Process and intermediates for preparation of certain nematicidal sulfonamides

Abstract

To provide a method for preparation of certain nematicidal sulfonamides.SOLUTION: The method includes forming a compound represented by the formula G. [where each of R4, R5, R6 and R7 independently represent H, halogen, SF5, C(=O)(C1-C8 alkyl), C(=O)O(C1-C8 alkyl), N(C1-C8 alkyl)(C1-C8 alkyl), C(=O)N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), or the like.]SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is the benefit of U.S. Provisional Patent Application No. 62 / 741,877 (filed October 5, 2018). The entire contents of the above application are hereby incorporated by reference. It is incorporated. [Background technology]

[0002] Certain nematicidal sulfonamides and methods for preparing them are described, for example, in International Publication No. WO 2005 / 013311. Brochure No. 2010 / 129500, Brochure No. 2012 / 054233, and 2014 / 109933. However, The specific synthesis steps already disclosed still have certain drawbacks. There remains a need for alternative methods of preparing nematode sulfonamides. Summary of the Invention [Means for solving the problem]

[0003] In one aspect, the present invention provides a compound of formula C, formula D, or formula F: [ka] [In the formula, each R 1 , R 2 , and R 3 are independently H, SF 5 , N(C 1 ~C 8 Alkyl) (C 1 ~C 8 alkyl), C(=S)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl) , S.O. 2 N(C1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), OSO 2 (C 1 ~C 8 Al Kill), OSO 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 alkyl), N(C 1 ~C 8 a RuKil)SO 2 (C 1 ~C 8 alkyl), or C 1 ~C 8 Alkyl, C 1 ~C 8 Halo Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 10 Cycloalkyl , C 3 ~C 10 Halocycloalkyl, C 4 ~C 10 Alkylcycloalkyl, C 4 ~C 1 0 Cycloalkylalkyl, C 6 ~C 14 CycloalkylCycloalkyl, C 5 ~C 10 Alkylcycloalkylalkyl, C 3 ~C 8 Cycloalkenyl, C 1 ~C 8 Alkoxy , C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Cycloalkoxy, C 3 ~C 8 Halocycloal Koxy, C4 ~C 10 Cycloalkylalkoxy, C 2 ~C 8 Alkenyloxy, C 2 ~ C 8 Alkynyloxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkylsulfinyl, C 1 ~C 8 Alkylsulfonyl, C 3 ~C 8 Cycloalkylthio, C 3 ~C 8 Cycloalkane Rusulfinyl, C 3 ~C 8 Cycloalkylsulfonyl, C 4 ~C 10 Cycloalkyla Lukirchio, C. 4 ~C 10 Cycloalkylalkylsulfinyl, C 4 ~C 10 Cycloa Alkyl alkyl sulfonyl, C 2 ~C 8 Alkenylthio, C 2 ~C 8 Alkenyl sulfide Nill, C 2 ~C 8 Alkenylsulfonyl, C 2 ~C 8 Alkynylthio, C 2 ~C 8 Alki Nilsulfinyl, C 2 ~C 8 alkynylsulfonyl, or phenyl; or R on adjacent ring atom 1 , R 2 , and R 3 Two of them together form a 5- to 7-membered carbon ring. or a heterocyclic ring, each ring containing carbon atoms and up to two O, up to two S and up to three heteroatoms independently selected from up to three N wherein up to two carbon atom ring members are independently selected from C(=O) and C(=S). Such a ring is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Al Kenil, C. 2 ~C 4 Haloalkenyl, C 2 ~C 4 Alkynyl, C 2 ~C 4 Haloalkynyl , C 3 ~C 7 Cycloalkyl, C 3 ~C 7 Halocycloalkyl, C 4 ~C 8 Alkyl sil Roalkyl, C 4 ~C 8 Haloalkylcycloalkyl, C 4 ~C 8 Cycloalkyl Lu, C 4 ~C 8 Halocycloalkylalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 HelloA Lukoxi, C 2 ~C 8 Alkoxycarbonyl, C 2 ~C 6 Haloalkoxycarbonyl, C 2 ~C 6 Alkylcarbonyl and C 2 ~C 6 haloalkylcarbonyl optionally substituted with up to three substituents selected arbitrarily; M is an inorganic or organic cation. A process for preparing a compound of the formula: (a) Formula A [ka] The compounds were separated into o-dichlorobenzene (ODCB), chloroalkanes, and chloroarenes. and a sulfonic acid (e.g., chlorosulfonic acid ClSO 3 H), sulfur Acid (H 2 SO 4 ), and oleum to form a compound of formula B: [ka] and forming a compound of (b) reacting a compound of formula B with (i) a nitrite salt, MNO 2 [For example, NaNO 2 ] or nitrite es Tert-butyl nitrite (e.g., tert-butyl nitrite (tBuNO 2 ) and alkyl nitrites ( ii) at least one inorganic acid (e.g., hydrochloric acid HCl), at least one organic acid, or and contacting the mixture with a second acid selected from the group consisting of a carboxylic acid having formula C: [ka] and forming a compound of formula (I).

[0004] The compound of formula C can be represented in alternative chemical structures as the following equilibrium states: [ka]

[0005] In some embodiments, R 1 , R 2 , and R 3 is not a halogen.

[0006] In some embodiments, each R 1 , R 2 , and R 3 are independently H, C 1 ~C 6 Al Kill, C. 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, or is phenyl. In some embodiments, R 1 and R 3 is H. Some In the embodiment, R 2 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Arco Kishi or C 1 ~C 6 In some embodiments, R 2 is CH 3 , C.H. 2 CH 3 , C.F. 3 , O.C.H. 3 , OCF 3 , or OCH 2 CH 3 Some In embodiments, R 2 is OCH 3 It is.

[0007] In some embodiments, M is sodium, potassium, ammonium, lithium, and and mixtures thereof. In some embodiments, M is an inorganic cation selected from In some embodiments, M is trimethylammonium, triethylammonium, ammonium, tri-n-propylammonium, triisopropylammonium, and and tributylammonium.

[0008] In some further embodiments, the second acid is hydrochloric acid (HCl), hydrobromic acid (HBr), , Phosphate (H 3 PO 4 ), sulfuric acid (H 2 SO 4 ), and boric acid (H 3 BO 3 ) are selected In some further embodiments, the second acid includes formic acid, acetic acid, propionic acid, or an inorganic acid. Examples of sulfonic acids include organic acids selected from the group consisting of citric acid, malic acid, and sulfonic acid. As for the acid, para-toluenesulfonic acid, methanesulfonic acid, and mixtures of isomers Toluenesulfonic acid is an example of the second acid. In some embodiments, the second acid is hydrochloric acid (HCl ).

[0009] In some embodiments, the method provided includes a step (c) for preparing a compound of formula D. ) also includes: (c) The compound of formula C from step (b) is dissolved in copper (Cu) powder and a copper salt (e.g., CuI, C uBr, CuCl, or CuCl 2 ) and optionally, If not already provided, a first chloride source is provided, followed by at least one inorganic base (e.g. a first base selected from the group consisting of ethyl alcohol, at least one organic base, or a mixture thereof; by contacting with a base of formula D: [ka] forming a compound of

[0010] In some embodiments, the inorganic base is ammonia, sodium hydroxide, or potassium hydroxide. In some embodiments, the inorganic base is selected from sodium hydroxide. In some embodiments, the organic base is sodium methoxide, sodium ethoxide, , sodium iso-propoxide, sodium n-propoxide, potassium methoxide, Potassium ethoxide, potassium 1-propoxide, potassium 2-propoxide, methyl a amine, ethylamine, dimethylamine, trimethylamine, triethylamine, and pyrimidine. In some embodiments, the first base is selected from sodium methoxide or Ammonia (ammonium hydroxide or NH 4 Contains OH).

