TW200904811A - Use of 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester for preparing the tryptase inhibitor [4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-(4-bromo-3-methyl-5-propoxy-thiophen-2-yl)-methanone - Google Patents

Abstract

This invention is directed to a five step regio-specific synthesis of 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid compound of formula 16 comprising the steps of acetalating 3-methyl-thiophene-2-carbaldehyde in an alcohol solvent; iodinating the acetalated 3-methyl-thiophene-2-carbaldehyde in an non-protic polar or hydrocarbon solvent to yield the corresponding iodinated and acetalated 3-methyl-thiophene-2-carbaldehyde product; treating the iodinated and acetalated product with water to yield the corresponding 5-iodo-3-methyl-thiophene-2-carbaldehyde; oxidizing the 5-iodo-3-methyl-thiophene-2-carbaldehyde to the corresponding 5-iodo-3-methyl-thiophene-2-carboxylic acid in ketone solvent; Ullmann coupling of the 5-iodo-3-methyl-thiophene-2-carboxylic acid with alkali metal propoxide salt using a copper catalyst in propanol to yield 3-methyl-5-propoxy-thiophene-2-carboxylic acid; esterifying 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 3-methyl-5-propoxy-thiophene-2-carboxylate; brominating the 3-methyl-5-propoxy-thiophene-2-carboxylic acid to yield the corresponding alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate; and basic hydrolyzing the alkyl 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylate with base to yield 4-bromo-3-methyl-5-propoxy-thiophene-2-carboxylic acid.

Description

200904811 IX. Description of the invention: [Technology of the invention] i or j The present invention relates to 4,_3_methyl-5 oxapyrrolidin-1-yl ester in the preparation of 姨'^° 吩 _2 鲮 鲮 鲮 2 5-Actyl)-hexanitro(tetra):yl;;=yl)-indoleone as an intermediate in the process. _ _5_丙减 ° 塞11 I [Prior Art] W02001/13811 was exposed - this ^ 入 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Biting a small base] (aryl or heteroaryl) ketone, and describes the degradation process of neuropeptides involved in various biological processes including tryptase and bronchial relaxation by tryptase (Caughey, et al., j.

Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi, et al" J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951; i5 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. Clin. Invest., 1989, 83, pages 175-179) ), thereby determining the potential use of such compounds. W02005/097780 more specifically discloses a (benzoquinone 2 decylamine)-hexahydron-by-l-ylthienyl ketone compound of the formula A (ie ([4-(5-aminomethyl)- 2-fluorophenyl)-hexahydropyranyl-1-yl]-(4-bromo-3-indolyl-5-propoxyindol-2-yl)-methanone, 200904811

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 the following compounds 16 and 10, and the subsequent deprotection of the coupling product, as shown below.

Intermediate compound 16 was prepared according to the following multi-step preparation method 200904811

NaH KOH cs2 o person 41%

M©ONa 86% ¢11-13)

