TWI290133B - Process for preparation of tamsulosin and its aralkylamine derivatives - Google Patents

Abstract

The present invention discloses a new process for the synthesis of tamsulosin and its aralkylamine derivatives, especially (R)-(-)-5-{2-[2-(2-alkoxyphenoxy) ethylamino] propyl}-2-alkoxybenzenesulfonamides having the following formula 1 (where R1 and R2 represent C1-C4 alkyl groups) and their hydrochloride thereof, and other various pharmaceutical used salts. Tamsulosin hydrochloride (R1=Et, R2=Me, in its hydrochloride salt form) is an antagonist of alpha-A adrenoceptors in the prostate. Tamsulosin HCl occurs as white crystals, which melt with decomposition at approximately 230 DEG C. It is sparingly soluble in water and in methanol, slightly soluble in glacial acetic acid and in ethanol, and practically insoluble in ether.

Description

</ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; And other kinds of sleeping medicines that can be used in medicine. This method is more efficient in preparation than the conventional method in which the total yield of the tamsulosin compound of the synthetic formula 1 is high and the number of reaction steps is small. In the present invention, the use of optically pure starting materials provides a more specific specification of the desired starting material product to meet pharmaceutical requirements. In addition, fewer reaction steps will advantageously result in impurities contained in the desired drug being within the upper limits of the specification. [Prior Art] It is described in U.S. Patent No. 5,447,958 that the above-described tamsulosin compound of the formula 1 has an excellent effect against hypertension, heart failure, angina pectoris and prostate enlargement. Further, the above-mentioned patent discloses a method for preparing a tamsuloxin compound of the formula 1, which is obtained by reacting a decanoate of the following formula 2A and an amine of the formula 3:

H2N〇2S^p^^NH2 Lu Me

2A wherein, the sulfonamide salt of the formula 2B (the citrate of the sulphate compound of the formula 2A) can be synthesized by the preparation of the scheme i, which is prepared by starting from the phenylamine compound of the formula 4A, and sequentially producing the ruthenium compound, The intermediate product of the 6A light amine compound, and finally the formula of the amine salt. Process 1 · 7 1290133

NHAC 1=c, 〇h 2. NH3, THF r.t., 1.0 h

The synthesis of the phenylamine compound of formula 4A is disclosed in U.S. Patent No. 4, 〇〇〇, 197 and

Med·Chem. 1973, 16, 480-483, by condensation of 4-methoxyphenylacetone with (R)-methylbenzylamine followed by hydrogenation of the N=N double bond and reductive debenzylation Base reaction. The total yield of the phenylamine compound of formula 4A is 25%, and its purity to palmar isomer is greater than 99%. In Synth Commun. 1998, 28, 1935 - 1945, Yamada et al. describe a method of synthesizing a phenylamine compound of the formula 4A using an optically pure L-tyrosine as a starting material. An advantage of this reaction is that the product formed is optically pure. Preparation of Intermediate The phenylamine salt of the formula 4B (the decanoate of the phenylamine compound of the formula 4A) comprises a total of 8 steps, and if it extends to the intermediate compound of the formula 5A, it is 9 steps. Yamada's process is condensed in flow Ο · Process 2: 8 1290133

SOCI2 EtOH

PhCH2OCOCI Cbz=PhCH2OCO 8

NHCbz 9

Mel, K2C03 DMSO

NaBH4 H20 ^NHCb. 1. TsCU-Bu4NHSO, || Nal, THF(aq) 2. NaOH (aq&gt;, benzene Me〇 \ OTs 12

NHCbz 11

Me〇

H2&gt; Pd/C (10%) THF, 10% HCI’ MeO

HCI 4B NH2 is prepared starting from the tyrosine compound of formula 7 in Scheme 2, and the amine compound of formula 8, the phenolamine compound of formula 9, the hydrazine oxime ester compound of formula 9, the formula ol 醯An amine compound, a phenyl hydrazine compound of the formula 12, an iodine compound of the formula 13 and an ether oxime compound of the formula 14 'finally prepare a phenylamine salt of the formula 4B. [Summary of the Invention]

The present invention relates to a novel method for synthesizing an amine sulfonyl substituted phenethylamine derivative and tamsulosin, in particular a stansole compound having the following formula 1 (in the formula 1, Rl &amp; R represents a Ci-C4 alkyl group) and Its citrate, and various other pharmaceutically acceptable salts. Η

H2N02S R2〇Me 1 As previously mentioned, the synthesis of the stansole compound of formula 1 (R1 = ethyl, R2 = methyl) is related to the key intermediate of the formula 5A guanamine compound. Herein, the present invention, as shown in the following Scheme 3 9 1290133, discloses a novel method for preparing a key intermediate of the formula 5A guanamine compound, which comprises a phenolphthaleic acid compound of the formula 15A, a phenolphthalein compound of the formula 16A, and a formula 17A. An intermediate such as an ether decylamine compound and an alcohol ether oxime compound of the formula 18A, and these compounds are novel intermediates newly prepared.

