JP2001527557A - Synthetic method of carbapenem intermediate - Google Patents

Abstract

(57) Abstract: Formula (I) (wherein, R or represents halo, represents. A C _{1 to 6} alkyl P is not the or substituted substituted with OP is a protecting group), a compound represented by (A) reacting a compound represented by the formula (II) with chlorosulfonic acid to produce a compound represented by the formula (III); (b) converting the compound (III) to NHR ^a (wherein, R ^a and R ^b represents H or C _{1 to 6} alkyl.) R ^b is reacted with to produce a compound of formula (IV), HNO ₃ (c) a compound (IV) To produce a compound of formula V, (d) reacting compound (V) with a reducing agent to produce a compound of formula (VI), and (e) compound (VI) With an acid to produce a compound of formula (I). A method is disclosed. Also included are intermediate compounds useful in the synthesis of carbapenem side chains.

Description

DETAILED DESCRIPTION OF THE INVENTION                       Synthetic method of carbapenem intermediate Background of the Invention   The invention described herein relates to intermediate compounds useful in the synthesis of carbapenems. You. Carbapenem has a broad spectrum of antimicrobial properties, including Gram-positive, Gram-negative and anaerobic microorganisms. It is an antibiotic with a bacterial spectrum.   Carbapenems for which the naphthosultams of the invention are useful are carbape The side chain attached to the nem nucleus contains a naphthosultam ring system. Naftos in second place Examples of Carbapenems Substituted with Latum-Containing Side Chains Applied on April 24, 1996 U.S. application Ser. 60 / 016,184, the teachings of which are incorporated herein by reference. Incorporated by reference. The naphthosultam substrate can be directly on the carbapenem nucleus or Via a linking moiety such as a sulfur atom, a methylene group or a higher molecular weight alkylene group Has been added.   One or more substituents may also be added to the naphthosultam substrate. Nuff generated Tosultam is properly bound to carbapenem If active, it is an active base drug.Summary of the Invention   Formula I: (In the formula, R represents halo, or P is substituted or substituted with OP which is a protecting group. Unconverted C_{1 ~ 6}Represents alkyl. ) A method for synthesizing a compound represented by   (A) Formula II:(Wherein R is defined as above.) Is reacted with chlorosulfonic acid to give a compound of formula III: Producing a compound represented by   (B) Compound III is converted to NHR^aR^b(Where R^aAnd R^bIs H or C_{1 ~ 6}Al Represents a kill. ) To react with Formula IV: Producing a compound represented by   (C) Compound IV is converted to HNO_ThreeAnd reacting with the formula V Producing a compound represented by   (D) reacting compound v with a reducing agent to form a compound of formula VI:Producing a compound represented by:   (E) reacting compound VI with an acid to produce a compound of formula I A method comprising:   Also included are intermediate compounds useful in the synthesis of carbapenem side chains.Detailed description of the invention   The invention will be described using the following definitions unless otherwise specified.   The alkyl is a C.sub.4 which may be linear or branched._{1 ~ 6}It means an alkyl group.   Halogen and halo are chlorine, bromine and Means iodine. Preferred halo include bromo and iodo. Most preferred Is halo is bromo.   The acids used here are strong acids such as hydrochloric acid, formic acid, sulfuric acid, and toluenesulfonic acid. Means acid.   The method described herein involves cyclizing an appropriately substituted naphthalene sulfonamide Providing an appropriately substituted 1,8-naphthosultam. One of the present invention In an aspect, the invention provides a compound of formula I: (In the formula, R represents halo, or P is substituted or substituted with OP which is a protecting group. Unconverted C_{1 ~ 6}Represents alkyl. ) A synthesis of a compound represented by   (A) Formula II: (Wherein R is defined as above.) Is reacted with chlorosulfonic acid to give a compound of formula III: Producing a compound represented by   (B) Compound III is converted to NHR^aR^b(Where R^aAnd R^bIs H or C_{1 ~ 6}Represents alkyl. ) To react with Formula IV: Producing a compound represented by   (C) Compound IV is converted to HNO_ThreeAnd reacting with the formula VProducing a compound represented by   (D) reacting compound V with a reducing agent to form a compound of formula VI: Producing a compound represented by:   (E) reacting compound VI with an acid to give a compound of formula I Manufacturing And a synthesis comprising   In a preferred aspect of the invention, R represents methyl. Another preferred embodiment of the present invention In a preferred aspect, R is halo, preferably Br or I, and most preferably Represents Br.   In another preferred aspect of the invention, R^aAnd R^bOne of them is H or C_{1 ~ 6} Alkyl, the other being C_{1 ~ 6}Alkyl. In particular, both are C_{1 ~ 6}Alkyl And most preferably both represent ethyl.   