MeOHI 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 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. The present invention relates to a tryptase inhibitor [4-(5-aminomercapto-2-fluorophenyl)-hexarum oxime-1 -yl]-(4_>odor-3-methyl-5-propyl A method for the preparation of oxy σ sept-2-yl)-formamidine, which comprises the steps of: ίο 4-bromo-3-indolyl-5-propoxy η-cephen-2-pyruic acid 2,5 -Dioxo-pyrrolidene-1 -yl ester and 2,2,2-trifluoro-N-(4-fluoro-3-hexahydropyridin-4-ylphenylhydrazino)-acetamide hydrochloride and A strong base or a tertiary amine base undergoes an intellectual coupling reaction of 醯200904811 in an alcohol solvent to form 2?-- 2,2,2_2 mice-Ν-{3-Π-(4-bromo-methyl-, Milky porphin-2·singyl)_hexahydroindole _4_yl]_4_qi_yl}-acetamide; and using 2,2,2-trifluoro-N-{3-fW4 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, -(5-Aminoguanidino-2-ylphenyl)-hexa-4-indenyl]-(4-o-3-indol-5-propoxythiophen-2-yl)-methanone. SUMMARY OF THE INVENTION The present invention will be more fully understood from the following detailed description. DEFINITIONS As used above and throughout the description of the invention, including the scope of the appended claims, the following abbreviations and terms are understood to have the following meanings unless otherwise stated: "Metal" means bell, sodium, potassium Or | color. "Test metal alkoxide" means a form of a salt obtained by treating propane with a strong base. Examples of strong bases are Cs2C03, alkali metal bases such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), 20 or alkyl metal such as alkyl lithium, alkyl potassium, sodium alkyl and alkyl. The alkyl group of the magnesium ' is a CN5 alkyl group, and more preferably a butyl group such as Cs0Pr, NaOPr, LiOPr or KOPr. "Amidoxime coupling" means the formation of a coupling reaction of guanamine. "Bromide" means a bromine source 'eg Br2 or ° 200904811 "Copper catalyst" means a steel catalyst capable of promoting the Ullmann coupling reaction 'selected from CuSCN, CuBr, Cul, CuCU, CuBF4, CuPF6, Cu〇 Tf, CuPF6, CuBr2, CuCl2, and Cu20. Coupling cosolvent means another inert organic solvent such as THF, toluene, methyl THF or -methoxyethane which can be used in combination with a propane coupling solvent. "Brewing" means the conversion from a carboxylic acid group to its corresponding ester. "Coupling agent" means a compound selected from the group consisting of CDI, DCC, PFP, HOBT, and HBTU for effecting the g reaction. "hydrolyzed cosolvent" means an inert polar organic solvent such as an ether such as 1,4-dioxin, tert-butyl decyl ether, isopropyl ethyl ether and diethyl sulfonate. "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. By y iodinating agent is meant ι 2, diiodoethylene, ια, or NBI. "1" means "in the presence of a strong test condition and a deuterated agent into an aprotic polar solvent" means benzyl ether (TBME), isopropylethyldioxane, and the like. A solvent such as diethyl ether, tert-butyl hydrazine, THF, 1,4-dioxane or n hydrocarbon 3 = 2 is a solvent such as toluene, xylene or heptane. For example, chloroform or methylene chloride. 3 Prime Minister Helium or Gas) "Inert solvent" means a non-f-polar solvent, hydrocarbon solvent, tooth 200904811 hydrocarbon solvent, nitrile solvent such as acetonitrile, or organic acid solvent such as acetic acid or propionic acid. "Strong base" means an alkali metal base such as NaH, NaHMDS, KHMDS, LiHMDS, lithium diisopropylamide (LDA), or an alkyl metal base such as a hospital base, a potassium base, a succinyl group, and An alkyl group in which the leuco is a Cu 5 alicyclic alkyl group (linear, branched or cycloalkyl), more preferably a butyl group. "Terminal amine base" means a CN5 organic base in which the nitrogen does not have a hydrogen atom such as triethylamine. [Embodiment] 10 In a specific embodiment of the method of the present invention, the mothization is carried out in THF. In another embodiment of the method according to the invention, the test used for iodination is LDA. In another embodiment of the method according to the invention the 'iodinating agent is 15 work 2 . In another embodiment of the method according to the invention, the iodination is from about -80 ° C to about 0. In another embodiment of the method according to the invention, the alkali metal propoxide is NaOPr. 20 In another embodiment of the method according to the invention, the 'copper catalyst is Cul In another embodiment of the method according to the invention 'depending on the solvent used and the pressure employed, the coupling reaction is effected under heating from about 70 ° C to about 120 ° C. -12- 200904811 In another embodiment of the process of the invention, the solvent used in the coupling reaction with co2 is THF. In another embodiment of the process according to the invention, the strong base used in the coupling reaction with CO 2 is n-butyllithium. 5 In another embodiment of the method according to the invention, the coupling reaction with CO 2 is carried out at a temperature below -14 ° C, and more preferably from about -22 ° C to about -14 ° C. In another embodiment of the method according to the invention, the solvent used for the esterification is dioxane. ίο In another embodiment of the method according to the invention, the coupling agent for esterification Is carbonyl diimidazole. In another embodiment of the method of the invention, the esterification is carried out at about room temperature. In another embodiment of the process according to the invention, the 15 inert solvent for bromination is a halogenated hydrocarbon More preferred is dioxane. In another embodiment of the method according to the invention, bromination is effected at a temperature of from about 0 ° C to about 100 ° C. In accordance with the invention In another embodiment of the method, the brominating agent is

