TW408116B - Carbapenem intermediates 1, 8-naphthosultams and preparation thereof - Google Patents

Abstract

A process for synthesizing a compound of formula I: is disclosed wherein R represents halo or C1-6 alkyl, unsubstituted or substituted with OP, wherein P represents a protecting group, comprising: (a) reacting a compound of the formula II: with chlorosulfonic acid to produce a compound of formula III: (b) reacting compound III with NHRaRb, wherein Ra and Rb represent H or C1-6 alkyl, to produce a compound of formula IV; (c) reacting compound IV with HNO3 to produce a compound of formula V: (d) reacting compound V with a reducing agent to produce a compound of formula VI: and (e) reacting compound VI with acid to produce a compound of formula I. Intermediate compounds that are useful in the synthesis of carbapenem side chains are included as well.

Description

V (d) reacting compound V with a reducing agent to produce compound VI:

R

(Please read the notes on the back before filling this page)

VI and (e) react compound VI with an acid to produce compound I. In this way, the synthesis of the intermediate compound of the cabaziranib branch is completed. Description of the invention The description of the present invention is defined as follows and is not included if specified otherwise. The + gauge * base represents a straight or branched Ci.6 gauge base. Xi Jing and Dian Ji respectively represent disordered matter, > odorant and broken matter, as appropriate. Preferred halo groups are bromo and oxo. The best is bromo " acid represents a strong acid, such as hydrochloric acid, formic acid, sulfuric acid, methanesulfonic acid and the like. Synthetic methods include the cyclization of a substitutable naphthalene sulfonamide to produce substitutable 1,8-naphthosultams. From -6- This paper size applies the Chinese National Standard (CNS) A4 specification (2 丨 0 · 〆297mm). Orders from the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Printing and publishing. 5. Description of the invention (408116 A7 B7. Background of the invention) It is an intermediate compound related to the synthesis of carbapenib. Carbapanib is an antibiotic with a wide range of antibacterial properties. The antibacterial range includes Gram-positive, Gram-negative and anaerobic microorganisms. Carbapannib branches of amines contain a thiothiazide ring system, which is linked to the second position of the carbapannib nucleus. An example of a carbapanibyl with a thiothioamide branch at the 2 position has been disclosed in the US patent application Case No. 6060 / 016J84 'Application date is April 24, 1996, and is hereby incorporated by reference. The thiothiamine plane is connected directly or via a linking portion to the cabazione nucleus, such as the sulfur atom' methylene Or high-carbon alkylene. The thiothiazamide plane can also be linked to one or more substituents. This thiothiazamide product is combined with cabazione to be an effective drug. SUMMARY OF THE INVENTION A method for synthesizing compound I : Please read the note on the back side first, and then — Temple Order Printed by another Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

R

Wherein R represents a commercial group or a C 丨 _ 6 alkyl group, which may be substituted without substitution or 〇P, and P represents a protecting group: (a) the compound Π: 4 · * This paper size applies the Chinese National Standard (CNS) Λ4 specification (210X297 males)

Patent Application No. 87107245 A7 Revised Chinese Manual (February 88) 4008116b7 5. The description of the invention (20) and ethanol (20 liters) were placed in a flask. H) wt% / Pd / C (water weight 50 wt%, 0.17 kg) mixed with water (ganglia ml), and then wash the strips with water (80 ml) and ethanol (6 liters) down in the resulting pulp Potassium formate (1'74 kg) was added to one part of the body. The slurry was heated to 60 ° C for an hour 'and refluxed for an additional hour. When the residual amount relative to the reactant was less than 0.2% SM by HPLC test, it indicated that the reaction was completed, and the total reaction / reaction mixture was cooled to 20. C, and then add concentrated hydrochloric acid (2.73 liters) for more than 20 minutes. The resulting slurry was filtered through a solkafl0cTM pad, and the filtered product was washed with 10% hydrochloric acid (13 liters in total) dissolved in ethanol, and then placed in a 72 liter clean flask, heated to reflux (8 1 DC) 3- 4 hours to obtain a complete cyclization reaction. The solution was cooled to 40 ° C and concentrated to a slurry. Cool again to 20 ° C and add water (7.5 liters) for more than 30 minutes. After that, it was cooled to pc and left for 15 minutes. The slurry was filtered and washed with water (5 liters). The crystals are put into a nitrogen streamer and dried overnight. (Please read the precautions on the back before filling out this page.) Consultation with the Consumer Standards Bureau of the Ministry of Economic Affairs on the consumption cooperation of the staff. Printed on -23 This paper applies Chinese national standards (CNS ) Α4 specification (210 X 29? Mm) 408116 at B7 V. Description of the invention (2)

R

Reacts with kinetic acid to produce compound ΠI:

R

(Please read the precautions on the back before filling in this text.) Printed by the Ministry of Military Affairs of the Central Bureau of the Ministry of Labor, printed by Hezhusha (b) The compound III and NHRaRb are reacted to produce compound IV, where Ra and Rb represent Η or Cu alkyl:

R

(c) Reaction of compound IV with nitric acid (ΗΝ03) to produce compound V: -5- This paper size applies Chinese National Standard (CNS) A4 specification (210X29; / mm) 4081i &

(2H-stub [l, 8-cd] isoxazole-6-acetic acid 1,1-dioxide) (3): W-NMR (250.1MHz, CD3CN) δ 8.43 (br s? 1H), 7.85 (d, J = 7.42Hz, 1H), 7.67-7.45 (m, 3H), '6.89 (d, J = 7.22Hz, 1H), 3.76 (t, J = 6.54Hz, 2H), 3.23 (t, J = 6.52Hz, 2H), 2.67 (br s, 1H);] 3C-NMR (62.5 MHz, DMSO-d6) δ 142.5, 135,8, 130'3, 130.1, 129.7, 129.5, 120.4, 119.9, 116.1, 105.8, 61.9, 35.8; IR 3530, 3200, 1640, 1580, 1490, 1420, 1350, 1300, 1285, 1240, 1210, 1170, 1150, 1130, 1060, 1020, 825, 750 cm4; Melting point: 175-177 ° C; theoretical value for element analysis C12HuNS03; C, 57.82; H, 4.45; N, 5.62; S, 12 · δ6. Actual value: C, 57 · 65; H, 4.65; N, 5.57; S, 1247 (0.24% Gray weight).

