TW472041B - Process for preparing 4-substituted-1H-indole-3-glyoxamides - Google Patents

Abstract

A process for preparing 1H-indole-3-glyoxamides useful for inhibiting SPLA2 and novel intermediates useful in the preparation of such compounds. A process for preparing a compound of the formula I or a pharmaceutically acceptable salt or prodrug derivative thereof wherein: R1 is selected from the group consisting of C7-C20 alkyl; where; R10 is selected from the group consisting of halo, C1-C10 alkyl, C1-C10 alkoxy, -S-(C1-C10 alkyl) and halo(C1-C10)alkyl, and t is an integer from 0 to 5 both inclusive; R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O-(C1-C2 alkyl), -S-(C1-C2 alkyl), aryl, aryloxy, and HET; R4 is selected from the group consisting of -CO2H, -SO3H, and -P(O)(OH)2 or salt or prodrug derivatives thereof; and R5 is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkoxy, halo(C2-C6)alkyl, bromo, chloro, fluoro, iodo and aryl; which process comprises the steps of (a) halogenating a compound of formula X, where R8 is (C1-C6)alkyl, aryl or HET; with SO2Cl2 to form a compound of formula IX, (b) hydrolyzing and decarboxylating a compound of formula IX, to form a compound of formula VIII, (c) alkylating a compound of formula VII, with a compound of formula VIII, to form a compound of formula VI, (d) aminating and dehydrating a compound of formula VI, with an amine of the formula R1NH2 in the presence of a solvent that forms an azeotrope with water to form a compound of formula V, (e) oxidizing a compound of formula V, by heating with a base and a compound of the formula RSOX where R is -(C1-C6)alkyl, or aryl or substituted aryl and X is -(C1-C6)alkoxy, halo or -OCO2(C1-C6)alkyl to form a compound of formula IV, (f) alkylating a compound of the formula IV, with an alkylating agent of the formula XCH2R4a where X is a leaving group and R4a is -CO2R4b, -SO3R4b, -P(O)(OR4b)2, or -P(O)(OR4b)H, where R4b is an acid protecting group, to form a compound of formula III, (g) reacting a compound of formula III, with oxalyl chloride and ammonia to form a compound of formula II, (h) optionally hydrolyzing a compound of formula II, to form a compound of formula I; and (I) optionally salifying a compound of formula I.

Description

472041 A7 B7 V. Description of the invention (1) The present invention relates to a method for preparing certain 1H-W indole-3-ethylenediamines. The compounds are suitable for inhibiting sPLA2-regulated fatty aunts in conditions such as septic shock. 'Release' and related intermediates suitable for use in the preparation of these compounds. Some 1H-indole-3-ethylenediamines are known to be mammalian spla2 < strong and selective inhibitors, suitable for treating diseases such as: septic shock, adult dyspnea syndrome, pancreatitis, trauma, bronchus Asthma, allergic rhinitis, rheumatoid arthritis, and sPLA: related diseases. For example: Ep〇 Publication No. 06751 10 discloses these compounds. Many different patents and publications describe methods for preparing these compounds using 4-hydroxy-indole intermediates. M. Julia (Marc Julia), J. Iggol (Jean Ig〇len) and Η. Iggol (Hanne Igolen) described in Bull. Soc. Chim. France, 1962, ρρ. Ι〇60_ 1068 article & quot Recherches en serie indolique. VI sur tryptamines substituees1 'illustrates some of the 4 丨 3_ ethylenediamine and its conversion to tryptophan derivatives. E. Romeo et al. Article in The Journal of Pharmacology and Experimental Therapeutics, Vol. 262, No. 3, (pp. 971-978), 2-Fang -3-4 丨 Indole ethylenediamine (FGIN-1): a new type of strong specific ligand for the mitochondrial DBI receptor (MDR) (2-Aryl-3-Indoleglyoxylamides (FGIN-1) : A New

Class of Potent and Specific Ligands for the Mitochondrial DBI Receptor (MDR) indicates that some 2-aryl-3-Methoxyethylenediamines have research use in the mammalian central nervous system. Chemical Abstracts, Vol_ 67, 1967, 73028h -4-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) • II n —Ml III —inn I In y— I nn (Please read the caution page on the back first). -I line _ Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives 472041 A7 _ B7 V. Description of the invention (2) '' N-fluorenylindionate in mass spectrometry Eight columns of 11 π T (Fragmentation 〇f N-benzylindoles in Mass Spectrometry) abstract description of a variety of phenol substituted with a major group, including those who have an ethylenediamine group in the 3 · position. Patent No. 3., 449,363 describes trifluoromethylindole with ethylenediamine group at the 3-position of the core of the μ. US Patent No. 3,35 1,630 describes α_substituted 3 _Indolylacetic acid compound and a method for preparing the same and its ethylenediamine intermediate. US Patent No. 2,825,734 describes the use of 3 _indole ethylenediamine intermediates such as: 1-phenethyl-2-ethyl- 6-Leptyl-N-propyl-3-Θ 丨 Indole ethylenediamine prepared 3_ (2-amino-1-# is ethyl (4) Method of indole (see Example 3). US Patent No. 4,3 97,850 Method for preparing isoxazolylzolinamide using ethylenedioxamine indole as an intermediate. US Patent No. 3,3 80,1,594 illustrates analgesics prepared using 3-pyridylethylenediamine intermediates. A. Aleman hy, EF Fernandez Alvarez, 0_ Ν · 罗佩 (0 · Nieto Lopey) and MER Heraez in "Article of Bulletin De La Societe Chimique De France, 1974, 12, pp. 2883-2888" No. 565 · -Enzyme Inhibitors, XII.- (block propylamino-2-ethyl) -3- 丨 method for making beer " (No. 565 ·-Inhibiteurs d enzymes. XII.-Preparation de (propargylamino-2 ethyl) -3 indoles) A variety of hydrogenated pyridyl_3-ethylenediamines substituted on the 6-membered ring of the indole core. G. Kolenz and C. Christa Labes are described in Liebigs Ann. Chem. , 1975, pp. Ι 979. ι 933 Article “Diphenylaniline-5- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love) ----- 3-*- ί — --- · II (Please read the note on the back of this page first) ήπ · -line. Printed by the Consumers ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 A7 -------- B7 Employees’ Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed 5. Description of the invention (3) Iridol conversion of (3) group_2,3-dihydro-2,3-pyrrolidone (Ind〇1_Umlagerung v〇n l-DiPhenylamin〇-2,3_dihydr〇_2,3_pyrr Oliden) illustrates phenyl substituted 3-ethylenediamine. Dou ^ This method adopts j .. raw, Yan Ji_induan—zhong-. For example: U.S. Patent No. 5,654,326 U_S, which is fully incorporated herein by reference, discloses a method for preparing a 4-substituted_1H_pyridine_3_ethylenediamine derivative, which includes Substituted 4-methoxyindole (prepared as described by RD. Clark et al., Synthesis, 1991, pp. 871-878, the contents of which are incorporated herein by reference) with sodium hydride in two In methylformamide, react at room temperature (20-25 ° C) and then treat with arylmethyl halide at ambient temperature to produce the 1-arylamidinium indole and then use boron tribromide 0-Demethylation in methyl chloride (Tsung-Ying Shem) and CA Winter (Adv. Li Ru & J., 1977, 12, 176) (Incorporated herein) to produce 4-hydroxyindole. The alkylation of hydroxyindole is accomplished by using sodium bromide in dimethylformamide and using sodium hydride as a base. From the α _ [(indox-4-yl) oxy] phosphanate, it is first reacted with grasshopper gas, then with ammonia, and after hydrolysis with sodium hydroxide in methanol, it can be converted into ethylenediamine. The method for preparing a 4-substituted-1fluorene-indole-3-ethylenediamine derivative as described above is useful. However, this method uses expensive reagents and organic solvents that are harmful to the environment to produce furan-containing by-products, and the yield of the desired product is quite low. Another method for the preparation of appropriately substituted propionyl acetate is the halogenation with thion gas. After treatment with hydrochloric acid, the hydration intermediate is reacted with appropriately substituted cyclohexanedione to undergo hydrolysis and decarboxylation. Treatment of alkylated di-6 with appropriate amine-This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) ---- Jir-* ------ pack --- (please Please read the note on the back page first) Order '. Wire. -1-472041 A7 ------- B7 ______- 5. Explanation of the invention (4) Outline of 4-ketoindole produced at high boiling point In a hydrocarbon solvent (such as carbitol), it is refluxed in the presence of a catalyst (such as Pd / C) to be oxidized to 4-transyl 4 丨 indole, which can be re-systematized and converted to the required ethyl alcohol as described above. Diamine. However, this method is limited to the use of high-temperature oxidation and must recover valuable metal catalysts. Although the above-mentioned method for preparing a 4-hydroxyindole intermediate is satisfactory, a more effective transformation method is still needed. The method of the present invention uses a sulfination step. Generally, the 'sub-acidification' reaction uses a hydride base, which delays the initiation of exothermic reactions and gas release. This reaction condition is not liked under commercial conditions. Applicants in this case have discovered a method for preparing an acidified intermediate that has nothing to do with delaying the initiation of an exothermic reaction and can avoid the blistering phenomenon associated with gas release. Pattai's Chemistry of Sulfinic Acids, Esters and Their Derivatives ^ John Wiley and Sons, 1990, p. 11 A method for synthesizing sulfinate and its salt using various activators is explained. In another aspect of the present invention, the applicant has found a method that can be used commercially for the preparation of sulfinate vinegar, which has a high yield and avoids the production of ^^ (produce color, especially sulfones), and uses cheap reagent . Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs --------..------ Packing --- (Please read the precautions on the back page first)-The present invention provides a preparation of 1HJ 丨Improved method of indole ethylenediamine. In this method, the reagent can be used with low cost, easy to obtain, and mild conditions, and the total yield is better. At the same time, it can avoid the occurrence of taste and side effects. In addition, this method can transform more kinds of substituents on indole. Other objects, features, and advantages of the present invention will be better understood from the following and the scope of patents attached to the green application.円 This paper is a national standard (CNS) A4 specification (210 X 297 public love) of the country of wealth 04 72 4 A7 _B7 V. Description of the invention (5) The present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof or Methods of prodrug derivatives;