• The overall yield of the compound of the formula 1 in the synthesis of the tamsulosin is higher than the conventional method and the reaction step is less, making it more efficient in preparation. Furthermore, the present invention uses optically pure starting materials to provide compounds of a particular specification to meet pharmaceutical requirements. In addition, fewer reaction steps will advantageously control the impurities contained in the desired drug to within the upper limits. The present invention also discloses "the key cap type 21A _ benzene sulfonate compound, and = 3 deserts to prepare the formula stansole compound, using 2-ethoxyphenyl (10) as the starting material, and using chlorohydrin and 19A_ compound reaction, and decyl alcohol compound, and then with p benzene continued to test, in order to obtain _ bond intermediate formula 1290133 benzene sulfonate compound. The advantage of using the ether benzene hydrazine compound of formula 21A in place of formula 3 bromide is that it simplifies the reaction steps and avoids contamination by hazardous waste. The method for producing the ether phenyl sulfonium compound of the formula 21A is as shown in the following Scheme 4, after converting the ether phenol compound of the formula 19A into the ether phenyl alcohol compound of the formula 20A to prepare an ether benzoquinone compound of the formula 21A.

HO

Process 4: EtO

19A

By the established method, the intermetallic compound 5A guanamine compound is converted into the formula 6a, and the compound is then subjected to an acidic condition to obtain a hydrazine salt. The hexahydroamine salt is then reacted with a compound of formula 21A to produce the desired tamsulosin =losin' formula u R1 = ethyl, R2 = methyl). The step of synthesizing the scleroside compound of formula i is shown in Scheme 5. Process 5:

[Embodiment] The present invention relates to a novel process for preparing an aminesulfonyl substituted phenethylamine derivative and an acid salt thereof to form an amine salt. The process for preparing the phenolphthalic acid compound of the formula 15 from the starting material of the formula 7 tyrosine (L-Tymsine) is as follows in Scheme 6. Process 6:

The preparation method uses a deuteration agent and a solvent; the deuteration agent is RC Ο X, (RC0) 20 or a combination thereof, wherein R is an alkyl group or an aryl group, X is a halogen or a leaving group; the solvent is a hydrocarbon Alkanes, ethers, dimethylformamide, dimethylhydrazine, ketones, urea or any combination thereof. A process for preparing a phenolphthalein compound of the formula 16 from the phenolphthalic acid compound of the formula 15 is as shown in the following Scheme 7. Process 7 ·’

Wherein, the method uses ruthenium chloride and R'OH; ruthenium chloride phosphorus trichloride, phosphorus pentachloride, phosphonium pentachloride (P〇Cl5), sulfinium chloride, ethylene dichloride or a combination thereof; And the R' group represents an alkyl group or an aryl group. A method of preparing an ether oxime ester compound of the formula 17 from the phenolphthalein ester compound of the formula 16 is as described in Scheme 8 below. Process 8: 12 1290133

The method uses an alkylating agent, a base and a solvent; wherein the alkylating agent is a dialkyl sulfate, an alkyl iodide, an alkyl bromide or a combination thereof; the alkali is an aminide, a carbonate, a hydrogencarbonate, a guanamine, The alkoxide or a combination thereof is water, a ketone, a hydrocarbon alkane, an ether, dimethylformamide, dimethylhydrazine, a ketone, urea or a combination thereof. A method for preparing an alcohol ether oxime compound of the formula 18 from the ether ketamine compound of the formula 17, as shown in the following Scheme 9, 0.

The method uses a reducing agent and a solvent; wherein the reducing agent is lithium aluminum hydride (LiAlH4), diisobutylaluminum hydride (DIBAL), potassium triisobutylborohydride (K-selectride), lithium triisobutylborohydride ( L-sdectride), boron hydride (BH3), sodium borohydride (NaBEU) or a combination thereof; the solvent is ether, alcohol, water, alkane, dimethylformamide, dimethyl hydrazine, Urea or a combination thereof. According to the following Scheme 10, the hydrazine 18 alcohol ether decylamine compound can be used to prepare the hydrazide compound of the formula 5

