TW402597B - Methods for the preparation of biphenyl isoxazole sulfonamides - Google Patents

Abstract

A method for the preparation of a compound of the following formula Ia: and enantiomers and diastereomers, and salts thereof, wherein: R1 and R2 are each directly bonded to a ring carbon and are each hydrogen; X is O; Y is N; R3 and R4 are independently hydrogen or C1-6 alkyl; R11, R12, R13 and R14 are each independently hydrogen; J is O; K is N; L is C; P is 0; (b) deprotecting the nitrogen of said formula Iva compound or salt thereof to form said compound of the formula Ia or salt thereof.

Description

A7 B7

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 4CI2587 V. Description of the Invention (1) The present invention relates to a method for preparing biphenylisoxazole sulfonamides and their intermediates, and also relates to novel methods made by this method. Intermediate. The biphenylisoxazole sulfonamides made by the method of the present invention are endothelin antagonists and are particularly useful for treating hypertension. The method of the present invention can prepare biphenylsulfonamides of the following formula I and their mirror isomers, non-image isomers and salts (preferably pharmaceutically acceptable salts are preferred), the formula I The structure is as follows: (工) 0

Each phenyl ring of the biphenyl group may be unsubstituted or substituted with one or more substituents, respectively. Preferred substituents of the biphenyl group include the R11 to R1 4 groups described herein, and especially when the biphenyl group is a 2-biphenyl group, the group is located at one position. Compared with r2 Λτ > method of the present invention, the compound of formula la can be prepared as follows: Wood paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page)

A7 B7 V. Description of the invention (R1 R2

R1 (la) 0

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs and its mirror isomers, non-mirror isomers, and salts (especially pharmaceutically acceptable salts). The above symbols are defined throughout the specification as follows: one of X and Y is N and the other is 0; R1, R2, R3, and R4 are each directly bonded to the carbon of the ring, and each is Ύ ( a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkane, cycloalkenyl, cycloalkenyl, aryl, aryloxy, aralkyl or radical, which Each may be substituted by Z 1, Z 2 and Z 3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) — C (0) H or-C ( 0) R5; (h) -C02H or one C02R5; (i) -Z4-NR6RT; Alkyl-based aromatic paper oxygen This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the back Please note that this page is to be filled out again) -5-Consumption cooperation by employees of the Central Bureau of Standards, Ministry of Economic Affairs, printed A7 _ b7__ V. Description of the invention (3) (j) Z4-N (R 10)-Z5-NR8R9; or (k ) R 3 together with R 4 may also form an alkylene or an alkylene (the alkylene or alkylene may be replaced by Z1, Z 2 and Z 3), and together with the carbon atoms attached to it, form four to eight members. Saturated, unsaturated or aromatic ring f R5 is alkyl, alkenyl, bulk, cycloalkyl ' Alkyl group, a cycloalkenyl group, a cycloalkenyl group, an aryl group, or aralkyl group, each of which can be Z1, Z2 and substituted with Z 3;

Re, R7, R8, Re and Ri0 are each (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, or aralkyl, each Can be replaced by Z1, Z 2 and Z 3; or

Re together with R7 may form an alkylene or alkylene (the alkylene or alkylene may be replaced by Z1, Z 2 and Z 3) and form a three- to eight-membered saturated ring together with the nitrogen atom attached to it. Or unsaturated ring; or any one of R8, R9, and R1Q constitutes an alkylene or alkylene (the alkylene or alkylene may be substituted by Z1, Z 2 and Z 3) together with it Atoms form a saturated or unsaturated ring of three to eight members; R 11, R 12, R w and r " each are (a) hydrogen; (b) alkyl, alkenyl, bulk, alkoxy , Cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl, aryl, aryloxy, aralkyl, or aralkoxy ', each of which may be substituted by Z 1, Z 2 and Z 3 (C) Heterocyclyl, substituted heterocyclyl or heterocyclic oxy; This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) -------- ο equipment— (please first Please read the notes on the back and fill in this page) Order-6-Printed A7 -44½ ^ --- ^-by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 5. Description of the invention (4) (d) Halo; (e) Hydroxyl; (f) cyano; (g) nitro; (h) -C (0) H or C (〇) R5; (i) — C02H or-C02R5; (j) -SH, -S (0) nR5, -S (0) m — OH, -S (0) m-〇R5——0- S (0) m- 0 R 5 ′ -0-S (0) m0H or-0- S (0) m- 0 R 5; (k) -Z4-NR6R7; or (1)-Z 4- N ( R 10) -Z5-NR8R9; Z 1, Z 2 and Z 3 are each (a) hydrogen; (b) fluorenyl; (c) hydroxyl; (d) courtyard; (e) alkenyl; (f) aromatic (G) aralkyl; (h) alkoxy; (i) aryloxy; (J) aralkoxy; (k) heterocyclyl, substituted heterocyclyl, or heterocyclooxy; 1) -SH, one S (0) nZ6, one S (0) m- ----------- (Please read the notes on the back before filling this page) The size of the paper is applicable to China Standard (CNS) A4 specification (210X297 mm) -7-A7 B7 V. Description of the invention (5) OH, — S (0) τη_ζ6, — 0 — S (0) m_Z6, —0-S (0) m. H or-Ο- s (0) m- 0 Z 6; (m) keto; (n) nitro; (o) cyano: (p) -C (0) H or -C (0) Z6; (q) _C〇2H or —CO2Z6: (r) -Z4-NZ7Z8; (s) -Z4-N (Z11)-Z5-H; (t) — Z4 — ΝίZO11)-? 5 — Z6; or (u ) — Z4-N (Z 1 1)-Z5-NZ7Z8; each of z 4 and z 5 is (a) a single bond ; (B)-Z 9- S (0) η- Z 10-; (c)-Z 9- C (0)-Z 10-; (d) — Z9-C (S) —Z 10-; ( e)-Z 9- 0-Z 10-; printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) (f) — Z 9_ S — Z i〇—; (g ) Z9-〇-C (0)-Z 10-: or (h) -Z9-C (0)-O- Z10-; z 6 is an alkyl group; one to three selected from halogen, aryl, aryloxy Alkyl and alkoxy radicals; alkyl radicals; alkenyl radicals; alkynyl radicals; cycloalkyl radicals; cycloalkyl radicals substituted with one to three radicals selected from alkyl, aryl, alkenyl and alkoxyaryl radicals Thick and benzene-containing cycloalkyl; aromatic oxygen substituted by one or two peptones; the paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) A7 B7 402597 V. Description of the invention (6) (Please read the notes on the back before filling out this page) group; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; aryl; via methylenedioxy or one to four selected from alkyl, di Aryl groups substituted with alkylamino, cyano, halogen, trihaloalkyl, alkoxy, and trihaloalkoxy groups; or heterocyclic Or substituted heterocyclic groups; Z 7 and Z 8 are each hydrogen, alkyl, cycloalkyl 'cycloalkylalkyl, cycloalkenylalkyl, aryl, or aralkyl, or Z 7 together with Z 8 An alkylene or an alkenyl group together with a nitrogen atom attached thereto forms a three- to eight-membered saturated or unsaturated ring; each of Z 9 and Z 1D is a single bond, an alkylene group, an alkylene group, or an alkylene group Z 11 is (a) hydrogen; or (b) alkyl, alkylcycloalkyl substituted with one or two or three halogens, cycloalkylalkyl, cycloalkenylalkyl, aryl, • Or Fangyuanji or Z7, Z8, and any of Z11, which form an alkylene or an alkenyl group, and together with the atoms connected to it, form a three- to eight-membered saturated or unsaturated ring, Central Bureau of Standards, Ministry of Economic Affairs Printed by the employee consumer cooperative J is 0, S, N or NR15; K and L are N or C, but at least one of K or L is C; R15 is hydrogen, alkyl, hydroxyethoxymethyl or methoxyethyl Oxymethyl; each m is 1 or 2; each n is 0, 1, or 2; and P is an integer of 0 or 1 to 2. The compound of formula I or a salt thereof can be prepared by a method including the following steps: The size of this paper is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 5. Description of the invention (7) (a) In the presence of palladium (〇) contact In the case of a medium (and preferably a base), an SS ester of formula II or a salt thereof is contacted with a halophenyl compound of formula III or a salt thereof to form a nitrogen-protected compound of formula IV or a salt thereof. The structures of Formula III and Formula IV are as follows:

(II) wherein the benzene ring of formula II may be further substituted, for example by one or more of the groups described in the definition of R11 to R14 in the text

Halo (III) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling in this page) where the benzene ring of formula III can be further replaced, for example by one or more of the relevant R in the text 11 to R 1 4 are substituted by the groups described in the definition, especially when the biphenyl of the compound of formula I or a salt thereof is 2-biphenyl. The R1 '> / ^ | Bit, R2> v〇x (CH2) p- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -10-Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (8 )

(IV) wherein each phenyl ring of the biphenyl group may be unsubstituted or substituted with one or more substituents, respectively; and (b) deprotect the nitrogen atom of the compound of formula IV or a salt thereof to form a formula I compound or a salt thereof. The term "Prot" as used in Formula II and throughout the specification means a nitrogen protecting group and may be any suitable nitrogen protecting group such as 2-ethoxyethyl, 2-methoxypropyl, methoxyethoxymethyl, Or as described in European Patent Application Publication No. 569193 (1993), methoxyethoxymethyl (MEM) is preferred. The halo group of formula III is preferably bromine or iodine, with iodine being most preferred. In a preferred implementation system, the compound of formula I a or a salt thereof can be prepared by a method including the following steps: (a) In the presence of a palladium (0) catalyst (and preferably a base), formula II a Ester or its salt h3c ch3 H3C- ^ J_I-CH3 (工 工 a)

ΐ-C〇 > prot / ~~ \ R3 R4 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (may read the precautions on the back before filling this page)

11 i9S & 97 A7 B7 V. Description of the invention (9) Contacting a halogen phenyl compound of formula I I la or a salt thereof

Jl2 (Ilia) (Please read the notes on the back before filling this page) to form a nitrogen protected compound of formula I v a or its salt R1