R1 Among them: R1 is selected from: C7-C2Q alkyl; (Please read the precautions on the back first, write this page)

Order ··. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy Among them: R10 is selected from: halogen, -CVCm alkyl, -C "C10 (alkoxy), -SJCVCw alkyl) and halogen (CrC10): i finished And t is an integer from 0 to 5; R2 is selected from the group consisting of 氲, halogen, -CrC3 (alkyl), -C3-C4 (cycloalkyl), -C3-C4 (cycloalkenyl), -0 ( -01-(: 2 alkyl), -S (-CrC2) alkyl, aryl, aryloxy, and HET; R4 is selected from: -C02H, -S03H, and -P (0) (0H) 2 or Its salt or its drug derivative -8- This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 472041 A7 B7 V. Description of the invention (6 substances; and R5 is selected from: hydrogen,-(CrC6) Alkyl,-(CrC6) alkoxy, halogen (cvc6) alkoxy, halogen (C2-C6) alkyl, bromine, gas, fluorine, iodine and aryl; the method includes the following steps: a) by formula X Compound 0 0, cA ^ r2

X where R8 is (CVC6) alkyl, aryl or HET; with S02Cl2i 'to form a compound of formula IX (please read the precautions on the back to write this page)

0 Q

σ γ R C1 IX; b) hydrolysis and removal of carboxyl group from compound of formula IX

0 Q

· 〇 · Ya R C1

IX Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs to form a compound of formula VIII c) From compound of formula VII C1.

VIII -9- This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 mm) 472041 A7 B7 Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (7 Formed by alkylation with a compound of formula VIII Compound of formula VI d) from compound of formula VI

r5VC ^ 0

VII C1

VIII 1 n n 4 * 1 I-— -I vwd · 11 n I— I in n (Please read the precautions on the back first to write this page) 〇

R 〇

R VI. VI and formula RiNI ^ are subjected to amination and dehydration in the presence of a solvent capable of azeotroping with water to form a compound of formula V. Human R ~ 'V; order; -line. -10- This paper size applies to China Standard (CNS) A4 specification (210 X 297 mm)

0H

472041 A7 B7 V. Description of the invention (8) e) From the compound of formula V

Heating with a base and a compound of formula RSOX, wherein R is-(CrC6) alkyl, aryl or substituted aryl, and X is-(CrC6: r ^ oxy, halogen or -OCOJCVCJJ ^ group, and oxidizes to form compound of formula IV IV; f) Ordered by the compound of formula IV, mnn * ni nt n HI 1 * HI ^^ 1 (please read the notes on the back to write this page) .:

0H

VI r! R line _ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs and alkylated with the formula XCH2R44_fe alkylating agent, where X is a radical and the ruler is -C02R4b, -S03R4b, -P (0) (0R4b) 2 Or -P (〇) (〇R4b) H, wherein R4b is an acid protecting group, forming a compound of formula III

OCH R

R III; This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 472041 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (g) Compounds of formula III

R

III reacts with oxalic acid and ammonia to form a compound of formula 11

h) Hydrolyze the compound of formula 11 if necessary

R

II forms a compound of formula I; and i) optionally forms a salt from a compound of formula I. Another embodiment of the present invention provides a method for preparing a compound of formula I, which comprises the following steps: a) From a compound of formula V

A

N R 2

V ________ir n m n n I n I (Please read the notes on the back to write this page first) Order-line. -12- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

0H

R 472041 A7 B7 V. Description of the invention (10) Heating with a base and a compound of formula RSOX, where R is-(Crc6) alkyl, aryl or substituted aryl and X is-(CrC6) alkoxy, halogen or- (^ (^ (^-(^ Alkyl, oxidized to form a compound of formula IV

OH IV; b) by a compound of formula IV

IV is alkylated with an alkylating agent of formula XCH 2 R 4 a, where X is a leaving group, and R 4 a is -CO2R4b, -S03R4b, -P (〇) (〇R4b) 2, or -P (〇 ) (〇R4b) H, where R4b is an acid-protecting group, forming a compound of formula 111. — 1 I -II —- —1 — 11 — 1 I-(Please read the precautions on the back to write this page) Order:- line·

〇CH R R

R Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs III; c) from compounds of formula III

III This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 472041 A7 B7 V. Description of the invention (11) Reaction with grasshopper chlorine and ammonia to form the compound of formula 11

R

R II; and d) optionally hydrolyze the compound of formula 11

II to form a compound of formula I; and e) optionally forming a salt from a compound of formula I. Another specific embodiment of the present invention is to provide a method for preparing a compound of formula I, which includes the following steps: a) from a compound of formula V (please read the notes on the back first to write this page) employee consumption of the Intellectual Property Bureau of the Ministry of Economic Affairs Cooperative print * 1 clothing

Treated with a base and a compound of formula RSOX, where R is-(CrC6) alkyl, aryl, or substituted aryl, and X is-(CrC6) alkoxy, halogen, or -OCOJCVC ^), and is oxidized to form Compound 14 of Formula V 1- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 472041 A7 B7 V. Description of the invention (12)

S R

V R

-—I Heating formula V1 to form compound of formula IV

OH

R IV, · ---- 1 --- h ------ pack --- (Please read the precautions on the back first to write this page) b) from the compound of formula IV

OH

R

IV

Alkylated via the formula XCH2R4a alkylating agent, where X is a leaving group and 1143 is -C〇2R 4b n I. V-·-" 1 mouth · -line · Printed by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 3R4b, -P (〇) (〇R4b) 2, or -P (〇) (〇R4b) H, where 1145 is an acid protecting group to form a compound of formula 111

R c) From the compound of formula III -15- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) 472041 A7 B7 V. Description of the invention (13)

^ III reacts with grass gas and ammonia to form a compound of formula π

II; and d) if necessary, hydrolyze the compound of formula 11 I — I * i _ I I (please read the precautions on the back to write this page) Order ··

R 丨 line _ forms a compound of formula I; and the present invention provides a novel intermediate of formula V 1 printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