Process 10 =

1. acid halides, solvent 2. acids, MXn, M, solvent

The method uses hydrazine halide, solvent, organic acid compound, MXn and M; wherein hydrazine is toluene sulfonium chloride (TsCl), methyl sulfonium chloride (MsCl), sulfoxide chloride 13 1290133 (soci2), thioindigo Chlorine (so2ci2), phosphorus trichloride (PC13), phosphorus pentachloride (PC15), phosphonium pentachloride (Ρ〇α5), ethylene dichloride or a combination thereof; solvent is tetrahydrofuran, ketones, hydrocarbons , ethers, dimethylformamide, dimethyl argon, dichloromethane, chloroform, tetrachloromethane, urea or a combination thereof; the organic acid compound is oxalic acid ((COOH) 2), RCOOH or a combination thereof, wherein R is hydrogen, alkyl or aryl; hydrazine is lithium, sodium, potassium, magnesium, calcium, zinc, stuffing, palladium, copper, cobalt, manganese, iron, nickel or cadmium, and X is chlorine , bromine, iodine or acetate, and the enthalpy of η is 1-3 depending on the valence of the metal. According to the above, the preparation of the stansole compound of the formula 1 is related to the key intermediate compound of the guanamine compound, and the guansulfuron compound of the formula 1 can be synthesized from the guanamine compound of the formula 5 obtained above. The invention may be further understood by the following examples, which are not to be construed as limiting. - Example 1

An aqueous solution containing tyrosine compound of formula 7 (20.01 g, 110.4 mmol) (120 mL of acetic anhydride (13.51 g, 132.4 mmol) was added. After heating for 4 to 5 hours, the solution was concentrated by distillation to give a pale yellow color. The residue was dissolved in acetone (80 mL), and the unreacted tyrosine of formula 7 was removed by filtration. The filtrate was concentrated under reduced pressure and the residue was redissolved in ethyl acetate. 1 〇〇mL), washed with water (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a crude phenolic acid compound of formula 17.62 g, 78.93 mmol): mp (recrystallized from methanol) 152-153 °C; optical rotation [α 】 mutually = +50.9720. 咁 NMR (D20,400 MHz) δ 2·07 (s,3 Η? COCH3 ) 2.82-2.86 (m5 1 Η, ArCHH), 2.96-3.01 (m, 1 Η, ArCUH) y 3.67-3.70 (m? 1 H, CHCOO), 6·70 (d, J = 8.0 Hz, 2 H , ArH), 7.01 (d, J = 8.0 Hz, 2 H, ArH); IR (neat) 3207 (s), 2961 (m), 1609 (s), 1591 (s), 1513 (s), 1455 ( s), 1417 (s), 1363 (s), 1331 (s), 14 1290133 1267 (m), 1245 (8), 1214 (m), 1154 (m), 1112 (m), 1099 (m), 1042 (m), 984 (w), 939 (w), 897 (w), 877 (m), 841 (8), 794 (m), 740 (m), 713 (w ), 649 (m), 575 (s), 529 (s), 493 (m), 433 (m) cm-1· Example 2

16A

For diethyl ether solution (300 mL) containing the phenolphthalein compound of formula 15A (10.01 g, 44.84 mmol), phosphorus trichloride (18.46 g) was added dropwise over 60 minutes under ice-cold cooling (5 °C). , 134.4 mmol) After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (EtOAc) (EtOAc)EtOAc. Dark yellow solid of the amine ester compound 16A (8.225 g, 32.73 mmd)·· mp (recrystallized from 50% ethyl acetate in hexane) 126·(Μ28·0 〇C; optical rotation [α] = _17632. 1H NMR (CDC13, 400 MHz) δ 1·24 (t, J = 6.8 Ηζ, 3 H, CH2C//3), 1.97 (s, 3 H, COCH3) 2.95-3.08 (m, 2 H, ArCH2), 4.16 (q, J = 6.8 Hz, 2 H, COCH2), 4.79-4.82 (m, 1 H, CHCOO), 6.71 (d, J = 8.0 Hz, 2 H, ArH), 6.94 (d, J = 8.0 Hz) , 2 H,ArH); IR (neat) 3384 (br)? 3020 (m)? 2927 (m)? 2851 (m)5 1733 (s), 1652 (s), 1615 (s), 1542 (m) 5 1516 (s), 1446 (m), 1376 (m), 1219 (s), 1125 (w), 1026 (w), 828 (w), 769 (s), 668 (m), 518 (m) Cm-1. Example: ^NHAc

