TW200904810A - 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester, its regio-specific synthesis and intermediate thereto - Google Patents

Abstract

The present invention is directed to 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester, and intermediate, 3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester, thereto. The present invention is also directed to the regio-specific synthesis of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester compound comprising the steps of iodinating 3-methyl-thiophene with an iodinating agent in the presence of a strong base in an non-protic polar or hydrocarbon solvent to yield 2-iodo-4-methylthiophene; Ullmann coupling the 2-iodo-4-methylthiophene with an alkali metal propoxide salt using a copper catalyst in propanol to yield 4-methyl-2-propoxythiophene; coupling the 4-methyl-2-propoxythiophene with CO2 using strong base in an non-protic polar or hydrocarbon solvent to yield 3-methyl-5-propoxy-thiophene-2-carboxylic acid; esterifying the 3-methyl-5-propoxy-thiophene-2-carboxylic acid with N-hydroxysuccinimide in the presence of a coupling agent in an non-protic polar, hydrocarbon or halohydrocarbon solvent to yield 3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester; and brominating the 3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester with a brominating agent in an inert solvent to yield 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2, 5-dioxo-pyrrolidin-1-yl ester.

Description

200904810 IX. Description of the invention: [Technical field to which the invention pertains] The present invention and 4-bromo-3-methyl-5-propoxy-amp; phenoxy acid dioxane-l-yl ester Protease inhibitor fd [4_(5_Aminomethyl_2_5fluorophenyl W1) (4-filled '3-mercapto-5-propoxy phenyl-2-phenyl)_曱_ It can be used as an intermediate in the preparation process. The present invention also relates to its specific region-specific synthesis and 3-methyl-5-propoxy porphin-2_weilic acid 2,5-dioxy port Y-l-ester, the latter in the preparation of 4-bromo-3-methyl-sa,. propyl-propylthiophene-2-carboxylic acid 2,5-dioxopyrylpyrrol-1-yl Used as an intermediate. 10 [Prior Art] wmcm/mn discloses some compounds, including [(phenylhydrazine)-acridine_;!-yl](aryl or heteroaryl) A as a tryptase inhibitor Ketones, and describes the degradation of neuropeptides involved in various biological processes including tryptase and vasodilation and relaxation of the trachea (Caughey, et al., J. Pharmacol.

Exp. Ther., 1988, 244, pages 133-137; Franconi, et al., J. Pharmacol. Exp. Ther" 1988, 248, pages 947-951; and Tam, et al., Am. J. Respir. Cell Mol. Biol" 1990, 3, pages 27_32) and the regulation of a group of amine reactivity in the bronchus (Sekizawa, et al., J. 2〇 Clin. Invest·, 1989, 83, pages 175-179), thereby The potential use of such compounds is determined. WO 2005/097780 discloses more specifically a (benzoguanamine)-acridin-1-ylthienyl fluorenone compound of the formula A, ie ([4-(5-aminomercapto-2-fluorophenyl)) -Acridine-1-yl H4-bromo-3-indolyl-5-propoxythiophen-2-yl)-methanone), 200904810

Its preparation method and its use in diseases which can be treated by inhibiting tryptase. W02005/097780 also discloses that the compound of formula A is prepared by the coupling reaction of compounds 16 and 10 below, and the subsequent deprotection of the coupling product, as shown below.

Intermediate compound 16 was prepared according to the following multi-step preparation method.

41%

11

MaH CS3;

MeOMa

MaOH 77%

Although the intermediate 16 can be prepared by the above process, it employs a wide variety of steps, using an acyclic intermediate having an unpleasant odor characteristic, and is not prepared from a readily available thiophene-based starting material. This process requires an additional step in the conversion of the 5 ester group of compound 15 to the corresponding acid group in compound 16, for example, manipulation of the carboxyl functional group in the intermediate of compound 16. SUMMARY OF THE INVENTION The present invention relates to 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxy ε 11 pyrrol-1-yl vinegar. The invention further relates to the synthesis of a specific region of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 2,5-di 200904810 hand:small ester compound, comprising the following steps: = species _ existence conditions In the case of a non-polar solvent or a solubilized H--chemical agent, 3·methyl^(tetra) is formed to form 2-A-4-methylthiophene; 3-type copper catalyst is carried out in propanol. Cardiomethyl phenanthrene is coupled with a Ullmann coupling to propylene fluoride to form 4-methyl-2-propoxythiophene; in a protic polar solvent or hydrocarbon spray (4) to make 4-methyl _2_?oxythiophene is coupled with co2 to form 3-methyl-5-propoxythiophene-2-furoic acid; in the presence of a coupling agent, in an aprotic polar solvent, smoke/trol Esterification of 3-methyl-5-propoxy porphin-2-carboxylic acid with N-succinimide in a halogenated hydrocarbon solvent to form 3-mercapto-5-propoxythiophene-2_酉 2,5-monooxo 17 each is a 1-methyl group; and 3-methyl-5-propoxythiazine-2-carboxylic acid 2 is treated with a brominating agent in an inert solvent. 5-dioxazolidine _1_yl ester is brominated to form 4_bromo-3_ decyl-5-propoxythiophene-2-indole 2,5-dioxypyridyl _Ι_ alkyl ester. The present invention still further relates to 3,5-dioxapyrrolidinyl 3-(indolyl)-5-propoxythiophene-2-carboxylic acid having the following structural formula,