S R

IV 2 R This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 472041 Printed and printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 ---------- B7_____ '--- --- V. Description of the invention (14)-wherein RhV and R5 are as defined above and RHC6 is formed into a group, an aryl group or a substituted aryl group. These compounds are suitable for use in the preparation of compounds of formula. Another aspect of the present invention provides a method for preparing formula RS0x, wherein the ruler is-(CVC6) fluorenyl, aryl, or substituted aryl, and is also melamine); (CrC2) 0: H is treated with an alcohol of the formula 〃, 0II RSOM where R is-(CrC6) alkyl, aryl or substituted aryl and R is an alkali metal. The compounds of the present invention use certain terms as defined below: When used herein, the term "alkyl" or "as part of another substituent" refers to a straight or branched chain unless otherwise defined Monoalkyl hydrocarbon radicals such as: methyl, ethyl, n-propyl, isopropyl, n-butyl, third butyl, isobutyl, second butyl, third butyl, n-pentyl, isopentyl Group, neopentyl, heptyl, hexyl, octyl, nonyl'decyl, etc. The term "(crc10) alkoxy" as used herein refers to, for example: methoxy, ethoxy, n-propyl Oxy'isopropoxy, n-butoxy, tertiary butoxy, n-pentoxy, isopentyloxy, neopentyloxy, heptyloxy, hexyloxy, octyloxy, nonyloxy, Decyloxy, and similar groups, use an oxygen atom to attach the rest of the molecule. A " (Cr C4) cycloalkyl '' includes cyclopropyl and cyclobutyl. The term "C r C4 cycloalkenyl" includes a cyclopropenyl or cyclobutenyl ring having a double bond at the 1-or 2- position. The term " halogen " includes fluorine, gas, bromine, or chi. The term “π halogen (Crci0) alkyl” refers to (CVC ^ o) alkyl via 1 to 3 self-atoms-17- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (please first (Read the notes on the back and write this page): Γ.-* 装. Ί Thread, 472041 A7 B7_________ V. Description of the invention (15) Substitution, using an alkyl group to attach the rest of the molecule. I halogen (c Includes the term "from the base (c2-c)". The fluorenyl "halo (CrC6) alkoxy"-the term refers to a halogen-substituted alkoxy group using the oxygen of the alkoxy group to attach the rest of the molecule ~ "Aryl π — The word refers to a group having the following ring structure characteristics: · Ben, penta-indene, fluorene, chamomile ring, heptyl, phenanthrene, E, etc. The aryl group may be subjected to 1 to 3 as needed. (Ci_Cs) alkyl (preferably fluorenyl), (C "C6) alkoxy or halogen (preferably fluorine or chlorine). The term" aryloxy "refers to the use of An aryl group of the oxygen linker attaches to the rest of the molecule.-The term "leaving group" refers to a substituent having a non-common electron pair that can be separated from the substance in a nucleophilic substitution reaction. The term "leaving group" includes commercial elements, sulfonates, acetates, etc. The HET-words include, "Beyond" ratio, "Dense disease", "well" ratio, "Bizazole", furan, pyrimidine, pyrimidine Azole, isothiazole, humidiazole, oxadiazole, imidazole, triazole, and tetrazole. Zazuka can use any carbon in the heterocyclic ring to attach the rest of the molecule. Printed by the Consumer Cooperative of the Intellectual Property Bureau, Ministry of Economic Affairs II ^ -I n 1 .Γ n I 1 n III (please read the note on the back to write this page first). The salt of the compound of formula I is another aspect of the present invention. If the compound of the present invention has an acidic functional group, it can form Various salts that are more water-soluble and physiologically more suitable than the parent compound. Representative pharmaceutically acceptable salts include (but are not limited to) ... alkali metal and alkaline earth metal salts such as ... files, sodium, potassium, calcium, Salts of magnesium, ming, etc. Salts are easily prepared from the free acid, which is treated with a solution of an acid by alkali or by an acid with an ion exchange resin. The definition of a pharmaceutically acceptable salt includes: the present invention A fairly non-toxic inorganic and organic base addition salt of a compound, eg derived from Fully testable -18- This paper size applies to Chinese National Standard (CNS) A4 (210 χ 297 mm) 472041 A7 ------ B7_____ V. Description of the invention (16) Nitrogen test ammonium, four Grades and salts formed by amine cations and compounds of the present invention (see, eg, SM Berger et al., &Quot;pharmaceut; [cai Salts), J. Phar. Sci .. 66: 1- 1 9 (1977)). The term "acid protecting group" used in this paper is like that commonly used in synthetic organic chemistry. For example, a remote group can prevent acid radicals from participating in the reaction of other functional groups on the molecule, but can be removed if necessary. . These groups have been discussed in T. Greene, "Protective Grups in Organic Synthesis", Chapter 5, (Johnson & Sons, New York ( Jonh Wiley and Sons, New York, 1981) 'This document is incorporated by reference in a stupid way. Examples of acid protecting groups include acid esters or amidine derivatives, such as methyl, methoxy Methyl, methylthiomethyl, tetrahydropyranyl, methoxyethoxymethyl, benzyloxymethyl, phenylaryl, ethyl, 2,2,2-trifluoroethyl, 2-methylthio Ethyl: tertiary butyl, cyclopentyl, trityl, p-bromobenzyl, trimethylsilyl, N, N-dimethyl, pyrrolidinyl, hexahydropyridyl, or o-nitropyridinoline. The preferred acid-protecting group is methyl. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs --------! ------- pack --- (Please read the note on the back first (Page)-Line · Prodrug refers to the derivative of the compound of the present invention, which has a chemically or metabolically cleavable group, and has pharmacological activity in vivo through solvolysis or under physiological conditions The compounds of the present invention. The derivatives of the compounds of the present invention are active in both acid and base derivatives, but the acid derivatives can be used for favorable dissolution, histocompatibility, or delay in mammalian organisms. Advantages of release (see “Design of prodrugs” in Bundgard, pp. 7_9, 21_24, ElSevier, Amsterdam, 1985). Prodrugs include acids Derivatives, -19- This paper size is applicable to Chinese National Standard (CNS) A4 specifications (210 X 297 issued) '-~~., 472041 A7 V. Description of the invention (17) For example: the acidic parent compound and suitable alcohol Responsive characters Panren, S η, — the next day or the acidic mother's… should be made amidine. The preferred prodrugs are simple lipids derived from the acid compounds on the side of the compound (Eg Zixin ester, Γ purpose, isopropyl alcohol, butyl vinegar, second butyl vinegar, third butyl vinegar) or aryl aryl thiol methoxy group. It is necessary to prepare a diacetate-type prodrug, such as: (fermented oxenyl vinegar or ((k-oxyalkyl) oxy) oxy) alkyl esters. The compounds of the preferred formula prepared by the inventive method are among them: R1 is (CH.

— II--I .----— I- 装 — I (Please read the notes on the back to write this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs where (R10) t is selected from: Shangsu, _Ci_Ci 〇alkyl, _c "CiO (alkoxy), _s_ (CrC10) alkyl; and Ci! Ci (Ci_) alkyl, and an integer of # 0 to $; R2 is from prime, cyclopropyl, hydrazone R4 is -C02H; and R5, R6 and R7 are fluorene. Preferred compounds of formula V 1 are among them: where R is aryl and R10 is selected From: halogen, _ (Ci_C | 〇) alkyl, _ (Ci_Ci〇) alkoxy, -S- (匸 丨-<: 10) alkyl, and halogen ((:: 丨 _ (^ 〇) alkyl And 1 is an integer from 0 to 5; R2 is selected from: halogen, cyclopropyl, methyl, ethyl, 0-methyl, or S-methyl; and R5 is fluorene. Even more preferred is the compound of formula V1 ： -20- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) Order · -line · 472041 A7 B7 (CH,)

V. Description of the invention (18) R is phenyl or tolyl; R1 is R10 selected from: halogen,-(CrC4) alkyl,-(C "C4) alkoxy, -SCCVCJ group and halogen ((^-( R2 is methyl, t is 2; R2 is methyl, ethyl, or propyl; and R5 is fluorene. Preferred substituents for compounds of formula V1 include the following:

CH (ch2) 〇2- (a) R1 is ----.--------- ^ Shang --- (Please read the notes on the back first and write this page) Order: -CH ；, ίο Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs' (b) R1 is (c) R1 is-(CrCu) courtyard; (d) R1Q is selected from:-(CrC6) alkyl and-(CVCJ alkoxy; e) R10 is selected from: -S (CrC6) alkyl and halogen (CVQ) alkyl; (f) t is an integer from 0 to 3 (including 0 and 3); (g) R2 is selected from: hydrogen, halogen,- (eve)) alkyl and -occvc ^) alkyl (h) R2 is selected from: -0 (CrC2) alkyl and -SCCVCJ ^; (i) R2 is selected from: aryl and aryloxy;--21 .Line _ This paper size applies to Chinese national standards (CNS> A4 (210 X 297 mm), 472041 A7 B7_ V. Description of the invention (19) (j) R2 is HET; (k) R5 is selected from: hydrogen, ( CVC6) alkyl and ((^-(: 6) alkoxy); ⑴ R5 is selected from ·· halogen (CVC6) alkoxy and halogen (c2-C6) alkyl; (m) R5 is selected from: bromine, chlorine , Fluorine and iodine; (n) R5 is aryl. The compounds that can be prepared according to the method of the present invention include: ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1 -(Benzyl) _1Η-raldol-4-yl) oxy) acetic acid; (Π-2-((3- (2-amino- 1,2-dioxoethyl) -2-methyl-1- (benzyl) _ιη-indole-4-yl) oxy) propionic acid; ((3- (2 -month: * • yl-1 , 2 -monoethyl) -1-((1,1, -biphenyl) -2-ylmethyl) -2-methyl-1Η-Θ 丨 indol-4-yl) oxy) acetic acid; (( 3- (2-amino-1,2-monolactyl) -1-((1,1'-biphenyl) -3-ylmethyl) -2-methyl-1H- is called indole- 4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -1-((1,1'_biphenyl) _4-ylmethyl) -2- Methyl-1H-zolin-4-yl) oxy) acetic acid; ((3- (2-aminoamino-1,2-dioxoethyl) -1-((2,6-dichlorophenyl) methyl Yl) -2-methyl-1H-indole-4-yl) oxy) acetic acid; ((3- (2-amino-1,2- · -oxyethyl) -1-((4-gasbenzene (Methyl) -2) methyl-1H-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -2-methyl-1 -((Naphthyl) methyl) _1H_oxindole_4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- ( Benzhydryl-4-yl) oxygen) acetic acid; -22- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------ · ------- Fruit --- (Please read first Note on this page) _ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 A7 B7 V. Description of the invention (20) ((3- (2-amino-1,2-dioxyethyl) -1 -((3-Gaphenylmethyl) -2 -ethyl-1H-indole-4-yl) oxy) acetic acid; ((3- (2-benzyl-1,2 -monolactyl) -1 -((1,1'-biphenyl) -2-ylmethyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid; ((3- (2-amino-1, 2-dioxoethylbiphenylylmethyl) _2-propyl-1Η-4indole-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxyethyl) -2-cyclopropyl-1- (benzylbutorol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-monolactyl) -1-((1, 11-biphenyl) -2-ylmethyl) -2 -cyclopropyl-lfi-pyridin-4-yl) oxy) acetic acid; 4-((3- (2-amino-1,2-dioxo Ethyl) -2-ethyl-1- (benzyl) -lH-pyridin-4-yl) oxy) butanoic acid; ((3- (2-amino-1,2-dioxoethyl) -2 -Ethyl-1- (benzyl) -1Η-ρ 弓 -4-yl) oxyacetic acid; ((3- (2-amino-1,2-dioxyethyl) -2- Ethyl-6-fluorenyl-1- (benzyl) -lH-11indol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxoethyl -2,6-dimethyl-1- (benzylindol-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxoethyl) -2-methyl- 1- (benzyl) -lH-pyridin-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxoethyl) -6-ethyl-2-methyl 1- (benzyl) _1H-indole-4-yl) oxy) acetic acid; ((3- (2-amino-1,2-dioxoethyl) -2,6-diethyl-1 -(Benzylpyridyl-4-butoxy) oxy) acetic acid; -23- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --I .---.--- ---- Equipment --- Please read the note on the back to write this page) Order · Line · Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs ) Α7 Β7

((3- (2-Aminododecyl 2-dioxyethyl) _2_methyl_6_phenoxy small (benzylindol-4-yl) oxy) acetic acid; earth) '1 ^ ((3 -(Amineoxyethylamido) _2_ethyl_6_methyl small (phenylamidinyl) _ih indolyloxy) acetic acid; and `` Earth '' ((3- (2-amino_1) 2_Di (Oxyethyl) _2 • ethyl_6_phenoxy_! · (Benzyl group, sulfol-4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof. Among these compounds, preferred compounds include: (0- (2-amino-, 2, _dioxoethyl) _2_ethyl (benzylbu ... ... indole-dooxyacetic acid; ((3- ( 2-amine grave_1, 2_dioxyethyl) _2_ethyl_6_fluorenyl_1_ (benzyl) -1Η-called 丨 ___-___ Γ _____ 1 * II Please read the notes on the back first On this page) 4- (4-yl) oxy) acetic acid; ((3- (2-amino_ 丨, 2_dioxyethyl) _2,6_dimethyl] _ (benzyl 丨 indol_ 4- (Oxy) oxy) acetic acid; (0- (2-amino_ι, 2-dioxoethyl) _2_methyl-1- (phenylfluorenyl) _1Η_oxy) acetic acid; ((3- (2-amino -1,2_dioxyethyl) _6-ethyl_2-methyl_methyl-4-yl) oxy) acetic acid; ((3- (2-amino_1) 2_dioxyethyl) _2 , 6_diethyl_ 丨 _ (benzylindol_4-yl) oxy) acetic acid; ((3- (2-amino-L2-dioxoethyl) _2_methyl_6_benzene Oxy_ 丨 _ (benzyl) — βindole-4, yl) oxy) acetic acid; ((3- (aminooxyethylamidine) _2-ethyl_6_methyl_ 丨 _ (phenylmethyl) _1Η_Ρ? 丨 indolyl) oxy) acetic acid; and ((3- (2-amino-U-dioxyethyl) _2_ethyl_6_phenoxy_i_ (benzyl) indol-4- Base) Stupid methyl staple-thread. 24- This paper size is applicable National Standard (CNS) A4 (210 X 297 g) 472041 A7 B7 V. Description of the invention (22) Indole-4-yl) oxy) acetic acid or a pharmaceutically acceptable salt thereof. Among these compounds, more The preferred compounds are: ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylfluorenyl) -1Η-θ 丨 indol-4-yl) oxy) acetic acid With ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (benzyl) -1H-pyridin-4-yl) oxyacetic acid. According to this method The best compound to be prepared is: ((3-(2-amino-1,2-dioxyethyl) -2-ethyl-1- (benzyl-4-hexyl) oxyacetic acid or its medicine The method of the present invention provides a good method for synthesizing a compound of formula I using a reagent that is inexpensive and easy to obtain, as shown in the following Figure I:

Figure I (Please read the note on the back first, write this page)

-25-

Line · This paper size is in accordance with Chinese National Standard (CNS) A4 (210 > = 297 mm) 472039 A7 V. Description of Invention (23)