[0011] The optional first chloride source is thionyl chloride (SOCl 2 ), POCl 3 , P.C. l 5 , oxalyl chloride, and phosgene, or any salt or chloride, such as NaCl l (i.e., MCl, where M is an organic or inorganic cation as defined herein) The acid may be selected from acids containing HCl.

[0012] In some embodiments, the method provided further comprises a step (d) for preparing a compound of formula E ) also includes: (d) The compound of formula D from step (c) is reacted with thionyl chloride (SOCl 2 ), POCl 3 , P Cl 5 a second chloride source selected from oxalyl chloride and phosgene, and a solvent; N,N-disubstituted formamides in S1 (e.g., dimethylformamide (DMF) and / or or N-formylpiperidine) to form a compound of formula E: [ka] forming a compound of

[0013] In some embodiments, the solvent S1 is water, C 7 ~C 10 Aromatic Hydrocarbons, Haloalkanes benzene, halogenated benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, In some embodiments, the solvent is selected from the group consisting of acetonitrile, ... The solvent S1 is water, toluene, dichloromethane, 1,2-dichloroethane, 1-chlorobutane. , acetonitrile, or a combination thereof. In some embodiments, the solvent S1 In some embodiments, the solvent S1 is acetonitrile. In some embodiments, solvent S1 is a mixture of water and acetonitrile. In an embodiment, solvent S1 is a mixture of acetonitrile and toluene.

[0014] In some embodiments, the method provided includes a step (e) for preparing a compound of formula F. ) also includes: (e) Reacting the compound of formula E from step (d) with ammonia (ammonium hydroxide or NH 4 O H), a second amine selected from trimethylamine, triethylamine, and mixtures thereof; and optionally an inorganic or organic base in a solvent S2 to form a compound of formula F: [ka] forming a compound of

[0015] In some embodiments, the inorganic base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the inorganic base is sodium hydroxide. In an embodiment, the organic base is sodium methoxide, sodium ethoxide, sodium iodophosphate, sodium methoxide, sodium ethoxide, sodium meth ... so-propoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide thiol, potassium 1-propoxide, potassium 2-propoxide, and pyridine. In some embodiments, the organic base is sodium methoxide.

[0016] In some embodiments, the solvent S2 is water, C 7 ~C 10 Aromatic Hydrocarbons, Haloalkanes benzene, halogenated benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, In some embodiments, the solvent is selected from the group consisting of acetonitrile, ... The solvent S2 is water, toluene, dichloromethane, 1,2-dichloroethane, 1-chlorobutane. , acetonitrile, or a combination thereof. In some embodiments, solvent S2 In some embodiments, solvent S2 is a mixture of water and acetonitrile. In some embodiments, solvent S2 is a mixture of acetonitrile and toluene. It is a mixture of.

[0017] In some embodiments, solvent S1 is the same as solvent S2. Solvent S1 is different from solvent S2.

[0018] In some embodiments, the present invention provides a compound according to formula 1: [ka] A process for preparing a compound of the formula: (A) Formula 2 [ka] The compounds were analyzed using o-dichlorobenzene (ODCB), chloroalkanes, and chloroarenes. and a sulfonic acid (e.g., chlorosulfonic acid ClSO 3 H), sulfur Acid (H 2 SO 4 ), and oleum to form a compound of formula 3: [ka] and forming a compound of (B) The compound of formula 3 is reacted with (i) nitrite, MNO 2 [For example, NaNO 2 ] or nitrite es Tert-butyl nitrite (e.g., tert-butyl nitrite (tBuNO 2 ) and alkyl nitrites ( ii) at least one inorganic acid (e.g., hydrochloric acid HCl), at least one organic acid, or and contacting the mixture with a second acid selected from the group consisting of a carboxylic acid of formula 4: [ka] wherein M is an inorganic or organic cation; (C) The compound of formula 4 is dissolved in copper (Cu) powder and a copper salt (e.g., CuI, CuBr, CuCl , or CuCl 2 ), and optionally, any other copper source not already provided. If not, a first chloride source is added, followed by at least one inorganic base (e.g., NaOH). , at least one organic base, or a mixture thereof. So, Equation 5: [ka] and forming a compound of (D) The compound of formula 5 in step (C) is reacted with thionyl chloride (SOCl 2 ), POCl 3 , PCl 5 a second chloride source selected from oxalyl chloride and phosgene, and a solvent S1 N,N-disubstituted formamides (e.g., dimethylformamide (DMF) and / or N-formylpiperidine), to form a compound of formula 6: [ka] and forming a compound of (E) The compound of formula 6 is reacted with ammonia (ammonium hydroxide or NH 4 OH), trimethyl a second base selected from an amine, triethylamine, and mixtures thereof, and a solvent; contacting with an optional inorganic or organic base in S2 to form a compound of formula 1; and, The present invention provides a method comprising:

[0019] The compound of formula 4 can be represented in alternative chemical structures as the following equilibrium states: [ka]

[0020] In some embodiments, M is sodium, potassium, ammonium, lithium, and and mixtures thereof. In some embodiments, M is an inorganic cation selected from In some embodiments, M is trimethylammonium, triethylammonium, ammonium, tri-n-propylammonium, triisopropylammonium, and and tributylammonium.

[0021] In some further embodiments, the second acid is hydrochloric acid (HCl), hydrobromic acid (HBr), , Phosphate (H 3 PO 4 ), sulfuric acid (H 2 SO 4 ), and boric acid (H 3 BO 3 ) are selected In some further embodiments, the second acid includes formic acid, acetic acid, propionic acid, or an inorganic acid. Examples of sulfonic acids include organic acids selected from the group consisting of citric acid, malic acid, and sulfonic acid. As for the acid, para-toluenesulfonic acid, methanesulfonic acid, and mixtures of isomers Toluenesulfonic acid is an example of the second acid. In some embodiments, the second acid is hydrochloric acid (HCl ).

[0022] In some embodiments, the inorganic base is selected from sodium hydroxide and potassium hydroxide. In some embodiments, the inorganic base is sodium hydroxide. In an embodiment, the organic base is sodium methoxide, sodium ethoxide, sodium iodophosphate, sodium methoxide, sodium ethoxide, sodium meth ... so-propoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide thiol, potassium 1-propoxide, potassium 2-propoxide, and pyridine. In some embodiments, the organic base is sodium methoxide.

[0023] The optional first chloride source is thionyl chloride (SOCl 2 ), POCl3 , P.C. l 5 , oxalyl chloride, and phosgene, or any salt or chloride, such as NaCl l (i.e., MCl, where M is an organic or inorganic cation as defined herein) The acid may be selected from acids containing HCl.

[0024] In some embodiments, the solvent S1 is water, C 7 ~C 10 Aromatic Hydrocarbons, Haloalkaline benzene, halogenated benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, In some embodiments, the solvent is selected from the group consisting of acetonitrile, ... The solvent S1 is water, toluene, dichloromethane, 1,2-dichloroethane, 1-chlorobutane. , acetonitrile, or a combination thereof. In some embodiments, the solvent S1 In some embodiments, the solvent S1 is acetonitrile. In some embodiments, solvent S1 is a mixture of water and acetonitrile. In an embodiment, solvent S1 is a mixture of acetonitrile and toluene.

[0025] In some embodiments, the solvent S2 is water, C 7 ~C 10 Aromatic Hydrocarbons, Haloalkaline benzene, halogenated benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, In some embodiments, the solvent is selected from the group consisting of acetonitrile, ... The solvent S2 is water, toluene, dichloromethane, 1,2-dichloroethane, 1-chlorobutane. , acetonitrile, or a combination thereof. In some embodiments, solvent S2 In some embodiments, solvent S2 is a mixture of water and acetonitrile. In some embodiments, solvent S2 is a mixture of acetonitrile and toluene. It is a mixture of.

[0026] In some embodiments, solvent S1 is the same as solvent S2. Solvent S1 is different from solvent S2.