R2 'pll. K (IVa) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and (b) Deprotect the nitrogen atom of the compound of formula I V a or its salt to form the compound of formula I a or its salt. The method for preparing the compound of formula I or a salt thereof according to the present invention has the advantages of high yield. The generation of impurities can be reduced to a minimum or even no impurities are generated. The invention further provides novel intermediates for the method and novel methods for preparing such intermediates. Listed below are definitions of terms used in the description. These definitions apply to the entire description, whether that term appears alone or as part of another basis, unless otherwise specified in a particular case—1 — ϋ «1 · — 1 ^ 1 1 ^ 1 — ^ 1 '^^ 1 ^^ 1 ^^ 1 I n * ^ $ * ^^ J ^ in ^ i ϋ ··-ϋ— .1 >« —ϋ ^ ^ 1 —Bn ammmte —flu n. ·-· A ^ ia ^^ 1 · 1 m In ^^ 1 tn m ^^^ 1 I 1 ^ 1 — ^ n This paper size applies to China National Standard (CNS) A4 (210X297 mm) 12 A7 _B7_ printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. 5. Description of the invention (10). Terms used. "Alkyl J or" alkane "means a straight or branched chain hydrocarbon group having 1 to 10 carbon atoms (preferably 1 to 7 carbon atoms), and" low alkyl "means having 1 to 10 carbon atoms. An alkyl group of 4 carbon atoms "" alkoxy "means an alkyl group of 10-. "Aryl" or "aryl" means phenyl, naphthyl, and biphenyl. "Alkenyl" refers to a straight-chain or branched hydrocarbon group having at least one double bond and containing 2 to 10 carbon atoms. Among them, one containing two to four carbon atoms is preferred. "" Alkynyl "means a straight-chain or branched hydrocarbon group having at least one para-bond and containing 2 to 10 carbon atoms, with one containing two to four carbon atoms being preferred. "Alkyl group" refers to a straight-chain bridge with 1 to 5 carbon atoms (such as _ (CH2) X-, where X is 1 to 5) connected by a single bond, which can be substituted by 1 to 3 lower alkyl groups. Was replaced. "Alkenyl" refers to a straight chain bridge having 2 to 5 carbon atoms connected by a single bond and containing at least one or two double bonds, which may be substituted by 1 to 3 lower alkyl groups. Examples are: CH = CH — CH = CH-, ch2-ch = ch-, CH2-CH = CH-CH2-, C (CH3) 2CH = CH-, and —CH (C 2 H s)-CH = CH- . "Alkynyl" refers to a straight chain bridge having 2 to 5 carbon atoms connected by a single bond and containing one parameter bond, which may be substituted by 1 to 3 lower alkyl groups. Examples are Cs-, CH2— CeC —, --------- 0¾-- (Please read the precautions on the back before filling out this page) The paper size of the book is applicable to the Chinese National Standard (CNS) A4 specification ( 210X297 mm) -13-A7 B7 Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs V. Invention Description (11) 1 1 C Η (C Η 3-)-C = <-and--C Ξ 1 1 C — C Η (C 2: Η Ε,) C Η 2 — 0 1 1 The factory base J refers to the formula C (0) base 〇1 Xu 1 I Γ ring base J and factory cycloene The radical J refers to a preliminary 1 I 1 cyclic hydrocarbon group having 3 to 8 carbon atoms. The back group is an alkyl group having 1 or more hydroxyl groups. Example 1 I For example, C Η 2 C Η £: 〇Η > — C Η 2 C Η 2 0 Η C Η 20 Η Matters 1 1 — C Η (C Η 2〇Η: 1 2 and similar bases 0 Script 1 Factory halogen J and factory halogen J refer to fluorine, chlorine, bromine and iodine. Page 1 1 Factory heterocyclic J, factory heterocyclic J, and factory heterocyclic J refer to optionally 1 1 substituted, fully saturated or unsaturated Generation of aromatic or non-aromatic cyclic groups> Examples 1 1 such as 4 to 7-membered single-ring system 7 to 1 1-membered double-ring system, or 10 to order | 1 5-membered ring system > At least one carbon atom-containing ring has at least 1 I and one hetero atom. The hetero atom-containing heterocyclic group may have one, two, or three selected white nitrogen atoms, oxygen atoms, or sulfur in each ring. Atom heteroatom 9 1 1. Among them, nitrogen heteroatom and sulfur heteroatom can be selectively oxidized and nitrogen heteroatom 1 can be selectively quaternized (quatern i ze d) C * 1 I This heterocyclic group May be either-a heteroatom or carbon atom is connected to e 1 1 I • Examples of monocyclic heterocyclic groups include • 1 1 I pyrrolidyl, pyrrolyl, pyrazolyl oxetamy1, pyrazolinyl, 1 1 I imidazolyl, imidazolinyl imidazolidyl \ oxazolyl, chevalyl, isoxazolyl 1 1 oxazolyl , Isoxazolyl m oxazolyl% Pi oxadizolyl, isomidazolyl \ isom 1 1 azolyl, isowalyl, furanyl > tetrakifuranyl, sulfonyl, dioxin 1 1 paper Standards apply to Chinese National Standard (CNS) A4 specifications (210X297 mm> -14-A7 B7 V. Description of the invention (12) azole, hexahydropyridyl, hexahydropyridyl, 2-ketohexahydropyridyl, 2 monoketohexahydropyridyl, 2-ketopyrrolidinyl, 2-ketoazepinyl, 4-hexahydropyridinone, pyridyl, pyrazolyl, pyrimidinyl, datrayl, tetrahydropiperan Group, morpholinyl 'thiamorpholinyl, cemorpholino, cemorpholino, 1'3-dioxolane, tetrahydro-1, 1-dioxoyl, and the like. Examples of bicyclic heterocyclyls include: indodo, benzothiazolyl, benzoxazolyl, benzoxyl, quinuclidinyl, quinoline, tetrahydroisoquinolinyl, isoquinoline Base, benzimidazolyl, benzonanyl, imdolizmyl, benzoenyl, chromonyl, lavender, benzopiperanyl, fluorenyl, quinolyl, oxazolyl, pyrrolidyl, furan Pyridyl (such as furan [2,3-c] pyridyl, B-furan [3,2-6] pyridyl] or furan [2,3-6] pyridyl), dihydroisopyridyl, dihydro Quinazolinyl (such as 3,4-dihydro-4 ketozolinyl), tetrahydrofurolinyl, and the like. Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling out this page) Examples of cyclic heterocyclic groups include: Π oxazolyl, benzongyl fluorenyl, morpholinyl, acridine Base, morphinyl, u-based and the like. "Substituted heterocyclic ring" means a heterocyclic ring substituted with one, two or three or less groups: (a) Alkyl group, especially low alkyl group; this paper uses China National Standard (CNS) A4 (210X297 mm) a? B7 V. Description of the invention (13) (b) hydroxyl (or protected hydroxyl); (c) tooth group; (d) keto group (ie = 0); (e) amine group, Alkylamino or dialkylamino; (f) alkyloxy; (.g) carbocyclo groups, such as cycloalkyl; (h) carboxy; (i) heterocyclooxy; '(j) alkyl Oxocarbonyl, such as unsubstituted lower alkoxycarbonyl; (k) Carboxamido'alkylaminoformamido or dialkylaminocarboxenyl; (1) fluorenyl; (m) nitro; (η) ) Cyano; (_〇) carboalkoxy; (P) sulfonylamino, sulfonamidinyl, or sulfonamidinyl;

(q) R 5- C-N II. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the notes on the back before filling this page) 0 R 6 (r) R5-S02-N- R 6 (s ) Aryl group; (t) alkylcarbonyloxy group; (u) arylcarbonyloxy group; this paper size is applicable to China National Standard (CNS) A4 specification (2 丨 OX297 mm) -16-

5. Description of the invention (14) (v) arylthio; (W) aryloxy; (X) alkylthio; (y) formamyl; (z) aralkyl; or (a >) An aryl group substituted with a radical, cycloalkyl, alkoxy, hydroxy, amino, alkylamino, dialkylamino, halo or trihaloalkyl. "Heterocyclooxy" refers to a heterocyclic group bonded via an oxygen bridge. Throughout this specification, all radicals and their substituents may be selected to provide stable moieties and compounds. The compounds of formula I and their intermediates can form salts which are also encompassed within the scope of the invention. The preferred salts for use in isolating or purifying the compounds of the present invention are those that are pharmaceutically acceptable (i.e., non-toxic and physiologically acceptable), although other salts may be used. Printed by the Consumers' Cooperatives of the Bureau of Standards for Loss of Standards of the Ministry of Economic Affairs (please read the notes on the back before filling this page) The compounds of formula I and their intermediates can be used with alkali metals (such as thorium, potassium, lithium), alkaline earth metals (such as calcium, Magnesium), organic bases (such as dicyclohexylamine, tertiary butylamine, benzathine, N-methyl-D-g 1 ucamide, hydrabam_ine) and amino acids (such as arginine, lysine and similar Substances) to form salts. These salts can be prepared by reacting these compounds with the desired ions in a medium in which the salts can be precipitated or reacting in an aqueous medium and then freeze-drying. When such as R 1 to R 4 or R 11 to R 14 etc. When the substituent contains a basic moiety (such as an amine group or a substituted amine group), the compound of formula I and its intermediates can form salts with various organic and inorganic acids. These salts include: Applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) with the paper size of hydrochloride. -17-Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs < aas87 b77. V. Description of the invention (15 ) Acid, hydrogen bromide, methanesulfonic acid, sulfuric acid, acetic acid and maleic acid; benzene sulfonate, tosylate and various other sulfonates; nitrate, phosphate, borate, Acetate, tartrate, maleate, citrate, succinate, benzylate, ascorbate v salicylate and the like. These salts can be prepared by reacting these compounds in an amount equivalent to an acid in a medium in which the salts can be precipitated or reacting in an aqueous medium and then freeze-drying. In addition, if substituents such as R1 to R4 or R11 to R14 have a basic moiety (such as an amine group), zwitterions ("internal salts") can be formed. In the compounds of the present invention, some groups (such as R1 to R4 and R11 to R14 substituents) may contain asymmetric carbon atoms, so the compounds of the present invention (such as those represented by Formula I and their salts) may be in the form of mirror image isomers, Non-mirror isomeric forms and racemic mixture forms are included in the scope of the present invention. Furthermore, compounds such as the compound of formula I and its salts may be mirror isomers even without asymmetric carbon atoms, and these mirror isomers are also included in the scope of the present invention. In U.S. Patent Application No. 08 / 493,331 by Murugesan et al. (Filed July 24, 1995) and a portion of its continuing application No. 08 / 603,975 (filed February 20, 1996) Substituted biphenyl isoxazole sulfonamides) are proposed in endothelin antiseptics, starting materials and methods. Coupling and Deprotection of Compounds of Formula II and Formula III · Compounds of Formula I or their salts can be formulated esters of Formula II or their salts and formulas This paper is in accordance with Chinese National Standard (CNS) A4 (210X297 mm) (Please (Please read the note on the back before filling in this page) 0 ^ ------ ^ ------ © ---------------- _ 18 _ 4Q3597 A7 B7 5. Description of the invention (16) The halophenyl compound of III or its salt is coupled and the nitrogen formed in the aforementioned coupling step is deprotected by protecting compound IV or its salt. (Please read the precautions on the back before filling out this page) The coupling of Formula II and Formula III compounds or their salts is in the presence of a palladium (0) catalyst (with palladium acetate / triphenylphosphine or other palladium (II) salts / Triphenylphosphine, phenylphenylphosphine palladium or ginseng (diamidinone) dipalladium is preferred) and is preferably carried out with a base (preferably potassium carbonate or sodium carbonate aqueous solution) to form formula IV Nitrogen protected compounds or their salts. The preferred ratio of palladium (II) salt to triphenylphosphine is between 1: 1 and 1: 3, see A. Suzuki et a 1., Pure & Applied Chemistry, 6 3, 4 1 9 — 4 2.2 (1 9 9 1); A. Martinetal.,

Acta. Chem. Scand., 47, 221 (1993); catalytic conditions described in H. Jendralla et al., Liebig Ann., 1253 (1995). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. If the halophenyl compound I I I is a compound of formula I I I a, in some cases it may be necessary to protect the heteroatoms J and K or L to facilitate the coupling reaction. For example, when J and K or L is N, one of the groups may be protected with a suitable protecting group such as a third butoxycarbonyl group. The specific R ^ -Ri4 group can be selected to suit the reaction conditions, and the specific Ru-R14 group can be converted into other R11-R14 groups before or after coupling by a suitable method known. The coupling method is preferably carried out at a temperature as low as about 25 to about 100 '(optimally as low as about 25 to about 75) and a pressure of about 1 atm under argon or nitrogen. The molar ratio of the ester II or its salts to the dentate phenyl compound III or its salts should preferably be about 1: 1 to about i. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) _ 19 -A7 B7 4Q2597 V. Description of the invention (17): 1.2. The amounts of palladium (0) catalyst and base are selected to catalyze the affinity reaction, and should preferably be about 2.5 mol% to about 10 mol (please read the precautions on the back before filling this page). % And about 2.5 equivalents to about 7 equivalents. The solvent used is preferably selected from aqueous or organic liquids, such as acetone, ethanol, toluene, tetrahydrofuran, dimethoxyethane and water, or a mixture thereof, and a mixture of toluene and ethanol is preferred. The amount of the solvent is preferably such that the amount of the ester II or a salt thereof is about 4 to about 9% by weight based on the combined weight of the solvent and the ester I I or a salt thereof. The following are examples of the dosage ranges of several solvents / esters II / bases: tetrahydrofuran (30-70m 芡), toluene (100-200m 又) 'ethanol (80 — 1-60m 义) / brewer ester Ι · Ι (1 5 — 20g) / 2M aqueous sodium carbonate solution (100-150m). Residual palladium catalysts printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs should be contacted with a chelating agent (such as thiocyanuric acid) ("TMT") before or after removing the protective group of the compound of formula IV or its salts. Way to remove it. After removal of the protecting group of Formula IV or a salt thereof, crystallization is performed to form an appropriate crystal form of the compound of Formula I or a salt thereof is also contemplated by the present invention. The crystallization process should be achieved by supersaturated ethanol solution (with or without co-solvents such as heptane or water), especially when seed crystals are added with the desired crystal form. The crystallization process is best performed by a method as described in the examples herein. The compound of formula III and its salts can be prepared by a similar method as disclosed in US patent application 0 8/4 9 3,3 31 and the foregoing partial application. Formula I I a or a salt thereof is preferably prepared by the novel method described herein, and compound II and a salt thereof are also preferably prepared by the novel method described herein. This paper size applies to Chinese national standards (CNS > A4 size (210X297 mm) ~ -20-Printed on A7 by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ___ _B7_ V. Description of the invention (18) Formed by this coupling method The step of deprotecting the compound of formula IV or its salts can be performed by any suitable method, such as those similar to those disclosed in US patent application 08/4 9 3, 3 31 and the foregoing. When "Prot" is MEM, it is better to deprotect by heating in a mixture of HC5 aqueous solution and ethanol. Formula II Preparation of Compounds of Formula II Esters and their salts can be formed by the novel methods provided herein. The formula esters or their salts of formula II can be prepared by a method including the following steps: (Please read the precautions on the back before filling this page) < 1

〇leaving group (V) (a) In the presence of an organic base and an organic solvent, contact a compound of formula v or a salt thereof with an amine of formula VI or a salt thereof to form a compound of formula VII or a salt thereof, formula V The structures of VI, VI, VI I are as follows: wherein the phenyl group of formula V may be further substituted (for example, by one or more groups described in the definition of R11 to R14), and the halogen group is preferably bromine, chlorine, Or boiling, and bromine is the best;

(VI) This paper size applies to China National Standard (CNS) 8-4 specifications (210X297 public directors) ------- G policy ------, 玎 ------ ^ -21-仪 2537 A7 B7 V. Description of Invention (19)

(VII) wherein the phenyl group of formula VII may be further substituted (for example by one or more of the groups described in the definition of R11 to R14); (b) the nitrogen atom of the compound of formula VII or a salt thereof Protect to form compounds of formula VI II or salts thereof

(VIII) wherein the phenyl group of formula VI II may be further substituted (for example by one or more groups as described in the definition of R 11 to R 14): (c) with alkyl lithium or aryl lithium The compound will lithify the SV ;! II compound or its salt, and then contact the phosphonium product with boric acid: rr ester, and then hydrolyze to form formula IX phosphonium acid or its salt: employee of the Central Standards Bureau of the Ministry of Economic Affairs Printed by Consumer Cooperatives

Wherein the phenyl group of formula IX may be further substituted (for example, by one or more groups described in the definition of R 11 to R 14); and (d) the compound of formula IX or a salt thereof (That is, 2,3-dimethyl-2,3-butanediol) is contacted with water to remove the compound of formula II or a salt thereof. (Please read the notes on the back before filling this page)