R

Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, which is dissolved in suitable rolling monuments, 丨 φ,,' A. (i) with aprotic solvents (such as toluene 彳 is preferred. Other suitable solvents include (for (T winter) cars and U—not limited to): Tetrahydrofuran (THF), Dimethyl ____, Dioxin Land 'or Propylamine. The substrate / solvent solution is H-wave treated or heated slightly if necessary to accelerate dissolution. The amount of the solvent used should be sufficient to ensure that all the compounds in the ancient palates remain in solution until the desired reaction is completed. ^ The solution is treated with alkali, and the alkoxide base is more reasonable than ξ: "Rw group, aryl is (C 丨 -C6): t-membered oxygen, dentin, or u (JL〇2 (CrC6) alkyl. Sulfin Acidifying reagents can be prepared according to the method of JW Witte (W. et al., J. 0rg Chem, 1967, 32, Le.). Preferred sulfinating reagents include methyl p-tolyl sulfinate and benzoic acid g. Paratoluene is a different ingredient. Preferable alcohol bases include: sodium, potassium, or lithium alkoxide or ethanolate base. Particularly preferred is potassium methoxide. Other suitable bases include (but are not limited to): sodium hydride Or LDA. The usual amount is about 0.75 to 10 equivalents of the starting material; preferably about 1 to about 3 equivalents; about 2 equivalents is best. The reaction can be carried out at about 15C to reflux temperature, and substantially at 1 It is redundant until 24 o'clock. When the intermediate V1 is isolated, the reaction is performed at a temperature of 150 ° C to 50 ° C, and the reaction temperature is preferably 25 ° C to 40 ° C, and 30 ° C is better. 60. 匚 to -26- This paper size is applicable to Chinese National Standard (CNS) A4 (210 x 297 mm). A salt must be checked. (Please read the precautions on the back first. ^ -—— 装 --- ^ fill in (This page)-Line · 47 2041 A7 B7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. 5. Description of the invention (24) The reaction of the intermediate V to V will proceed quickly when it is fed at a stream temperature, preferably 75 ° C to 85 ° C. It is more preferably 800c. The amount of sulfinating reagent is not important, but the amount is the pyrrole starting material (V) (-Molar equivalent or excess, it is most suitable to complete the reaction. In another method of VA, Replace the sulfinating reagent with the formula R2〇SSR2 ◦ disulfide (where R2 is alkyl or aryl). The sulfide intermediate is oxidized by using an appropriate oxidant (such as hydrogen peroxide or methane perbenzoic acid) Completed. '4 indole (IVM) is easy to use XCH2R4a alkylating agent, in which 乂 is a suitable leaving group, the rule "is a protected renyl group, fluorenyl group or phosphonate, it is better to be protected by kuyi" It is chemically treated in the presence of methyl bromide. Methyl bromoacetate is the preferred calcining agent. Suitable bases include: potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium carbonate, potassium bicarbonate, or potassium hydroxide. Potassium carbonate is preferred. The alkylating agent is not important, but the amount of the alkylating agent exceeds the starting material-mordane Most suitable to complete the reaction. This reaction is best performed in an organic solvent, = ketone, acetonitrile or dimethylformamide. Other suitable solvents include: not more than): methanol, toluene, tetrahydrofuran, methyl ethyl Ketone, acetonitrile, or butyl methyl ether. The reaction is carried out at a temperature of about (TM⑼.C), preferably 'and substantially about: the reaction can be completed within 1 to 24 hours, depending on the choice; reactants And such as: the conditions of the reaction temperature. When needed, phase-shifting reagents such as: tetrabutylammonium can be used. The method for the production of ethyl amine II can be easily completed in a two-step method from 0.2 to 1.5 millimoles. Grasshopper (in the middle of the mole concentration with the starting material is preferred. The dissolution profile is preferably digas methane, gas imitation, trigas acetamidine, or toluene. Suitable temperature to ambient temperature, ^ is preferred. Physical and Chemical Limitation of Hydrogen Content Limit Temperature ----.------------ Loading --- <: Please read the note on the back first and write this page) ---- 27 This paper size applies China National Xuan Standard (CNS) A4 specifications (21 ×, 472041 A7 V. Description of the invention (25) Use two to treat this solution with ammonia; it can be a gas, or the best. / D 30% ammonia solution. The reaction is mainly carried out at about _25π to 2 and is about -2. It is better to complete the reaction in substantially 10 minutes. The reaction can be completed using tests such as: unloading of hydroxide, hydroxide or ^ .. Among them, sodium hydroxide is preferred, which is in a low carbon number alcohol solvent (such as ethanol, isopropanol, etc.) or in a solvent such as tetrahydrogran, dioxin and acetone. Standard analysis techniques (such as: HPLC) can be used to track the reaction in Figure I to determine when the starting materials and intermediates are converted to products.... Can be separated from the intermediates ... and IV. For example, when separating the intermediate jv, It can be extracted with a suitable solvent (such as toluene) by using three or three solvents and a solvent with water (IV solution. The initial pH of the aqueous layer must be greater than 12. Layering, The whole water layer is in the range of P—Η to 1 to 12, preferably 9 to 11.5, and 11 is the best. It is best to use the extraction method to extract the intermediate IV in the water layer using an organic solvent that can dissolve the intermediate. The water layer The initial pH must be greater than 12. The concentration of the base is preferably about 0.5 N to 5Nk, and more preferably about .5 1 ^ to 2 5 N. The optimal concentration of the base is 2N. Suitable agents for mutual feeding include: ( (But not limited to): methanol, acetone, isopropyl hydrazone to Ethyl, dioxolane, or tetrahydrofuran. Methanol is preferred. Although the order is not important, when the organic solvent is added to the intermediate IV to be extracted IV After the intermediate, the pH of the aqueous solution containing the intermediate is preferably adjusted. The following figure 1 (a) illustrates the above preparation of the intermediate IV (dual furnace method. Standard chromatography can be used to separate and purify the intermediate V 1. -28- Paper Standards: National Standards (CNS) A4 Specification (21〇X 297) ----------------------- (Please close the cautionary note on the back (Page) Order · .Line. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 A7

Relevant art experts are easy to understand; the above methods are jealous to obtain or easily use known techniques. Products made from commercially available starting materials can be prepared from commercial products. Starting material ν 'is prepared according to the following methods. · °

Mil ------------------ (Please read the notes on the back of the book I) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

.. _ Line 472041 A7 B7 V. Description of the invention (27) R8 is (c "c6) alkyl or aryl group. Propyl acetate substituted by Tongdang is first halogenated with sulfur gas, and its dosage is the best. It is equimolar with the starting material and is carried out at a temperature of about 0 ° C to 25 ° C, preferably below 15 ° C, to prepare IX. IX &lt; The hydrolysis and removal of carboxyl reaction system uses an aqueous acid (such as: hydrochloric acid ) Complete reflux after about 1 to 24 hours. Neutralize the solution containing carboxyl removal product νιπ, adjust the pH to about 7.0-7.5, and then combine with cyclohexanedione νπ (equivalent molar concentration is preferred) and alkali (such as hydroxide Sodium is preferred) to produce a triketone monohydrate VI precipitate, which can be purified and isolated if necessary. The reaction is preferably carried out at a temperature of from 20.0 to ambient temperature, and qualitatively at about 1 to The reaction can be completed within 4 hours. The above reaction is best performed according to the "single furnace method", and the reactants are added to the reaction container in the order specified above. Preferably, the reaction can be carried out in a non-single-isolated compound or νιπ compound to avoid exposure to such volatile tear gas. The method for preparing V is based on the reflux of VI in a high boiling point non-polar solvent (preferably toluene) which can be azeotropic with water, and R1NH2 of equal formula, wherein R1 &amp; Solvents with a boiling point of at least 100 ° C are preferred, such as: toluene, xylene, croton, benzene, 1,2-digasethane, or 1,3,5-trimethylbenzene. Pressure reactor. A sufficient amount of solvent should be used to ensure that all compounds remain in solution until the reaction is substantially complete in about 1 to 24 hours. 〇 In a preferred process 〇, a sulfination reagent is prepared in an acid-catalyzed reaction, which is an appropriate aryl sulfinate of the formula RS-OM, where M is an alkali metal (with sodium right), and R is- (CrC6) Alkyl, aryl or substituted aryl (Phenyl or -30- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) --- L --- *- ----- Install --- Please read the note on the back to write this page) Order .., line _ Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 A7 ____B7 V. Description of the invention (28) It is preferred to react with acid (preferably hydrochloric acid). The reaction is preferably carried out under severe conditions, preferably 15 to 3 CTC, and 20 to 25. (: Better, in an alcohol solvent (preferably methanol) corresponding to the desired ester 2) RSII. Other suitable solvents include ethanol and isopropanol. In another process, one equivalent of the required alcohol is used. The reaction is performed in a suitable aprotic solvent (such as: A. More preferably, the reaction uses an excess of alcohol and is operated in a solvent, preferably in a solvent-free alcohol corresponding to the desired ester product. It is best to use <!! Moore's acid line relative to the sulfinate starting material. The following examples further illustrate the method of the present invention, and these examples also illustrate the method of preparing the intermediate compounds of the present invention. These examples are for illustrative purposes only and do not limit the scope of the present invention in any formula. Method 1 (Earth) p-toluenesulfinic acid formazan formula --- Γ ---------- ---- (Please read the note on the back first and write this page) Order ·-. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