[0027] In another aspect, the present invention provides a compound of formula G: [ka] [In the formula, each R 4 , R 5 , R 6 , and R 7 are independently H, halogen, or SF 5 , C(=O )(C 1 ~C 8 alkyl), C(=O)O(C 1 ~C 8 alkyl), N(C 1 ~C 8 Al Kill)(C 1 ~C 8 alkyl), C(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Al Kill), C(=S)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), SO 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 alkyl), OC(=O)(C 1 ~C 8Alkyl), OC (=O)O(C 1 ~C 8 alkyl), OC(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 alkyl), N(C 1 ~C 8 Alkyl)C(=O)O(C 1 ~C 8 alkyl), N(C 1 ~C 8 Alkyl)C(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), OS O 2 (C 1 ~C 8 Alkyl), OSO 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl ), N(C 1 ~C 8 Alkyl)SO 2 (C 1 ~C 8 alkyl), or C 1 ~C 8 Alkyl , C 1 ~C 8 Haloalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 1 0 Cycloalkyl, C 3 ~C 10 Halocycloalkyl, C 4 ~C 10 Alkylcycloalkenyl Kill, C. 4 ~C 10 Cycloalkylalkyl, C 6 ~C 14Cycloalkyl Lu, C 5 ~C 10 Alkylcycloalkylalkyl, C 3 ~C 8 Cycloalkenyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Cycloalkoxy, C 3 ~C 8 Halocycloalkoxy, C 4 ~C 10 Cycloalkylalkoxy, C 2 ~C 8 Arken Ruoxi, C 2 ~C 8 Alkynyloxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkyl Sulfinyl, C 1 ~C 8 Alkylsulfonyl, C 3 ~C 8 Cycloalkylthio, C 3 ~ C 8 Cycloalkylsulfinyl, C 3 ~C 8 Cycloalkylsulfonyl, C 4 ~C 10 Cycloalkylalkylthio, C 4 ~C 10 Cycloalkylalkylsulfinyl, C 4 ~C 10 Cycloalkylalkylsulfonyl, C 2 ~C 8 Alkenylthio, C 2 ~C 8 a Alkenylsulfinyl, C 2 ~C 8 Alkenylsulfonyl, C 2 ~C8 Alkynylthio, C 2 ~C 8 Alkynylsulfinyl, C 2 ~C 8 Alkynylsulfonyl, or phenyl or R on adjacent ring atom 4 , R 5 , R 6 , and R 7 Two of them, together, form a group of 5-7 members. may form a carbocyclic or heterocyclic ring, each of which may contain carbon atoms and up to two O, up to two up to three heteroatoms independently selected from up to three S, and up to three N containing a ring member, where up to two carbon atom ring members are independent of C(=O) and C(=S). Such a ring is selected from the group consisting of C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C 4 Haloalkenyl, C 2 ~C 4 Alkynyl, C 2 ~C 4 Haloal Kinnill, C. 3 ~C 7 Cycloalkyl, C 3 ~C 7 Halocycloalkyl, C 4 ~C 8 Alki Cycloalkyl, C 4 ~C 8 Haloalkylcycloalkyl, C 4 ~C 8 Cycloalkyl Alkyl, C 4 ~C 8 Halocycloalkylalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Haloalkoxy, C 2 ~C 8 Alkoxycarbonyl, C 2 ~C 6 Haloalkoxycarbonyl Lu, C 2 ~C 6 Alkylcarbonyl and C 2 ~C 6 The group consisting of haloalkylcarbonyl and optionally substituted with up to three substituents independently selected from A process for preparing a compound of formula H [ka] Compounds of the formula (a) trimethylamine, triethylamine, pyridine, alkylpyridine and 3-picoline (i.e., 3-methylpyridine); and (b) a solvent. In the presence of catalyst S3, thionyl chloride (SOCl 2 ), POCl 3 , PCl 5 , oxalyl chloride and phosgene to form a compound of formula G: [ka] and forming a compound of formula (I).

[0028] In some embodiments, the solvent S3 is water, C 7 ~C 10 Aromatic Hydrocarbons, Haloalkanes benzene, halogenated benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, In some embodiments, the solvent is selected from the group consisting of acetonitrile, ... The solvent S3 is water, toluene, dichloromethane, 1,2-dichloroethane, 1-chlorobutane. , acetonitrile, or a combination thereof. In some embodiments, solvent S3 In some embodiments, solvent S3 is acetonitrile. In some embodiments, solvent S3 is a mixture of water and acetonitrile. In an embodiment, solvent S3 is a mixture of acetonitrile and toluene.

[0029] In some embodiments, the present invention also provides a compound of formula 7: [ka] A process for preparing a compound of the formula: (a) Formula 8 [ka] The compound is reacted with trimethylamine, triethylamine, pyridine, and amine in the presence of solvent S3. Reagent A selected from alkylpyridine, and 3-picoline (i.e., 3-methylpyridine); Upon contacting, a compound of formula 9: [ka] and forming a compound of (b) The compound of formula 9 is reacted with thionyl chloride (SOCl 2 ), POCl 3 , PCl 5 , oxychloride and a chloride source selected from salyl and phosgene to form a compound of formula 7. The present invention relates to a method comprising:

[0030] In another aspect, the present invention provides a compound of formula J: [ka] [In the formula, each R 1 , R2 , and R 3 are independently H, SF 5 , N(C 1 ~C 8 Alkyl) (C 1 ~C 8 alkyl), C(=S)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl) , S.O. 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), OSO 2 (C 1 ~C 8 Al Kill), OSO 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 alkyl), N(C 1 ~C 8 a RuKil)SO 2 (C 1 ~C 8 alkyl), or C 1 ~C 8 Alkyl, C 1 ~C 8 Halo Alkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 10 Cycloalkyl , C 3 ~C 10 Halocycloalkyl, C 4 ~C 10 Alkylcycloalkyl, C 4 ~C 1 0 Cycloalkylalkyl, C 6 ~C 14 CycloalkylCycloalkyl, C 5 ~C 10 Alkylcycloalkylalkyl, C 3 ~C 8 Cycloalkenyl, C 1 ~C 8 Alkoxy , C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Cycloalkoxy, C 3 ~C 8 Halocycloal Koxy, C 4 ~C 10 Cycloalkylalkoxy, C 2 ~C 8 Alkenyloxy, C 2 ~ C 8 Alkynyloxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkylsulfinyl, C 1 ~C 8 Alkylsulfonyl, C 3 ~C 8 Cycloalkylthio, C 3 ~C 8 Cycloalkane Rusulfinyl, C 3 ~C 8 Cycloalkylsulfonyl, C 4 ~C 10 Cycloalkyla Lukirchio, C. 4 ~C 10 Cycloalkylalkylsulfinyl, C 4 ~C 10 Cycloa Alkyl alkyl sulfonyl, C 2 ~C 8 Alkenylthio, C 2 ~C 8 Alkenyl sulfide Nill, C 2 ~C 8 Alkenylsulfonyl, C 2 ~C 8 Alkynylthio, C 2 ~C 8 Alki Nilsulfinyl, C 2 ~C 8 alkynylsulfonyl, or phenyl; or R on adjacent ring atom 1 , R 2 , and R 3 Two of them together form a 5- to 7-membered carbon ring. or a heterocyclic ring, each ring containing carbon atoms and up to two O, up to two S and up to three heteroatoms independently selected from up to three N wherein up to two carbon atom ring members are independently selected from C(=O) and C(=S). Such a ring is C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Al Kenil, C. 2 ~C 4 Haloalkenyl, C 2 ~C 4 Alkynyl, C 2 ~C 4 Haloalkynyl , C 3 ~C 7 Cycloalkyl, C 3 ~C 7 Halocycloalkyl, C 4 ~C 8 Alkyl sil Roalkyl, C 4 ~C 8 Haloalkylcycloalkyl, C 4 ~C 8 Cycloalkyl Lu, C 4 ~C 8 Halocycloalkylalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 HelloA Lukoxi, C 2 ~C 8 Alkoxycarbonyl, C 2 ~C6 Haloalkoxycarbonyl, C 2 ~C 6 Alkylcarbonyl and C 2 ~C 6 haloalkylcarbonyl is optionally substituted with up to three substituents selected arbitrarily; Each R 4 , R 5 , R 6 , and R 7 are independently H, halogen, or SF 5 , C(=O)(C 1 ~C 8 alkyl), C(=O)O(C 1 ~C 8 alkyl), N(C 1 ~C 8 Alkyl)( C 1 ~C 8 alkyl), C(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 alkyl), C(=S)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), SO 2 N(C 1 ~C 8 a Rukill) (C 1 ~C 8 alkyl), OC(=O)(C 1 ~C 8 alkyl), OC(=O) O(C 1 ~C 8 alkyl), OC(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alki le), N(C 1 ~C 8 Alkyl)C(=O)O(C 1 ~C 8 alkyl), N(C1 ~C 8 Alkyl)C(=O)N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), OSO 2 (C 1 ~C 8 Alkyl), OSO 2 N(C 1 ~C 8 Alkyl)(C 1 ~C 8 Alkyl), N( C 1 ~C 8 Alkyl)SO 2 (C 1 ~C 8 alkyl), or C 1 ~C 8 Alkyl, C 1 ~C 8 Haloalkyl, C 2 ~C 8 Alkenyl, C 2 ~C 8 Alkynyl, C 3 ~C 10 S Chloroalkyl, C 3 ~C 10 Halocycloalkyl, C 4 ~C 10 Alkylcycloalkyl , C 4 ~C 10 Cycloalkylalkyl, C 6 ~C 14 cycloalkylcycloalkyl, C 5 ~C 10 Alkylcycloalkylalkyl, C 3 ~C 8 Cycloalkenyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Haloalkoxy, C 3 ~C 8 Cycloalkoxy, C 3 ~C8 Ha Cycloalkoxy, C 4 ~C 10 Cycloalkylalkoxy, C 2 ~C 8 Alkenyleo Kishi, C 2 ~C 8 Alkynyloxy, C 1 ~C 8 Alkylthio, C 1 ~C 8 Alkylsul Finil, C. 1 ~C 8 Alkylsulfonyl, C 3 ~C 8 Cycloalkylthio, C 3 ~C 8 Cycloalkylsulfinyl, C 3 ~C 8 Cycloalkylsulfonyl, C 4 ~C 10 Sik alkylalkylthio, C 4 ~C 10 Cycloalkylalkylsulfinyl, C 4 ~C 10 Cycloalkylalkylsulfonyl, C 2 ~C 8 Alkenylthio, C 2 ~C 8 Arke Nilsulfinyl, C 2 ~C 8 Alkenylsulfonyl, C 2 ~C 8 Alkynylthio, C 2 ~C 8 Alkynylsulfinyl, C 2 ~C 8 Alkynylsulfonyl or phenyl Is there; or R on adjacent ring atom 4 , R 5 , R 6 , and R 7 Two of them, together, form a group of 5-7 members. may form a carbocyclic or heterocyclic ring, each of which may contain carbon atoms and up to two O, up to two up to three heteroatoms independently selected from up to three S, and up to three N containing a ring member, where up to two carbon atom ring members are independent of C(=O) and C(=S). Such a ring is selected from the group consisting of C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 2 ~C 4 Alkenyl, C 2 ~C 4 Haloalkenyl, C 2 ~C 4 Alkynyl, C 2 ~C 4 Haloal Kinnill, C. 3 ~C 7 Cycloalkyl, C 3 ~C 7 Halocycloalkyl, C 4 ~C 8 Alki Cycloalkyl, C 4 ~C 8 Haloalkylcycloalkyl, C 4 ~C 8 Cycloalkyl Alkyl, C 4 ~C 8 Halocycloalkylalkyl, C 1 ~C 8 Alkoxy, C 1 ~C 8 Haloalkoxy, C 2 ~C 8 Alkoxycarbonyl, C 2 ~C 6 Haloalkoxycarbonyl Lu, C 2 ~C 6 Alkylcarbonyl and C 2 ~C 6 The group consisting of haloalkylcarbonyl and optionally substituted with up to three substituents independently selected from (a) a method for preparing a compound of formula F [ka] The compound was dissolved in trimethylamine, triethylamine, pyridine, alkylpyridin, and tetramethylamine in solvent S4. In the presence of a reagent B selected from lysine and 3-picoline (i.e., 3-methylpyridine), , formula G [ka] by contacting a compound of formula K: [ka] and forming a compound of (b) contacting a compound of formula K with an acid A1 in a solvent S5 to form a compound of formula J. The present invention provides a method including:

[0031] In some embodiments, the acid A1 is hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H 3 PO 4 ), sulfuric acid (H 2 SO 4 ), and boric acid (H 3 BO 3 ) an inorganic acid selected from In some embodiments, the acid A1 comprises hydrochloric acid (HCl). In an embodiment, the acid A1 is formic acid, acetic acid, propionic acid, citric acid, malic acid, and sulfonic acid. In some embodiments, the acid A1 comprises an organic acid selected from the group consisting of sulfonic acids. Examples of sulfonic acids include para-toluenesulfonic acid, methanesulfonic acid, and isomers thereof. In some embodiments, the contacting step may include a mixture of toluenesulfonic acid. does not use a base.

[0032] In some embodiments, the solvent S4 is water (H 2 O), C 7 ~C 10 Aromatic hydrocarbons, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonitrile, or the like In some embodiments, the solvent S4 is selected from the group consisting of water, toluene, acetonitrile, acetonitrile, or a combination thereof. In some embodiments, solvent S4 is In some embodiments, solvent S4 is acetonitrile. In some embodiments, solvent S4 is a mixture of water and acetonitrile. In an embodiment, the solvent S4 does not include ethers, esters, and / or halogenated hydrocarbons. stomach.

[0033] In some embodiments, solvent S5 is water (H 2 O), C 7 ~C 10 Aromatic hydrocarbons, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonitrile, or the like In some embodiments, the solvent S5 is selected from the group consisting of water, toluene, acetonitrile, acetonitrile, or a combination thereof. In some embodiments, solvent S5 is In some embodiments, solvent S5 is acetonitrile. In some embodiments, solvent S5 is a mixture of water and acetonitrile.

[0034] In some embodiments, solvent S4 and solvent S5 are the same. In some embodiments, solvent S4 and solvent S5 are different. In some embodiments, solvent S4 is acetonitrile. nitrile and solvent S5 is a mixture of water and acetonitrile. In this embodiment, solvent S4 is a mixture of water and acetonitrile, and solvent S5 is a mixture of water and acetonitrile. In some embodiments, the solvent S4 is an ether, an ester, and / or a halo. In some embodiments, the solvent S5 is an ether, an ester, , and / or halogenated hydrocarbons.

[0035] In some embodiments, R 1 , R 2 , and R 3 is not a halogen.

[0036] In some embodiments, each R 1 , R 2 , and R 3 are independently H, C 1 ~C 6 Al Kill, C. 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, or is phenyl. In some embodiments, R 1 and R 3 is H. Some In the embodiment, R 2 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Arco Kishi or C 1 ~C 6 In some embodiments, R 2 is CH 3 , C.H. 2CH 3 , C.F. 3 , O.C.H. 3 , OCF 3 , or OCH 2 CH 3 Some In embodiments, R 2 is OCH 3 It is.

[0037] In some embodiments, each R 4 , R 5 , R 6 , and R 7 are independently H, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoki In some embodiments, R 1 and R 3 is H. In some embodiments, R 5 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 In some embodiments, R 5 teeth, CH 3 , C.H. 2 CH 3 , C.F. 3 , O.C.H. 3 , OCF 3 , or OCH 2 CH 3 It is. In some embodiments, R 5 CF 3 In some embodiments, R 7 Ha, Hello In some embodiments, R 7 is Cl.