CH2CH2OH

P: \ rrsU \ TCC \ CHfNESB \ 529S7SUP.DOaLUI

V (d) reacting compound V with a reducing agent to produce compound VI:

R

(Please read the notes on the back before filling this page)

VI and (e) react compound VI with an acid to produce compound I. In this way, the synthesis of the intermediate compound of the cabaziranib branch is completed. Description of the invention The description of the present invention is defined as follows and is not included if specified otherwise. The + gauge * base represents a straight or branched Ci.6 gauge base. Xi Jing and Dian Ji respectively represent disordered matter, > odorant and broken matter, as appropriate. Preferred halo groups are bromo and oxo. The best is bromo " acid represents a strong acid, such as hydrochloric acid, formic acid, sulfuric acid, methanesulfonic acid and the like. Synthetic methods include the cyclization of a substitutable naphthalene sulfonamide to produce substitutable 1,8-naphthosultams. From 1-6- This paper size applies Chinese National Standards (CNS) A4 specifications (2 丨 〇 · 〆297mm) Ordered by the Central Standards Bureau of the Ministry of Economy Staff Consumer Cooperatives U8O 繁 * a 4081ί6 877107 Supplementary Notes to Chinese Patent Application No. 4-5, February 18th (6-methyl-2H-fluorene [l, 8-cd] isoxazole 1,1_dioxide H6):] H-NMR (250.1MHz, DMSO-dfi) δ 11.35 (br s, 1H), 8.03 (d, J = 7.33Hz, 1H), 7.68-7.60 (m5 3H), 6.96 (dd, J = 2.7Hz, 5.17Hz, 1H ), 2.72 (s, 3H); 13C-NMR (62.5 MHz, CD3OD) δ 141.9,137,1,131.7,131.6,130.3,129.6,121.9,120.4, U7.0,106,8,18.7; IR 3260, 1590, 1625, 1495, 1340, 1290, 1215, 1155, 840, 795, 755 cm-1; Melting point: 221-225 ° C; Theoretical value of elemental analysis C „H9NS〇4; C, 60_26; H, 4.14; N, 6.39 S, 14.62. Actual value: C, 60.07; H, 4.16; N, 6.35; S, 14.27.

U: \ PTS \ WKC \ CHINESE \ 52967SUP.DOC 3 -2- 408116 A7 B7 V. Description of the Invention (4) In terms of the invention, the present invention includes synthetic compound I:

R

Η where R represents a dentyl group or a <^ _ 6 alkyl group, which may be substituted by OP, and P represents a protecting group by the following method: (a) compound II:

R

Among them, R is as defined above, and reacts with kinetic acid to produce compound ΙΠ: (Please read the precautions on the back before filling out this page) Printed by Guigong Consumer Cooperative, Bureau of Standards and Decision, Ministry of Economic Affairs ^

R

This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) No. 87107245 Special Supplement ψΙT Chinese Supplementary Manual (eight + eight February) (2Η-naphthalene [l, 8-cd] isopyrazole -6-acetic acid 1,1-dioxide) (14): Ih-NMR (250.1MHz, DMSO-de) δ 12.66 (br s, 1H), 11.42 (br s, 1H), 8.10 (d, J = 7.38Hz, 1H), 7.77 (d, J-7.43Hz, 1H), 7.66-7.59 (m, 2H), 6.96 (dd, J = 5.13Hz and 2.70Hz, 1H), 4.12 (s, 2H); 13C -NMR (62.5 MHz, DMSO-de) δ 172.4, 137.8, 135.8, 131.2, 130.5, 130.3, 130.1, 120.3, 120.0, 116.2, 106.0, 38.0; IR 3320, 1695, 1630, 1590, 1500, 1420, 1375? 1310, 1280, 1255, 1220, 1145, 970, 920, 900, 820, 805, 750, 740, 630, 600 cm4; Melting point: 247-25 ° C; Theoretical value of elemental analysis C12H9NS04; C, 54.7S; H, 3.45; N, 5.32; S, 12.18, actual value: C, 54.74; H, 3.5; N, 5.35; S, 12.13 (0_22./. Gray weight) 0

xrv P: \ PTS \ WKC \ CHINESE \ 529S7SUP.DOC \ LUl

R

The Ministry of Economic Affairs, Central Bureau of Standards and Commerce, Co-operative Cooperative, India

408116 A7 V. Description of the invention (5) (b) Reaction of compound III with NHRaRb to produce compound IV, where Ra and Rb represent fluorene or Cu alkyl:

R

(c) reacting compound IV with nitric acid (ΗΝ03) to produce compound V:

NO2 S02NRaRb V (d) Compound V reacts with a reducing agent to produce compound VI: NH2 S02NRaRb V] and (e) Compound VI reacts with an acid to produce compound I. In the present invention, it is preferred that R represents a fluorenyl group. On the other hand, the better one is -8- The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X2? 7mm) (please read the notes on the back before filling this page)

408116 A7 B7 V. Description of the invention (6) R represents a halogen group, of which bromine (Br) and iodine (I) are preferred, and the most preferred is bromine (Br). In still another aspect, one of Ra * Rb represents fluorene or Ci.6 alkyl, and the other represents C 6 fluorenyl. A special case is that both are C: _ 6 by radical, and most particularly both are ethyl. · Another preferred part of the present invention &gt; _ A method comprising the synthesis of compound X:

X where compound XI is first: (Please read the notes on the back before filling this page)