MeO C02Et

17A 15 1290133

To a solution of the phenolphthalein compound of formula 16A (8.021 g, 31 · 92 mmol) in acetone (35 mL) was added triethylamine (7.365 g, 72.78 mmol) and dimethyl sulfate (5.473 g, 43.39). After stirring at a temperature of 25 ° C for 20 hours, water (50 mL was poured into the solution to stop the reaction, and extracted with toluene (50 mL). The organic layer was treated with 10% aqueous sodium hydroxide ( 25 mL) was washed with brine (25 mL) and dried over magnesium sulfate, filtered, and then evaporated. Mmd): mp (recrystallized from ethyl acetate) 140-142 °C vortex ratio [α 】$ = —1.6950. 屯NMR (CDC13, 400 ΜΗζ) δ 1.21 (t, J = 6·8 Hz, 3 H, CH2Cii3), 1.92 (s, 3 H, COCH3), 3.02-3.09 (m, 2 H, ArCH2), 3.95 (s, 3 H, OCH3), 4.14 (q, J = 6.8 Hz, 2 H, COCH2 ), 4.76-4.81 (m, 1 H, CHCOO), 6.76 (d? J = 8.0 Hz, 2 H, ArH), 7.02 (d, J = 8.0 Hz, 2 H, ArH); IR (neat) 3282 ( m), 3075 (w), 2968 (m), 2933 (m), 2837 (w), 1716 (w), 1651 (s), 1614 (8), 1557 (8), 15 14 (8),1456 (8),1374 (8), 1300 (m), 1248 (s), 1178 (m), 1146 (w), 1114 (w), 1035 (m), 975 (w), 815 (w), 775 (w), 608 (w), 562 (w), 523 (w), 419 (w) cm-, Example 4

^^^NHAc

wide,. H

18A was added to a solution of lithium hydride containing lithium aluminum hydride (LiAlH4, 6.083 g, 160.3 mmol) in a stirred solution of 140 liters of ether amide compound (7.088 g, 26.72 mmol) of a solution of diethyl ether (5 〇mL). After stirring at a temperature of 25 ° C for 10 hours, excess lithium aluminum hydride was slowly added to acetone (20 mL hydrazine) under ice-water at 5-10 ° C. The mixture was neutralized with EtOAc (EtOAc) (EtOAc) (20 mL), brine (20 mL), EtOAc (EtOAc m.克,16.03 mol):mp (recrystallized from ethyl acetate and hexanes) 13⁄4-130 °C; optical rotation [α] $ = -10.9440.; 1H NMR (CDC13, 400 MHz) δ 1·95 (s ,3 H,NCOCH3),2·40 (br,1 Η, ΟΗ), 2.75-2.85 (m,2 Η,ArCH2),3.57-3.67 (m,2 Η,CH20),3·74 (s,3 Η, OCH3), 4.08-4.14 (m, 1 H, CHN) 6.84 (d, J = 8.4 Hz, 2 H, ArH), 7.12 (d, J = 8·4 Hz, 2 H, ArH); IR (neat) 3512 (br), 3002 (w), 2948 ( m), 2834 (m), 1892 (w), 1645 (8), 1577 (m), 1551 (m), 1511 (8), 1441 (m), 1377 (m), 1300 (s), 1245 (8), 1177 (8), 1083 (m), 1041 (s), 821 (m), 614 (m) cm-1· Example 5

To a solution of the alcohol ether oxime compound of formula 18A (10.01 g, 44.83 mmol) in tetrahydrofuran (50 mL), toluene (15.67 g, 82.19 mmol). After stirring for 1.5 hours under reflux, the reaction mixture was slowly poured into a saturated aqueous solution of potassium carbonate. The aqueous layer was extracted with ethyl acetate (3×20 mL), and then evaporated and evaporated. The residue was dissolved in tetrahydrofuran (160 mL) containing EtOAc (EtOAc) (EtOAc) After stirring for 1 minute in reflux, lithium (wire, 1.488 g, 214.4 mmol) was added to the solution. The resulting solution was stirred at the same temperature for 2 hr, filtered over Celite, washed with ethyl acetate and evaporated. The residue was dissolved in water (50 mL), EtOAc (EtOAc) The organic layer was washed with water (40 mL) and evaporated, evaporated, evaporated, evaporated, evaporated. Solid (6.711 g, 32.37 mmol): mp (recrystallized from ethyl acetate) 90-91 °C; optical rotation [α] + 9.9083°; !H NMR (CDCIs, 300 MHz) δ 1.08 (d, J = 5.4 Hz, 3 H? CCH3), 1.92 (s, 3 H, COCH3), 2.60 - 2.77 (m5 2 H, ArCH2), 3.76 (s, 3 H, OCH3), 4.HM.25 (m, 1 H, 17 1290133 CHMe), 6.81 (d, J = 7.8 Hz, 2 H, ArH), 7.06 (d? J = 7.8 Hz, 2 H, ArH); IR (neat) 3276 (10), 3077 (4), 2969 (10), 2933 (4) , 2836 (four), 1716 (four), 1647 (s), 1615 (s), 1542 (s), 1513 (s), 1456 (four), 1374 (10), 1300 (four), 1247 (s), 1178 (10), 1035 (four), 814 (four), 755 (w), 518 (w), 420 (w) cm-,