It can be used as an intermediate in the preparation of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxypyrrolidine 4 - 200904810. DETAILED DESCRIPTION OF THE INVENTION The present invention will be better understood by the following detailed description. DEFINITIONS As used above and throughout the description of the invention, including the scope of the appended patent application, the following abbreviations and terms are understood to have the following meanings unless otherwise stated: "alkali metal" means bell, sodium, potassium or cesium. "Test metal alkoxide" means a form of a salt obtained by treating propane with a strong base. An example of a strong base is Cs2c〇3, an alkali metal base such as

NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), or an alkyl metal such as alkyl lithium, potassium alkyl, sodium alkyl and alkyl magnesium, wherein the alkyl group is a Cu alkyl group, Preferred is butyl, for example, CsOPr,

NaOPr, LiOPr or KOPr. "Amidoxime coupling" means the formation of a coupling reaction of guanamine. "Bromide" means a source of bromine, such as Br2 or NBS. "Copper catalyst" means a copper catalyst capable of promoting a Ullmann coupling reaction selected from the group consisting of CuSCN, CuBr, Cul, Cua, CuBF4, CuPF6, CuOTf, CuPF6, CuBr2, CuCl2, and Cu20. "Coupling cosolvent" means another inert organic solvent which can be used in combination with a propane coupling solvent such as THF, toluene, 2-mercaptoTHF or dimethoxyethane. 200904810 "Deuteration" means the conversion of a slow acid group to its corresponding ester. "Coupling agent" means a compound selected from the group consisting of cdi, dcc, pfp, h〇b1^ HBTU, etc. for effecting an esterification reaction. The "hydrolysis cosolvent" means an inert polar organic solvent such as an ether such as 1,4-dioxan, tert-butylfluorenyl bond (butyl), isopropylethyl ether and diethyl ether. "Alkaline hydrolysis" means the use of an alkali metal hydroxide such as a hydroxide of lithium, sodium or potassium or a hydroxide of an alkaline earth metal to effect hydrolysis. "Hardener" means 12, 2 moth ethylene, or hydrazine. "Iodination" means the reaction with an iodinating agent in the presence of a strong base. Non-shell-like polar solvent means a solvent such as ethyl bond, tert-butyl fluorenyl _ (TBME), isopropyl ethyl ether, thf, 1,4-dioxane or 1,3-dioxane, etc. . The "hydrocarbon solvent" means a solvent such as toluene, xylene or heptane. "Halohydrocarbon solvent" means a hydrazine 3_5 halogen (preferably fluorine or chlorine) hydrocarbon, such as chloroform or dichlorohydrazine. (Monthly/Valley) is an aprotic polar solvent, a smoke solvent, a halogenated gluten, a nitrile, a gluten such as acetonitrile, or an organic acid solvent such as acetic acid or propionic acid. a base of an alkali metal such as NaH, NaHMDS, KHMDS'LiHMDS, lithium diisopropylamide (LDA), or an alkyl metal base such as an alkyl lithium, a potassium alkyl group, a sodium alkyl group and an alkyl magnesium, wherein the alkane The base is a c16 alicyclic alkyl group (linear, branched or cycloalkyl), and more preferred is butyl. "Terminal amine test" is a C! _5 organic test, in which the nitrogen does not have a hydrogen source. -12- 200904810 Sub, for example triethylamine. [Embodiment] In a specific embodiment of the method according to the invention, iodination is carried out in 5 THF. Another embodiment of the method according to the invention In the other embodiment of the method according to the invention, the iodinating agent is 12. ίο In another embodiment of the method according to the invention, iodination is Achieved at a temperature of from about -80 ° C to about 0 ° C. Another embodiment of the method according to the invention The alkali metal propoxide is NaOPr. In another embodiment of the process according to the invention, the copper catalyst 15 is Cul. In another embodiment of the method according to the invention, depending on the solvent used and the pressure used The coupling reaction is carried out under heating at a temperature of from about 70 ° C to about 120 ° C. In another embodiment of the process according to the invention, the solvent used for the coupling reaction with CO 2 is THF. In another embodiment of the process of the invention, the strong base used in the coupling reaction with CO 2 is n-butyllithium. In another embodiment of the process according to the invention, the coupling reaction with CO 2 is below - The temperature preferred at 14 ° C, the preferred temperature -13 - 200904810 is from about -22 ° C to about -i 4 〇 c. The solvent in another embodiment of the method according to the invention is chloroform. The coupling agent in another embodiment of the method of the invention is carbonyldiimidazole. In another embodiment of the method according to the invention, it is carried out at about room temperature. Another method of the invention The inert solvent in the particular embodiment is an IS-based hydrocarbon; more preferred is dichlorodecane. In another embodiment of the method according to the invention, from about 〇 ° C to about 1 Torr. Implemented in another embodiment of the method according to the invention