CH

/ N—S HX ° 2 Central Laboratories of the Ministry of Economy

XI reacts with a chelating agent to produce compound XII: CH? -Li

Li ’° 2

XII -9- This paper size applies to Chinese national standard (CNS) Λ4 size (210X297 mm) 408116 A7 B7

XIV

X. Description of the invention (7) The lithium compound is then reacted with carbon dioxide (C02) to produce a chemical compound XIV: h and then reduced to a compound X with a reducing agent. In another part of the present invention, the method for synthesizing compound X is ch? ch2oh

Print compound XI (please read the precautions on the back before filling this page)

Η XI — fp chemical reaction to produce compound X Π -10 The paper size is applicable to China National Standard (CNS) A4 (210X 297 mm) 408116 ^ V. Description of the invention (8)

The lithium compound is reacted with formaldehyde (HCHO) to produce X:

X In addition, another intermediate compound included in the present invention is represented by Formula I

Η I (please read the notes on the back before filling out this page): Ordered by the Central Ministry of Economic Affairs, Central Bureau of Standards and Weapons and Consumer Cooperatives ¾ where R represents a halo group or a C _ 6 alkyl group, which can be replaced by Ο Ρ, where P Represents a protecting group. Another intermediate compound contained in the present invention is represented by the formula V: -11-The paper size applies to the Chinese National Standard (CNS) A4 specification (2 丨 0 × 2? 7 mm) 408116 A7 B7 V. Description of the invention (9)

R

Wherein, R represents a radical or a C6_6 alkyl group, which may be substituted by OP, and P represents a protecting group;

Ra and Rb represent fluorene or C] .6 alkyl. Another intermediate compound included in the present invention is represented by Formula XI: (Read the precautions on the back before filling in this page)

· Ordered by the Central Bureau of Standardization of the Ministry of Economic Affairs and the Consumers' Cooperatives ^ XI. Another intermediate compound included in the present invention is represented by the formula XII ...

XII Another intermediate compound contained in the present invention is represented by the following formula: -12- This paper size applies to Chinese National Standard (CNS) Λ4 specification (210X297 ^ #) The Ministry of Mobilization, the quasi-mind-work consumer cooperative, printed in purple 408116 a?, _B7 Truth and invention description (10) '

In general, the reaction of 1-halogenated or 1-alkylated compounds with gas sulfonic acid can be performed in organic solvents such as nitro organic compounds (such as nitromethane and nitrobenzene) and halogenated organic solvents (such as Including o-, m-, p-benzene), methylene chloride, three gas methane, carbon tetrachloride, two gas ethane and trifluoroacetic acid (TFA)). T F A is the best solvent. Typical reaction temperatures range from about -40 ° C to about 1 oo ° C. It is better to fish. C to about 25 ° C. Thiamine is usually produced in an unreacted organic solvent. For example, secondary and tertiary alcohols such as isopropanol, tributanol, aromatics such as toluene, and dibenzobenzene, hexyl alcohol, methyl alcohol, esters, tetrahydro '• furan, and many others as described above Gaseous solvents. The traditional reaction temperature is between -50 ° C and reflux temperature. The reaction with nitric acid is generally carried out in trifluoroacetic acid, sulfuric acid, nitrobenzene or a chloride organic solvent as described above. The temperature range is about -300 ° C to 60 ° C, and preferably from about 0 ° C to about 20 ° C. The reduction of the nitro group to an amine and the formation of a ring can be performed in any solvent at a temperature between about -40 ° C and the reflux temperature. The reducing agent used in the present invention includes H VP d and other equivalent catalysts.-13- Paper size is applicable to China National Standards (CNS) A4 specifications (210X297 common 1 ~~~ (Please read the Please note this page to fill in this page) »» Ji-Hi. 408116 A7 B7 V. Description of the invention (11 chemical agents' P d / C and accompanying chemical conversion agents, such as formic acid, ammonium formate, any metal ammonium, any trialkyl Ammonium phosphonate or cyclohexene 'gaseous tin, etc. Can be used to form cyclic acids, including hydrochloric acid, sulfuric acid, trifluoroacetic acid and formic acid. Hydrochloric acid is preferred. The chemical reaction (the extension of the bond) can generally be performed at Such as THF and acid (such as acetic acid) in the solvent, the temperature is about -1 000 ° C to about 70. (:. The reaction included in the test 'generally diamine base, such as diisopropyl alcohol Amine surface. The reduction reaction of carboxylic acid to produce alcohol is usually produced in solvents such as THF or ether. Suitable reducing agents include borane in THF and similar reagents. The reaction temperature is generally between about _50. &Lt;: The question about the reflux temperature. The carbopanib synthesized by the present invention is properly protected, The activated 2_hydroxymethyl_carbaba-2-em-3-carboxylate is reacted with thiothiazamide to change the branched chain to the desired one and then remove the protecting group to obtain the final product. This method is simple The following flow chart is described: (Please read the notes on the back before filling out this page) • * Order the Ministry of Economic Affairs + Central Standard 扃 Working Consumer Cooperatives Yinfan -14- China National Standards (CNS) A4 specifications are applicable for each paper size (210X297 mm) V. Description of the invention (12 408116 A7 B7

Flowchart A

A1 C02P ^ 1) 2) Activate the OH group to facilitate the placement of 迤 'with sulphur. Amine reaction — p and I P ** = protecting group

co2p *,

Remove the protection to form the final CP or (谙 Please read the notes on the back before filling in this purchase) .J ·-.. · Order by the Central Government Bureau of the Ministry of Economic Affairs, employee elimination; printed by the cooperative HO u u R1