II

Na HC1

MeOH

In a 3-liter three-necked round bottom flask of 5 liters was added 2845 liters of formazan γ ^ (5 times the volume) and -31-Standard (CNS) A4 specification (0 X 297 mm) 472041 A7 B7____ V. Description of the invention (29 ) Pass in 165.58 grams (1.4 equivalents, 4.47 mols) of anhydrous HCI, add HC1 to ill Li — I- III — —--I (Please read the notes on the back first to write this page)

It exotherms during MeOH. Use the cooling method and adjust the addition speed to keep the temperature of the flask between 20 and 25 ° F. Toluene sulfinate steel (1.0 equivalent, 569 g, 3-19 mol) was added and stirred at room temperature for 1 to 4 hours. Add 2850 ml (5 times the volume) and then 2850 ml of toluene (5 times the volume). The mixture is stirred for 1 to 30 minutes to separate the layers. After the layers were separated, the aqueous layer was taken, and each was re-extracted with 1425 ml (2.5 times the volume) of toluene for a total of 2 times. All toluene layers were combined and washed twice with 1,425 ml (2.5 times the volume) of a 1 M sodium bicarbonate solution. The layers were separated and the benzene layer 眞 2 was concentrated to about 3 times the volume. All were concentrated in a rotary evaporator to at least a quantity of oil. The final weight yield was 476.78 grams of ester, 87.7% of theoretical weight. Production method 2 ((2-ethyl-1- + methyl) -1Η-ρ5budol-4-yl) oxy) methyl acetate

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, and taking 2-(2-oxobutyl) cyclohexyl-1,3-dione (100 g, 0_5 mol), released in toluene (600 ml) in. The mixture was heated to 85 ° C and stirred for 5 minutes. Add benzylamine (56.3 g, (M Mol, 1.05 eq.) Dropwise in about 30 to 45 minutes. Tim-32- This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 male®) 472041 A7 B7 V. Description of the invention (30) After the addition, the mixture turns into an amber solution. Heat the solution to remove water until the reaction temperature reaches 110 ° C. Stir the reaction at 11.0 ° C for 1 hour, and then distill The solvent was eliminated until 300 ml of toluene remained. To this solution containing 2-ethyl-1,5,6,7-tetrahydro-1- (benzyl) -4H-indole-4-one was added Methyl toluene sulfinate (127.5 g, 0.75 mol) in 300 ml of toluene and methanol (11 0.5 g '1.5 mol) solution. The reaction mixture is under nitrogen at a reaction temperature between 30 ° C and 40 ° C. And stirred for 2 hours. TLC showed that the starting material was completely consumed. The reaction was then cooled to 10 ° C and the reaction was stopped by adding water (500 ml). After stirring for 30 minutes, 'toluene (500 ml) was added and the layers were separated. Benzene solution containing 2-ethyl-5-[(4_tolyl) sulfenamidinyl] -1-benzyl-5,6,7-trihydroxandin-4-one heated at 80 ° C 2 Up to 3 small At this time, the reaction was confirmed to be complete by TLC. The solution was cooled to room temperature. 250 ml of MeOH and 3 12 ml of 2 N NaOH were added, and the mixture was stirred for 30 minutes. The layers were separated and the organic was extracted with 125 ml of MeOH and 1 56 ml of 2 N NaOH. Layer. Separate layers and combine aqueous layers. Add toluene (250 mL) to the aqueous layer and adjust the pH of the aqueous layer to 1 with 1 N HCI. Separate the layers and dilute the organic layer with 1500 mL of acetone. Add potassium carbonate powder (5 i. 8 g, 1. mol) and methyl bromoacetate (93.6 g, 0.6 mol). The mixture was stirred at 60 ° C for 16 hours. The solid was filtered through polypropylene and washed with acetone (300 ml). A portion of the filtrate (60 g, or 5% of the total) was evaporated and the yellow solid was recrystallized from isopropanol (55 ml) to give the title compound as an off-white solid (6.5 g, 82% yield). Example 1 Preparation of ((2-ethyl-1- (phenylamidino) -1Η-called indol-4-yl) oxy) acetic acid methyl ester A. 2-ethyl-1,5,6,7-tetrahydro -1- (phenylhydrazone) -4H-W indole-cardione production method-33- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ---- ^ --- · ------- install-(Please read first * 51 ^^ Write this page) Order. • Line. Printed by the Consumers ’Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 472041 A7 B7 Printed by the Employees’ Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (31) Take 2- (2-Oxybutyl) cyclohexane-1,3-dione (1000 g, 4.995 mol) was suspended in toluene (6000 ml, 6 volumes). The mixture rises to 85 »c and stirs for $ minutes. Benzylamine (562 6 g, 5.25 mol, eq.) Was added dropwise over about 30 to 45 minutes. After the addition of the mixture ', it turned into an amber solution. The solution was heated, and the water was removed by stagnation until the reaction temperature reached 11 ° C. The reaction was allowed to proceed at 10 ° C. (: 2 hours, and then about 4,000 ml of solvent was distilled off under normal pressure at this time. The solution was transferred to a flask 'Zai Luofa into a glass box-colored viscous oil, directly used in the next step, the weight of sudden oil = 1372.24 grams of theoretical weight = 1253.7 grams of efficacy = 87% Mohr yield = 95.2% B. 2-ethyl- ( Method for the preparation of benzyl) -14-indole-4_ol Sodium hydride (400 g, 9.96 moles, 2.5 equivalents) was suspended in butyl hf (500 ml, 5 times the volume). Added to the suspension The above compound a (U49 g, 3.98 moles, 1 equivalent), stirred at 20 to 25 ° C until the bubbling ceases. Add methyl p-toluenesulfinate (1121 g, 6.59 moles, 1.65 equivalents), The mixture was heated to 30 ° C. After about 2.5 hours, the mixture became darker when the gas was released and an exotherm was observed to 47 ° C. TLC showed that the starting material had been completely consumed. The reaction was then cooled to 0 to 5 C 'slowly Slowly add deionized water (500 ml, 5 times volume) to stop the reaction. Then use glacial acetic acid (600 g, 10 moles, 25 equivalents) The reaction was stopped. The mixture was diluted with toluene (5000 ml, 5 times the volume) and washed with saturated sodium bicarbonate (2500 ml, 2.5 times the volume). The upper organic layer was saturated with another 2500 ml of saturated gas. Combined water Layer, extracted back with toluene ($ 000 ml '5 times volume). Combine the organic layers and heat to a gentle reflux (approximately (please read the note on the back first to write this page)). Line. -34- This paper size Applicable> National National Standard (CNS) A4 specification (210 X 297 mm) 472041 Α7 B7 V. Description of the invention (32) 80 ° C) and stirred for 2 hours, at this time, the reaction was confirmed by TLC. The dark solution Concentrated to about 4000 ml under normal pressure, washed with saturated sodium bicarbonate (1500 ml X 2). The organic layer was dehydrated with magnesium sulfate, emptied and concentrated to a dark viscous oil, and used directly in the next step, step. C _ Preparation of ((2-ethyl-1-phenylfluorenyl-1H-M 丨 in-4-yl) oxy) methyl acetate 2-ethyl-5-[(4-tolyl) sulfinamilide] A sample of -1-fluorenyl-5,6,7-trihydrofluoran-4-one was purified by column chromatography using 50% ethyl acetate in hexane. Rf 0.32 was clearly separated The diastereomers of the fluorene are separated and the mixture of the sub-minor diastereomers is isolated (Rf 0.32 and 0.26). The 'Hi ^ CNMR experiment was performed on these two samples: TLC Rf 0.32 (1 / 1 Hexane / Et0Ac). A NMR (CDC13, 300 MHz) Ti 7.51 (dd, J = 6.6, 1.6, 1 H), 7.31-7.26 (m, 5 Η), 6.88 (d, J = 6.4, 2 H ), 6.38 (d, J = 8.1, 1 H) s 6.38 (t, J = 1, 1 H), 5.03 (s, 2 H), 3.48-3.42 (m, 1 H), 3.05-2.97 (m, 1 H), 2.68-2.54 (m, 2 H), 2.43-