Example 6

NHAc

Add chlorosulfonic acid (10.1 g, 85.8 mmol) hydrazine solution to the hydrazine sulfonate (10.1 g, 85.8 mmol) solution of the formula 5A at a temperature of 〇-10 °C for 1 〇 hr at 5.00 ° C. The reaction mixture was poured into EtOAc (EtOAc)EtOAc. The organic layer was washed with EtOAc EtOAc. The residue was redissolved in tetrahydrofuran (20 mL), then concentrated aqueous ammonia (15 N, 30 mL). The solution was concentrated under reduced pressure and the residue was purified eluted with water (2················ Mm): mp (recrystallized from methanol) 198-199 〇C; optical rotation [α 】 blue = +13.2634. ; iHNMR (〇2〇, 400 MHz) δ 0.99 (d, J = 6·8 Hz, 3 H, CCH3), 1.68 (s, 3 H, COCH3), 2·43-2·49 (m, 1 H , ArC//H), 2.69-2.74 (m, 1 H, ArC_, 3.72 (s, 3 H, OCH3), 3.80-3.86 (m, 1 H, CHMe), 7.01 (d, J = 8.8 Hz, 1 H,ArH), 7.33 (d, J = 8.8 Hz, 1 H, ArH), 7.48 (s, 1 H, ArH); IR (neat) 3132 (br), 1654 (s), 1609 (m), 1536 (m), 1496 (m), 1401 (s) 5 1320 (m), 1283 (m), 1253 (m), 1176 (w), 1148 (s), 1070 (m), 1024 (m), 977 (w), 927 (w), 860 (w), 838 (w), 828 (w), 761 (m), 701 (w), 669 (w), 614 (m), 599 (m), 572 (m), 535 (m), 505 (m), 450 (m) cm-1; ESI-MS m/z 287.27 (M + ΗΓ). Example 7 18 1290133

Nh2

HCI

Aqueous hydrochloric acid (5.0%, 25 mL) containing sulfonamide compound of formula 6A (0.541 g, 1.88 mmol) was heated under reflux for 16 hours. The solution was concentrated under reduced pressure and dissolved in hot methanol (3 mL) and ethyl acetate (10 mL). The precipitate was collected and dried in vacuo to give a white solid (0.449 g, 1.60 mmol) of sulfonamide salt of formula 2B in 85% yield: mp (recrystallized from methanol) 272-273 °C (decomposition); Rate [α] Bu-9.2040.屯NMR (D20, 400 ΜΗζ) δ 1.14 (d, J = 6·4 Hz, 3 H, CCH3), 2.79-2.82 (m, 2 H, ArCH2), 3.43-3.56 (m5 1 H, CHMe), 3.84 (s, 3 H, OCH3), 7.10 (d, J = 8.4 Hz, 1 H, ArH), 7.42 (d, J = 8.4 Hz, 1 H, ArH), 7.58 (s, 1 H, ArH); IR (neat) 3329 (s), 3196 (s), 3150 (8), 3025 (8), 2944 (s), 2701 (w), 2590 (w), 2501 (w), 1611 (m), 1553 (m), 1496 (s), 1402 (s), 1327 (s), 1282 (m), 1255 (m), 1154 (s), 1075 (m), 1017 (m), 928 (m), 828 (w), 804 (m), 703 (m), 601 (s), 572 (m), 536 (m), 507 (m) cm-1; ESI-MS m/z 245.15 (M + ; Anal· Calcd for C10Hi7N2 〇3SC1: C, 42·78; H, 6.10; N, 9.98. Found: C, 42.76; H, 6.15; N, 9.93. Example 8

For aqueous sodium hydroxide solution (1·〇 N, 300 mL) containing the ether phenol compound of formula 19A (13.82 g, 0·1000 mol), chlorohydrin (33.12 mL, 0.5001 mol) was added. After stirring at a temperature of 25 ° C for 48 hours, the reaction mixture was extracted with ethyl acetate (3×100 mL). The organic layer was dried over MgSO4, filtered and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj CDC13, 400 MHz) δ 1.44 (t, J = 7.2 Hz, 3 H, OCH2C//3), 3.85 (t, J = 7.2 Hz, 2 H? C//2〇H), 4.05-4.12 (m, 4 H, OC//2CH3 + OC//2CH2OH), 6.88-6.97 (m, 4 H, ArH); IR (neat) 3547 (br), 3066 (m), 2977 (8), 2931 (8), 2877 (s) , 1739 (m), 1649 (m), 1593 (s), 1503 (s), 1455 (s), 1393 (m), 1324 (m), 1253 (s), 1219 (s), 1123 (s) , 1041 (s),922 (8) cm-1