! · Qian ^ I E Ί, J /-halo ^

R1

A7 B7 V. Description of the invention (20) In a preferred implementation system, the esters of formula II a or their salts can be made by a method including the following steps = (a) in the presence of an organic base and an organic solvent, A compound of formula V a or a salt thereof is contacted with an amine or a salt of formula VI a to form a compound of formula VI I a or a salt thereof. The structure of formula Va, VI a, VI I a is as follows: leaving group. (Va ) (Via) (Please read the notes on the back before filling this page) halo

S,

(Vila) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

(b) Protecting the nitrogen atom of the compound of formula V or a salt thereof to form a compound of the formula V I halo

This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) (Villa) -23-V. Description of the invention (21) (c) Compounds of formula VIII a or their salts with alkyl lithium or aryl lithium compounds Lithium-like, then contacting the lithiated product with a trialkyl borate, and then hydrolyzing to form a pivalic acid of formula IX a or a salt thereof: (h〇) 2b

(d) contacting the compound of formula I Xa or a salt thereof with water and removing water to form the compound of formula I Ia or a salt thereof. The term "leaving group" as used herein refers to any suitable leaving group, such as a halo group, with a chloro group being preferred. Any suitable organic base can be used in step (a), and preferably includes amines such as pyridine or trialkylamine. The organic agent used in step (a) is preferably a haloalkane, such as dichloromethane or 1,2-dichloroethane. The organic base (such as pure pyridine) can also be used as a solvent. Printed by employee consumption cooperation (please read the notes on the back before filling this page) As mentioned above, the compound of formula VIII or its salts can be prepared from the compound of formula V or its salts and the amine compound or its salt of formula VI Contact, and then protect the nitrogen atom of the compound of formula VII or a salt thereof, and then it is preferably as low as about -40 to about -10.5 (especially about 7000 to about -100). The compound of formula VIII or its salt is lithiated with an alkyllithium or aryllithium compound at the temperature of) to form a compound of the following formula or its salt. The paper size applies Chinese National Standard (CNS) A4 specification (210X 297) Mm) -24-402597 a7 _ 1 __ —- 5. Description of the invention (22) 1

(Please read the notes on the back before filling out this page) The phenyl group can be further substituted (for example, by one or more groups described in the definition of R1 4) to form a compound of the following formula or Its salts are better:

Li

At temperatures of about -40 to as low as about -105, especially at about -70 to as low as about 1100, a trialkyl borate (such as triisopropyl borate 'or preferably boric acid) is used. Trimethylate treatment of this lithiated compound or its salts yields the following phosphonates or their salts

The phenyl group printed by the Shell Standard Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs can be further substituted (for example, by one or more of the groups described in the definition of R 11 to R 14) to form boron of the following formula Ester or its salt is better: This paper size is applicable to China National Standard (CNS) A4 (210X297 Gongchu) -25-A7 B7

(alkyl-Ο) 2B

402 ^^ 7_ V. Description of the invention (23) 'I14 R3 R4 \ Then this compound or its salts can be hydrolyzed with a suitable acid (preferably a water-soluble acid, such as aqueous hydrochloric acid solution) or a suitable base. Instead, a boric acid of formula Ix or a salt thereof is formed. The advantage of this hydrolysis step to form osmic acid IX or a salt thereof is that osmic acid has higher stability than osmic acid ester. The foregoing steps and the starting materials of formulas V, VI and their salts can be prepared similarly to European Patent Application Publication No. 569,193 (1993) and US Patent Application No. 08 / 493,331 and parts thereof Proceed as described in the application. Subsequently, osmic acid I X or its salts can be brought into contact with alcohol and the water can be removed to form the corresponding ester I I or its salts. Water can be removed by several methods, such as adding a desiccant (such as magnesium sulfate) or heating with a solvent (such as toluene) to remove water azeotropically. This reaction is preferably carried out at a temperature of about 110 to as low as about 120 (most preferably as low as about 1 12 to about 115) and a pressure of about 1 atm under argon or nitrogen. The molar ratio of osmium peptone I X and its salts is preferably about 1: 1 to about 1-1: 1, and the solvent used is preferably selected from organic liquids such as toluene. The amount of the solvent is preferably such that the amount of acetic acid IX or a salt thereof is about 4 to about 10 based on the combined amount of the solvent and the acid I X or a salt thereof.

Phenylic acid IX or its salts (preferably with Phenylic acid I Xa or its salts) can be directly coupled with ® phenyl compound III or its salts to form formula IV Winter paper scale Applicable Chinese National Standard (CNS) 8-4 Threat (210X297 public epidemic): ~ ----------- (Please read the notes on the back before filling out this page)-、 π Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs-26 Printed by the Consumer Standards Cooperative of the Ministry of Standards of the People's Republic of China 402597 V. Description of Invention (24) Compounds or their salts. This method, especially when the halophenyl compound III or a salt thereof is iodophenyl compound III or a salt thereof (preferably iodophenyl compound III a compound or a salt thereof) is also expected by the present invention. . It may be advantageous to replace osmic acid IX or its salts with henyl ester II or its salts, because henyl ester IX compounds are quite stable, and the amount of impurities generated after coupling with halophenyl compound III or its salts is small, but Higher yields of compounds of formula IV or their salts are obtained. Preparation of Formula I I I: Compounds of formula III Halophenyl compounds and their salts can be prepared by similar methods as described in US Patent Application 0 8/4 9 3, 3 31 and some of the foregoing continuing applications. The oxazole ring-containing compound of formula I I I a and salts thereof can also be formed by the novel methods described herein. According to the present invention, the formula 1 II a (1) oxazole or a salt thereof can be prepared by a method including the following steps: (a) in the presence of a base and a solvent, the phenylphosphonium halide compound X or a salt thereof and the formula The amine acetal of XI or its salt is contacted to form a hydrazone acetal of the formula XI or its salt, wherein the structure of the formula X, XI, XII is as follows

This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling in this page)

-27------------ V. Description of the invention (25) A7 B7

O-alkyl (XI) alkyl-0

12 halo (XII): and (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

(b) Cyclizing an acetal of formula XII or its salt in the presence of a cyclizing agent to form an oxazole phenyl halide compound of formula III a (l): (Illa (l)) starting material Phenylarsenic compound X or a salt thereof is commercially available or can be prepared by those skilled in the art. The halo group of the halohalogen moiety is preferably chlorine; the halo group which is in para-position with the halohalogen moiety is preferably bromine, chlorine, or iodine, and iodine is most preferred. The starting material acetal XI or its salts can also be applied to the Chinese National Standard (CNS) A4 specification (210X25 »7 mm) from a private paper scale. '-28-Impression of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 4iiS97 _B7 _ 5 2. Description of the invention (26) It can be obtained through purchase or can be made by those with ordinary skills in the technical field. The alkyl group of the acetal moiety is preferably a methyl group or an ethyl group, and most preferably a methyl group. The base used in step (a) may be any suitable base, preferably an alkali metal carbonate, bicarbonate, or hydroxide, and bicarbonate (in a solvent of water and / or acetone) Or potassium carbonate (solvent such as dichloromethane) is the best. The cyclization reaction is carried out by contacting amidoacetal XII or a salt thereof with a cyclizing agent, and the cyclizing agent can be any compound capable of causing a cyclization reaction. Ea ton reagent (that is, methanesulfonic acid and pentoxide Phosphorus) or polyphosphoric acid (ρ ο 1 yph 〇sph 〇ricacid, (PPA) is more preferred, and E at ο η reagent is the best. This cyclization reaction should be as low as about 125 to about 150 (It is best to be at a temperature as low as about 130 to about 13 5) and a pressure of about 1 atm under argon or nitrogen. The amount of cyclizing agent is selected to achieve the cyclization reaction, and If using Eaton's reagent, it should be about (catalyst / matrix) 8mL / g to about 15 m L / g * Eaton reagent is a solution of P205 in methanesulfonic acid and can be used for this cyclization A preferred solvent for the reaction. Examples of compositions of Eat on reagents include 7.5 to 15% by weight of 卩 205 in methanesulfonic acid. Compounds of formula III a and their salts can also be used in the present invention. One-step method (reversecoupling) to prepare a compound of formula I a or a salt thereof, the method comprising The following steps: (a) In the presence of a trialkyl borate, use a lithium alkyl or aryl lithium compound to compare a compound of formula III a or a salt thereof (compared with a compound of formula I z ia (l) or a salt thereof) Good) Lithified and then hydrolyzed to form this paper. The paper size is applicable to Chinese National Standard (CNS) A4 (210X297 mm) --------------- II ------ Q (Please read the notes on the back before filling this page) A7 B7 V. Description of the invention (27) XI II osmic acid or its salts, where the structure of formula III is as follows:

R 12 (Ilia), (Please read the notes on the back before filling this page)

(XIII) Printed by the Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, halo

R1 0

(b) in the presence of a palladium (0) catalyst and preferably a base, contacting a compound of formula XI II or a salt thereof with a compound of formula VI II a or a salt thereof to form a nitrogen-protected compound of formula IV a Or its salts, the structure of the formula VI II a and formula IVa is as follows:) // (Villa) This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm)-30-4 abstract 97 V. Description of the invention (28) R2 r \

(IVa);: and (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (c) Deprotect the nitrogen atom of the compound of formula IV a or its salt to form a formula I a compound or a salt thereof. The lithiation in this method is carried out in the presence of trialkyl borate, and then hydrolyzed (which can be performed under the conditions described in the preparation method of the national acid of formula IX and its salts herein) in ) The process of coupling under the condition of a catalyst and preferably a base and the process of deprotecting the nitrogen-protected coupling products can be in accordance with the conditions described herein for the coupling of compounds of formula II and formula III and their salts and their deprotection. Performing "lithiation" produces a compound or a salt thereof having the following structure, r

This paper size applies the Chinese national standard (CNS > A4 specification (210 × 297 mm) -31-4D25W_ b7_ V. Description of the invention (29) When contacted with trialkyl borate, the following ester or its salt is obtained Class r * R2