Br2. In another embodiment of the method according to the invention the alcohol solvent used is ethanol. In another embodiment of the method according to the invention, the reaction is carried out at a temperature of from about room temperature to about 30 °C. In another embodiment of the method according to the invention, the test used is triethylamine. In another embodiment of the process according to the invention it is to be carried out with an aqueous base solution, aqueous NaHH solution. In another embodiment of the method according to the invention it should be carried out at a temperature of from about 5 ° C to about 30 ° C. For esterification, for esterification, esterification is used for desertification, bromination is, brominating agent is amide amination, amination, amination, oximation, deprotection, deprotection, anti-deactivation 14-200904810 EXAMPLES Preparation Details Raw materials can be purchased or prepared by applying or modifying known methods, or utilizing their apparent chemical equivalents. 5 The present invention will be better understood by reference to the following typical non-limiting examples of the invention. The following examples are provided to more fully illustrate the specific embodiments of the invention. However, they should not be construed as limiting the broad scope of the invention in any way. In the nuclear magnetic resonance spectroscopy (NMR) listed below, the chemical shift is expressed in ίο ppm and the tetradecyl decane is used as an internal standard. The abbreviations have the following meanings: br = broad peak, dd = doublet, s = singlet; m = multiplet. The synthesis of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxapyrrolidin-1-yl ester described in the following examples can be represented by the following scheme I.

15 not intended I ^^ONa

-15- 200904810 Example 1 · 2-Iodo-4-mercaptothiophene Add a 3-methylthiophene (135 mL) to a 3-liter 4-neck flask equipped with an overhead stirrer, rubber septum, thermocouple, and nitrogen inlet/outlet. , 1.38 mol) and THF (1 L). The mixture was cooled to -20 ° C and LDA was added via a 12 gauge (12 gauge) tube over a 35 minute period (8 〇〇 mL of Aldrich 2.5 Μ solution in THF / hexane / ethylbenzene). The rate was cooled as necessary to maintain the reaction temperature at -25. (: between -15 ° C. After the end of the addition, the mixture is stirred for 3 minutes and the temperature is maintained below 〇 〇 c. 10