P〇 u u R1

Extend the chain and add one or four groups to

mco2m ^ co2p, in Flowchart A, the thiothiazol branched group is initially protected with Carbaplatin-2-em -3 ~ Huan with appropriate protection and activated methylol groups at the second position. &amp; Salt reaction. -15- This paper size applies to China's standard house rate {CMS) A4 specification (2) 0X297 mm 408116 37 Central Laboratories of the Ministry of Economic Affairs FF; India ’s cooperatives ¾ V. Description of invention (13 Schmidt S .M. Et al. (Schmitt, SM etal) have revealed in position 2 (6): 780-787 (1998) in the antibiotic phase-can replace -CHWH cabapani, this part also For reference. A few acid groups on CZ Panny C-3 are usually protected as a carboxy protecting group, such as p-nitrobenzyl (PNB), propylpropyl, p-methoxybenzyl, trisamino, Trimethylethylsilylethyl and its analogs. In addition, the hydroxyl groups on the 6-hydroxyethyl branch are optionally protected with hydroxyl protecting groups, such as trimethylsilyl (TMS), diethylsilyl (TES), and methylsilane on the third butyl group. (TBDMS), tertiary butyldiphenylsilyl (TBDps), ethynyl'fluorenyloxycarbonyl (alIylOXyCarbonyl), 2-trimethylsilylethoxyalkyl, 2-trimethylsilylethoxy Gas ethoxycarbonyl and so on. The method for adding sulfamethoxamine branched chain group (SCG) to cabaziran is to add a solution containing hydroxymethyl-carbapanib and phenylthiocarbamate chain in a suitable solvent such as (tetrahydrofuran). (THF), ether, acetonitriie, dimethylformamide (DMF), benzene, dihydrazone (MS))), etc., and an appropriate activator (such as diethylazodicarboxylate) (DEAD) / triphenylphosphine, diisopropylazodicarboxylate (DIAD) / tributylphosphine, etc.), the reaction is completed at a temperature of about -20 (5C to 35 ° C for 5 to 90 minutes). Another method is to mix thiothiazamide, carbapanil, and azobiscarboxylate or phosphine, and add another activator (phosphine or azobiscarboxylate, respectively). ): ^ In the mixture.-But thiothiazamide, carbapanil and activator are mixed, and the reaction can be performed for about 5 to 90 minutes at a temperature of about -20c to 35c. The mixture after the reaction can be After the standard process, it can produce a crude 2 _sulfur ^ ----- -16- This paper size is applicable) Λ specifications (Jing first read the note on the back ##. 呗 and then fill the bent ears) * Order- -Ί. ------ ^ / Ί --------------- The Central Bureau of Standards of the Ministry of Economic Affairs only cooperates with consumers. • Society print t 4081i76 _______ B7 V. Description of the invention (14) Amine methylcarba Peni, depending on the condition, purified by recrystallization, or chromatographed on silica gel, and then eluted with an appropriate solvent or two or more mixed solvents, among which the solvent is hexane, ethyl acetate, ether , Benzene, dioxanane, chloroform, acetone, methanol, etc. The compounds that usually involve the substitution of the electrovalence substituents should be upgraded before the removal of the protective group. For those that are in the branched chain In the case of compounds containing a mesial group, the hydroxyl group is first converted to a suitable leaving group (such as Sandun salt, methanesulfonium salt, tosylsulfonium salt, iodide, gaseous compound, bromide, etc.) to activate it. Then use a four-based compound (such as N-methyl imidazole, N- (2-transethyl) imidazole, N-methyldiazabicyclooctane, aminomethyldonylmethyl), 4_aza_ 1-Azobicyclo [2,2,2] -octane, 1- (3-Hydroxypropyl- ^ yl-widenazaaza · 1-azobicyclo- [2,2,2] -octane , Pyridimorph and electrophile (Analog of nitrogen atom) to replace the free radical, and insert the positive valence substituent into the branch. In addition, the 'electric valence substituent' can also be added to the naphthyl thiamide branch before the sulfamethoxamine is added to cabaziran. , Or insert after removing the protection. It is best to insert the valence substituent before removing the protection. The method of converting the radical to the appropriate leaving group is to put the substituted compound in an appropriate agent (such as : Digas methane, tetramethane, ether, benzene, etc., add activators (such as: trifluoromethanesulfonic anhydride, pinanesulfonic anhydride, toluenesulfonic anhydride, methylsulfonium, benzenesulfonium) Tosylsulfonium gas, etc.), and in the presence of a base (such as: diethylamine, tributylamine, diisopropylethylamine, etc.), the temperature is about _ 100 C to 0 ° C. The reaction can be completed in about 5 to 120 minutes . The intermediate product obtained by this reaction contains a leaving group. If this solution is added to an appropriate solvent (such as acetone, methyl ethyl ketone, etc.) together with an excess of sodium decomposing or decomposing, ---- -17- this paper National Standard 7 ^ y7 ^: (210χ297) (Please read the precautions on the back before filling this page)