B (O-alkyl) 2. The compound printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. The compound used or prepared in the method of the present invention should preferably contain one or more of the following substituents (where appropriate, all Substituents are preferred): X is 0 and N is Y; the ring containing K, L and J is 2-oxazole; P is zero; R1 and R2 are each hydrogen, alkyl, alkoxy, aryl, Hydroxyalkyl, —C02R5 or Z4_NReR7, preferably low alkyl or hydrogen; R 3 and R 4 are each alkyl, and low alkyl is best, especially methyl; R11, R12 'RU and R14 Each is hydrogen, hydroxy, amino'heterocyclyl, alkenyl, alkoxy, carboxamide or substituted lower alkyl, wherein R 12 to R 1 4 are hydrogen and R 11 is hydrogen, hydroxyl, amine, heterocyclic The most preferred are alkenyl, alkenyl, oxo, carboxamide or substituted low oxo. Compounds of interest include (in particular) compounds having at least one of the following definitions (i) to (iv): (i) at least one of R11, R12, R13 or R14 is a heterocyclic ring, (谙 read the Note: Please fill in this page again) Order 1C. This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297mm) -32-A7 ___B7__ V. Description of the invention (3〇) Substituted heterocyclic ring or heterocyclic oxy group ; (Ii) at least one of Z1, Z2 or Z3 is aryl, heterocyclic, substituted heterocyclic or heterocyclooxy; (iii) Zβ is selected from one to three selected from halogen, aryl, aryloxy and An alkyl group substituted by an alkoxy group, at least one of which is not an aryl group; an alkyl group substituted by two or three aryl groups; and one to three selected from an alkyl group, an aryl group, an alkenyl group, and an alkoxy group Cycloalkyl substituted with aryl; cycloalkyl with thick and benzene ring; aryloxy substituted with one or two halogens; aryl substituted with methylenedioxy; Alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy, and trihaloalkoxy substituted aryl groups; Heterocyclyl: The substituted or (i ν) Ζ11 as with one, two, or three prime _ alkyl. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs using a compound of formula I or its amidine as an endnthel in antagonist (please read the notes on the back before filling this page) The compound of formula I or its salts is ET_1, ET-2 and It is an antihypertensive agent and / or an antagonist of ET-3, which can be used to treat conditions related to an increased amount of ET (such as dialysis, trauma, and surgery) or to treat all conditions associated with endothelin. By administering a composition containing one of the compounds of the present invention or a combination of compounds of the present invention, the blood pressure of a mammal (e.g., a human) suffering from hypertension can be reduced. The compounds of formula I or their salts can also be used for hypertension and coma due to pregnancy (primary daughters and daughters), acute portal hypertension, and hypertension secondary to treatment with erythropoietin. The compounds of the present invention can also be used to treat diseases related to cell functions such as kidney, blood vessel, and glomerular aneurysm, including acute and chronic renal failure, and the blood scale is applicable to the Chinese National Standard (CNS) A4 specification (2 丨 0X297). (%) _ _ Yi 2597 A7 B7 V. Description of the invention (31) Tube injury, senile renal damage and renal damage related to dialysis, renal sclerosis (especially hypertensive renal sclerosis), poisonous kidney (including Toxic nephropathy associated with contrast and contrast agents and eyclosporine), renal hemostasis, primary bladder and urinary tract reflux, angiosclerosis and similar conditions. The compounds of the invention are also useful in the treatment of diseases related to paracrine and endocrine function. The compounds of the present invention are also useful in the treatment of endotoxemia or endotoxin shock and hemorrhagic shock. The compounds of the invention can also be used in hypoxia and hemostatic diseases, and as anti-hemostatic agents for the treatment of, for example, cardiac hemorrhage, renal hemorrhage, and cerebral hemorrhage, as well as reperfusion (neperfusi ο η) (such as occurs after cardiopulmonary bypass surgery Patients), coronary and cerebral vasospasm, and similar diseases. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. In addition, the compound of the present invention can also be used as an arrhythmia prevention agent; anti-angina 1 agents: inhibitors of cardiac fibrillation; antiasthma, anti-arteriosclerosis agent (Anti-atherosclerotic and anti-arteriosclerotic agents); Cardiopulmonary bypass cardioplegia solution additives; Dissolving thrombus treatment additives; and anti-releasing agents. The compounds of the present invention can be used for the treatment of myocardial infarction and peripheral vascular diseases (such as Raynaud's disease and Taka y as hu's disease); for the treatment of cardiac hypertrophy (such as hypertrophic cardiomyopathy); for the treatment of primary pulmonary hypertension in adults and newborns Blood pressure (such as pl exogenic, embolism (emb ο 1 ic), and pulmonary hypertension or other trauma secondary to heart failure, radiation, and chemotherapy injury; treatment of central nervous system vascular diseases such as stroke, migraine, and subarachnoid Bleeding; treatment of CNS behavioral diseases; treatment of gastrointestinal diseases such as ulcerative colitis, Crohn's disease, damaged gastric mucosa, ulcers, and hemorrhagic bowel disease; treatment of bile or -34-(Please read the note on the back first Please fill in this page again for this matter) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 10 ^ 597_ V. Description of the invention (32) Biliary related diseases such as cholangitis; treatment of pancreatitis; regulation of cells Growth; treatment of benign prostatic hypertrophy; restenosis after angioplasty or any procedure that includes transplantation; treatment of congestive heart failure, including inhibition of fibrosis Vitamin degeneration; inhibition of left ventricular enlargement, remode ling and dysfunction; and treatment of hepatotoxicity and Sudden death. The compounds of the present invention can be used to: treat sickle cell disease, including pain crisis of this disease; Harmful consequences of tumors, such as hypertension due to hemangiopericytoma; treatment of early and advanced liver disease and injuries, including atandant complications (such as hepatotoxicity, fibrosis, and liver stiffness); treatment of the urethra and / or bladder Treatment of liver and kidney syndromes; treatment of immune diseases related to vasculitis, such as lupus, systemic sclerosis, mixed cryoglobulin blood; and treatment of fibrosis related to renal dysfunction and toxic liver disease. The compounds of the present invention can be used to treat diseases of metabolism and neurology; cancer; insulin-dependent and insulin-independent diabetes mel 1 itus; neuropathy; retinopathy; maternal dyspnea syndrome; dysmenorrhea, epilepsy, hemorrhagic and hemorrhagic stroke , Bone remodeling, psoriasis, and chronic inflammatory diseases such as rheumatoid arthritis, Osteoarthritis, sarcomatosis, and eczema dermatitis (all types of dermatitis). The compound of formula I and its salts of the present invention can be combined with the following: en. Dothelin conversion enzyme (ECE) inhibitors, such as P 'hosphorami-don; Thromboxane receptor antagonist; thrombin (fibrinase) inhibitors (such as hirudin and analogs): growth factor inhibitors, such as PDGF activity regulators; activation of blood plates Factor (PAF) antagonists; angiotensin II (AI I) receptor antagonists This paper applies Chinese National Standard (CNS) 8-4 specifications (210X297 mm) (谙 Please read the precautions on the back before filling this page ) --------------- Shenyi ----- 1T ---- Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs -35-4Q2537 at B7 V. Description of the invention ( 33); Renal enzyme inhibitors; Angiotensin-converting enzyme (ACE) inhibitors * such as captopril, zofenopril, fosinopril, ceranapr i 1, a 1acepr i 1, enalapril 'delapril' pentopr i1, quin-april, ramipril, lisinopril, And salts of these compounds; Central Standard of the Ministry of Economic Affairs Printed by employee consumer cooperatives (read the precautions on the reverse side and then fill out this page) Neutral peptide internal enzyme (NEP) inhibitors; double NE P- AC E inhibitors; Η MGG ο Α reductase inhibitors, such as Pravastatin And mevacor; partyene synthetase inhibitors; bile acid sepuestrants, such as quest ran; calcium tract blockers; potassium activators;-adrenergic stimulants; arrhythmia preventive agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide 'hydrof1umeth i az i-de' bendrof 1 uraethiazide 'methy1ch1 orothiazide' tr-i ch 1 orometh i az i de 'po 1 y th i az i de or benzoth i az i de and ethacryn ic acid' tricrynafen 'chlorthalidone' furosemide , Musolimine, bumetan i de 'triamterene, amiloride, and spironolactone salts of these compounds; and thrombolytic agents, such as histoplasminogen activator (t PA), recombinant t PA streptococcal kinase, urinary hormone, prourokinase, and Aniseylated activator complex (APSAC). If formulated in a fixed dose, such a combination product uses the compound of the present invention within the dosage range described below and other pharmaceutically effective agents within the allowable dosage range. The compounds of the present invention can also be formulated together with antifungal agents and immunosuppressive agents such as am p h o t e r c i η B, c y c 10 s p o r i n e and their analogues to resist the vasoconstriction and toxic nephropathy secondary to these compounds. The compounds of the present invention can also be used in conjunction with hemodialysis. This paper size applies to China National Standard (CNS) A4 (210X297 mm) -36-Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ 〇S59? ^ V. Description of the invention (34) The compound of the present invention can be taken orally The intestinal method administers an effective amount to various mammals (such as humans) known to suffer from these diseases, and the dosage ranges from about 0.1 to about 100 mg / kg, and from about 02 to about 50 mg / kg is better, and more preferably about 0.5 to about 25 mg / kg (or about 1 to about 2500 mg, and more preferably about 5 to about 2000 mg), one dose per day or divided into 2 daily — 4 doses. The effective substance may be used in a composition (e.g., lozenge, capsule, solution or suspension) containing a compound of formula I or a mixture of compounds of formula I in a dosage of about 5 to about 500 mg per unit dosage form or a topically applied dosage form for treating wounds. . It can be mixed with physiologically acceptable vehicles or carriers, excipients, binders, preservatives, stabilizers, flavoring agents, etc. in a conventional manner, or with topical carriers such as P last i base (mixed with polyethylene gelled mineral oil). The compounds of the present invention can also be administered topically to treat peripheral vascular diseases, so they can be formulated as creams or ointments. The compounds of formula I can also be formulated as compositions such as sterile solutions or suspension tablets for parenteral use. About 0.1 to 500 mg of the compound of the formula I per unit dosage form is mixed with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, and the like. The amount of the effective substance in these compositions or preparations is an appropriate amount capable of achieving the above range. The medicine uses the following preferred embodiments to further explain the technical contents of the present invention. This paper size applies to China National Standard (CNS) Α4 specification (210X297 mm) ----------- (Read the notes on the back and then fill out this page) -Order -37-4QSS97 A7 B7 V. Description of the invention (35) Example 1: Preparation of fluorene ester II N — ί (2 —shenoxyethoxy) formamidine — Ν — (3,4 -dione 5 —isoxazole) ) 2— (4,4,5,5,1,4,4,1,1,1,3,2 ~ dioxoboropentacyclopentazone-^-yl) benzidine h3c ch3 ch3 ° \ / °

A · _2_-bromo-N — (3, 4 — 2 application of a 5 — base scourge of a certain) benzamidine (#Xianwen read the note on the back side and fill in this page) Printed by Consumer Cooperatives

In a 2 L three-bottle flask equipped with a top mechanical stirrer, a 250 m addition funnel and an argon line, add 2-bromobenzenesulfonyl chloride (150g, 587mmo 芡, commercially available) and anhydrous D-pyridine. (15 0m {). The resulting pale yellow solution was cooled in an ice / salt bath to-18 ° C (internal temperature). Under the stirring state, the paper size can be added to the Chinese National Standard (CNS) A4 specification (210X297 mm) within one hour by adding the paper size. -38-_by _ V. Description of the invention (36) Liquid funnel is added dropwise with 5 —amine group 3 , 4-Dimethylisoxazole (69.1 M, 616111111, and commercially available) anhydrous pyridine (195 mL) solution, the internal reaction temperature during the addition does not exceed ~ 6 ° C, and After that, the ice / salt bath was removed, and the reaction mixture was returned to room temperature after the chain. After stirring for 1 hour, it was stirred at 40 ° C for 21 hours. The reaction mixture was cooled to room temperature, and then poured into a mixture of ice water (3 L) and celite (37.5 g. After stirring for 20 minutes, it was filtered and washed with water (250 mL x 3). Charcoal (4 5 g) was added to the filtrate, and the mixture was stirred at room temperature for 40 minutes, and then filtered through a piece of diatomaceous earth. This diatomaceous earth piece was washed with water (50 OmL X 3), under vigorous stirring for 2 hours Cold HC (6 N, 750mL) was added dropwise to acidify the filtrate. At this time, product precipitation occurred. After adding HC J2, the mixture was stirred for 1 hour. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ( Please read the notes on the back before filling this page} Filter the mixture, wash the solid part with cold water (750 mL x 4), and dry it for 3 days under suction to obtain the title compound (171 g) as a yellow-white solid. Yield 88% (HPLC area percentage: 97.4%). Thin layer chromatography (TLC): Rf = 0.47 (1 ^ 81: 11 ^ 11 silicone: ethyl acetate (£ 1; 0 eight (;)) : Hexanes / 1: 1 * Visualization CAM or UV) 的 Another method for preparing the title compound in this step: 2 under argon —Bromobenzenesulfonyl chloride (50g, 196 mm〇5) and anhydrous 1,2—Dichloroethane Academy (125mL) Joined in this paper scale Applicable to China National Standard (CNS) A4 specification (210X 297mm) -39-4025B7 A7 B7 V. Description of the invention (37) A 1 L three-necked flask. The resulting colorless solution was cooled to 0 ° C, and then anhydrous pyridine (40 mL, 396 mm 0 P) was added, followed by solid 5-amine. _3,4-Dimethylisoxazole (241.lg, 196mm〇i). After the addition was completed, the ice bath was removed and the reaction mixture was heated to 5 5 ° C 2 for 1 hour. The crude reaction mixture of the compound. B. 2 —Bromo-N — (3,4, 2-dimethyl-1, 5_yloxazole, etc.) _ N — Γ (2_methoxyethoxy, 1), a certain 1 pus ( Please read the notes on the back before filling out this page}

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs Add potassium sulfonate (130.5g, 944mm〇i2) and anhydrous dimethylformamide (DMF, 286mL) to an equipped with a mechanical stirrer under argon In a 1 L three-necked flask, stir this heterogeneous mixture at room temperature for 15 minutes. The title compound (1 25 g, 378 mmo) 2) from step A) was added as a solid, and the mixture was stirred at room temperature for another 15 minutes. Methoxyethoxymethyl chloride (MEMC j ?, 47.5 mL, 415.8 mmo) was added dropwise via the addition funnel within 40 minutes, and the reaction mixture was stirred for 40 minutes after the addition was completed. The reaction was monitored by HPLC. . Dilute the reaction mixture with ethyl acetate (40 OmL) and stir for 5 paper sizes. Applicable to China National Standard (CNS) A4 specifications (210X297 mm) -40-fine 591? B; 5. Description of the invention (38) minutes Filter it. The solid portion was washed with ethyl acetate (200 mL × 2) and hexanes (250 mL × 2). The filtrate was treated with charcoal (25 g), stirred at room temperature for 1 hour, and then filtered through a celite pad. The diatomaceous earth tablets were washed with ethyl acetate (50 mL x 3), and the ethyl acetate layers were combined and washed with Na2CO3 (1M, 500 mL) to cause precipitation in the aqueous layer. (750 mL) was added to suppress precipitation, and the aqueous layer was separated and discarded. The organic layer was washed with water (750 mL) and brine (500 mL x 2), dried over Na2S04, filtered, and concentrated to form a yellow semi-solid (157.3 g, 99% isocyanate). The residue was dissolved in ethanol (125 mL), and then placed in a freezer (0 ° C) for 20 hours. Crystallization occurred. The solid portion was filtered off and dried to obtain a yellow-white solid. The title compound (75.65% yield, HPLC area percentage = 98.2%), DLC = Rf = 0.5 5 (Whatman's gelatin:

EtOAc: Hexanes / 1: 1, Visualization: CAM or UV) 〇 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) Another method for preparing the title compound in this step : The reaction mixture derived from another method of preparing the title compound of Step A was cooled to room temperature, and concentrated under reduced pressure at 40 ° C. on a rotary evaporator to a dark, thick oil (102 g). This dark oil (98g, 1 88mmoj?) Was dissolved in anhydrous dichloromethane (240mL), followed by diisopropylethylamine (97mL, 4 equivalents), and then methoxyethoxylate was added dropwise. Methyl chloride (25. 7 m L > 2 2 5. 6 This paper size applies to Chinese National Standard (CNS) A4 specifications (210X297 mm) -41-Fine 53? A7 _; _B7_ V. Description of the invention (39) mm〇 交). The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure on a rotary evaporator to a thick oil, and then dissolved in EtOAc (400 mL), and charcoal (10 g) was added. This charcoal mixture was stirred at room temperature for 30 minutes and filtered through a piece of diatomaceous earth. The diatomaceous earth pieces were washed with EtOAc (100 mL x 3) and hexanes (200 mL x 2), and the filtrate was transferred to a After the liquid funnel, washed with water (100mLx2), HC (0.5N, 100mL x 2), water (100mLx2), and brine (100mLx2), then dried over Na2S04, filtered, and concentrated to Thick oil (64.9 g, 83% mass balance).