In another 5 liter bottle with a top stirrer, cold bath, nitrogen flow and thermocouple, 'hard (454 g, 1.3 equivalents) in THF (1.65 L), stir for 20 minutes to ensure completeness Dissolve and cool to -2 °c. When the solution was cooled to -10 ° C, iodine began to precipitate. The anion solution was allowed to warm up and was added over a 40 minute period through a conduit, and the rate of addition was adjusted as needed to maintain the reaction temperature at < 5 ° C or below. When the addition was complete, the mixture was allowed to warm to 10 °C over 2 hours. The reaction was diluted with MTBE (1 mL) and quenched with semi-saturated ammonium chloride (10 mL). Use G5 N deuterated sodium sulphate (2 X... Leave the organic layer in-minute for 4 hours and extract all the separated water. Pass the organic layer at 175 mbar through = to 1.2 L. HPLC analysis in the aqueous phase or crane The output is = product. A small amount and unquantified unreacted sulfhydryl group (4) in the wash == -16- 20 200904810 = , the recovered raw materials, the formation of the unqualified isomers, > 1 疋 转 • The fact that there is no product in the middle of the 'reaction reaction reagent, the reaction is calculated to be 73%. Dense multiple peaks), 6.91 (1H, 1hnmr(cdci3,5)7〇5 (1Hj dense multiplet), ( 2.21, 3H, s). Example 2: 4-mercapto-2-propoxythiophene 10 20 In the presence of Dean ~ Stark trap, (Dean_starktrap) and top reflux type cold (four) 1 hair machine, (4) In the 3 = 3 bottle of thermocouple and nitrogen inlet/outlet, the solution obtained by the example i i 2 l and the positive propylene (1 L) δ The mixture is heated to reflux and the effluent is extracted, and the propylene is burned. Partial displacement (about UL removal and addition of 5 〇〇 mL of n-propyl) until the liquid space temperature phase % cooled the mixture to c, and added solid tert-butyl Sodium (192 g, 2 m. about 2 equivalents), exotherm causes the temperature to rise to about 75 ° C. The mixture is maintained between 85 ° and , until all solids are dissolved. The reaction mixture is then cooled to 5 〇 〇 'Add a slurry of freshly prepared copper iodide 1 (10 〇 mmo b Bg) in n-propane (5 〇 ml). The mixture was heated to 95 c C. After reaching the reaction temperature for 3 〇 minutes, HPLC analysis showed The reaction was complete. Dilute the mixture with heptane (1 L). Add diatomaceous earth (190 g) 'The resulting slurry was stirred for 6 min while cooling to room temperature. The mixture was filtered and washed with heptane (500 mL) The cake was sequentially 5% EDTA in di-sodium azide (3X500 mL), water (3 x 500 mL). Copper iodide was just ground in a spider and sonicated for 5 minutes in the form of a n-propane slurry. -17- 200904810 and The filtrate and washings were washed with brine (500 mL) to give a dark organic layer, which was concentrated to <200 mL (170 mbar, 60 〇, 159 g of dark brown liquid, i. The required compound is 51A%. The main impurities are heptane and ethylbenzene (from purchased LD) a) and 2_ ang-3-methyl 1 thiophene. 4 NMR (CDC13 ' δ) 6.18 ( 1H, d) ; 6.02 ( 1H, d) ; 3.98 (2H ' t) ; 2.15 (3H ' S) ; 2.80 (2H,m) ; 1.05 (3H,t). Example 3: 3-Methyl-5-propoxythiophene-2-carboxylic acid 15 20 The crude 4-methyl-2-propoxythiophene of Example 2 (calculated 79 g, 506 mmol) was transferred to Top stir, thermocouple, nitrogen inlet/outlet, pressure balanced dropping funnel and rubber septum in a 2 liter 3-neck flask and diluted with 600 mL THF. The mixture was cooled to _22 〇c, and 25 μg of n-butyllithium (283 mL, 1.4 eq.) of heptane was added through an addition funnel in μ minutes, and the temperature range was -22. To -14. . , stable at about _21:C. 3. After a minute, the temperature is maintained at seven. Below c, the reaction mixture sampling analysis (by Mirin) shows reduction. Make the dioxide: ^5. . In the compound, the gas flow rate is controlled to maintain the reaction temperature drop by 1 C〇2 until no more exotherm occurs and the reaction temperature begins to lower the sodium bismuth solution (600 mL·) to terminate the reaction and add 矽 frozen t $ g) The mixture was spoiled for 30 minutes and filtered through a filter or cloth. Use 〇: 5 ^ hydrogen ^ sodium (3GmL) washed cake. After combining the sputum and the washing solution, the glaring solution was obtained and washed with g-burn (3 X 200 mL). The pH of the aqueous phase "Week # to 6.8" at this time formed a thick crop/black tar. The solution -18-200904810 45, ίρ gets a large % Γ - lightly plucked the filtrate. Continue to adjust the pH to wash, / two redundancy, use the filter cloth to pass the data, use ice water (10) rainbow); air dry in 2 3 h and then vacuum dry (12 hours, yellow solid (4)" g, ^) 2, acid, 1H NMR (CDCl3, a), 12 〇 H, s); ^ (3H, s), l_82 (2H 'm); 1.05 (10), t). Example 4: 3_Methyl _5 ergyl 2 s 2,5 dioxo ketone added to a 2 liter 3-neck flask with overhead stirring, cold bath, thermocouple