40811 ^ V. Description of the invention (15) When the reaction is performed at a temperature of about -10 ° C to 50 ° C for about 0.25 to 24 hours, the leaving group will be converted into another leaving iodine. In many cases, it can be directly High purity iodine was obtained without further purification. In order to facilitate the processing, non-crystalline iodine can be dried from benzene to obtain solids which are non-crystalline and easy to handle. ^ Use the activated intermediate to react with the activator to replace the activated hydroxyl or iodine. In some cases, activation and replacement can be done simultaneously. Add the activator to a suitable solvent containing a solution of a hydroxy-substituted compound and an appropriate base (eg, dichloromethane, tetrahydrofuran, ether, DMF, benzene, hydromethane, DMSO, etc.). The resulting activated intermediate was treated with naphthylthioxamine at a temperature of from 1-3 moles' temperature to 700C to 50C for about 15 to 120 minutes. In some cases, it is designed to allow the activation interrogator to form in a certain solvent; after the activation intermediate is isolated, the replacement reaction is performed in a different solvent. In other cases, the substitution reaction can be performed without isolating the intermediate, and in the case where Q * has a base effect, it can even proceed simultaneously with the activated intermediate. In the case of the Central Laboratories of the Ministry of Economic Affairs and the Ministry of Industry and Labor Cooperatives, in those cases where iodine is used to complete the optimal displacement reaction, the iodine solution is combined with almost equal equivalents (0.9 to ΐ · 05 mol equivalent) of thiothioamide. . Non-nucleophilic salts can be added, such as silver trifluoromethanesulfonate and silver tetrafluoroborate. Although this reaction does not require the participation of silver salts; the addition of appropriate salts can speed up the reaction. In addition, the salts are very helpful in removing the replaced iodine from the reaction mixture, and make the subsequent steps more efficient. The resulting mixture is then subjected to standard procedures well known in the art to obtain the crude product, which can then be purified by recrystallization or chromatography if necessary. ___- 18 &quot; This paper size applies Chinese National Standard (CNS) grid (210X297) 嫠 Α7 Β7 GAL1ί6 V. Description of the invention (16) (Please read the precautions on the back before filling this page) Another kind of regular price The method of inserting a branch chain can be applied to a branch containing a nitrogen atom, and the nitrogen atom can be used with an appropriate alkylating agent (such as: oxane, bromomethane, benzyltrichloroacetimide, trifluoro Methyl methanesulfonate, triethyl welding tetrafluoroborate, etc.) are quaternized. The quaternization of the nitrogen atoms in the branched chain can be achieved by reacting the compound solution with a slightly excess (0.05 to 1.2 mole equivalents) alkylating reagent. Usually, the standard technology well known to those skilled in the art is used to remove the protective group from the penultimate intermediate, and then the entire synthesis of the final product is completed. The final product from which the protecting group is removed can be purified by standard techniques (eg, ion exchange chromatography, HPLC on reversed-phase silica gel, MPLC on reversed-phase polystyrene gel) or recrystallization if necessary. The final product can be structurally characterized using standard techniques such as NMR, IR, MS, and U V. For the convenience of processing, the non-crystalline final product can be freeze-dried from water to obtain a non-crystalline and easy-to-handle solid. The more expensive R includes halo, methyl, ethyl, and propyl, and may be substituted by P, where P represents a hydroxy protecting group. Representative protection groups P are printed by the Central Standards Bureau of the Ministry of Economic Affairs, Industrial and Commercial Cooperatives, including trimethylsilyl (TMS), triethylsilyl (TES), and third butyldimethylsilyl ( TbdMS), tertiary butyldiphenylsilyl (l ^ DPS), ethenyl: allyloxycarbonyl 2-trimethylsilylethoxycarbonylditrifluoroethoxycarbonyl, and the like. More valuable radium and radium include fluorene, methyl, ethyl, and propyl. The most preferred one is ethyl. Preferred NHRaRb is therefore dimethylamine, monoethylamine or dipropylamine. This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 408116 V. Description of the invention (17) The "reducing agent" used here is used to react with compound V to place the nitro group at position 8 Converted to, amine. Suitable reducing agents include a combination of rhenium 2 and a metal 'such as: Pd / C, osmic acid and metal, trialkylammonium formate and metal, cyclohexane and metal, tin gasification, and the like. Example 1 Gas sulfonation

Me00

I.CISOgH 2.Water

Me

(Please read the precautions on the back before filling in this I.) Printed by the Central Bureau of the Ministry of Economic Affairs, printed only by the Consumer Cooperative, put methyl hydrazone (2.63 kg) and trifluoroacetic acid (13.2 liters) into a three-necked flask . The two-phase mixture was stirred and cooled to 5 in an ice-water bath. C. Add gas sulfonic acid (2..93 liters) and maintain temperature below 20 ° C for more than 30 minutes. Then at 10 ~ 20. (: The reaction was interrupted with deionized water for more than 15 minutes. The crystallized product was added to water to form a white slurry. After the reaction vessel was washed with TFA / water (1: 1, 1.0 liter), the washing solution was poured into Discontinue the container. This mud is filtered with a poly-wife filter and washed with water. The resulting product is placed in a nitrogen streamer and drained overnight. Example 2 Sulfonamide 20- This paper is scaled to the rate of homework in China (CNS) A4 specification (2l0x29? Mm)

Me

经济 #-Printed by the Central Standards Bureau's Consumer Cooperatives 408116 a? B7 V. Invention Description (18)

S02NEt2 Put sulphur methyl chloride (4.0 kg) and isopropanol (120 liters) in a flask. Add more diethylamine (3.73 liters) over minutes. An exothermic reaction occurs up to about .65 ° C, and the substance begins to dissolve. The progress of the reaction was monitored by HPLC. Cool the Luo solution to 20 C and add 4 liters of water. The mixture was shaped from the amine product (2 g) and placed at 20 ° C for 20 minutes. Residual water (32 liters) was added over 1 hour. -The resulting slurry was left at 2000c for 20 minutes. The slurry was filtered through a 23 '' polypropylene filter and washed with water (12 liters). The resulting product was dried in a nitrogen flow device overnight. &quot; Example 3 Nitrification

Place N, N-diethyl_1-fluorenyl-4-naphthosulfonamide (30 g) and trifluoroacetic acid (TFA) (150 ml) in a tube equipped with nitrogen, a mechanical stirrer, and an additional funnel And the temperature tester in the 2 liter flask 1 "The solution obtained is cooled to HOC, -21-this paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) (read the note on the back first, and then fill in the notes if necessary) (This page)

Printed by the staff of the Central Bureau of Standards of the People's Republic of China on the elimination of cooperatives 408U6w ---------------- B7 V. Description of the invention (19) and adding concentrated sulfuric acid (30 ml) for more than 2 minutes. The solution was cooled to -3c. While maintaining the reaction temperature at -3 to + 50 ° C, 1 oxalic acid (62 mL) was added to the falling liquid and rapidly stirred for more than 30 minutes. The reaction was monitored by HPLC. When the JIPLC analysis shows that the reactant is less than 1/0 (200 nm area relative to the product), the reaction is complete. Water (375 ml) was added to the solution for more than minutes. Use an ice-water bath to maintain the interruption temperature at 25 ° C. (: The following. The resulting slurry was left at 20 ° C for 30 minutes, filtered and washed with water (H) 0 ml). The obtained mud was dried in a nitrogen flow device until the water content was less than 35/0 w / w. The semi-dry solid was put into acetic acid acetate (75 ml) to form a slurry, and it was left at 30 ° C for 30 minutes. Hexane (50 ml) was added for more than 20 minutes, and the slurry was allowed to stand at 20 ° C for 30 minutes. The slurry was filtered, washed with hexane (100 ml), and placed in a nitrogen streamer. Work all night. Example 4