[0038] In some embodiments, the present invention also provides a compound of formula 10: [ka] A method for preparing a compound of formula 1, comprising: [ka] The compound was dissolved in trimethylamine, triethylamine, pyridine, alkylpyridin, and tetramethylamine in solvent S4. In the presence of a reagent B selected from lysine and 3-picoline (i.e., 3-methylpyridine), , Equation 7 [ka] by contacting a compound of formula 11: [ka] and forming a compound of (b) contacting the compound of formula 11 with an acid A1 in a solvent S5 to form a compound of formula 10 and

[0039] In some embodiments, the acid A1 is hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H 3 PO 4 ), sulfuric acid (H 2 SO 4 ), and boric acid (H 3 BO 3 ) an inorganic acid selected from In some embodiments, the acid A1 comprises hydrochloric acid (HCl). In an embodiment, the acid A1 is formic acid, acetic acid, propionic acid, citric acid, malic acid, and sulfonic acid. In some embodiments, the acid A1 comprises an organic acid selected from the group consisting of sulfonic acids. Examples of sulfonic acids include para-toluenesulfonic acid, methanesulfonic acid, and isomers thereof. In some embodiments, the method includes the steps of: No base is used.

[0040] In some embodiments, the solvent S4 is water (H 2 O), C 7 ~C 10 Aromatic hydrocarbons, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonitrile, or the like In some embodiments, the solvent S4 is selected from the group consisting of water, toluene, acetonitrile, acetonitrile, or a combination thereof. In some embodiments, solvent S4 is In some embodiments, solvent S4 is acetonitrile. In some embodiments, solvent S4 is a mixture of water and acetonitrile.

[0041] In some embodiments, solvent S5 is water (H 2 O), C 7 ~C 10 Aromatic hydrocarbons, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonitrile, or the like In some embodiments, the solvent S5 is selected from the group consisting of water, toluene, acetonitrile, acetonitrile, or a combination thereof. In some embodiments, solvent S5 is In some embodiments, solvent S5 is acetonitrile. In some embodiments, solvent S5 is a mixture of water and acetonitrile.

[0042] In some embodiments, solvent S4 and solvent S5 are the same. In some embodiments, solvent S4 and solvent S5 are different. In some embodiments, solvent S4 is acetonitrile. nitrile and solvent S5 is a mixture of water and acetonitrile. In this embodiment, solvent S4 is a mixture of water and acetonitrile, and solvent S5 is a mixture of water and acetonitrile. In some embodiments, the solvent S4 is an ether, an ester, and / or a halo. In some embodiments, the solvent S5 is an ether, an ester, , and / or halogenated hydrocarbons.

[0043] The present invention also relates to a compound of formula 4 and / or formula 5 [ka] The present invention relates to compounds having the structure: wherein M is an inorganic or organic cation.

[0044] In some embodiments, M is sodium, potassium, ammonium, lithium, and and mixtures thereof. In some embodiments, M is an inorganic cation selected from In some embodiments, M is trimethylammonium, triethylammonium, ammonium, tri-n-propylammonium, triisopropylammonium, and and tributylammonium. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] As used herein, the terms "comprises," "comprises," and "includes" are used interchangeably. ising," "includes," "including," "Has," "Having," "Contains" "Containing," "Characterized by," "zed by," or any other variation thereof, subject to any limitations expressly indicated. For example, compositions containing a list of elements, mixtures The components of the composition, process, method, article, or apparatus are not necessarily limited to those elements. Any composition, mixture, process, method, article or apparatus not expressly listed herein or any such It may contain other elements not specific to the

[0046] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When in the claims, such phrases are recited excluding the impurities ordinarily associated with them. The phrase "consisting of" should be used more precisely than immediately following the preamble. Rather, when it appears in a clause in the body of a claim, it limits only the elements recited in that clause. However, other elements are not excluded from the claim as a whole.

[0047] If applicants refer to the invention or any part thereof with a non-limiting term such as "comprising," Where a term is used to define something, this description essentially translates to the term "unless otherwise expressly stated." "consisting of" or "consisting of" should also be construed as describing such an invention. It should be easily understood that.

[0048] Further, unless expressly stated to the contrary, "or" is intended to be an inclusive "or." For example, condition A or B can be any one of the following: A is true (or exists) and B is false (or exists) A is false (or does not exist) and B is true (or exists) and A and A and B are both true (or exist).

[0049] Also, the indefinite articles "a" and "an" preceding an element or component of the present invention are ) is intended to be non-restrictive regarding the number of instances (i.e., occurrences) of an element or component. Thus, "a" or "an" means one or at least one. The singular form of the element or component should also be read as including, to indicate that the number is clearly singular. Includes plurals unless intended.

[0050] The term "ambient temperature" or "room temperature" as used in this disclosure refers to a temperature between about 18° C. and about 28° C. Refers to...

[0051] In the above list, the term "alkyl" includes straight or branched chain alkyl, e.g., methyl, Examples of butyl are butyl, ethyl, n-propyl, i-propyl, or the different butyl isomers. As used in the fine print, haloalkane means an alkane containing a halogen atom (fluorine, chlorine, bromine, or iodine). ). Examples of haloalkanes are C H 2 Cl 2 , ClCH 2 CH 2 Cl, ClCH 2 CH 2 CH 2 CH 3 , and CCl 3 CH 3Halogenated benzenes include those that contain a halogen atom (fluorine, chlorine, bromine, or iodine). Examples of halogenated benzenes are benzenes that are partially or completely substituted with halogens. Examples include chlorobenzene, 1,2-dichlorobenzene, and bromobenzene. C 7 ~C 10 Aromatic hydrocarbons contain one benzene ring substituted with an alkyl group. It is a compound that 7 ~C 10 Examples of aromatic hydrocarbons are toluene, xylene, and ethylene. C isopropylbenzene, and cumene (isopropylbenzene). 5 ~C 10 aliphatic charcoal Hydrocarbons are straight or branched chain hydrocarbons. 5 ~C 10 Examples of aliphatic hydrocarbons include: These include n-hexane, mixed hexane, n-heptane, and mixed heptane. 5 ~C 10 Alicyclic hydrocarbons are cyclic hydrocarbons which may be substituted with straight or branched chain alkyl groups. C 5 ~C 10 Examples of alicyclic hydrocarbons are cyclopentane, methylcyclopentane, Cyclohexane, and methylcyclohexane.

[0052] A first aspect of the present invention relates to a compound represented by formula 1: [ka] The present invention provides a method for preparing a compound of formula (I).

[0053] In some embodiments as shown in Scheme 1, a compound of Formula 2 is reacted with sulfuric acid The arylsulfonic acid compound of formula 3 can then be converted to the arylsulfonic acid compound of formula 3 via can be diazotized to form a compound of formula 4, which can then be reacted via the Sandmeyer reaction and converting it to a chloroarylsulfonate sodium salt compound of formula 5, where M is an inorganic or organic cation. The compound of formula 5 is then reacted with thionyl chloride and Using catalytic dimethylformamide (DMF), chloroarylsulfonyl chlorides of formula 6 are prepared. The subsequent addition of aqueous ammonia gives the compound of formula 1. It is possible. [ka]

[0054] In some embodiments, M is sodium, potassium, ammonium, lithium, and and mixtures thereof. In some embodiments, M is an inorganic cation selected from In some embodiments, M is trimethylammonium, triethylammonium, ammonium, tri-n-propylammonium, triisopropylammonium, and and tributylammonium.

[0055] The reaction shown in Scheme 1 involves the reaction of water, C 7 ~C 10 Aromatic hydrocarbons, haloalkanes, halo Genoyl benzene, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonite The reaction can be carried out in a solvent selected from the group consisting of toluene, ... In some embodiments, water, toluene, dichloromethane, 1,2-dichloroethane, 1-chloroethane, Other suitable solvents include but are not limited to acetonitrile, acetonitrile, cyclohexane, cyclohexanediaminetetraacetate ... Suitable solvents include xylene, ethylbenzene, and cumene.