Br2. In another embodiment of the method according to the invention, the alcohol solvent used for the amidoximation is ethanol. In another embodiment of the method according to the invention, the guanidine coupling is effected at a temperature of from about room temperature to about 30 °C. In another embodiment of the process according to the invention, the base used in the amilylation coupling -13-200904811 is triethylamine. In another embodiment of the method according to the invention, the deprotection reaction is carried out using an aqueous solution of the test, aqueous NaOH. In another embodiment of the method according to the invention, the deprotection reaction is effected at a temperature of from about 5 ° C to about 30 ° C. EXAMPLES Preparation Details Raw materials can be purchased or prepared by applying or modifying known methods, 10 or using their apparent chemical equivalents. The invention may be better understood by reference to the following 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. Is In the nuclear magnetic resonance spectroscopy (NMR) listed below, the chemical shift is expressed in ppm and tetramethyl 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-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxapyrrolidin-1-yl ester described in the following examples can be represented by the following scheme I. -14- 20 200904811 Schematic i /\^ONa

Example 1: 2-Iodo-4-mercaptothiophene 5 To a 3-liter 4-neck flask equipped with an overhead stirrer, a rubber septum, a thermocouple, and a nitrogen inlet/outlet, 3-mercapto π-cetin (135 mL, 1.38) was added. Mol) and THF (1 L). The mixture was cooled to -20 ° C and LDA (800 mL of Aldrich 2.5 溶于 solution in THF / heptane / ethylbenzene) was added over a 35-minute period over a 12 gauge tube to adjust the rate of addition and Cool down to maintain the reaction temperature between -25 ° C and -15 ° C. After the addition was completed, the mixture was stirred for 30 minutes and the temperature was maintained below 0 °C. In a 5 L liter flask equipped with an overhead stirrer, cold bath, nitrogen stream and thermocouple, iodine (454 g, 1.3 eq.) was dissolved in THF (1.65 L) and stirred at room temperature for 20 min to ensure completeness Dissolve and cool to -20 °C. When the solution was cold -15 - 200904811 but reached -10 ° C, iodine began to precipitate. The anion solution was allowed to warm to 〇cC and a solution of iodine was added through the catheter over a period of 4 minutes, and the rate of addition was adjusted as needed to bring the reaction temperature dimension to -15 ° C or below. When the addition was complete, the mixture was allowed to warm to 5 °C over 2 hours. The reaction was diluted with MTBE (1.0 L) and quenched with semi-saturated ammonium sulfate (500 mL). The organic layer was washed with 0.5 N sodium thiosulfate (2 x 75 mL), 2×1 L water (2×1 L) and brine (200 mL). The organic layer was allowed to stand in a separator for 4 hours and all of the separated water was withdrawn. The organic layer was concentrated to 12 l by rotary evaporation at 30 ° C and 175 mbar. 10 HPLC analysis essentially no product was detected in either the aqueous phase or the distillate. A small amount of unreacted 3-indolyl porphin is lost during washing and evaporation. Based on the recovered raw materials, the formation of the unqualified isomers, and the fact that no product is present in the washing liquid or the rotary evaporation solvent, the yield of the reaction is calculated for the purpose of estimating the Ullmann coupling reagent. 73%. 15 H R (CDCl3 ' §) 7.05 (out, dense multiplet), (6.91 (1H, dense multiplet)), (2.21, 3H,. Example 2. 4-mercapto-2-propoxy n-plug In the σ, there is a Dean-Stark trap and a top 2. A flow-through condensing H 1 part, a liquid space thermocouple, and a nitrogen inlet/outlet in a 3 liter 3 颂 flask. Example 丨 丨 丨 丨 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 1.2 In the work room, the degree of the dish reached 96. (:. The mixture was cooled to 5〇〇c and added to the solid•16·200904811