Prepare a 72-liter round-bottomed jar with a nitrogen tube, thermocouple, and ordinary stirrer. 2.20 kg of 1-methyl-4-diethylpyramine _5_tip_ylbenzene-22- This paper is a good standard for China National Standards (CNS) A4 specifications (2 × 〇 × 297 mm) (Please Read the note Ji-sw 'on the back before filling in this tile) _____ \ V -Γ 、 /. --- 1Τ —------ \-

Patent Application No. 87107245 A7 Revised Chinese Manual (February 88) 4008116b7 5. The description of the invention (20) and ethanol (20 liters) were placed in a flask. H) wt% / Pd / C (water weight 50 wt%, 0.17 kg) mixed with water (ganglia ml), and then wash the strips with water (80 ml) and ethanol (6 liters) down in the resulting pulp Potassium formate (1'74 kg) was added to one part of the body. The slurry was heated to 60 ° C for an hour 'and refluxed for an additional hour. When the residual amount relative to the reactant was less than 0.2% SM by HPLC test, it indicated that the reaction was completed, and the total reaction / reaction mixture was cooled to 20. C, and then add concentrated hydrochloric acid (2.73 liters) for more than 20 minutes. The resulting slurry was filtered through a solkafl0cTM pad, and the filtered product was washed with 10% hydrochloric acid (13 liters in total) dissolved in ethanol, and then placed in a 72 liter clean flask, heated to reflux (8 1 DC) 3- 4 hours to obtain a complete cyclization reaction. The solution was cooled to 40 ° C and concentrated to a slurry. Cool again to 20 ° C and add water (7.5 liters) for more than 30 minutes. After that, it was cooled to pc and left for 15 minutes. The slurry was filtered and washed with water (5 liters). The crystals are put into a nitrogen streamer and dried overnight. (Please read the precautions on the back before filling out this page.) Consultation with the Consumer Standards Bureau of the Ministry of Economic Affairs on the consumption cooperation of the staff. Printed on -23 This paper applies Chinese national standards (CNS ) Α4 specification (210 X 29? Mm) 5. Description of the invention (21 408116 Α7 Β7 Example 5 Lithium oxidation monocarboxylation reaction

l. LDA, THF, -10 ° C 2 * COj, N-S 〇2

Η

Ν-S Η

MW-219.25 CnHjNC ^ S

. 2 MW = 263.2 C12H9N04S (please read the note on the back before filling out this page)-Printed by Jizhong Central, Bijie Industrial Co., Ltd. Place THF (5 liters) in a nitrogen tube, stirrer, temperature probe And an additional funnel in a 20 liter flask. Add diisopropylamine (134 liters). The resulting solution was cooled to -15 ° C, and then n-butyllithium (60 liters) was added by titration, and the temperature was maintained at -15. (: To 00c to produce lithium diisopropylamidamine (LDA). 'Additionally THF (10 liters;) and 1 kg of 1-Me NH sulfanilamide] were placed in a swinging stirrer and A nitrogen tube in a 50 liter flask. The other gases in the solution were purged with nitrogen, cooled to "15 <5C", and then LDA was titrated and maintained at a temperature between -15 ° C and -50 ° C to produce a dianion solution. The dianion solution was placed at: i5 ° C for 30-minutes. Place THF (10 liters) in a 100 liter flask with a stirrer, a nitrogen tube, and a grabber at a temperature of 4 at the time of production and cool the solution to _2〇 (5c) by using air / nitrogen to exclude other gases. , And then completely dry the C02 bubble into τ HF until saturation. Slowly add the dianion solution to this carbonation solution. # Ί ---------------, hr

A __ -24-This paper size is applicable (CNS) Λ4 specification (2! 〇χ! 97 men I 1.-4081x6 A7 B7 V. Description of the invention (22 liquids, and confirm that the resulting slurry is sufficient Mix. After heating to 10 ° C, add 10 liters of 2 N HC1 and let stand for 30 minutes. The solution was concentrated to about 10 liters due to atmospheric pressure &lt; to remove THF and start crystallization. The slurry was placed at 15 ° C for 30 minutes, filtered, washed with water (10 liters), and then drained in a decanter. Example 6 Reduction of Methane