and nitrogen inlet/outlet. _Methyl _5_propoxy porphin_2_ ship (85 〇g, like Cong 〇 1), N-Hui imine (68_3 g,! · 4 #量) and chloroform (7〇) 〇mL) 'Stir at room temperature. It exotherms when mixing and the temperature rises by 3. Oh, a brown solution is formed. The cold bath contains room temperature water and is only used to absorb a slight exotherm. In 4 batches, 26 g of solid carbonyl diimidazole 〇〇 4 g, 1.1 equivalents were added every 1 minute. The temperature rise of 2_3C>C and the slow release of the gas will occur each time it is added. After the last addition, the mixture was stirred at room temperature for 3 hours or stirred overnight. The reaction of the mixture was quenched with half-saturated ammonium chloride (2 mL) and washed with water (3 X 150 mL) and brine (150 mL). The product was isolated by exchange with a solvent of heptane at 170 mbar and 30 °C. After the solid was formed, the mixture was cooled to room temperature and 5 ° C to give a bright yellow solid. The mixture was filtered off with a filter cloth, washed with heptane, air-dried in a glassware for 20 minutes, and then further vacuum dried (3 〇 °C' 1.5 inch Hg column), that is, 3-mercapto-5-propoxythiophene-2-carboxylic acid 2,5--19·200904810 dioxin 51 each -1-yl group S (i〇 4 g, 83%). >JMR (CDC13' δ) 6.20 (1H, s); 4.05 (3H, t); 2_95 (4H, s); 2.51 (3H, s); 1.82 (2H, m); 1.05 (3H, t). 5 Example 5: 4_Bromo-3-yl-nonyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxapyrrolidin-1 -yl ester in a thermocouple, ice bath and top stir 2 A 3-neck round bottom flask was charged with 2-methyl-5-propoxythiophenecarboxylic acid 2,5-dioxopyrrolidine small ester (81 g, 273 mmol), isopropanol (5 〇〇 mL) and DCM. (350 mL), 10 gives a very dilute slurry. The mixture was cooled to <5QC, and a solution of bromine (22 mL, 328 mmol, 1.2 eq.) in heptane (80 mL) was added dropwise over a temperature range of 4 to 11 °C. This very dilute slurry was further diluted, but the mixture was not completely homogenized. The solvent was added over a period of 19 minutes and analyzed when the reaction was completed. The 15 reaction was diluted with DCM (600 mL) and quenched with 1N sodium thiosulfate (250 mL). The organic layer was washed with water (2×350 mL). HPLC analysis at this time showed that approximately 6 3% of the original material was unreacted. This is probably due to the fact that the material is attached to the glass so that it is not detected during solution analysis. Drying the organic phase (Na2S04) and concentrating (30 °C '125 mbar)' gave a brown solid which was redissolved in DCm (7 〇〇 2 〇 mL) and used at 5 ° C (4 mL ' 78 A solution of mmol, 0.3 eq. of heptane (20 mL) was taken to complete the reaction. The organic phase was partitioned between 25 mL of EtOAc (EtOAc) (EtOAc) (EtOAc) The solvent volume (3 〇 0 C, 125 mbar) was reduced to 300 mL· and 400 mL of heptane was added (to some degree of crystallization). -20-200904810 The mixture was concentrated to dryness by rotary evaporation to give 104 s brown solid. The crude product was recrystallized from refluxing IPA (500 mL) and dried (4 〇〇c, 1.5 inch Hg column) to give 93 g of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2 , 5-dioxopyrrole-1-yl ester, as a brown solid (Μ%). NMR (CDC13' δ) 4.19 (2H, t); 2.92 (4H, s); 3.59 (3H s s); 1.95 (2H, m); 1·〇8 (3H, t). Example 6: [4_Amidinomethylfluorophenyl]-foxidine small group]_(4U_indolyl-5-propoxy.cephen-2-yl)-methanone in a 5 liter 3 neck Add 2,2,2-trifluoro-N-(4-fluoro-3-acridin-4-ylbenzyl)-acetamide hydrochloride (176.7 g, 0.518 mol) and 1.51 L to a round bottom flask. Anhydrous EtOH. The mixture was stirred and triethylamine (215 mL, 1.55 mol) was added. The mixture was spoiled for 3 minutes and then 2,5-dioxapyrrolidin-1-yl 4-yl-3-indolyl-5-propoxythiophene-2-carboxylate (194 g, 0.516 mol) was added. The exotherm caused the mixture to warm to 26%. The reaction mixture was spoiled for 18 hours and then partitioned between 丨5 l water and 1.5 L TBME. The organic phase was washed successively with water (2 x 〇.5 L), 1 NHC1 (0.5 L) aqueous solution and brine (0.2 L). The deep amber color organic phase was filtered through a short Si〇2 pad (h:=().5,,, Φ=3,5") and eluted with 0.3 L of EtOAc. No significant color reduction was observed. To 7DC, add 194 mL of 50% aqueous NaOH solution. The exotherm causes the mixture to warm to 24. After 3 hours, the mixture is washed with water (2x 1 L, 1 x 〇_8 L) and brine (0.5 L), then sulfuric acid. The organic phase was dried with sodium. The solution was cooled to 13. (:, 4N HCl in 1,4-dioxane (135 mL, 0.54 mol) was added dropwise. The mixture was stirred from 21 - 200904810 3 The product was isolated by filtration (relatively slow), washed with hydrazine and dried with air for 15 hours to give 130.2 g (50%) [4-(5-aminomercapto-2-fluorophenyl)-acridine- 1-Methoxy]-(4-bromo-3-indolyl-5-propoxythiophen-2-yl)-methanone as a pale beige solid.