Sodium tert-butoxide (192 g '2 mol, ca. 2 equivalents) exothermed to raise the temperature to about 75 °C. The mixture was maintained at 75 and 85. (Between: until all solids were dissolved. The reaction mixture was cooled to 5 ° C and a freshly prepared copper iodide (100 mmo 19 g) slurry in n-propane (50 ml) was added. The mixture was heated to 95. (: After HPLC reaction was carried out for 30 minutes, HPLC analysis showed the reaction was completed. The mixture was diluted with heptane (1 L). Shishizao soil (190 g) was added, and the resulting slurry was stirred 60. The mixture was cooled to room temperature at the same time. The mixture was filtered and the filter cake was washed with heptane (500 mL), washed sequentially with 5% aqueous EDTA solution (3 X 500 mL), water (3 X 500 mL) and brine (500 mL) The filtrate and the washing liquid obtained a dark organic layer, which was concentrated to < 2 〇〇 mL (170 mbar' 60 〇, which gave a pale brown liquid of 159 g, which was required to be 51 A% by iH NMR analysis. The main impurities are heptane, ethylbenzene (from purchased LDA) and 2-iodo-3-mercaptothiophene. H NMR (CDC13 ' δ) 6.18 (1Η, d); 6.02 (1H, d ; 3.98(2H, t), 2,15(3H ' S) ; 2·80(2Η ' m) ; l_〇5(3H,t). Example 3: 3-mercapto-5-propoxy Sighing _2_slow acid will be the crude 4_A of Example 2 w feed group (calc = 20 is transferred to the top with stirring, thermocouple, gas gas inlet / outlet, a pressure equalizing dropping funnel and a rubber septum 2 Well 3