NaBH4 / BF3

THF

OH

MW = 249.29 C12HnN03S Ο

OH Η MW. = 263.2 C12H9N04S (please read the precautions on the back before filling in this tile) Indo Slave of the Poverty Alleviation Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs prepared a nitrogen tube, thermocouple, plus funnel and ordinary mixing bowl 50 liter round bottom flask. Place dry NH-thiamine carboxylic acid (1.14 kg) and THF (18 liters) in it. The slurry was cooled to 15 ° C. Add NaBH4 (327 grams) and slowly add BF3 etherate (1.42 liters). The slurry was placed at 15-2 CTC and the progress of the reaction was monitored by HPLC. The slurry was cooled to 10 ° C, and methanol (1.2 liters) was slowly added to suppress the boride of the older brother. Add 2N HC1 (11 liters) slowly and let stand for 30 minutes. The suppressed reaction mixture was evaporated under normal pressure to remove volatile materials. The obtained solution is cooled to 55 ° C, and the seed crystals start to crystallize, and it is cooled to -25. The paper size is applicable to the Chinese National Standard Xin (CNS) Λ4 specification (210X297 mm) 408116 B7 V. Description of the invention (23) 15 ° C exceeds 1 hour. After standing for 30 minutes, the slurry was filtered, washed with 10 liters of water, and dried in a nitrogen flow device. Example 7 Dilithium tritiated monohydroxymethane inversion PTH (2 ml) was placed in a nitrogen tube, Stir bar and temperature probe in a 10 ml flask. Add diisopropylamine (0.14 ml). The solution was cooled to -15 ° C, and then n-butyl 41 (0.66 ml) was titrated and maintained at a temperature between -15 ° C and 0 ° C to produce lithium diisopropylamidamine (LDA). Separately, THF (2 ml) and 1-Me NH thiothiamine (0.07 g) were placed in a 20 ml flask equipped with a stirrer and a nitrogen tube. The other gases in the solution were purged with nitrogen, cooled to -15 ° C, and then ldA was titrated and maintained at a temperature between -15 ° C and -5 ° C to produce a dianion solution. The di-anion solution was placed at -15. (: Next 30 minutes. In addition, Ding HF (2 ml) and p-formaldehyde (0-12 g) were placed in a 20 ml flask equipped with a stir bar, nitrogen turbulence tube and temperature probe, and the nitrogen was used to Exclude other gases. Cool the solution to _20. (: ^ Print the dianion solution through the Central Bureau of Standards and the Ministry of Industry and Consumer Cooperatives (please read the note ¥ on the back before filling out this page). In the acetaldehyde solution, make sure to mix thoroughly. After heating to 100 ° C, add 10 ml of 2N HC1 and let stand for 30 minutes. The solution was concentrated to 16 ml due to atmospheric pressure. To remove THF and start crystallization. The resulting slurry was placed at ^ 5QC for 30 minutes, filtered and washed with water (10 ml), and then dried in a nitrogen flow device. ___ -26- Paper-like degree of wealth ―County 4081i &amp; 'Repair

(2H-stub [l, 8-cd] isoxazole-6-acetic acid 1,1-dioxide) (3): W-NMR (250.1MHz, CD3CN) δ 8.43 (br s? 1H), 7.85 (d, J = 7.42Hz, 1H), 7.67-7.45 (m, 3H), '6.89 (d, J = 7.22Hz, 1H), 3.76 (t, J = 6.54Hz, 2H), 3.23 (t, J = 6.52Hz, 2H), 2.67 (br s, 1H);] 3C-NMR (62.5 MHz, DMSO-d6) δ 142.5, 135,8, 130'3, 130.1, 129.7, 129.5, 120.4, 119.9, 116.1, 105.8, 61.9, 35.8; IR 3530, 3200, 1640, 1580, 1490, 1420, 1350, 1300, 1285, 1240, 1210, 1170, 1150, 1130, 1060, 1020, 825, 750 cm4; Melting point: 175-177 ° C; theoretical value for element analysis C12HuNS03; C, 57.82; H, 4.45; N, 5.62; S, 12 · δ6. Actual value: C, 57 · 65; H, 4.65; N, 5.57; S, 1247 (0.24% Gray weight).

CH2CH2OH

P: \ rrsU \ TCC \ CHfNESB \ 529S7SUP.DOaLUI U8O Η * a 4081ί6 Chinese Supplementary Explanation of Patent No. 810702745 Drawing February 18) (6-Methyl-2H- 荇[l, 8-cd] isoxazole 1,1-dioxide H6):] H-NMR (250.1MHz, DMSO-dfi) δ 11.35 (br s, 1H), 8.03 (d, J = 7.33Hz, 1H), 7.68-7.60 (m5 3H), 6.96 (dd, J = 2.7Hz, 5.17Hz, 1H), 2.72 (s, 3H); 13C-NMR (62.5 MHz, CD3OD) δ 141.9,137,1,131.7 , 131.6, 130.3, 129.6, 121.9, 120.4, U7.0, 106, 8, 18.7; IR 3260, 1590, 1625, 1495, 1340, 1290, 1215, 1155, 840, 795, 755 cm-1; Melting point: 221-225 ° C; theoretical value for elemental analysis C9H9NS04; C, 60-26; H, 4.14; N, 6.39; S, 14.62. Actual value: C, 60.07; H, 4.16; N, 6.35; S, 14.27.

U: \ PTS \ WKC \ CHINESE \ 52967SUP.DOC 3 -2- Patent Supplement No. 87107245 (Chinese version) (eight + eight February) (2Η-naphthalene [l, 8-cd] isopyrazole-6 -Acetic acid 1,1-dioxide) (14): Ih-NMR (250.1MHz, DMSO-de) δ 12.66 (br s, 1H), 11.42 (br s, 1H), 8.10 (d, J = 7.38Hz , 1H), 7.77 (d, J-7.43Hz, 1H), 7.66-7.59 (m, 2H), 6.96 (dd, J = 5.13Hz and 2.70Hz, 1H), 4.12 (s, 2H); 13C-NMR (62.5 MHz, DMSO-de) δ 172.4, 137.8, 135.8, 131.2, 130.5, 130.3, 130.1, 120.3, 120.0, 116.2, 106.0, 38.0; IR 3320, 1695, 1630, 1590, 1500, 1420, 1375? 1310, 1280, 1255, 1220, 1145, 970, 920, 900, 820, 805, 750, 740, 630, 600 cm4; melting point: 247-25 ° C; theoretical value of elemental analysis C12H9NS04; C, 54.7S; H, 3.45; N, 5.32; S, 12.18, actual value: C, 54.74; H, 3.5; N, 5.35; S, 12.13 (grey weight of 0_22./.) 0

xrv P: \ PTS \ WKC \ CHINESE \ 529S7SUP.DOC \ LUl

Claims (1)