Claims (1)

10 20 200904810 , the scope of application for patents: L buys the acid 2,5_: oxygen small 2 · the method of applying for the compound of the first item of the patent range, the package, the existence condition τ in the hydrocarbon solvent, with - _ 丨王/合μα used in the 峨 峨 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 4_methyl-synthesis and Ullmann coupling reaction of metal propanolate to produce ^_methyl-2-propoxy porphin; in the non-sheller polar solvent or hydrocarbon solvent, strong test 4_ Methyl-2-propoxy-ceremonase is coupled with C〇2 to form 3-methyl-5-propoxythiophene-2-carboxylic acid; in the presence of a coupling agent, aprotic polarity Esterification of 3-methyl-5-propoxythiophene-2-carboxylic acid with N-succinimide in a solvent, a hydrocarbon solvent or a halogenated hydrocarbon solvent to form methyl _ propyloxythiophene-2-carboxylate Acid 2,5-dioxapyrrolidinyl ester; and 2,5-dioxypyrrole 3-methyl-5-propoxythiophene-2-carboxylic acid with a brominating agent in an inert solvent Bromination of an alkyl ester to form 4-bromo-3-indenyl _5_ _2_ thiophene carboxylic 2,5_-dioxo pyrrolidin-1-yl purpose g. 3. As in the method of Patent No. _2, the reaction of the towel is carried out in THF. •23· 200904810 15 20 The strong test of the second part of the patent application scope is LDA. For example, the method used in the mothification reaction is as in the second paragraph of the patent application scope. : The temperature of the pin to _: The neutralization reaction of = is the method of the patent _ 2, wherein the alkali metal C is the copper catalyst as in the second paragraph of the patent application scope, as in the second paragraph of the patent application scope Yes (5). The 70 〇Γ w m method in which the coupling reaction is carried out under heating of about H) L C . It should be carried out in the middle of the case where the coupling with (3) 2 is reversed η. The method of item 2, wherein the coupling with the coupling reaction of (3) 2 is n-butyl lithium. 12. If the second item of the patent application scope is 2, it is lower than the Russian 'the coupling with C〇2 to the milk to the approximate number ^ ^ ^ (4) 'The preferred temperature is about 13. If the patent application scope 12 Where: (to a method of about _14.^ 贞) where the temperature range is about 14.2 ϊ = range item 2, wherein vinegar is in the second neutron 15.:== range of the second item, wherein Coupling-16. The method of claim 2, wherein the treatment is carried out at about room temperature 4. 5. 6. 9. -24- 5 200904810 17. 18. 19. 20. For example, in the method of claim 2, the inert solvent is dichlorodecane. The method for the bromination reaction of the second aspect of the patent range 〇°c to about 100%^, θ, The bromination reaction is carried out in the target range of about νc. For example, in the second aspect of the patent application, the method of the scorpion 1*, wherein the brominating agent is Br2, a type having the following formula: Methyl _5_propoxy </ RTI> thiophene diacid 2,5-dioxy π pirox-1 - vinegar, -25- 200904810 VII. Designation of representative drawings: (1) The representative representative of the case is: (No). (2) A brief description of the component symbols of this representative figure: None. 10 15 VIII. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: Benefit. *, ,, 20