This thick oil was dissolved in ethanol (E t OH, 65 mL), cooled to 0 ° C in an ice bath, seeded with the title product of this step, and stirred at 0 ° C for 6 hours. As a result, crystallization occurred. The solid was filtered and dried by suction to obtain the title compound of this step as a yellow solid (total yield 62%, HPLC area percentage = 98.2%), TLC: R f = 0.5 5 ((Whatman's Mortar: EtOAc: Own House / 1: 1, Visualization: CAM or UV). · Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) C. 2_ Boric acid Base N— (3,4—dimethyl-1, 5-base ox beer) —N—f (2-methyl-2-ethyl) methyl] benzenesulfonamide This paper standard applies to Chinese National Standards (CNS) A4 specifications (210X 297 mm) -42-Magic 2597 5. Description of the invention (40)

mm 〇β) Add a dry 1 l three-necked round bottom flask equipped with a mechanical stirrer, gas adapter, thermocouple, and septum at the top, then thoroughly degas and place under argon Tetrahydrofuran (THF'185 mL) was added via a syringe, and the mixture was cooled to about -10 ° C (internal temperature). Add n-butyllithium (n-BuLi, 42.5mL, 10lmmo, and a concentration in hexane of 2. 3 8M) dropwise over 16 minutes while maintaining the internal temperature at -9 and -10 Between 1 ° C. This light yellow-orange solution was stirred for another 16 minutes at approximately 198 ° C to -10 ° C. Trimethyl borate was added dropwise within 14.5 minutes (16.0 printed by the Consumers' Union of the Central Standards Bureau of the Ministry of Economic Affairs --------— Page) m L * 14 0. 9mmoj2) in THF (24 mL) while maintaining the internal temperature between -96 ° C and -99 ° C. Allow the mixture to stir for approximately 44 minutes between approximately -9 3 ° C and _1 0 ° C, and then for approximately 39 minutes at approximately -93 ° C to 72 ° C. HC 芡 (3. ON ′ 120mL, 360mmo again) was added to the reaction mixture (this solution exothermed to about 7 ° C), and stirred for 20 minutes (

-7 ° C to +6 ° C). Separate the two layers with a separatory funnel. Wash the aqueous phase with toluene (3xl20mL) and tertiary butyl methyl ether (MTBE, 3 X 10 OmL). Combine the organic phases and use the salt. $ (4 X This paper is for Chinese countries. Standard (CNS) A4 specification (210 X 297 mm) 402597 A7 B7 V. Description of the invention (4l) 10 OmL) Washed, dried with Na2S04 and concentrated on a rotary evaporator to about 10 OmL, containing the content of this step Title compound (HPLC area percentage: 97.7%). Another method for preparing the title compound in this step: Place the title compound of Step B (20.0 g, 47.7 mmo 5) in a 50-mL three-necked flask equipped with a stir bar, and fill with argon. Replacement 0.5 hours. Anhydrous THF (20 OmL) was then added via a syringe, and the flask was cooled to 178 ° C in an acetone / dry ice bath. Add phenyllithium (P h L i 5 3 7. 1 ml L »48. 2mmo 以) at a concentration of 2.5 minutes in the addition funnel, its concentration in cyclohexyl-1 ® I is 1. 3M ， 系 依J. Organomet. Chem., 18 6,: Titration in the manner described in L 5 5 (198 0), and measured 1.3 M). The rate of addition of P h L i is such that the internal temperature of the reaction mixture is maintained below -75 ° C, the resulting solution is stirred at 78 ° C for 15 minutes, and then the solution is stirred for 15 minutes Trimethyl borate (10.8 m L »9 5 .4mmo_C) in THF (5mL) Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) The solution is dripped through the cannula It was added to the reaction mixture, and the trimethyl borate / TF F solution was cooled in an ice-water bath before the addition. The addition rate is maintained so that the internal temperature in the reaction mixture does not exceed -73 ° C. The reaction mixture was stirred at 78 ° C for 0.5 hours, and then a solution of acetic acid (15 ml) in THF (10 ml) was added dropwise to stop the reaction. The acidified solution was stirred at 78 ° C for 1 hour. After 0 minutes, the temperature of the solution returned to 0 ° C. Add 1 NHC i? (2 5 m L) drop by drop (the paper size of 1 N applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 402597 A7 B7 V. Description of the invention (42) (#First read the back Note: Please fill in this page again.) HC 芡 is made by diluting 4 2mL of 1 2N HCJ2 with 50 OmL of water. Excess acid is used to ensure complete suspension of the reaction. This HC solution is added in an ice / water bath before adding. Cooling). The reaction mixture was then returned to room temperature and extracted with tert-butyl methyl ether (TBME, 4 × 25OmL). The organic layers were combined and extracted with a 0.5 N aqueous NaOH solution (4 × 2 5 OmL). The aqueous layers were combined and back-extracted with TBME (1 × 100 mL). The aqueous extract was cooled to 0eC, and 6N HCP was added dropwise under rapid stirring to adjust the pH to 2.0 (p Η meter). The acidified solution was extracted with TBME (4 × 2 5 OmL), and the organic layer was pooled and dried with M g S 0 4. Then the suspension was filtered and the filtrate was concentrated to obtain a light brown oil. This step Gallic acid title compound (17 lg, 93%, HPLC area percentage 88%.) HPLC conditions: column: YMC ODS-A, 6X 250mm; monitoring at 233; flow rate 1. 5mL / min; solution A (%) : H2〇 / MeOH / H3P〇4 9 0: 1 0: 0.2; Solvent B (%): H2〇 / MeOH / H3P〇4 10: 90: 0. 2; Employees' Cooperatives of Central Standards Bureau, Ministry of Economic Development India gradient: 40% B to 100% B, linear gradient of 10 minutes' 100% B for 5 minutes, 40% B for 4 minutes; the residence time of the title compound in this step is 8. 3 minutes. This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) -45-40B597 A7 B7 _ V. Description of the invention (43) · D · N — [2 —methoxyethoxy) methoxyΊ — N — (3_L. 4 — two application of a 5 -isoxazolyl) one? · One (4,4 '(Please read the precautions on the back before filling out this page) 5, Fi — Tetramethyl) — 1, 3, 2 — Dihydroborane # 1 — 2 — Benzene Amine H3C ch3 H3C · ^ ch3 V / 0

The mixture from Step C was diluted with toluene (1.70 mL) to a total volume of about 270 ml, and the flask was fitted with a Deam-Stark gate and a magnetic stirrer. Add brew (11. 6 g * 9 8. 2 mm 0 j?), And heat the mixture to reflux for about 1.2 5 hours. The water was drained from the Deam-Stark gate and printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, and the solution was used as in Example 3. (98% conversion, 93.6% HPLC area percentage). Reverse HPLC column: YMC-Ra ck 'ODS-A: '15 〇x6mm, S — 5mm, 120A, and monitored at 233 mm; solvent: A = 90% water, 10% methanol and 0.2% H3P04; B = 10% water, 90% methanol and 0.1% H3PO4; flow rate: 100mL per minute: concentration gradient: from 40% B to 100% B in 10 minutes, duration: 100% Β This paper again applies the Chinese National Standard (CNS) A4 specification (210X297 mm 1 — -46-4QS & B7 A7 ____B7_ V. Description of the invention (44) 5 minutes, gradually reduced to 40% B and maintained for 5 minutes The residence time of the title product of this example is 11. 5 minutes. Another method for preparing the title compound of this example: The surface acid (17. lg, 44 · 5mmoj2) obtained by another method of preparing the title compound of step C Dissolved in anhydrous toluene (425mL) and brewed solution (5.51g, 46.7mmoj?). Place the flask in an oil bath and heat it to 120 ° C for 2 hours (Note: the reaction will be in the first 40 minutes Complete) and use Deam-Stark gates (flasks and gates are covered with foil; the mixture is quickly boiled in about 0.5 hours and printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (read Read the back of the precautions to fill out this page)

Teng) and condenser continuously remove water. An aliquot (finished by finishing with 3,000 and 3 times azeotrope) was analyzed by Η P L C to show that the osmic acid starting material was completely converted into the title compound of this example. The reaction mixture was cooled to room temperature, and concentrated to obtain a toluene solution of the title compound of this example. The PLC area percentage was 86%. It can be estimated that the yield of conversion of osmic acid to the ester was 100%. A portion of the crude solution of the title compound of this example was used in 3 ". The residence time of the title compound of this example was 12.4 minutes (using the HP LC conditions for the osmic acid starting material as described above). Example 2: Preparation of halophenyl compound III (4-Iodine) oxazole The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) I-47-Wei §§97 V. Description of the invention ( 45) A7 B7

A. N — (2, 2 — Dimethanil) — 4 —Iodosexamide—

(Please read the notes on the back before filling this page) Add KHC〇3 (80. 0g, 0.80mj?) To the amine-based printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economy 0 ° C Iodine 笮 6 0. Add ice bath 1. Acetaldehyde dimethyl acetal (82.9 g, 86.0 mL, 7.9 mo $, commercially available) with water (900 mL) and acetone (0 mL), and then put the entire solution Let cool in an ice bath. A solution of 4-chloromethane (200. 0 g »0.775 moi?) In acetone (0 mL) was added dropwise to the aminoacetaldehyde dimethyl condensate through an addition funnel over 1.5 hours under mechanical stirring. The funnel and the wall of the flask in the aldehyde solution were washed with acetone (50 mL) and removed. The reaction mixture was allowed to stir at room temperature for 3 hours (the reaction was complete within 5 hours). The reaction mixture was concentrated in a rotary evaporator to remove 1.0 L of solvent. The paper size is applicable to the Chinese National Standard (CNS) A4 (2ΐ〇χ297mm) -48-A7 B7 ^ 08597 V. Description of the invention (46), and then EtOAc (4x350 mL) extraction. After the organic layer was concentrated, washed with saturated NaHC03 (lx250ml), and then washed with water (lx250ml), and then dried over anhydrous MgS04 ((Please read the precautions on the back before filling in this page) 50. 〇g) after drying and filtering Pressure concentration gave a white solid (during the evaporation of the solvent, this solid occasionally fell from the flask wall) "The solid was dried under vacuum for 12 hours (246. 5g, 98%, HPLC area percentage = 99.7%). Melting point (mp) = 89 — 90 ° C '

Elemental analysis (%) CnHwNOsI Calculated value: C39. 42; H4. 21; N4. 18 Measured value: C39. 42; H4. 22; N4. 07 B. 2 (4 —Iodobenzene) The central standard of oxazole Bureau's Consumer Cooperative printed P5 (2 0 g) at a temperature of 95 ° C under argon and vigorous mechanical agitation, and each time about 50 g was added with methanesulfonic acid (2 0 0 0 m L). Adding P205 several times prevents it from forming a hard lump on the bottom of the flask. The result was a clear, light brown solution. See Eaton et al., J. Org. Chem, 38, 4071-4073 (1973). A 31 ^ three-necked round-bottom flask containing the £ &1; 〇11 reagent (200〇1] 11 ^) was fitted with a condenser and the title compound of Step A (20.0 g, 0.6 Omoj ?) Join. The reaction mixture was heated in an oil bath under normal argon (heating the reaction mixture to the desired temperature is better than placing the mixture in a preheated oil bath). After TLC monitoring, the paper size is in accordance with China National Standard (CNS) A4 (210 X W7 mm) -49-A7 B7

5. Description of the invention (47) The results show that the first step of the reaction is that the dimethyl acetal group is hydrolyzed to the corresponding aldehyde (R f = 0.1 1): I Ο

Next, for the cyclization reaction, the temperature of the oil bath was adjusted to maintain the internal temperature of the reaction mixture between 130 and 134 ° C (the temperature of the oil bath was maintained between 138 and 141 ° C). After 7 · 5 hours, take a portion (using water and E t OA c extraction for finishing and finishing). Analysis by TL C showed that the starting material completely disappeared and a single spot was formed on the thin layer ---- a new spot ---- ----- Φ ------ '1T ------ ©-(Please read the note on the back of the book first and then fill out this page) Printed in argon by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs The reaction mixture was cooled to 30 ° C, and then equal three equal portions were vigorously stirred with a mechanical stirrer and the outer portions were poured into an ice / water slurry (approximately 6.0 L) in a brown-grey precipitate. The suspension was stirred for 2 hours, and then the sintered glass funnel was filtered with a porosity to suction the filtered body, washed with ice water (1 L), and the filter cake was broken. The solid was obtained for 5 days to obtain a gray powder (151.7 g, 93% of the substance (151.7 g) was dissolved in acetonitrile (2L) and warmed gently; a small amount of black hairy solids were left in the flask, and then divided into about a portion and cooled. As a result, solids are collected and air-dried through a medium). This coarse (dissolved with a heat gun) is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) -50-A7 B7 fine 59 * at the scale of Timing Paper. V. Description of the invention (48) plus activated charcoal (15 2g) After stirring the mixture at room temperature for 1 hour, the mixture was filtered through a piece of diatomaceous earth (100. 0g). After the diatomaceous earth tablets were washed with acetonitrile (2 × 100 mL), the filtrate was reduced. Concentrate to approximately 1 18 OmL (in a 5 L round bottom flask). The flask was heated with a heat gun until the solids were completely dissolved. Then, boiling water (295 mL) was added to the hot solution in two portions, and the flask was heated to near boiling and swirled gently after each addition. Reheat the solution to near boiling, cover the flask, and let it stand at room temperature for 48 hours (some crystals are found within 1.5 hours), then store at 4 ° C for 4 days to evacuate The crystals were collected by filtration, and then washed with an ice-cold solution of acetonitrile: water (4: 1, 150 mL), and then air-dried for 20 hours to obtain the title compound of this example as extremely pale yellow crystals. The crystals were further processed under vacuum. Dry (107.2 g, 66%, HPCL area percentage = 99.7%). The yellow solid obtained by concentrating the mother liquor was recrystallized to collect a second batch of crystals of the title compound (27.4 g, 17%, HPLC area percentage = 98.4%). 10 7-109