2.39 (m, 5 H), 2.23-2_18 (m, 1 H), 1.18 (t, J = 7.5, 3 H). 13C NMR (CDC13, 75 MHz) ci 185.53, 143.86, 141.41, 139.45, 138.25, 136.15, 129.67, 129.02, 127.71, 125.47, 124.76, 120.10, 102.43, 71.62, 47.14, 21.77, 21.48, 19.92, 19.35, 12.17. TLC Rf 0.32 and 0.26 (1/1 hexane / EtoAc). iH NMR (CDC13, 500 MHz 'Rf 0.26 resonance cannot be resolved) 82 (Mountain J = 7 2, 2 h), 6 33 (s, 1 H), 4.94 (dd, J = 16.9, 23.9, 2 H), 4.01 (dd, J = 4.7, 9.1, 1 H) ° nc nmr (cdci3, all resonances observed) 5 186 98, 186.33, 144.82, 142.03, 140.06, 139.00, 137.58, 136.98, 136.85, 130.42, 130.1 1, 129.70 , 129.65, 129.26, 128.37, 126.61, 126.27, 125.39, 120.91, -35- The scale of the scale is applicable to the Chinese National Standard (CNS) ^ 4 specifications (2 丁 〇_χ 297 meals) ---- 1 --- · ------- Installation—— (Please read the notes on the back to write this page) -ir-VJ · -line. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 04 2 7 A7 __B7__. V. Description of the invention (33) 120.74, 103.04, 102.77, 71.97, 69.72, 61.Q1, 47 78, 47 72 22.11, 21.90, 21.70, 21.30, 21.24, 20.68, 19.97 '19.71 1489 12.84, 12.79. D. ((2-Ethyl-1- (benzylindol-4-yl) oxy) acetic acid methyl chloride production method ---------_------- pack --- ( Please read the notes on the back first to write this page) The method 2 compound (25 g, 7 7 mol) printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs was dissolved in 17 5 ml of dichloromethane, and the ice bath Cool the solution. Add grass gas (7.1 ml, 81 mmol) dropwise and keep the reaction temperature below 35 ° C. After 30 minutes, a small amount of starting material is still visible, so add grass gas (0.5 Ml, 6 mmol). After 30 minutes, the reaction was diluted with 175 ml of digas methane, and 175 ml of water was added. Ammonium hydroxide (22 ml, 309 mmol) was diluted with 75 ml of water in an ice bath. Cool. Add the cooled ammonia solution to the reaction mixture dropwise, keeping the reaction temperature below 6.0. When the addition is complete, warm the reaction mixture to 30 ° C to dissolve all the solids. After cooling to room temperature, 'layering' The organic layer was washed with water. The organic solution was mixed with 15 g of activated carbon for 15 minutes. The mixture was filtered through yin salt. The filtrate was evaporated, and the resulting yellow solid was reconstituted from 325 ml of methanol. Crystals to give the title product ((2-ethyl-1- (benzyl) _fluorene-β-indol-4-yl) oxy) methyl acetate as a yellow solid (27.2 g, yield 89%). ·-Line ·

This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

Claims (1)