Example 9 EtO TsO\/\ Ό

21A To a solution of the ether phenyl alcohol compound of formula 20A (501.2 mg, 2.751 mmol) in dichloromethane (20 mL) at a temperature of 5-10 ° C, triethylamine (5 〇 9 mg, 5.03 mmol) Toluene sulfonium chloride (623 mg, 3.27 mmol). After the solution was stirred at a temperature of 25 ° C for 30 minutes, the reaction was quenched with saturated aqueous sodium sulfate (2 mL) and ethyl acetate (3 X 50 mL) And concentrated under reduced pressure to give a white solid of mp mp. ) δ 1.43 (t, J = 10.2 Hz, 3 H? OCK2CH3\ 2.51 (s, 3 H, ArCH3) 5 4.04 (q, J = 10.2 Hz, 2 H, OCi/2CH3), 4·36 (t, J = 6.9 Hz, 2 H3 〇C/f2CH2), 4.59 (t, J = 6.9 Hz, 2 H, OCH2C//2), 6.86-6.97 (m, 4 H, ArH), 7.10-7.22 (m, 4 H ,ArH); IR (neat) 3446 (br), 2982 (m), 2934 (m), 2884 (m), 1591 (8), 1558 (w), 1509 (8), 1478 (s), 1454 (s), 1407 (s), 1394 (8), 1371 (s), 1354 (8), 1279 (m), 1259 (s), 1247 (8), 1217 (s), 1178 (8), 1127 (8), 1066 (s), 1043 (s), 1031 (8), 977 (8), 929 (s), 905 (8), 8 () 9 (8), 776 (four), 749 (8), 776 (four) cm - 1 Example 10 20 1290133

To a solution of the sulfonamide salt of the formula 2B (1·12 g, 3.995 mmol) in ethanol (40 mL) was added sodium bicarbonate (672·2 mg, 8. After the solution was stirred at room temperature for 5.0 minutes, an ether benzenesulfonate compound of formula 21A (1.34 g, 4.00 mmol) was added. The solution was stirred at 90-100 ° C for 22 hours, the reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure and dried in vacuo. The semi-solid formed was dissolved in dichloromethane (50 mL) and the solid was filtered and washed with dichloromethane (3 X 5.0 mL) to recover the unreacted sulfonamide compound of formula 2A from the residual solid. The filtrate was concentrated under reduced pressure and the residue was dissolved in methylene chloride (50 mL) and washed with water (3 X 25 mL). The aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The organic layer of formula 2A was recovered from the organic layer. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The carbon (3 X 20 mL) was washed, and the ether phenol compound of the formula 19 was recovered by concentrating the carbon tetrachloride solution. Purification of the solid by column chromatography using silica gel (37% methanol in chloroform as a solvent) afforded 35% yield of formula 1 tamsulosin white solid (571.2 mg, 1,397 mmol): mp ( Recrystallization in dichloromethane and ethyl acetate) 129-131 ° C; optical rotation [α] Art II - Μ · 724 〇. 1H NMR (CD3OD, 400 MHz) δ 0·99 (d, J = 6·4 Hz, 3 H, NCHCi/s), 1·28 (t, J = 7.2 Hz, 3 H, OCH2C/i3), 2.49-2.54 (m,1 H,ArCHH),2·77-2·82 (m,1 H,ArCH//), 2.89-2.98 (m,3H,NCH2 + NCH),3.88 (s,3 H, OCH3), 3.93U7 (m, 4 H, CH2C//20 + CH3C7/20), 6.81-6.89 (m5 4 H, ArH), 7.03 (d, J = 8.4 Hz, 1 H, ArH), 7.36 (d , J = 8·4 Hz, 1 H, ArH), 7·63 (s, 1 H, ArH); IR (neat) 3284 (m), 2973 (m), 2939 (m), 1592 (m), 1504 (s), 1442 (m), 1324 (8), 1282 (m), 1249 (8), 1214 (m), 1154 (8), 1125 (m), 1073 (m), 1046 (m), 971 (w), 925 (m), 753 (m) cm-h ESI-MS m/z 409.40 (M + H+)· 21 1290133 Example 11