Elemental analysis COHeNO I Calculated value: C, 39.88; H2, 2.23; N > 5.17 Found: C, 40. 00; H, 2. 09; N, 5.14 Example 3: Preparation of Compounds of Formula T 豕 Paper Scale Shicai Guanjia County (CNS) A4 · (21QX297 Gonglu) (Read the precautions on the back before filling in this page)

P Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs --- --I-. 1-----I----I:-I--n, IT---I-- ---I-I n _ _ I-_ _ _ In --- -51-A7 B7 402597 V. Description of the invention (49) N— (3, 4 one dimethyl one 5_ isoxazole one) 4 (Waumou) [1,1 > __ Biphenyl 1-2-fluoramine-(2-coupling of acetamyl ester and halophenyl compound III

(Please read the notes on the back before filling out this page) 2-Jiyi [Printed by A. N-f (2-Methylhydroethoxy) A-M] at the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs] —N — (3 , 4-Dimethyl-5 -isoxazole)-4-oxazole-biphenyl]-2-amine M

A 2 L dry three-necked round-bottomed flask equipped with a top mechanical stirrer, gas connection, thermocouple, reflux condenser, and septum was charged with palladium acetate (Thai paper size applies to Chinese National Standard (CNS) A4 specification (210 × 297). (Mm) -52-A7 B7 V. Description of the invention (50)

Pd (OAc) 2'0.54 g * 2.38 mmoj?) And triphenylphosphine (Ph3P '1.6 g, 6, 44 mmoj?) Were degassed and placed in an argon atmosphere. THF (85 mL) was added and the mixture was heated at 65 ° C for 70 minutes. The solution will gradually change from rusty orange to bright yellow. Next, the title compound of Example 2 (25.9 g '95 .6 mm 〇5) and the crude title compound of Example 1 obtained above (see step D of Example 1, 44.45 g * 95.4 mm) ) Toluene (2 7 OmL) solution (degassed) was added via a syringe, and then degassed 9 5% ethanol (E t OH, 285mL) and 2.0 M Na2C03 solution (306mL '612mm〇i) . Let the resulting red solution be heated at about 75 ° C (internal temperature) for 1.5 hours and then remove the heating bath to allow the mixture to cool. Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this Page) to ambient temperature. Separate the layers with a separatory funnel, add; (2 5 Om L), and then wash the aqueous layer with CH2Cj? 2 (6x400mL). The organic layers were combined, dried over Mg S 04, treated with neutral charcoal (Nor it, 5.0 g), filtered through diatomaceous earth, concentrated, and placed under dynamic high vacuum for one night to obtain a red oil. The title compound of this step (62.4 g, 140%) (HPLC area percentage> 85%) 〇 Another method for preparing the title compound of this step: Preparation catalyst: ^ P d (OA c) 2 and triphenyl Base phosphine is added to a paper with a top end. The paper size is applicable to Chinese National Standard (CNS) A4 (2 丨 0X297 mm) -53-Printed by the Consumers Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs A7 B7 V. Invention Description In a 2 L three-necked flask with a mechanical stirrer, reflux condenser and argon inlet, this flask was slowly replaced with argon for 18 hours. Anhydrous, degassed THF (67 mL) was added via a syringe, and the flask was immersed in a Only preheat to 75 ° C oil bath and stir. After 20 minutes, the internal temperature reached 60 ° C, and the mixture was stirred for 1 hour. At this time, the color was wine-colored, and then cooled to room temperature under Slight head pressure argon. See]. 0 ^ .0116111., 1994, 59, 8151; 〇13-η 〇 m e 1; a 11 i c s, 1992, 11, 3 0.09. Coupling reaction: The title compound of Example 2 (10.0 g) was added to a portion of the toluene solution of acetic acid gallate prepared in another method of preparing the title compound of Step D in Example 1 (110 mL, 38. 74 mm of the acetic acid ester, 87% of the total volume of the crude acetic acid ester solution). After the reaction was spun, absolute ethanol (55 mL) was added, the flask was sealed with a septum, and spun again until a solution was produced. The solution was degassed by argon bubbling from the solution at a moderate rate for 1 hour, and then the solution was sent to the reaction tank containing the cooling catalyst solution through a cannula under normal argon. The flask was washed with anhydrous degassed ethanol (55 mL) and transferred to the reaction tank via a cannula under normal argon. Add degassed 2M Na2C03 solution (118mL) through the cannula, start stirring, and immerse the flask in an oil bath preheated at 78 ° C, and then bring the internal temperature to 6 9-70 ° (: .1 75 hours later, the results of HPLC and TLC analysis showed that the reaction was complete. After 2 hours of reaction, the mixture was cooled to 27 ° C. However, the paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) ----- ------------ ^ 4 ------ Order ------ ^ ----------------- f Please read the back first Note for refilling this page} -54-ύϋ ^ 597 Α7 -_____ Β7 _._; _ 5. Description of the invention (52). Then add water (100mL) and EtOAc (100 ml) under stirring. Then transfer the reaction Separate the layers into a separating funnel. The aqueous layer is extracted with EtOAc (3x100mL, 1x50 mL). After the organic phases are combined, the organic phase is washed with half brine (1 x60mL), and then stirred with anhydrous MgSO4 (40g). The solution was filtered, and the flask and the filter funnel were washed with EtOAc (2x100 mL). As a result, a crude coupling solution having a total volume of 78.5 mL was obtained. HPLC analysis showed that the crude HPLC area percentage was 88.9%. This solution Divided into several parts for purification evaluation, for example, printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (read the precautions on the back and then fill out this page) Take out 5 vol% of the crude coupling solution (ie, 39 m L), and Concentrate in a rotary evaporator. Dissolve the concentrated residue in toluene (12 mL), add C (0.9%, 100% by weight), and stir the mixture at 88 ° (: oil bath for 30 minutes, add three Polythiocyanate (TMT, 407 mg, 2.3 mmo, and the estimated Pd content was 50 mol equivalent), the mixture was stirred in an oil bath for 30 minutes, cooled in an ice bath, and filtered through celite The diatomite flakes were washed with toluene (2xl OmL), and then the filtrate was washed with 1N NaOH (2xlOmL). The phase separation process took about 3 minutes. The toluene layer was dried over Mg S 04, filtered and concentrated to obtain the The crude title compound of the step, 0-76 g, 87% mass balance. The palladium content was measured as < 1 ppm. Further experiments showed that 25 equivalents of TMT was sufficient to reduce P d to < 10 P p. M. 10% by volume (78 mL) of the crude coupling solution together with 50% by weight (: stir to about 60 ° C , And then let it cool for 30 minutes. The paper size applies the Chinese National Standard (CNS) A4 specification (210x297 male dragon) _ _ _ 4〇 ^ 597 A7 ______B7_ 5. Description of the invention (53) Filtered by diatomaceous earth after the clock, E t OA c rinse, repeat this step with fresh charcoal, and concentrate the solution to obtain 2. 29g (131% mass balance). This concentrated residue was azeotroped twice with anhydrous diethyl ether, and the residue was dissolved in ether (1 mL), and the solution was cooled to, and seed crystals of the title compound were added and stirred. As a result, a solid precipitated from the solution. After 1 hour, hexane (5 mL) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours. The mixture was collected and washed with an ice-cold ether: hexane 2: 1 solution to obtain the title compound (1. 07g, calculated from the title compound of Step i in Example i as 58%), a slight yellow powder, HPLC area percentage = 95.8% (in process) Η PLC conditions: column_YMC ODS-A, 6x250mm at 2 3 Monitor the flow rate at 3mm—1.5 mL / m.in Solvent A (%): H20 / Me0H / H3P04 9 0: 10: 0. 2 Solvent B (%): H20 / MeOH / H3P〇4 10: 90: 0. 2 Concentration gradient: 40% B to 100% B; linear gradient is 10 minutes, 100% B is 5 minutes, and 40% B is 4 minutes. The residence time of the title compound in this step was 12.8 min. The second other preparation method of the title compound in this step, reverse coupling method: Under argon, the title compound of Example 2 (10 g, 37.3 mmo 芡), anhydrous THF (250 mL), toluene (50 paper size) Applicable to China National Standard (CNS) A4 specification (210x297 mm) " '-56-(Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ 0 ^ 597 A7 ____B7__ 5. Description of the invention (54 mL) and triisopropyl borate (B (0iPr) 3, 50mL) Add an oven-dried 5 0 0 L round bottom flask. The resulting colorless solution was cooled to -7 5 ° C, and then n-butyllithium (36 mL, 1.45 M in hexane at a concentration of 1.43 mm, β) was added dropwise over 1 hour. During the addition, keep the internal temperature below -7 ° C. The reaction was stopped by adding a solution of acetic acid (4 ml :) in THF (25 mL) and concentrated in a rotary evaporator. Subsequently, toluene (100 mL) and methanol (100 mL) were added, and the solvent was removed at 40 ° C in a rotary evaporator. This step was repeated once more. The resulting residue was dissolved in NaOH (100 mL, 100 mmo) 2, IN), and extracted twice with hexanes (25 mL) and TBME (25 mL) to obtain the following compound: Ο1

B (ONa) 2 The aqueous layer was added to a mixture of NaHC03 (8.4 g, 100 mmoj ^) and EtOH (100 mL), and the title compound of Step B of Example 1 (14.4 g * 3 4 .4) was added. mmo $) in toluene (100 mL) was added to the resulting mixture. The resulting mixture was aerated and M gas was bubbled in the mixture for 15 minutes. While finishing the above reaction, in a 50mL round bottom flask, the paper size of this paper applies the Chinese National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling this page) ---- --Order ------ Annual Excitation -------------- A7 B7 Cut 2597 V. Description of the invention (55) Triphenylphosphine (676. 8mg, 2. 58mmo芡) (Please read the notes on the back before filling this page) and THF (30mL), and let argon bubble in it for 15 minutes. Next, Pd (OAc) 2 (193.4 mg, 0.86 mmoj) was added, and the mixture was heated to 65 ° C under argon. The mixture was cooled to room temperature and then added to the above ethanol / toluene / water mixture. The heterogeneous mixture was heated to 75 ° C for 6 hours. HP LC analysis showed that all starting materials had been completely consumed. The reaction mixture was allowed to cool to room temperature, and then concentrated in a rotary evaporator. Then, ethyl acetate (250 mL) and charcoal (10 g) were added, and the mixture was stirred at room temperature for 30 minutes, and then filtered through celite. The diatomaceous earth tablets were washed with ethyl acetate (25 mL x 4), and the filtrate was transferred to a 500 mL separatory funnel and washed with water (100 mL x 2) and brine (100 mL x 2). The organic layers were combined and washed with NaOH (200mLx2), TMBE (300mL) was added to minimize emulsification, water (200mL) and brine (20mL) were dried over Na2S04, filtered and concentrated to 17.5g (98% mass balance ). Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. Dissolve the crude product in ethanol (17.5 mL), take half of the solution (about 8.8 mL) and place it in a 0 ° C freezer for 2 days. There will be crystallization and solids will be filtered and pumped. It was air-dried and the obtained product was a yellow solid (6 g, calculated from the title compound of Example 2: the overall yield was 6 7%, HPLC area percentage = 99.1%). Η PLC conditions: m column—YMC ODS-A, 6X250 This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) -58-A7 --------- B7 V. Description of the invention (56) Monitor the flow rate at 1 to 5 mL / min at 233 mm Solvent A (%): H20 / MeOH / H3P〇4 (Please read the precautions on the back before filling this page) 9 0: 10: 0.2 Solvent B ( %): H2O / MeOH / H3P〇4 10: 90: 0.2 Concentration gradient: 40% B to 00% B; Linear gradient 1 () minutes' 100% B is 5 minutes, 40% B is 4 minutes. This step The residence time of the title compound is 12 8 minutes. B Tolerance 3 '4 Dimethyl 1 5 Lixazole a)-4 a:-(2-a violent one) [1, 1 /-biphenyl Base] one? · Add a bright yellow solution containing the crude title of step A. Compound (6.2.45 g) and 9 5% ethanol (62 OmL) printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs in one click. In a 3 L three-necked round-bottom flask with a top mechanical stirrer, thermocouple and reflux condenser, while stirring, quickly add 6N HCj? (620mL) and heat the mixture to reflux at 8 7 ° C, resulting in light orange The solution. The reaction mixture was cooled to room temperature, and then cooled to 0-4 ° C with an ice bath, and then basified with 5N NaOH (about 850 mL) to a pH of about 13. This sodium hydroxide solution was added slowly over 10 minutes without increasing the temperature above 30 ° C. The mixture was recooled to 0 ° C, water was added, and the precipitate was filtered and washed with water (200 mL). The filtrate is concentrated in a rotary evaporator under vacuum at about 40 ° C to remove most of the ethanol. During the concentration, the paper size will be in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) ~~ 402597 A7 A7 B7 5 Description of the invention (57) The sodium salt of the title compound of this example precipitated out. The suspension was cooled to about 10 ° C, filtered, and washed with brine (2 x 150 mL). The solid portion was air-dried for 15 minutes and transferred to a 2 L flask and dissolved in 1 L of hot water. This solution was washed with water (150 mL) after fine filtration, and then transferred to a 2 L separatory funnel. 0 The aqueous layer was washed with 1: 1 ethyl acetate: hexane (2X1L) and hexane (50 OmL), and the yellow aqueous layer was cooled to about 7 ° C while vigorously stirring, slowly from about 9.0 PH to pH 2.6 to precipitate the title compound of this example. After stirring for about 10 minutes, the slurry was filtered and washed with excess water to remove residual acid, and air dried to obtain 3 1 _ 5 g (84%) product as an offwhite solid. 5.0 g of the above solid was dissolved in ethyl acetate (25 mL), and treated with trimeric thiocyanate (TMT, 0.23 g). This TMT is a chelating agent. The addition of TMT consists in removing residual palladium from the product. Allow the mixture to boil gently and place in an oil bath at about 65. (： Heating at a temperature of 15 minutes. Add Norit charcoal (5.1g) to the mixture and print it by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling in this page) and continue to heat for 3 0 minutes, then the mixture was cooled in an ice bath, filtered through a celite bed and washed with ethyl acetate (25 mL). The furnace liquid was transferred to a separatory funnel, and HCj (iX75mIj) with 1_0N and After washing with water (1 x 7 5 mL), the HCj? Washing solution removes residual TMT. The organic layer is then treated with Nor it charcoal (0.5 g), heated to a gentle boiling, and filtered through a bed of diatomaceous earth. The filtrate is concentrated , Dissolve the residue in absolute ethanol (20mL), add water after boiling (this paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) w ~ 597 A7 _B7_ V. Description of the invention (58) 1 〇m L) β is seeded into the solution, allowed to cool with stirring and crystallize within 16 hours. The resulting crystals are filtered, washed with ethanol: water (1: 1, 10 mL), and dried under vacuum to give 4 Og The pure title compound of this example (combined with the title of Step A) The total yield is 66%, HPLC area percentage = 99. 02%). M.p = 14.5.1 ° C (high melting point polymorph) Example 4: Preparation of compound of formula I (please Read the precautions on the back before filling out this page} N — (3, 4 —Dimethyl-5 —isoamyl) ~ 4 ~ (2 —