[0056] The reaction depicted in Scheme 1 can be carried out over a wide range of temperatures, i.e., from 20° C. to 150° C.; or from 50° C. to The reaction may be carried out at a temperature ranging from 50°C to 180°C; or from 60°C to 100°C. Temperatures in the range of 60° C. to 80° C. are especially useful.

[0057] The process shown in Scheme 1 is more efficient than previously disclosed processes. This reduces the cost of producing the compound of formula 1. Other advantages include the avoidance of pyrophoric reagents. safer process, better volumetric efficiency, better reaction kinetics, and / or foaming The reduction of problems associated with

[0058] A second aspect of the present invention relates to a compound of formula 7: [ka] A method for preparing the compound of formula (I) is provided.

[0059] In some embodiments as shown in Scheme 2, the compound of formula 8 is an amine of formula 9 The salt can be converted to the acid chloride of formula 7. Triethylamine, pyridine, alkylpyridines, and 3-picoline (i.e., 3-methylpyridine). A reagent A selected from the group consisting of aryl, aryl, aryl and aryl groups can be used in this conversion process. [ka]

[0060] A third aspect of the present invention relates to a compound represented by formula 10: [ka] A method for preparing the compound of formula (I) is provided.

[0061] In some embodiments as shown in Scheme 3, a compound of Formula 1 and a compound of Formula 7 is selected from trimethylamine, pyridine, and 3-picoline (i.e., 3-methylpyridine). In the presence of a selected reagent B, the compound of formula 11 is formed by coupling reaction. Then, the compound of formula 11 is neutralized with an acid to form a compound of formula 10.

[0062] Subsequently, water and seed crystals are added to obtain the desired polymorph, as previously disclosed. This can induce crystallization of the crystalline phase.

[0063] Suitable acids are hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H 3 PO 4 ), sulfuric acid ( H 2 SO 4 ), and boric acid (H 3 BO 3 ) may be an inorganic acid selected from the group consisting of In an embodiment, the acid comprises hydrochloric acid (HCl). Other suitable acids include formic acid, acetic acid, propionic acid, and the like. The organic acid may be selected from carboxylic acid, citric acid, malic acid, and sulfonic acid. In some embodiments, the acid comprises a sulfonic acid. An example of a sulfonic acid is para-toluene. Sulfonic acid, methanesulfonic acid, and toluenesulfonic acid as a mixture of isomers are included. In some embodiments, the coupling step shown in Scheme 3 can be carried out using a base. In some embodiments, the coupling step shown in Scheme 3 does not involve the use of ether. Do not use solvents containing alcohols, esters, and / or halogenated hydrocarbons. [ka]

[0064] The coupling step shown in Scheme 3 involves the use of water, C 7 ~C 10 Aromatic Hydrocarbons, C 5 ~C 10 Aliphatic hydrocarbons, C 5 ~C 10 Alicyclic hydrocarbons, acetonitrile, or combinations thereof In some embodiments, the reaction can be carried out in a solvent selected from the group consisting of water, toluene, and the like. Alternatively, benzene, acetonitrile, or a combination thereof may be used. Solvents include xylene, ethylbenzene, and cumene.

[0065] The coupling step depicted in Scheme 3 can be carried out over a wide range of temperatures, i.e., 20°C to 150°C; Alternatively, the reaction may be carried out at a temperature in the range of 40° C. to 100° C. A temperature in the range of 50° C. to 100° C. Temperatures in the range of 50°C to 80°C; or 60°C to 75°C are particularly useful. do.

[0066] The molar ratio of the compound of formula 1 to the compound of formula 7 is 2:1 to 1:2; 1.5:1.0 to 1.0:1.5;1.2:1.0~1.0:1.2;1.1:1.0~1.0:1.1; and / or may be in the 1:1 range.

[0067] The processes shown in Schemes 2 and / or 3 are also advantageous in comparison with previously disclosed processes. This reduces production costs and avoids the use of pyrophoric reagents. The process shown also avoids pyrophoric reagents compared to previously disclosed processes. Safer processes, better volumetric efficiency, better reaction kinetics and less foaming problems 10. More efficient control of the polymorph of Formula 10 that is reduced and / or crystallized (e.g., selection of different polymorphs) ) and other advantages.

[0068] Preparation Example 1 Synthesis of compounds of formula 3 Overhead mechanical agitator, 10cm glass spring packing, modified Dean A 1 L round-bottom flask was fitted with a Stark trap, a thermometer, a condenser, and a nitrogen inlet and outlet. Lasco was charged with p-anisidine (67 g; 0.539 mol) and o-dichlorobenzene (O Charge DCB, 359.4 mL, 5.26 vol. 70% sulfuric acid (98 wt%, 5 0.1 g, 27.2 ml, 0.501 mol) was added to 20 g of water, and then <6 Add dropwise to the reactor while maintaining an internal temperature of 0° C. The reaction mixture was stirred for 30 minutes. The resulting off-white slurry was heated to 170° C. and refluxed at atmospheric pressure to remove water. The reaction mass was heated at 170–176 °C until the p-anisidine content was <7%. The reaction mass is filtered and washed with o-dichlorobenzene. The wet product (125.1 g, ca. 70 wt%, 0.431 mol) was purified by HPLC ( The crude product was obtained as a light grey solid having a purity of >97.5% by column chromatography.

[0069] Preparation Example 2 Synthesis of Compounds of Formulas 4 and 5 1 L round bottom flask equipped with overhead stirrer, thermocouple, and nitrogen inlet / outlet , concentrated hydrochloric acid (30% wt%, 314.2 g, 261.8 mL, 2,585 mol) and water (76.7 mL, 0.88 vol). The wet product (12 5.1 g, ca. 70 wt%, 0.431 mol) was added and the resulting slurry was cooled to <10°C. Cool at 40°C. Dissolve sodium nitrite (31.2 g, 98% A solution of 0.444 mol) is slowly added and the reaction is stirred for 1 hour. Sulfamic acid (2.1 g, 98%, 0.222 mol) was dissolved in water (43.6 mL). and adding the solution to the reaction mass to form the compound of formula 4.

[0070] Then, water (87.6 ml) was added, followed by copper powder (approximately 150 mesh, 3.4 g, 0.0 54 mol) is added to a second 1 L round bottom flask and the slurry is stirred at room temperature. Slowly transfer the mixture to the copper slurry and stir for approximately 2 hours. Cool the reaction mixture to <25°C. Cool and then add 50% NaOH (98% N) until the pH reaches 2.5-3.5. aOH, 35.1 g, 2.0 mol, dissolved in 33.7 g of water) is added dropwise. The resulting dark yellow slurry is stirred for an additional 2 hours and then filtered. After sucking dry, the formula obtained is: The product (108.0 g, 0.353 mol), which was compound 5, was determined to be >98% by HPLC. Obtained with a purity of %.

[0071] Preparation Example 3 Synthesis of compounds of formula 6 Install an overhead mechanical stirrer, Dean-Stark trap, thermometer, and condenser. Into a 1 L round bottom flask equipped with The resulting slurry is heated to remove the water content. Cool to 0-65 °C and add N,N-dimethylformamide (4.1 mL, 0.053 mol ), followed by thionyl chloride (64.2 mL, 0.883 mol) are added to the reactor. After a period of time, the reaction mass was distilled to approximately ½ volume and toluene (259.3 mL) was added to the slurry. The resulting slurry is passed through a pad of Celite (8.6 g) followed by further distillation. The pad was washed with toluene (86.4 mL), whereupon the compound of formula 6 was isolated from the filtrate. get.