H2N02S\^^^/N

HCI

Me

MeO

Tamsulosin · HCI

A solution of the solution of tamsulosin (2.011 g, 4.917 mmol) in methylene chloride (50 mL) was taken at a temperature of 〇 -5 ° C, and passed through an excess of dry hydrogen chloride gas for 1 hour. The formed precipitate was filtered and dried under vacuum at room temperature to give a white solid (2·〇91 g, 4 -9 mmol) of tamsulosin. 〇% methanol recrystallized from ethanol) 230-231 °C; = -53843^ iHNMR^O, 400 ΜΗζ)δ 1.1Φ-1.17 (m,6H5NCHC//3 + OCH2C//3),2·71-2.76 (m,1 Η, ArC//H), 2.95-3.00 (m,1 Η, ArC_,3·36-3·43 (m, 2 H,NCH2), 3.53-3·55 (m,1 H, NCH), 3.75 (s, 3 H, OCH3), 3.94-3.97 (m, 2 H, MeCH20), 4.04-4.19 (m, 2 H, OC//2CH2), 6.84~6·96 (m, 5 H,ArH), 7.35 (d, J = 8·8 Hz, 1 H,ArH), 7,54 (s,1 H,ArH); IR (neat) 3304 (m),3168 (m),2981 (m), 1610 (m), 1589 (m), 1500 (s), 1458 (m), 1392 (m), 1339 (s), 1251 (s), 1215 (s), 1160 (s), 1128 (s), 1072 (m), 1046 (m), 1018 (m), 820 (m), 749 (8), 718 (m) cm-1 In the present invention, a method for preparing tamsulosin and its related a method for the synthesis of aryl hydrazino derivatives. For the tamsulosin compound, the synthesis of L-tyrosine from the starting material is required. The conventional method is more short and has a higher yield. In addition, the key intermediates 15A to 18A required for the preparation of the tamsulosin of the formula 1 are also representative intermediates in the present invention. Brief description] No [Main component symbol description] Benefit 22

Claims (1)