This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 402597 A7 B7 Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 5. Description of the invention (59)

A 100 mL dry three-necked round-bottomed flask equipped with a magnetic stirrer, a gas connection, a thermocouple, and a septum was charged with the title compound (5.0 g * 1 1.9 m mo $) from Step 1 of Example 1. , Then thoroughly degas and place in an argon atmosphere. Add THT (23mL) via syringe, then cool the mixture to -10 ° C (internal temperature) and stir vigorously. While vigorously stirring the mixture, η — B u L i (5.30 m L »12. 6 mmoj?) Was added dropwise over 19 minutes while maintaining the internal temperature at a temperature of 195 ° C to -1 〇0 ° C. The light yellow-orange solution was stirred at a temperature of about -100 ° C for another 12 minutes. Trimethyl borate (2.0 mL, 17.6 mm) dissolved in THF (3.0 mL) was added dropwise over 12.0 minutes while maintaining the internal temperature at -9 ° C to _ Between 0 0 ° C. Allow the mixture to stir at about -95 ° C to -100 ° C for about 50 minutes, and then stir at a temperature of about -.78 ° C to -72 ° C for another 40 minutes. The borate was hydrolyzed by adding 1. ONiHC 芡 (2.0 mL, 2. Ommoj?) At about -7 ° C, the solution was returned to room temperature, and stirred for about 60 minutes. Add Na2C03 solution (55mL, 2.0M, 1 10mm ο β), thoroughly degas the mixture and put it in argon. This paper applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) (please read the back first) Please pay attention to this page before filling out this page) ------------ $ ------ 1Τ ---- 62 Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs ^ 02597 A7 B7 V. Invention Explanation (6〇) environment. Then use this substance as follows. (Purity 95.9

%, HPLC), YMC ODS-A column, 150 mm x 60 mm, S — 3 #m, 12 0A; flow rate 1 — OmL

/ 〇1 丨 1 !, the solvent system contains A (40%) (A: = 9 MeOH / l 0% H2〇 / 0.1.3P〇4) and B (60%) (B = 9 0% H2〇 / 10% MeOH / 〇2% H3P〇4, the solvent composition is 10% A at 15 minutes, and the solvent composition is A (4 0 at 15 minutes to 20 minutes) %) And B (60%). The retention time R t of the title compound in this step was 7.5 minutes. The detector was operated at 233 mm. B · N — [2 —methylethoxy) methyl Group] —N — (3,4 —dimethyl-5 —isoxazolyl) — 4 > —one oxazole 2 —yl — f 1, 1 / —biphenyl] 2-sulfonamido

Pd (0 A c) 2 (0.16g, 0.71mmoj?) And this paper size are applicable to the Chinese National Standard (CNS) A4 specification (210X297) Li) _ _ (Please read the notes on the back before filling out this page) 0 衣 -------- ΪΤ ----- Je --------------- ^ 597 A7 ___B7_ 5. Description of the invention (61) P h 3 P (0. 5g, l_ 9 3 mmoi?), Degassed and placed under argon. Add HTF (3 OmL), and heat the mixture at about 651 for about 70 minutes. The frequency will gradually turn rusty orange to yellow. A degassed solution containing the title compound of Example 2, methyl (85 mL) and EtOΗ (64 ml) was added via a syringe and then a degassed solution of the title compound of Step A was added. This red solution was heated at about 75 ° C (internal temperature) for 1.5 hours, then the heating bath was removed and the mixture was allowed to cool to ambient temperature. Separate the layers with a separatory funnel, then add water (50 m L) to the aqueous layer, and then extract the aqueous layer with E t 〇 A c (3 'X 2 0 m L). The organic layers were combined, washed with brine (1 X 7 5 ml), dried over Mg S 0 4 and treated with 5.0 g of Norit neutral charcoal. They were filtered through celite, concentrated, and placed in the air (about 0.1 mm H g) next night to give the title compound (6.17 g, 111%) as a red oil (purity> 80%, Η PLC). C Ν — (3,4 dimethyl-5 — oxoxazole) — 4 — _ (2 — dim beer) [1,1 > —biphenyl 1 _2 —Central Standard of the Ministry of Economic Affairs Printed by the Bureau's Consumer Cooperative (please read the precautions on the back before filling out this page). Add a crude product of Step B to a 2.5 OmL dry round bottom flask equipped with a reflux condenser and magnetic stirrer (6. 17g, theoretically 5.56g, ll. 9mmoiM, 95% OEtOH (60mL) and 6. ON HCi? (60mL), and heated under reflux for 2 hours. Then the mixture was cooled to about 5 ° C, and N a Ο Η Aqueous solution to a pH of about 13 (temperature rises below about 25 ° C), refined, and water (50 m L). Concentrate this solution at 40 ° C to remove large paper sizes. Applicable to Chinese national standards ( CNS) A4 specification (210X297 mm) -64-402597 A7 B7 5. Description of the invention (62) part of EtOH (about 5 5-60 mL), forming a white solid. Cool the mixture to 0 ° C for 20 minutes After filtering, the white solid produced was washed with brine (2 X 50 ml), and then emptied (about 0.1 mmHg) and dried for 12 hours. The white solid was dissolved in hot water (80 m L), fine filtration. Place the aqueous solution in a separatory funnel, and wash it with 1/1 E t OAc / hexane (2 × 5 OmL) and hexanes (75 mL). Let The solution was cooled to 0 ° C, stirred vigorously, and slowly added 1. ON of HC $ until pH = 1.0, and then the mixture was maintained at 0 ° C for 1 5 minutes. Filtered and water (3X5 OmL). Washed An off-white solid was obtained, and the solid was evacuated and dried for 3 hours. Then, the white solid was dissolved in Et OAc (6.5 mL), and trimeric thiocyanic acid (0.20 g, 1.13 mmo 芡) was added to make the mixture. Stir at 65 ° C for 30 minutes. Add charcoal (Norit neutral, 5.0 g), and print it at the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs (please read the precautions on the back before filling this page) 6 5 ° C was stirred for another 30 minutes. The mixture was cooled to 0 ° C, filtered through a celite pad, washed with E t 0 A c (3 X 50 m L), and concentrated to a volume of about 60 mL. ON N a 〇 Η (3 X 5 OmL) After washing, add NaC ^ (3. 0 g »6 3 7 mm ο ^) and brine (50 m L) into the aqueous layer, and cool the aqueous mixture to 0. ° C, filtered, and brine (2 X 50 m L). Dissolve the resulting white solid in hot water (20 OmL), cool to 0 ° C, stir vigorously, and then slowly add 1 · ON HC ρ until p Η = 1.0, keeping the mixture at 0 ° C 15 minutes. After filtering and washing with water (3 × 5 OmL), a nearly white solid was obtained. The solid was dried at 45 ° C for about 16 hours under empty air (0.1 mm H g) to obtain 2.4. This paper is in accordance with Chinese national standards. (CNS) A4 specification (210X297 mm) A7 B7 5. Description of the invention (63) g (50% yield) is a nearly white solid. This solid (2.55 g) was dissolved in 95% EtOH / water (9.0 ml / 5.0 ml) at 70 ° C, and then slowly cooled to ambient temperature (1.5 hours), Cool to 5 ° C for another night to obtain white crystalline material. After filtering and washing with cold 9 5% EtOH / water (3.0 mL / 5. 0 m L), empty (about 0.1 mm H g ) Drying for 48 hours to obtain 2. lg of the title compound of this example as a white solid (total yield of 46.9% based on the title compound of Step B). TLC (2/1 hexane / Et OAc, KMn 〇4 staining) showed that the reaction was complete after 2 hours. m. p = 14 3 · 0 7 ° C 〇 (Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperative, this paper is printed in accordance with Chinese National Standard (CNS) Α4 specifications (210 × 297 Mm)

Claims (1)

Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 402597 6. Application for Patent Scope Ten Yuan No. 1 86100922 Patent Application Chinese Application for Patent Scope Amendment Dec. 87, Republic of China Amendment 1. A compound for the preparation of formula I a And its mirror isomer, non-mirro isomer and salt method, the structure of the formula 1 a is as follows: Wherein R 1 and R 2 are directly bonded to the carbon of the ring, and are all hydrogen: X is 0; Y is N; R3 and R4 are each hydrogen or Chβ alkyl; R11, R12, R13, and R14 are all Is hydrogen; J is 0; K is N; L is C; P is 0. This method includes the following steps: (a) order the ester of formula II a in the presence of a palladium (0) catalyst and the selective use of rhenium The paper size of this paper or its salt is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) (Please read the notes on the back before filling in this page) Printed by the Consumer Standards Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs 402597 6. Application for Patent Scope Ten Yuan No. 1 86100922 Patent Application Chinese Application for Patent Scope Amendment Dec. 87, Republic of China Amendment 1. A compound for the preparation of formula I a And its mirror isomer, non-mirro isomer and salt method, the structure of the formula 1 a is as follows: Wherein R 1 and R 2 are directly bonded to the carbon of the ring, and are all hydrogen: X is 0; Y is N; R3 and R4 are each hydrogen or Chβ alkyl; R11, R12, R13, and R14 are all Is hydrogen; J is 0; K is N; L is C; P is 0. This method includes the following steps: (a) order the ester of formula II a in the presence of a palladium (0) catalyst and the selective use of rhenium The paper size of this paper or its salt is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) (Please read the notes on the back before filling in this page) Patent application scope H3c ch3 H3CJ-L-ch3 0, A8 B8 C8 D8 (工 工 a) B 'r \ (Where pro t is a gas-protecting group), in contact with a phenyl compound of formula III 3 or a salt thereof (CH2) P R2… J, I (Ilia) R '11. V r12 halo Printed by a cooperative (where halo is halogen) to form a nitrogen-protected compound of formula IV a or its salt (please read the precautions on the back before filling this page) This paper size applies to Chinese National Standard (CNS ') A4 specification (210X297 mm) A8 B8 C8 D8 々, patent application scope (Please read the notes on the back before filling this page) (b) Deprotect the nitrogen atom of the compound of formula I V a or its salt to form the compound of formula I a or its salt. 2. The method according to item 1 of the patent application, wherein the palladium (〇) catalyst is a palladium (I I) salt and triphenylphosphine. 3. The method according to item 2 of the patent application, wherein the palladium (I I) salt is palladium acetate. 4. The method of claim 1 in which the base is potassium carbonate or sodium carbonate aqueous solution. 5. The method of claim 1 in the scope of patent application, wherein the "prot" is methoxyethoxymethyl or 2-ethoxyethyl. 6. The method according to item 丄 of the scope of patent application, wherein the halogen group of the compound of the formula I! A or its salt is bromine, chlorine or iodine. 7 The method according to item 1 of the patent application, wherein the compound of formula I a or a salt thereof is crystallized from the solution after step (10). 8. The method according to item 1 of the patent application, wherein in step (a) Paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ST T After printing by employees of the Central Standards Bureau of the Ministry of Economic Affairs, the consumer cooperatives will be printed by employees of the Central Standards Bureau of the Ministry of Economic Affairs «Printed by cooperatives ^ 02597 | D8 VI. Patent Application Scope) Removal of residual palladium using a chelating agent. 9_ The method of item 1 in the scope of patent application, wherein the compound of formula Ia or a salt thereof is N — [(2-methoxyethoxy) methyl] _N— (3 , 4-dimethyl-1,5-isomethyl, 2- (4,4,5,5-tetramethyl-1, 3,2-dioxaborocyclopentane (di〇xa_borolan)- 2-yl) benzene mineral amine, the formula III a. The compound or its salt is 2- (4-iodophenyl) oxazole 'The compound of the formula I a or its salt is N- (3,4-dimethyl One 5 —isoamyl] _4 one (2-amyl) [1,1.biphenyl] -2_ basic amine. 10.—A compound such as Formula II or a salt thereof Prot represents a nitrogen protecting group, X is 0, Y is N; R 3 and R 4 are directly bonded to the carbon of the ring, and each is hydrogen or a C 1 -β radical. 1 1. The compound of item 10 in the scope of patent application is N — [(2-methoxyethoxy) methyl] —N— (3,4—dimethyl-5—isoxazolyl) One 2— (4,4,5,5—tetramethyl-1, this paper size applies to China National Standard (CNS) A4 specifications (210X297 mm) _ 4 ------------- -------- II ------ 0 -------------------- (Please read the notes on the back before filling this page) 7 9 5 iv J ¾ Printed by ABCD, Consumer Cooperatives, Central Standards Bureau, Ministry of Economic Affairs Six, the scope of the patent application 3, 2-dioxane cyclopentane-2 -yl) benzylsulfonamide ° 12.-a method for the preparation of hydrazone esters of the formula I or its salts "Prot" represents a gas-protecting group, X. 0; Y is N; * R 3 and R 4 are each hydrogen or C i_β radical; this method includes the following steps: (a) in the presence of an organic base and an organic solvent In the case of a compound of formula V or a salt thereof in contact with an amine of formula VI or a salt thereof to form a compound of formula VI I or a salt thereof, the structure of formula V, VI, VII is as follows: 0 leaving group (▽) where leaving group stands for leaving group; this paper size applies Chinese National Standard (CNS) A4 specification (210X297) 嫠 (Please read the precautions on the back before filling this page) 402597 A8 B8 C8 D8 Patent Application Scope (VI) (VII) where halo represents halogen; (b) protecting the nitrogen atom of the compound of formula VI or its salt to form a compound of formula VIII or its salt: (VIII) (Please read the precautions on the back before filling out this 1K) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs (C) The compound of formula VI with an alkyl lithium or aryl lithium compound And then contacting the lithiated product with trialkyl borate, followed by hydrolysis to form a sulfonic acid of formula IX or a salt thereof: r \ P R3 R4 Y (IX) This paper size adopts Chinese National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 __D8 ", the scope of patent application (d) makes the compound of formula IX or its salts contact The water is removed to form the compound of formula II or a salt thereof. The method according to item 12 of the scope of patent application is used to prepare a formula ester or a salt thereof of formula II, including the following steps: (a) in organic In the presence of a base and an organic solvent, a compound of formula V a or a salt thereof is contacted with an amine of formula VI a or a salt thereof to form a compound of formula VI I a or a salt thereof, formula Va, VI a, VI I a The structure is as follows: 0 ^ .-- (Please read the notes on the back before filling this page) 〇 leaving group where the leaving group is the leaving group, halo is the tooth element, and R 13 and R are each hydrogen; printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (Via) (Vila) Order ----------------- ^ ------- b) The nitrogen atom of the compound of formula V or its salt is guaranteed. Paper size is applicable to Chinese National Standard (CNS) A4 Specifications (21 × 297 mm) 402597 A8 B8 C8 D8 6. Apply for patent protection and form compounds such as formula vl II a or salts thereof .0 r ^ Y prot J \ R3 R4 (Villa) (c) Lithinate a compound of formula v III a or a salt thereof with an alkyl lithium or aryl lithium compound, and then contact the lithiated product with trialkyl borate , Followed by hydrolysis to form a hydrazone acid of formula IX or a salt thereof: (IXa) and the seal of the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs (d) The compound of formula I X a or a salt thereof is contacted with water and removed to form the compound of formula II or a salt thereof. 1 4 · The method according to item 13 of the scope of patent application protj is methoxyethoxymethyl or 2-ethoxyethyl. 15 The method according to item 13 of the scope of patent application The halogen group of the compound or its salt is bromine, chlorine or iodine. 16. The method according to item 13 of the scope of patent application is a halo group. 17. The method according to item 16 of the scope of patent application, wherein the formula is V where the leaving paper size is in accordance with Chinese National Standard (CNS) Λ4 specification (210X297 mm) where the leaving (please read the back (Please fill in this page again) 8 A8 B8 C8 D8 4JS597 6. Scope of patent application The basis is gas. (Please read the precautions on the reverse side before filling out this page) 1 8. If the method of item 13 in the scope of patent application, the organic base in step (a) is an amine. 19. The method of claim 18, wherein the organic base is pyridine or trialkylamine. 2 0. The method according to item 13 of the patent application, wherein the organic solvent is a haloalkane, or the organic base is used as a solvent. 2 1. The method according to item 13 of the patent application, wherein the alkyl group is The lithium or aryl lithium compound is n-butyllithium or phenyllithium. 2 2. The method according to item 13 of the patent application, wherein the process of lithiation or contact with the trialkyl borate is at 40 ° C. To a temperature of 1050 ° C. 2. The method according to item 13 of the scope of patent application, wherein the trialkyl ester is triisopropyl borate or trimethyl borate. 24. The method according to item 13 of the patent application range, wherein the water removal process is performed by adding a desiccant, or by azeotropic removal of water by heating with a solvent. Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs 25. The method of item 13 in the scope of patent application, wherein the compound of formula II or its salt is N — [(2-methoxyethoxy) methyl] —N— ( 3,4 dimethyl- 5-isoxazolyl)-2_ (4,4,5,5-tetramethyl-1,3,2-dioxaborocyclopentane- 2-yl) benzenesulfonate Amido, the compound of formula Va or a salt thereof is 2-bromobenzenesulfonyl chloride, and the amine of formula VI a or a salt thereof is 5-amino-3,4-dimethylisoxazole. This paper size is applicable to Chinese National Standard (CNS) A4 specification (; 210X297 gong) A8 B8 C8 D8 402597 ^ Application for patent scope 2 6. — Preparation of compounds such as formula I a and its mirror isomers non-mirror isomers Methods of substances and salts: R1, (CH2) p (la) (Please read the notes on the back before filling this page) R1 and R2 are carbons directly bonded to the ring, and they are both hydrogen: X is 0; Y is N; R3 and R4 are each hydrogen or Ci_e alkyl R 1 1, R 12, R 13 and R 14 are all hydrogen; J is 0, K is N; L is C; P is 0, this method includes the following steps: (a) in the presence of palladium (0) catalyst In the case of selective use of alkali, the osmic acid of formula IX a or its salt (h〇) 2b 〇 (IXa) This paper size is free to use the Chinese National Standard (CNS) A4 specification (210X297 mm) Order --- Γ Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs -10-403597 A8 B8 C8 D8 • Application scope (where .prot is nitrogen protecting group), contact with halophenyl compound of formula I I I a or its salt (Ilia) (where halo is halogen), and a nitrogen-protected compound of the formula I V a or a salt thereof Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs .0 R3 R4 (IVa): and (b) deprotect the nitrogen atom of the compound of formula I v a or a salt thereof to form a compound of formula la or a salt thereof. 27. The method according to item 26 of the scope of patent application, wherein the compound of the formula iL or its salt is n— (3,4 1dimethyl-1 5 _isocyanate) The paper standard is applicable to Chinese National Standard (CNS) A4 Specifications (210X297mm) -11 (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs A8 B8 C8 __ D8___ ", azole group for patent application)-4 '-(2-oxazolyl) [1,1 z -biphenyl]-2-sulfonamide, the compound of formula IX a or its salt 2-dihydroxyboryl-N-(3,4-dimethyl-5-iso, oxazolyl) -N-[(2 -methoxyethoxy) methyl] benzenesulfonamide disodium salt And the compound of formula IIIa is 2- (4-iodophenyl) oxazole. 28. A method for preparing an oxazolephenyl halide such as formula IIa (l) or a salt thereof, (Illa ( l)) where ha 1〇 is halogen; R1, R2, R11, and R12 are all hydrogen; this method includes the following steps: (a) in the presence of a base and a solvent, let phenylphosphonium halide X or a salt thereof and The amine acetal of formula XI or its salt is contacted to form aldehyde 111 or amine of formula XII, wherein the structure of formula X, XI, XII is as follows: This paper size applies to Chinese National Standard (CNS) M specification (210X297) (%) (Please first read the notes on the back of the field to complete this k) 402597 A8 B8 C8 D8 Patent Application Scope O-alkyl Ο-alkyl (X) h2n (XI) (XI; where alkyl is the courtyard base: and --------- Q ------ tT ^ ----- (Please read the notes on the back before filling this page) Central Standard of the Ministry of Economic Affairs (B) Cyclization of formula XII amidoacetal or its salts to form an oxazole phenyl halide of formula III a (1) or its salts in the presence of a cyclizing agent 29. The method according to item 28 of the scope of patent application, wherein in formula X, the halogen group of the halogen moiety is chlorine, and the halogen group which is in para-position with the halogen moiety is chlorine, bromine or Iodine. 30. The method according to item 28 of the patent application 'wherein the acetal paper size is applicable to Chinese National Standard (CNS) A4 specifications (210X29 7 cm). Printed by the Ministry of Standards Consumer Cooperatives 40S597 A8 B8 C8 D8 ^ The alkyl group in the patent application part is methyl or ethyl. 3 1. The method according to item 28 of the patent application range, wherein the base used in step (a) is an alkali metal bicarbonate, Carbonate or argon oxide 03. The method according to item 28 of the patent application, wherein the cyclizing agent is Eat on reagent, P205 (in methanesulfonic acid) ) Or polyphosphoric acid · 3 3. The method according to item 28 of the scope of patent application, wherein the oxazole phenyl halide of formula III a (1) or its salt is 2- (4-iodophenyl) oxazole, The phenylphosphonium halide or a salt thereof of the formula X is 4-iodoxysulfonium chloride, and the amine acetal or a salt thereof of the formula XI is an aminoacetaldehyde dimethyl acetal. 3 4. I a or its salts, 0 (la) --------------- Order --_----- ~ Yang (please read the notes on the back before filling this page) where X is 〇; Y is N ; R1 and R 2 are each directly bonded to the ring carbon R 3 and R 4 are each directly bonded to the ring carbon and all are hydrogen; each is hydrogen or C, the paper standard of this college applies Chinese National Standard (CNS) A4 specification (210X297 mm) -14-402597 A8 B8 C8 D8 :, patent application scope base; P is 0; R11, R12, R13 and R14 are all hydrogen; J is 0; K is N; L is C; this The preparation method comprises: (a) in the presence of a trialkyl borate, a lithium compound of formula III a or a salt thereof is lithiated with an alkyl lithium or an aryl lithium compound, and then hydrolyzed to form a sulfonic acid of formula XI II or a salt thereof The structures of Formula III a and Formula II IX are as follows: (Ilia) (Please read the notes on the back before filling out this page) Printed by the Staff Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs (XIXX); where halo is halogen; this paper size adopts Chinese National Standard (CNS) A4 specification (210X25 »7 mm) 402597 A8 B8 C8 D8", the scope of patent application (b) is in the presence of palladium (0) catalyst And in the case of selective use, contacting a compound of formula XI II or a salt thereof with a compound of formula V " 11a or a salt thereof to form a nitrogen-protected compound or a salt of formula IVa, the formula VI II The structure of a and formula IVa are as follows: halo 广 .....) L ^ {R3 (Villa) (Please read the precautions on the back before filling out this page) “P rot” stands for nitrogen protection base; printed by the staff consumer cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 0 R3 V (IVa) /: and (c) deprotect the nitrogen atom of the compound of formula I V a or a salt thereof to form a compound of formula I a or a salt thereof. 35. The method of claim 34, wherein the compound of formula Ia or a salt thereof is N— (3,4-dimethyl_5_isoxazolyl) _4 / one (2-oxazole Based) [1,1-1 biphenyl] A paper size applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) 402597 I D8 々: 'Application for patent scope 2-sulfonamide, the compound of formula III a Is 2- (4-iodophenyl) oxazole, and the compound of formula VI II a or its salt is 2-bromo_N — (3,4-dimethyl-2 —isoxazolyl) —N — [(2-methoxyethoxy) methyl] sulfenamide. 36.—Species such as formula N— (3,4-Dimethyl-5—isoxazolyl) —4 > _ (2-oxazolyl) [1,1 > monobiphenyl] -2—sulfofluorene 1 ° C。 The hydrazone melting point polymorph of an amine compound has a melting point of 143.07 to 145.1 ° C. (Read the precautions on the back before filling in this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs This paper is scaled to the Chinese National Standard (CNS) A4 (210X297 mm) _ 17