[0072] Preparation Example 4 Synthesis of Compounds of Formula 1 In a 1 L round-bottom flask, add 158.5 mL of ammonia water (28 wt %) under nitrogen atmosphere. , 2.346 mol) and acetonitrile (176.7 ml). The compound of formula 6 from is added to the solution and stirred for about 2 1 / 2 hours to give two separate layers. The lower aqueous layer was separated and diluted with toluene (1.0 vol) and acetonitrile for further stirring. (1.0 vol) to again give two separate layers. The combined organic layers were washed with activated carbon (3 0.0 wt%), then filtered through a Buchner funnel and concentrated to give the compound of formula 1. This was dried in a vacuum oven to obtain light brown granules having a purity of >99% by HPLC. A coloured solid is obtained.

[0073] Preparation Example 5 Synthesis of compounds of formula 7 Equip a 100 mL flask with a condenser, dropping funnel, thermocouple, heating mantle, and magnetic stirrer. In a three-neck flask, the compound of formula 8 (10.01 g, 37.5 mmol), acetonitrile ( 27 mL), and 3-picoline (2.824 g, 30.0 mmol). The mixture was heated to about 65° C., and then thionyl chloride (5.40 g, 44.9 mmol) was added to the acetone. The solution in nitrile (3 mL) was stirred for approximately 20 min while maintaining the temperature at 63-71 °C. After the addition is complete, the reaction mixture is heated at 70° C. for approximately 2 hours and then allowed to cool to ambient temperature. This gives the compound of formula 7 as a solution in acetonitrile.

[0074] Preparation Example 6 Synthesis of compound of formula 10 - Coupling Reactions Using Compounds of Formula 1 and 7 Another 125 mL 4-neck jacketed reactor equipped with a magnetic stirrer, cooling tube, thermocouple, and circulating bath. In a round-bottom flask, the compound of formula 1 (10.05 g, 44.9 mmol), 3-picoline (8.462 g, 90.0 mmol), and acetonitrile (10 mL). The mixture is heated to about 58° C., and then the compound of formula 7 is added while maintaining the reaction temperature at 55-60° C. The reaction is heated at about 60° C. for about 1 hour. Then, concentrated hydrochloric acid (about 37% by weight, 3.895 g, 39.4 mmol) and water (0 0.5 mL) is added to obtain a solution of compound 10 in acetonitrile. The solution is diluted with water for about 70 minutes. C., and then a slurry of seed crystals of formula 10 (0.195 g) in water (28 g) was added for about 2 After the addition of additional water (10 g), the resulting slurry was stirred for about 1.5 hours. The wet cake is refluxed for 10 min, cooled to ambient temperature, and then filtered. The compound of formula 10 was obtained as an off-white to light brown solid of approximately 9 0% yield and approximately 98% purity.

Claims

1. Formula G: 【Chemistry 14】 [In the formula, each R ４ , R ５ , R ６ , and R ７ are independently H, halogen, SF ５ , C(=O)(C １ ~C ８ alkyl), C(=O)O(C １ ~C ８ Alkyl), N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), C(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), C(=S)N(C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), SO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), OC(=O)(C １ ~C ８ alkyl), OC(=O)O(C １ ~C ８ alkyl), OC(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), N(C １ ~C ８ alkyl)C(=O)O(C １ ~C ８ Alkyl), N(C １ ~C ８ alkyl)C(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), OSO ２ (C １ ~C ８ alkyl), OSO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), N(C １ ~C ８ Alkyl)SO ２ (C １ ~C ８ alkyl), or C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Halocycloalkyl, C ４ ~C １０ Alkylcycloalkyl, C ４ ~C １０ Cycloalkylalkyl, C ６ ~C １４ Cycloalkyl, C ５ ~C １０ Alkylcycloalkylalkyl, C ３ ~C ８ Cycloalkenyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ３ ~C ８ Cycloalkoxy, C ３ ~C ８ Halocycloalkoxy, C ４ ~C １０ Cycloalkylalkoxy, C ２ ~C ８ Alkenyloxy, C ２ ~C ８ Alkynyloxy, C １ ~C ８ Alkylthio, C １ ~C ８ Alkylsulfinyl, C １ ~C ８ Alkylsulfonyl, C ３ ~C ８ Cycloalkylthio, C ３ ~C ８ Cycloalkylsulfinyl, C ３ ~C ８ Cycloalkylsulfonyl, C ４ ~C １０ Cycloalkylalkylthio, C ４ ~C １０ Cycloalkylalkylsulfinyl, C ４ ~C １０ Cycloalkylalkylsulfonyl, C ２ ~C ８ Alkenylthio, C ２ ~C ８ Alkenylsulfinyl, C ２ ~C ８ Alkenylsulfonyl, C ２ ~C ８ Alkynylthio, C ２ ~C ８ Alkynylsulfinyl, C ２ ~C ８ alkynylsulfonyl, or phenyl; or R on adjacent ring atom ４ , R ５ , R ６ , and R ７ two of may be taken together to form a 5-7 membered carbocyclic or heterocyclic ring, each ring containing ring members selected from carbon atoms and up to three heteroatoms independently selected from up to two O, up to two S, and up to three N, where up to two carbon atom ring members are independently selected from C(=O) and C(=S), such rings can be represented by the formula: １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Haloalkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Haloalkynyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ Halocycloalkyl, C ４ ~C ８ Alkylcycloalkyl, C ４ ~C ８ Haloalkylcycloalkyl, C ４ ~C ８ Cycloalkylalkyl, C ４ ~C ８ Halocycloalkylalkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Alkoxycarbonyl, C ２ ~C ６ Haloalkoxycarbonyl, C ２ ~C ６ Alkylcarbonyl, and C ２ ~C ６ and optionally substituted with up to three substituents independently selected from the group consisting of haloalkylcarbonyl. A method for preparing a compound of formula H: 【Chemistry 15】 in the presence of (a) a reagent A selected from trimethylamine, triethylamine, pyridine, alkylpyridine, and 3-picoline, and (b) a solvent S3. ３ , PCl ５ , oxalyl chloride, and phosgene to form a compound of formula G: 【Chemistry 16】 forming a compound of formula (I).

2. The solvent S3 is water, C ７ ~C １０ Aromatic hydrocarbons, haloalkanes, halogenated benzenes, C ５ ~C １０ Aliphatic hydrocarbons, C ５ ~C １０ 2. The method of claim 1, wherein the solvent is selected from an alicyclic hydrocarbon, acetonitrile, or a combination thereof.

3. Formula 7: 【Chemistry 17】 10. The method of claim 1 for preparing a compound of the formula (a) Formula 8 【Chemistry 18】 is contacted with a reagent A selected from trimethylamine, triethylamine, pyridine, alkylpyridine, and 3-picoline in the presence of a solvent S3 to obtain a compound of formula 9: 【Chemistry 19】 and forming a compound of (b) reacting said compound of formula 9 with thionyl chloride, POCl ３ , PCl ５ and a chloride source selected from the group consisting of oxalyl chloride and phosgene to form said compound of formula 7.

4. The solvent S3 is water, C ７ ~C １０ Aromatic hydrocarbons, haloalkanes, halogenated benzenes, C ５ ~C １０ Aliphatic hydrocarbons, C ５ ~C １０ 4. The method of claim 3, wherein the solvent is selected from an alicyclic hydrocarbon, acetonitrile, or a combination thereof.

