|2013-10-25|2022-02-08|苏州泽璟生物制药股份有限公司|Fluorine-containing deuterated omega-diphenylurea hydrate and crystal form thereof|
    WO2015085888A1|2013-12-09|2015-06-18|Jiangsu Medolution Limited|4-phenyl)ureido)-3-fluorophenoxy)-n-d3-methylpicolinamide monohydrate|
    CN105777625B|2014-12-24|2020-05-22|浙江海正药业股份有限公司|Method for preparing 4--N-methylpyridine-2-formamide|
    CN104910067A|2015-03-05|2015-09-16|南京工业大学|Regorafenib synthesis method by one kettle way|
    AR105607A1|2015-08-07|2017-10-18|Bayer Cropscience Ag|HETEROCYCLIC CONDENSED DERIVATIVES REPLACED BY 2-ARILO AS PESTICIDES|
    CN105348186B|2015-10-15|2018-05-22|青岛海洋生物医药研究院股份有限公司|Deuterated substituted bisarylurea compound and preparation method thereof and the application in anti-tumor drug is prepared|
    CN105924390B|2016-05-19|2018-07-10|广州南新制药有限公司|A kind of synthetic method of Mei Tafeini|
    CN106008276B|2016-05-20|2018-07-06|湖北出入境检验检疫局检验检疫技术中心|The synthetic method of the phenylurea analog herbicide of phenylurea analog herbicide or deuterated label|
    CN106083711B|2016-05-31|2018-09-25|北京康立生医药技术开发有限公司|A kind of synthetic method of Rui Gefeini|
    EP3619213A1|2017-05-02|2020-03-11|Bayer Aktiengesellschaft|2-aryl-substituted condensed bicyclic heterocyclic derivatives as pest control agents|
    CN108586330A|2018-04-18|2018-09-28|日照市普达医药科技有限公司|A kind of preparation method and applications of tumor|
    CN109078638A|2018-08-30|2018-12-25|海门海康生物医药科技有限公司|A kind of catalyst and preparation method thereof synthesizing deuterated methanol|
    CN110885298A|2019-12-13|2020-03-17|山东金城医药化工有限公司|Synthesis method of 4-chloro-3-phenylisocyanate|
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    优先权:
    申请号 | 申请日 | 专利标题
    CN201010127706.6A|CN102190616B|2010-03-18|2010-03-18|A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production|
    CN201010127706.6|2010-03-18|
    PCT/CN2011/071926|WO2011113367A1|2010-03-18|2011-03-17|Method and process for preparation and production of deuterated ω-diphenylurea|
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