1290133 —_ ______________] Year #月7日修(更)本本/公&quot;·告十, application patent scope: ~ 1. A method for preparing tamsulosin, which has the following formula 1 Molecular formula: The method includes: The sulfonate of the formula 2 is reacted with the ether compound of the formula 21 to obtain the tamsulosin of the formula 1; Wherein, R1 of the formula 1 tamsulosin is ethyl and R2 is a methyl group, wherein R in the formula 2 represents Me, that is, as shown in Formula 2A, and the citrate thereof is represented by Formula 2B; and the ether compound in Formula 21 Wherein R' represents Ret, and R" represents OTs, as shown by the ether benzenesulfonate compound of Formula 21A; NH, 21A: and HCI; and a preparation method of the sulfonate of the sulfonamide compound of the formula 2B, comprising: reacting the hydrazine compound of the formula 5A with (8) chlorosulfonic acid, and then reacting with (b) ammonia water and tetrahydrofuran to convert into The sulfonamide compound of the formula 6A is further obtained by the aqueous solution of the sulfonamide compound of the formula 2B, as shown in the following scheme: 23 1290133 2. The method for preparing tamsulosin according to claim 1, wherein the preparation of the guanamine compound of the formula 5A uses the following intermediates: (1) a phenol phthalic acid compound of the formula 15 shown below : HO Wherein R represents an alkyl group or an aryl group; (2) a phenolphthalein ester compound of the formula 16 shown below: Wherein R, R' represents an alkyl group or an aryl group; (3) The ether oxime ester compound of the formula 17 shown below: ^NHCOR RO C02R, wherein R, R', R" represents a hospital group or an aryl group; and (4) an alcohol ether oxime compound of the formula 18 shown below: 24 12,90133 wherein R and R' represent an alkyl group or an aryl group. 3. The method for preparing tamsulosin according to claim 1, wherein the ether benzenesulfonate compound (R) represents p-toluenesulfinate (MeC6H4S02 salt methylsulfonyl (MeS02)). The preparation is carried out by converting the ether phenol compound of the following formula 19 into an ether phenyl alcohol compound of the formula 20, and then preparing the ether benzene sulfonate compound of the formula 21; Wherein R represents an alkyl group or an aryl group. 4. A method of preparing tamsulosin having the formula of the following formula 1: Wherein, the method for forming the formula 1 Tanselexin comprises the starting material of the formula 7 tyrosine, the phenol phenolic acid compound of the formula 15, the phenol phenolamine compound of the formula 16, the ether oxime ester compound of the formula 17, the alcohol ether of the formula 18 The guanamine compound forms a guanamine compound of the formula 5, which comprises the steps of: reacting a sulfonate of the sulfonamide compound of the formula 2 with an ether compound of the formula 21 to obtain a tamsulosin of the formula H2N02S R«〇Me RO 2 wherein, R1 of the formula 1 is a ethyl group, and R2 is a methyl group. In the formula 2, R represents Me, that is, as in the formula 2A, and the citrate is as in the formula 2B. And; in the ether compound of the formula 21, R represents a segment, and R" represents 〇Ts, as shown by the ether benzenesulfonate compound of the formula 21A; 25 1290133 Nh2 HCI: and Wherein the preparation method of the sulfonate of the sulfonamide compound of the formula 2B comprises: reacting the hydrazine compound of the formula 5A with (a) a sulfonic acid chloride, and then reacting with (b) ammonia water and tetrahydrofuran to convert into a sulfonium of the formula 6A. The amine compound, and then the aqueous solution of the sulfonamide compound of the formula 2B, is obtained as the following scheme: c H2N02S NHA MeO^^ Me 6A wherein the 5-amine compound has the following molecular formula: And the preparation of the 5 guanamine compound uses the following intermediates: (1) The phenol phthalic acid compound of the formula 15 shown below: Wherein R represents an alkyl group or an aryl group, and the phenolphthaleic acid compound of the formula 15 is prepared from the starting material of the formula 7 carbamic acid. 26 1290133 The starting material of the formula 7 tyrosine has the following molecular formula: The preparation method uses a deuterating agent selected from the group consisting of RCOX, (RC0)20 or a combination thereof, wherein R is an alkyl group or an aryl group, wherein X is a halogen or a leaving group, wherein the solvent is It is selected from the group consisting of alkane, ether, dimethylformamide, dimethylhydrazine, ketones, urea or any combination thereof; • (2) the phenolphthalein compound of the formula 16 shown below: Wherein R, R' represents an alkyl group or an aryl group, and the phenolphthalein ester compound of the formula 16 is prepared from a phenolphthalic acid compound of the formula 15, the preparation method using ruthenium chloride and ROH, and the ruthenium chloride is selected from the group consisting of trichloro Phosphorus, phosphorus pentachloride, phosphonium pentachloride (P0C15), sulfinium chloride, ethylene dichloride or a combination thereof; (3) the ether amidine compound of the formula 17 shown below: Wherein R, R', R" represents an alkyl group or an aryl group, and the ether decylamine ester compound of the formula 17 is prepared from a phenolphthalein ester compound of the formula 16, which is prepared by using an alkylating agent, a base and a solvent. The alkylating agent is selected from the group consisting of dialkyl sulfate, alkyl iodide, alkyl bromide or a combination thereof, and the alkali is selected from the group consisting of an amine compound, cesium carbonate, cesium hydrogencarbonate, decylamine, alkoxide or a combination thereof, and a solvent. It is selected from the group consisting of water, ketones, hydrocarbon alkanes, ethers, dimethylformamide, dimethylhydrazine, ketones, urea or a combination thereof; (4) The alcohol ether oxime compound of the formula 18 shown below: 27 1290133 Wherein R, R' represents an alkyl group or an aryl group, and the alcohol ether oxime amine compound of the formula 18 is prepared from an ether oxime ester compound of the formula 17, which is a reducing agent and a solvent selected from the group consisting of a reducing agent and a solvent selected from the group consisting of a reducing agent and a solvent. Lithium aluminum hydride (LiAffiU), diisobutylaluminum hydride (DIBAL), potassium ketone (K-selectride), lithium triisobutyl borohydride (L-selectride), boron hydride (BH3), four Sodium borohydride (NaBHU) or a combination thereof, the solvent being selected from the group consisting of ethers, alcohols, water, alkane, di-methylmethylformamide, dimethyl sulfoxide, urea or a combination thereof, The guanamine compound is prepared from the alcohol ether oxime compound of the formula 18, which is prepared by using a hydrazine halide, a solvent, an organic acid compound, MXn and hydrazine, which is selected from toluene sulfonium chloride (TsCl), methyl sulfonate. Antimony chloride (MsCl), sulphur chloride (S0C12), sulphur chloride (S02C12), phosphorus trichloride (PC13), phosphorus pentachloride (PC15), phosphonium pentachloride (ρ〇α5), ethylene bismuth Chlorine or a combination thereof, the solvent is selected from the group consisting of tetrahydrofuran, ketones, alkane, ether, dimethylformamide, dimethyl hydrazine, dichloromethane, chloroform, tetrachloromethane, urea or Is a combination thereof, the organic acid compound is selected from the group consisting of oxalic acid ((COOH) 2), RCOOH or a combination thereof, and the R is hydrogen, a hospital or an aryl group, and the lanthanum is selected from the group consisting of lithium, sodium, potassium, magnesium, Calcium, zinc, platinum, palladium, copper, cobalt, manganese, iron, nickel or cadmium, X is chlorine, bromine, iodine or acetate, and η is 1-3 depending on the valence of the metal. 28