Dilute with THF. The mixture was cooled to ·22=f尧 bottle, and the n-butyl wire was added by adding a methane-burning solution of mL mW.4 equivalent) (the tearing method was quickly added, the temperature range was _22 to two. ' at 16 minutes Adding 1 hardened copper to the inside is freshly ground in a mortar and squeaked in the form of n-propanol poly-17- 5 14 c 'stable at about -21 ° C. Minutes 200904811 after 30 minutes 'maintains temperature At seven 〇 c卩, the reaction mixture was precipitated (d2〇 quenched) to show about 96% of the bellows. Carbon dioxide was bubbled into the mixture, and the gas flow was controlled to maintain the reaction temperature below _丨5.c. C 〇 was added until no more exotherm occurred and the reaction temperature began to decrease. The reaction was quenched with nitrous oxide in H 2 5 (_ mL) and EtOAc (50 g) was weighed. The mixture was stirred for 30 minutes and filtered with a cloth. 0.5 #NaOH (3 〇 洗 洗 饼 。 。 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽 遽When the solution is formed with a thick color/black tar, the solution is smeared with a cloth to obtain a lightly plucked filtrate. The pH value of the solution is adjusted to 4.5 即. The amount of brown sinking hall, using filter, cloth transition, washing with ice water (10 0 m L) 'air drying in glassware and drying with vacuum coal box (12 hours '30〇C '1.3 mbar)' is 3_ Methyl _5_propoxy. Cefone_2 carboxylic acid, as a beige solid (81.1 g, 80 〇 / 〇). NMR CCD Ch &gt; δ) 6.12 (1 Η &gt;s); 4.02 (3H &gt;t; 2.49(3H » s); is 1·82(2Η,m) ; 1.05(3H,t). Example 4: 2-mercapto-5-propoxy porphin-2-decanoic acid 2,5-dioxopyrrolidine ester was provided in 2 liters with top Hertz, cold, thermocouple and nitrogen inlet/outlet 2〇3 lyophilized with 3-methyl-5-propoxy porphin-2-furic acid (85.〇g, 424 mmolhN-sodium bromide (68.3 g, 14 equivalents) and dichloromethane (7 〇〇 mL), stirring at room temperature. When mixing, it exotherms and the temperature rises by 3. 匚, a brown solution is formed. The cold bath contains room temperature water, which is only used to absorb a slight exotherm. Add 26 〇g solid #,#, _ carbonyl diimidazole-18· 200904811 (104 g, 1.1 eq.) every 10 minutes. 2-3 ° C temperature rise and slow gas release will occur for each addition. After the addition was completed, the mixture was stirred at room temperature for 3 hours or stirred overnight. The reaction of the mixture was quenched with half-saturated ammonium sulfate (2 mL) and water (3 X 150 mL) and brine (15 mL) Washing. The product was isolated by solvent exchange with heptane at 5 170 mbar and 30 ° C. After solid formation, the mixture was cooled to room temperature and 5 ° C successively to give a bright yellow solid. The cloth was separated by filtration, washed with heptane, air-dried in a glassware for 20 minutes, and then further vacuum dried (3 ° C, 1.5 inches Hg) to obtain 3-mercapto-5-propoxythiophene-2-carboxylic acid. 2,5-Dioxypyrrolidine-1-1 fluorenyl (104 g, 83%) 4 NMR (CDC13, δ) 6.20 (1 Η, s); 4.05 (3H, t); 2.95 (4H, s 2.51(3H,s); 1.82(2H,m) ; l.〇5(3H,t) Example 5: 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 2 ,5-Dioxypyrrolidine 15 -1-ylindole is intended to be added to a 2-liter 3-neck round bottom flask equipped with a thermocouple, ice bath and top stir. 3-Methyl-5-propoxythiophene-2-carboxylic acid 2,5-Dioxapyrrolidin-1-yl ester (81 g, 273 mmol), isopropane (500 mL) and DCM (350 mL) gave a very dilute slurry. The mixture was cooled to &lt; At 5 ° C, a solution of bromine (22 mL, 328 mmol, 1.2 eq.) in heptane (80 mL) was added dropwise at a temperature of 4 to 11 ° C. The diluted salt 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 reaction was diluted with DCM (600 mL) and 1# thiosulfur The reaction was quenched with sodium acetate (250 mL). EtOAc &lt;RTI ID=0.0&gt;&gt; This is probably due to the fact that the material is attached to the glass so that it is not detected during solution analysis. The organic phase was dried (Na.sub.2SO.sub.4) and concentrated (30[deg.] C. The heptane (2 〇 mL) solution was treated to complete the reaction. The organic phase was partitioned between 250 mL of 1 W sodium sulphate (250 mL) and washed with water (2 X 250 mL) and brine (250 mL). Reduce the solvent volume (30 °C '125 mbar) to 300 mL and add 400 mL of heptane (to achieve some degree of crystallization). The mixture was concentrated to dryness by rotary evaporation to give a brown solid. The crude product was recrystallized from refluxing IPA (500 mL) and dried (40 ° C, 1.5 inch Hg) to give 93 g of 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylic acid 2 , 5-dioxypyrrolidine, i.e., a brown solid (91 〇/〇). NMR (CDC13' δ) 4.19 (2 Η s); 2.92 (4H, s); 3.59 (3H, s); 1.95 (2H, m); 1.08 (3H, t). Example 6: [4_(5-Aminoguanidino-2-fluorophenyl)-hexahydropyridine small group]_(4_演_3·Methyl-5-propoxythiophen-2-yl)-A Ketone in a 5 liter, 3-neck round bottom flask with 2,2,2•trifluoro_N_(4_fluoro_3_hexahydropyridin-4-ylbenzoinyl)-acetamide hydrochloride (176 7 g) , 〇518 m〇1) and 1.51 L of anhydrous EtOH. The mixture was stirred and triethylamine (215 mL, 1.55 mol) was added. The mixture was stirred for 3 minutes and then 2,5-dioxapyrrolidinyl 4-bromo-3-indolyl-5-propoxythiophene-2-carboxylate (194 g, 0.516 mol) was added. The mixture was warmed to 26. (:. Stir the reaction mixture for 18 hours' then distribute between 1·5 L of water and 1.5 L of TBME. Use -20-200904811 water (2 x 0.5 L), 1 N HCl (0.5 L) in water and brine ( 0.2 L) Wash the organic phase. The dark amber organic phase was filtered through a short SiO 2 pad (h = 0.5 s, φ = 3.5 s) and eluted with 0.3 L of EtOAc. No significant color reduction was observed. The solution was cooled to 7°. C, adding 194 mL of 50% aqueous NaOH solution, the exotherm causes the mixture to warm to 24 ° C. After 3 hours, the mixture is washed with water (2 X 1 L, 1 X 0.8 L) and brine (0.5 L), then used The organic phase was dried over sodium sulfate. The solution was cooled to <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; The product was isolated by filtration (substantially slow), washed with MTBE and dried with air for 15 hours to give 130.2 g (50%) of [4-(5-aminomercapto-2-fluorophenyl)-hexazaindole · 1 -yl]-(4-di-3-methyl-5-propoxy porphin-2-yl)-曱嗣' is a pale beige solid. -21 -