5. Formula J: 【Chemistry 20】 [In the formula, each R １ , R ２ , and R ３ are independently H, SF ５ , N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), C(=S)N(C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), SO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), OSO ２ (C １ ~C ８ alkyl), OSO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), N(C １ ~C ８ Alkyl)SO ２ (C １ ~C ８ alkyl), or C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Halocycloalkyl, C ４ ~C １０ Alkylcycloalkyl, C ４ ~C １０ Cycloalkylalkyl, C ６ ~C １４ Cycloalkyl, C ５ ~C １０ Alkylcycloalkylalkyl, C ３ ~C ８ Cycloalkenyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ３ ~C ８ Cycloalkoxy, C ３ ~C ８ Halocycloalkoxy, C ４ ~C １０ Cycloalkylalkoxy, C ２ ~C ８ Alkenyloxy, C ２ ~C ８ Alkynyloxy, C １ ~C ８ Alkylthio, C １ ~C ８ Alkylsulfinyl, C １ ~C ８ Alkylsulfonyl, C ３ ~C ８ Cycloalkylthio, C ３ ~C ８ Cycloalkylsulfinyl, C ３ ~C ８ Cycloalkylsulfonyl, C ４ ~C １０ Cycloalkylalkylthio, C ４ ~C １０ Cycloalkylalkylsulfinyl, C ４ ~C １０ Cycloalkylalkylsulfonyl, C ２ ~C ８ Alkenylthio, C ２ ~C ８ Alkenylsulfinyl, C ２ ~C ８ Alkenylsulfonyl, C ２ ~C ８ Alkynylthio, C ２ ~C ８ Alkynylsulfinyl, C ２ ~C ８ alkynylsulfonyl, or phenyl; or R on an adjacent ring atom １ , R ２ , and R ３ two of may be taken together to form a 5-7 membered carbocyclic or heterocyclic ring, each ring containing ring members selected from carbon atoms and up to three heteroatoms independently selected from up to two O, up to two S, and up to three N, where up to two carbon atom ring members are independently selected from C(=O) and C(=S), such rings can be represented by the formula: １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Haloalkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Haloalkynyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ Halocycloalkyl, C ４ ~C ８ Alkylcycloalkyl, C ４ ~C ８ Haloalkylcycloalkyl, C ４ ~C ８ Cycloalkylalkyl, C ４ ~C ８ Halocycloalkylalkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Alkoxycarbonyl, C ２ ~C ６ Haloalkoxycarbonyl, C ２ ~C ６ Alkylcarbonyl, and C ２ ~C ６ optionally substituted with up to three substituents independently selected from the group consisting of haloalkylcarbonyl; Each R ４ , R ５ , R ６ , and R ７ are independently H, halogen, SF ５ , C(=O)(C １ ~C ８ alkyl), C(=O)O(C １ ~C ８ Alkyl), N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), C(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), C(=S)N(C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), SO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), OC(=O)(C １ ~C ８ alkyl), OC(=O)O(C １ ~C ８ alkyl), OC(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), N(C １ ~C ８ alkyl)C(=O)O(C １ ~C ８ Alkyl), N(C １ ~C ８ alkyl)C(=O)N(C １ ~C ８ Alkyl) (C １ ~C ８ alkyl), OSO ２ (C １ ~C ８ alkyl), OSO ２ N (C １ ~C ８ Alkyl) (C １ ~C ８ Alkyl), N(C １ ~C ８ Alkyl)SO ２ (C １ ~C ８ alkyl), or C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Halocycloalkyl, C ４ ~C １０ Alkylcycloalkyl, C ４ ~C １０ Cycloalkylalkyl, C ６ ~C １４ Cycloalkyl, C ５ ~C １０ Alkylcycloalkylalkyl, C ３ ~C ８ Cycloalkenyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ３ ~C ８ Cycloalkoxy, C ３ ~C ８ Halocycloalkoxy, C ４ ~C １０ Cycloalkylalkoxy, C ２ ~C ８ Alkenyloxy, C ２ ~C ８ Alkynyloxy, C １ ~C ８ Alkylthio, C １ ~C ８ Alkylsulfinyl, C １ ~C ８ Alkylsulfonyl, C ３ ~C ８ Cycloalkylthio, C ３ ~C ８ Cycloalkylsulfinyl, C ３ ~C ８ Cycloalkylsulfonyl, C ４ ~C １０ Cycloalkylalkylthio, C ４ ~C １０ Cycloalkylalkylsulfinyl, C ４ ~C １０ Cycloalkylalkylsulfonyl, C ２ ~C ８ Alkenylthio, C ２ ~C ８ Alkenylsulfinyl, C ２ ~C ８ Alkenylsulfonyl, C ２ ~C ８ Alkynylthio, C ２ ~C ８ Alkynylsulfinyl, C ２ ~C ８ alkynylsulfonyl, or phenyl; or R on adjacent ring atom ４ , R ５ , R ６ , and R ７ two of may be taken together to form a 5-7 membered carbocyclic or heterocyclic ring, each ring containing ring members selected from carbon atoms and up to three heteroatoms independently selected from up to two O, up to two S, and up to three N, where up to two carbon atom ring members are independently selected from C(=O) and C(=S), such rings can be represented by the formula: １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, C ２ ~C ４ Alkenyl, C ２ ~C ４ Haloalkenyl, C ２ ~C ４ Alkynyl, C ２ ~C ４ Haloalkynyl, C ３ ~C ７ Cycloalkyl, C ３ ~C ７ Halocycloalkyl, C ４ ~C ８ Alkylcycloalkyl, C ４ ~C ８ Haloalkylcycloalkyl, C ４ ~C ８ Cycloalkylalkyl, C ４ ~C ８ Halocycloalkylalkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Alkoxycarbonyl, C ２ ~C ６ Haloalkoxycarbonyl, C ２ ~C ６ Alkylcarbonyl, and C ２ ~C ６ and optionally substituted with up to three substituents independently selected from the group consisting of haloalkylcarbonyl. (a) a compound of formula F 【Chemistry 21】 in the presence of a reagent B selected from trimethylamine, triethylamine, pyridine, alkylpyridine, and 3-picoline in a solvent S4 to form a compound of formula G 【Chemical 22】 by contacting a compound of formula K: 【Chemistry 23】 and forming a compound of (c) contacting said compound of formula K with an acid A1 in a solvent S5 to form said compound of formula J.

6. The acid A1 is hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H ３ P.O. ４ ), sulfuric acid (H ２ SO ４ ), and boric acid (H ３ B.O. ３ 6. The method of claim 5, wherein the inorganic acid is selected from the group consisting of:

7. The solvent S4 is water (H ２ O), C ７ ~C １０ Aromatic Hydrocarbons, C ５ ~C １０ Aliphatic hydrocarbons, C ５ ~C １０ 6. The method of claim 5, wherein the solvent is selected from an alicyclic hydrocarbon, acetonitrile, or a combination thereof.

8. Each R １ , R ２ , and R ３ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ The method of claim 5, wherein the alkyl group is haloalkoxy or phenyl.

9. R ２ But, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ The method of claim 5, wherein the alkyl group is a haloalkoxy group.

10. Each R ４ , R ５ , R ６ , and R ７ However, independently, H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ The method of claim 5, wherein the alkyl group is haloalkoxy or phenyl.

11. Formula 10: 【Chemistry 24】 6. A method according to claim 5 for preparing a compound of formula 1: 【Chemistry 25】 in the presence of a reagent B selected from trimethylamine, triethylamine, pyridine, alkylpyridine, and 3-picoline in a solvent S4 to form a compound of formula 7 【Chemistry 26】 by contacting a compound of formula 11: 【Chemical 27】 and forming a compound of (b) contacting said compound of formula 11 with an acid A1 in a solvent S5 to form said compound of formula 10.

12. The acid A1 is hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H ３ P.O. ４ ), sulfuric acid (H ２ SO ４ ), and boric acid (H ３ B.O. ３ 12. The method of claim 11, wherein the inorganic acid is selected from the group consisting of:

13. The solvent S4 is water, C ７ ~C １０ Aromatic Hydrocarbons, C ５ ~C １０ Aliphatic hydrocarbons, C ５ ~C １０ 12. The method of claim 11, wherein the solvent is selected from an alicyclic hydrocarbon, acetonitrile, or a combination thereof.

14. The solvent S5 is water (H ２ O), C ７ ~C １０ Aromatic Hydrocarbons, C ５ ~C １０ Aliphatic hydrocarbons, C ５ ~C １０ 12. The method of claim 11, wherein the solvent is selected from an alicyclic hydrocarbon, acetonitrile, or a combination thereof.

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