472041 Patent Application No. 〇106〇24 | Chinese Patent Application Amendment (February 89) Product VI. Patent Application Γ ^ Method for preparing compound of formula I or a pharmaceutically acceptable salt or prodrug derivative thereof Where = R is selected from .C7-C2Q alkyl; (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Central Bureau of Standards, Ministry of Economic Affairs, where: R10 is selected from: halogen, CrC10 alkyl., (^-(: 10 alkoxy, -S -(CrC10 alkyl) and halogen (crc10) alkyl, and t is an integer from 0 to 5; R2 is selected from: hydrogen, halogen, CrC3 alkyl, C3-C4 cycloalkyl, c3-C4 cyclofluorenyl,- O-OCrC ^ alkyl), -S-(-CrC2alkyl), aryl, aryloxy, and HET; R is selected from: -CO2H, -SO3H, and -P (0) (0H) 2 or Salt or prodrug derivative; and this paper size applies Chinese National Standard (CNS) M specification (210X297 mm) 472041 8 888 ABCD 6. The scope of patent application R is selected from hydrogen, (Crc6) alkyl, (Ci_C6) alkane Oxygen, halogen (C 丨 · alkoxy, southern (C2_C0) alkyl 'bromine, chlorine, fluorine, iodine. The method includes the following steps: earth, a) from compound X of formula X where R8 is (crc6) alkyl , Aryl or HET and S02Cl2 halogenated to form the compound of formula IX (Please read the precautions on the back before filling this page). '〇yr Cl IX; 1T b) Hydrolyze and remove carboxyl group IX from the compound of formula IX 〇〇Cl Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy to form the compound of formula VIII C1 VIII; Paper size applies to Chinese National Standard (CNS) A4 specification (210X297 public envy) 472041 A8 B8 C8 D8 6. Scope of patent application R ^ Ο VII is alkylated with a compound of formula VIII C 1 O A VIII to form a compound of formula VI R VI. (Please read the notes on the back before filling out this page) d) From the compound of formula VI 〇 R, 〇 〇 R 'VI Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and formula I ^ NΗ2 in the presence of a solvent capable of azeotroping with water, forming a compound of formula V for amination and deamination 0 R V / 3- This paper size applies to Chinese National Standard (CNS) Α4 size (210X297 mm) 472041 A8 B8 C8 D8 0H Scope of patent application e) From the compound of formula V RV is heated with a base and a compound of the formula RSOX, where R is-(q-Cd alkyl, aryl, or substituted aryl, and X is-(Ci-Ce) alkoxy, i prime, or -OCO ^ CVCe) alkane Group, oxidized to form compound IV of formula IV; f) from compound of formula IV (please read the precautions on the back before filling this page) 0H VI 2 R Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and alkylated with the formula XCH2R4a, where X is a radical and the ruler 43 is -C02R4b, -S03R4b, -P (0) (0R4b) 2, or- P (0) (〇R4b) H, in which R4b is an acid-protecting group, forming a compound of formula 111-4 This paper is in accordance with the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 472041 A8 B8 C8 D8 Patent application scope III ;.丨 (g) by compound of formula III R III reacts with grass gas and ammonia to form a compound of formula II I h) Hydrolyze the compound of formula II if necessary (please read the notes on the back before filling this page) * 1T Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs And II to form a compound of formula I; and i) If necessary, the compound of formula I can be formed into a salt: 5- This paper size uses the Chinese National Standard (CNS) A4 specification (210 × 297 mm)% · 472041 A8 B8 C8 D8 Patent application range 2. —A method for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug derivative thereof Where = R1 is selected from: C7-C20 alkyl; (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs where = R10 is selected from: halogen, CVCh) alkyl, (^-(: alkoxy, -SJCt-Cjo alkyl), and halogen (CrC10) alkyl, and t Is an integer from 0 to 5; R2 is selected from: hydrogen, halogen, CrC3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, alkyl), -S-GCVCz alkyl), aryl, aryloxy Base and HET; -6-This paper size is applicable to Chinese National Standard (CNS) A4 now (210X297 mm) 4/2041 A8 B8 C8 D8 The scope of patent application R is selected from c〇2H'-s〇3H, and- P (0) (0Η) 2 or a salt or prodrug derivative thereof; and R5 hydrogen selection, (Cl-c6) fluorenyl, (Ci_C6) carboxy, Ci_c6, lactol, and _ &lt;: 2-(: 6) alkyl, bromine, chlorine, fluorine, moth, and fangfu; the method includes the following steps: · e) from a compound of formula V VR and the base and the compound of formula RSOX in which R is-(CVC0 alkyl, aryl or substituted aryl, and X is _ (Ci_C6) alkoxy, and is oxidized to form a formula -0 CO 2 (CrC 6) alkyl IV compound OH • /. V I 2 R 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) 472041 OCH R4a R 'A8 B8 C8 D8 VI. Patent application scope and alkylation of alkylating agent of formula XCH2R4a, where X is a leaving group, and the rule "is -C02R4b, -S03R4b, -P (0) (0R4b) 2, or -P ( 0) (0R4b) H, where R4b is an acid-protecting group to form a compound III of formula III, g) From a compound of formula III (please read the precautions on the back before filling this page) OCH R1 ' R I I I reacts with grass gas and ammonia to form a compound of formula II Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs h) Hydrolyzed compound of formula II as required -8- The standard of this paper is applicable to China National Standard (CNS) A4 (210X297 mm) 472041 A8 B8 C8 D8 I I 6. Scope of patent application 2 forming a compound of formula I; and i) optionally forming a salt from a compound of formula I. 3. A method for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug derivative thereof Among them: R1 is selected from: C7-C2O alkyl; (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 -9- This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) -0-(-CrC2 alkyl), -S + CVC〗 alkyl), aryl, h =- 472041 A8 B8 C8 D8 The scope of patent application R10 is selected from the group consisting of: _ element, CrC10 xyl, Crc10 alkoxy, alkyl) and halogen (CpC 丨 〇) alkyl, and t is an integer from 0 to 5; 1 10 R2 selected From: hydrogen, halogen, CrC3 alkyl group, 0: 3-(: 4-cycloalkyl group, Γ_ group, a / b ^^^ 3 fluorenyl group, and HET; R4 is selected from: -C02H, -S03H, and -p (o) (〇h) 2 or a salt thereof; and, -R5 is selected from the group consisting of: hydrogen '(crc6) alkyl, (Crc6) alkoxy, self-defined oxygen, and halo (C2-C6 The method includes the following steps: Clay a) From the compound of formula X (please read the precautions on the back before filling this page) R \ 0 0 、 〇 X ^ w. Where R8 is (CrC6) alkyl, aryl, or HET; halogenated with S02C12 to form a compound of formula IX: 0 0 Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs b) Hydrolysis and removal of carboxyl groups from compounds of formula IX -10- 472041 A8 B8 C8 D8 6. Scope of patent application 〇 〇 〇 ΓΓΤ C1 IX forms a compound of formula VIII C1 乂 c) from compound VIII of formula VII, VII is alkylated with a compound of formula VIII 〇 C1 to form a compound of formula VI R VIII (Please read the notes on the back before filling out this page) R d) Compound VI of Formula VI, 11-This paper size applies to China National Standard (CNS) A4 (210X297 mm) 472041 A8 B8 C8 D8 Patent Application Range 0 R VI and formula I ^ NΗ2 in the presence of a solvent capable of azeotroping with water, water to form a compound of formula V for amination and de-R) From the compound of formula V 〇A- N R ′ R1 V; 〇 (Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and heated with alkali and formula RSOX compounds, where R is alkyl, aryl, or substituted aryl, and X is- (C i-C 6) alkoxy, dentin, or -OC〇2 (CrC6) alkyl, which is oxidized to form a compound of formula V1. R V1; e1) The compound of formula V1 is heated to form the compound of formula IV. 12- This paper uses Chinese National Standard (CNS) A4 specifications (210 X 297 mm) 472041 A8 B8 C8 D8. 6. Scope of patent application ./. V I 2 R e π) The compound of formula IV is first treated with a base and a solvent miscible with water, and then extracted and purified with an organic solvent; f) From the compound of formula IV Alkylated with an alkylating agent of formula XC Η 2 R4 a, where X is a leaving group and R4 a is -C02R4b, -S03R4b, -P (0) (0R4b) 2 or -P (0) (0R4b) H, where R4b It is an acid protecting group to form a compound of formula 111 (please read the precautions on the back before filling this page) R Printed by Central Government Bureau of Standards, Ministry of Economics, Consumer Goods Cooperative, g) OCH R Q- NIR R 3 Compound of formula III This paper is in Chinese standard (CNS) A4 size (210X297 mm) 472041 A8 B8 C8 D8 VI. The scope of the patent application reacts with grasshopper chlorine and ammonia to form a compound of formula II h) If necessary, hydrolyze the compound of formula 11 (please read the precautions on the back before filling this page) R II Printed by the Central Standards Bureau, Ministry of Economic Affairs, Masonry Consumer Cooperative, to form a compound of formula I; and i) If necessary, a salt of a compound of formula I can be formed. 4. A method for preparing a compound of formula I or a pharmaceutically acceptable salt or prodrug derivative thereof This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A8 B8 C8 D8 Patent application scope Among them: R1 is selected from: c7-c2G alkyl — (CH) • CH- and Printed by the Consumers' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs, where: R 0 is selected from the group consisting of Cl-Cio alkyl, CrC10 alkyl, -s- (crc10 2 alkyl), and Cl_cio alkyl. And t is an integer from 0 to 5; R is selected from hydrogen, halogen, ci_C3 alkyl, C3-C4 cycloalkyl, C3-C4 cyclofluorenyl, -0-(-crc2 alkyl), _s _ (_ Ci_c2 alkyl ), Aryl, aryloxy, and HET; R4i! 1: _co2H, _s〇3H, and -p (o) (oh) 2 or a salt or prodrug derivative thereof; and R5 is selected from: hydrogen, (Crc6) alkyl, (cc) alkanochi, Nanfeng (16) kyl, Cr (C6) alkynyl '1¾ (c2-c6) alkyl, bromine. The method includes the following steps: : Lice rolling, iodine and aryl; e) Compounds of formula V- 15- Applicable paper size (210 X 2_97 ^ iT ITilAw. (Please read the precautions on the back before filling this page) 472041 A8 B8 C8 D8 IX V Scope of Patent Application Heating with a base and a compound of formula RSOX, where R is-(CrCd alkyl, aryl, or substituted aryl, and X is-(Ci-Cj alkoxy, halogen, or -OCOXCi-Cd alkyl, and oxidizes to form the formula V1 Compound R 2 -R e1) The compound of formula V1 is heated to form a compound of formula IV eu) The compound of formula IV is first treated with a base in a solvent miscible with water, and then extracted and purified with an organic solvent; (Please read the notes on the back before filling (This page) OH Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs κ IV; f) from compounds of formula IV 2 V This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 472041 R 'R A8 B8 C8 D8 The scope of the patent application is alkylated with an alkylating agent of formula XCH 2 R4 a, where X is a leaving group and R4 a is -C02R4b, -S03R4b, -P (0) (0R4b) 2 or -P ( 〇) (〇R4b) H, where R4b is an acid protecting group to form compound III of formula 111, g) From compound of formula III (please read the precautions on the back before filling this page) OCH R Printed by the Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs. h) Hydrolyze the compound of formula 11 if necessary -17 This paper uses the Chinese National Standard (CNS) A4 size (210X297 mm) 472041 I I, the Ministry of Economic Affairs, Central Mongolia, F5, and Co., Ltd. to formulate a compound; and 0 to form a salt from a compound of formula 1 if necessary. 5) According to the patent application, please refer to the patent! Any of the 4 to 4 items of acidification reagents is selected from p-toluenyl sulfonic acid c, and its center is methyl sulfonate. , &Amp; 衧 or p-toluene j 6. According to any one of the items 1 to 4 of the scope of patent application, ((3- (2-amino-I, 2-dioxyethyl) _2 'method, which is The name 4-yl) oxy) acetic acid. ) 2 ethyl + (benzyl flower 7. According to any of the items 1 to 4 in the scope of the application for patents-items, ,, and, the test system is selected from the group consisting of: methanol unloading, sodium methoxide, C alcohol: sudden (e 8. according to The method of applying for item 7 of the patent scope, which includes the alcohol test 9. According to the method of the application of the item 8 of the scope [· 〒. Of 0.75 to H) equivalent. Among them, the content of "starting substance H) · According to the scope of patent application The method of item 9, of which the test is 11. According to the method of item 10 of the scope of patent application. benzene. The organic solvent of tannin is M12. The method of claim 3 or 4 of the patent scope, the solvent of t step and water miscibility is selected from the group consisting of: T alcohol, propyl g and isopropanol. Lithium, potassium hydroxide and sodium hydroxide. 、 13. According to the method of the 12th patent scope, # 中 is soluble in water 472041 A8 B8 C8 D8 6. The scope of patent application is methanol, and the base is sodium hydroxide. 14. The method according to item 13 of the scope of patent application, wherein the alkali concentration is 0.5N to 5N. 15. The method according to item 14 of the scope of patent application, wherein the alkali concentration is 1.5N to 2.5N. 16. The method according to item 15 of the scope of patent application, wherein the alkali concentration is 2N. 17. The method according to item 16 of the patent application scope, wherein the pH is 10.5 to 11.5. 18. The method according to item 17 of the scope of patent application, wherein the pH is 11. (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 -19- This paper uses Chinese National Standard (CNS) A4 format (210X297 mm)