Claims (1)

200904811 X. Patent application scope: L ~ species preparation [4-(5-aminomercapto-2-fluorophenyl)-hexahydroacridin-1-yl] (4-> odor-3-mercapto-5 -Propoxy °ephen-2-yl)-oxime, comprising the steps of: 10 4-bromo-3-methyl-5-propoxythiophene-2-carboxylic acid 2,5-dioxo Pyrrolidin-1-yl ester and 2,2,2-trifluoro-N-(4-fluoro-3·hexahydropyridin-4-yl-p-methyl)-acetamide hydrochloride and strong base or tertiary amine Amidoximation coupling reaction occurs in an alcohol solvent to form 2,2,2-tris-(^-{3-[4-(4-bromo-3-indolyl-5-propoxy porphin-2) -monoyl)-hexahydropyridin-4-yl]-4-fluoro-azainyl}-acetamide; and 2,2,2·trifluoro-Ν-{3-[1-(4) with a base -Bromo-3-methyl-5-propoxythiophene-2-carbonyl)-hexahydropyridine_4_yl]_4_fluoro-benzylideneamine deprotected to form [4-(5- Aminoguanidino-2-fluorophenyl hexahydropyridin-1-yl]-(4-/odor-3-methyl-5-propoxy0-cetyl-2-yl)-methanone. For the method of claim i, the alcohol solvent used in the (4) amination coupling reaction is ethanol. 20 3. 4. The method of application (4), wherein the lysine coupling reaction is about room temperature to about Take For example, in the case of the patent application, the method for the production of the hydrazine coupling reaction is triethylamine. The method of the solution is carried out in a solution of aqueous NaOH. The deprotection is the water used in the test. 6. The method of claim 1 wherein the deprotection is carried out at a temperature of about 5 ° C -22 · 200904811 to about 30 ° C -23- 200904811 VII. Designation of representative drawings: (1) The representative representative of the case is: (No). (2) The symbol of the symbol of the representative figure is simple: None. 10 8. If there is a chemical formula in this case Please reveal the chemical formula that best shows the characteristics of the invention: None. 20