No. 87107245 profit-making order filed B8 Chinese application for patent application 囡 Article is made too 〇07 along i 1 6 D8 application for patent application _ 1. A method for synthesizing compound I Η where R represents a C ^ 6 alkyl group, which may be unsubstituted or substituted by 0ρ, where P represents a protecting group; this method includes: (a) Let compound π: (Please read the notes on the back before filling this page ) ·% ^ Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and chlorosulfonic acid, where R is as defined above, yielding compounds such as compounds S02CI III (b) Make compound III and NHRaRb react to produce compound IV, in which Ra and Rb represent fluorene or (: 6 alkyl group: this paper size applies Chinese National Standard (CNS) A4) (210X297 mm) No. 87107245 profit-making order filed B8 Chinese application for patent application 囡 Article is made too 〇07 along i 1 6 D8 application for patent application _ 1. A method for synthesizing compound I Η where R represents a C ^ 6 alkyl group, which may be unsubstituted or substituted by 0ρ, where P represents a protecting group; this method includes: (a) Let compound π: (Please read the notes on the back before filling this page ) ·% ^ Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs and chlorosulfonic acid, where R is as defined above, yielding compounds such as compounds S02CI III (b) Make compound III and NHRaRb react to produce compound IV, where Ra and Rb represent fluorene or (: 6 alkyl group: Chinese paper standard (CNS) A4 format for this paper size (210X297 mm) 4081Ϊ6 8888 ABCD VI. Patent Application Park R a〇b S02NRaR IV (c) react compound IV with nitric acid (hno3) to produce compound V R No. S02NRaRb ... V (d) Compound V reacts with reducing agent to produce compound VI R (Please read the note on the back before filling out this page.) Set the policy of the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs and (e) react Compound VI with an acid to produce Compound I. 2. Method according to item 1 of the scope of patent application, where R represents methyl = 3. Method according to item 1 of the scope of patent application, wherein both Ra and Rb represent Η or ¢:,. 6 alkyl, and the other Represents C! .6 alkyl. 4. The method according to item 3 of the scope of patent application, wherein Ra-Rb represents q-alkyl. -2- This paper size is in accordance with the Chinese National Standard (CNS &gt; A4 size (210X297 mm). The Zhengong Consumer Cooperative of the China Standards Bureau of the Ministry of Economic Affairs has cracked 408116 ?! D8k, the scope of patent application 5. According to the scope of patent application No. 4 Method according to item, wherein Ra * Rb represents ethyl. 6 'According to the method in the scope of the patent application, the solvent used in step (a) reaction includes: nitromethane, nitrobenzene, Chlorobenzene, digasmethane, digasmethane, carbon tetrachloride, dichloroethane, and trifluoroacetic acid (TFA). 7. The method according to item 6 of the scope of patent application, wherein the solvent is trifluoroacetic acid. The method according to item 6 of the patent application park, wherein step (&) occurs at a temperature between -40 ° C and 10CTC. 9. The method according to item 1 of the patent application park, wherein step (b) Occurs in 'substantially non-reactive organic solvents.'-Method according to item 9 of the scope of patent application, wherein the solvent includes isopropanol, tertiary butanol, toluene, dimethylbenzyl, hexane, ether, ester , Tetrahydrofuran, and as described in item 6 of the scope of patent application A variety of chloride solvents. 11 'The method according to item 10 of the patent application, wherein the reaction temperature of step (b) is between -50 ° C and reflux temperature. 12. The method according to item 1 of the patent application, wherein The solvent used in step (c) includes organic solvents such as trifluoroacetic acid, sulfuric acid, nitrobenzene, and gaseous solvents. The method according to item 12 of the application, wherein the reaction temperature of step (c) is between -30 ° C. To 60 ° C. 14. According to the method of the patent application Fanyuan Item 13, wherein the reaction temperature of step (c) is between 0. C to 20. (:. -3- This paper scale is suitable for Chinese girls. (CMS &gt; A4 size (210X297mm) (please read the precautions on the back page and fill in the nest page)) Order the scope of patent application A8 BS C8 4081 pa I5. According to the method of applying for a patent _ item 丨, The reaction temperature of Buxiangyan is between -40 ° C and reflux temperature. According to the method of item 5 of Zhongshen Patent, wherein the reducing agent used in step (d) includes: hydrogen, formic acid ( f〇rmU acid) and its organisms such as ammonium formate, metal Ammonium acid (such as sodium, potassium, lithium, feed), --- c 丨 -6-carbamic acid, sodium borohydride, cyclohexene, and tin chloride. 17. According to the method of the first patent application, The acid used in the step reaction includes hydrochloric acid, sulfuric acid, trifluoroacetic acid, and methanesulfonic acid. According to the method of Patent Application No. 丨 7, the acid used is hydrochloric acid. 19 '-A method for synthesizing compound X: (Please read the notes on the back before filling this page) X Γ I * Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs Including the compound XI: XI 4-Paper music scale, using the Chinese family standard (CNS) A4 (210X297 mm) Apply for a patent Fan Yuan reacts with butyllithium at "• degree-5 ° C to 5 ° C to produce compound X i j Li The χΠ surface compound is then reacted with carbon dioxide (C02) to produce the compound χιν (Please read the precautions on the reverse side before filling out this page) rrr ίς νο Then use HCHO to reduce this compound to compound X at a temperature of -20 ° C to 20 ° C. 20.—A compound such as formula I: R N—S〇2 Η · where R represents a halogen or Ci.6 alkyl group, which can be obtained without substitution or through OP-5- This paper is based on Chinese National Standard (CNS) 8 4 Lin (210X297) . ^ .-, A8 B3 C8 D8 printed by 1K Industrial and Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs 6. The scope of application for patents, where p represents a protecting group &quot; 21, — a compound of the following formula: R V where R represents a halo group or a Ci .6 alkyl group, which may be unsubstituted or substituted with 0 P, and P represents a protecting group; represents a fluorene or a Cu alkyl group = 22. A compound according to item 21 of the scope of patent application, with Equation XI represents: (Please read the precautions on the back before filling this page) CH ^. XI 23. —A compound represented by the formula: ΧΠ 24. — A compound represented by the following formula: -6-This paper uses Chinese National Standards (CNS) ΑΊpresent (210X297 mm) A8 DO 408116 g88 6. Scope of patent application Η 02 C {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 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 × 297 mm)