In another preferred aspect of the invention, a compound of formula X:A method for producing a compound represented by the formula:   Formula XI: Is reacted with a lithiating agent to give a compound of formula XII: Producing a compound represented by   Lithiated compounds with CO_TwoAnd reacting with formula XIV: Producing a compound represented by:   Reacting this compound with a reducing agent to produce a compound of formula X   And methods comprising:   In another preferred aspect of the invention, a compound of formula X: A method for producing a compound represented by the formula:   Formula XI: Is reacted with a lithiating agent to give a compound of formula XII: Producing a compound represented by   The lithiated compound is reacted with HCHO to form a compound of formula X: Producing the compound represented by   And methods comprising:   In another aspect of the invention, a compound of formula I: (In the formula, R represents halo, or P is substituted or substituted with OP which is a protecting group. Unconverted C_{1 ~ 6}Represents alkyl. ) And intermediate compounds represented by   In another aspect of the present invention, Formula V: (In the formula, R represents halo, or P is substituted or substituted with OP which is a protecting group. Unconverted C_{1 ~ 6}R represents alkyl;^aAnd R^bIs H or C_{1 ~ 6}Alkyl Represents ) And intermediate compounds represented by   In another aspect of the invention, a compound of formula XI:And intermediate compounds represented by   In another aspect of the invention, a compound of formula XII: And intermediate compounds represented by   In another aspect of the invention, a compound of formula XIV: And intermediate compounds represented by   Generally, 1-halonaphthalene or 1-alkylnaphthalene and chlorosulfo Reaction with acid is a nitro-substituted organic compound, e.g. For example, nitromethane and nitrobenzene, and halo-substituted organic solvents, for example, Dichlorobenzene with ortho, meta or para substituted benzene, dichloromethane , Chloroform, carbon tetrachloride, dichloroethane and trifluoroacetic acid (TFA ) Can be carried out in an organic solvent such as Preferably, TFA is used as a solvent. Can be.   The reaction is typically carried out at about -40C to about 100C, preferably at about 0C to about 25C. Done.   The formation of the sulfonamide is typically performed in a non-reactive organic solvent. Examples Are secondary and tertiary alcohols such as isopropanol, tertiary butanol, Aromatic compounds, such as toluene, xylene, hexane, ether, ester, Includes tetrahydrofuran, and many chlorinated solvents as described above. The reaction is Typically, it is carried out at about -50 ° C to reflux temperature.   Reaction with nitric acid typically involves trifluoroacetic acid, sulfuric acid, nitrobenzene or It is performed in a chlorinated organic solvent as described above. The temperature range is typically about -30 C. to 60.degree. C., more preferably from about 0.degree. C. to about 20.degree.   The reduction and cyclization to form an amine from the nitro group is substantially The reaction can be carried out in any solvent at a temperature of about -40 ° C to a flowing temperature.   Reducing agents useful in the present invention include, for example, H_Two/ Pd and any other touch Medium: formic acid, ammonium formate, any metal formate, any trialkylammonium formate Pd / C with chemical carriers such as chromium or cyclohexene, and chloride Including tin etc.   Acids useful for cyclization include, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid and methanesulfur. Contains fonic acid. Preferably, hydrochloric acid is used.   Carboxylation (chain extension) is typically carried out with THF and ethers such as di- It is usually carried out in a solvent such as ethyl ether at a temperature of about -100 ° C to about 70 ° C. Can be. The base involved in the reaction is typically a lithium dialkylamide, such as , Lithium diisopropylamide.   Reduction to form alcohols from carboxylic acids typically involves THF or diethyl alcohol. The reaction is performed in a solvent such as toluene. Suitable reducing agents include borane in THF, and And similar reagents. The reaction is typically performed at about -50 ° C to reflux temperature. You.   The carbapenems synthesized in the present invention are suitably protected Activated 2-hydroxymethyl-carbapene-2-em-3-carboxylate And naphthosultam, and if necessary, denature the side chains thus introduced. And then removing the protecting groups present to provide the desired end product. It is prepared from This method is illustrated by the following general reaction scheme.                              Flow sheet A   According to the flow sheet A, the naphthosultam side chain group is first activated to the 2-position. Appropriately protected carbapen-2-em-3-cal having a hydroxymethyl group It can be reacted with boxylate.   -CH at position 2_TwoCarbapenem nuclei with OH substituents are described in Schmitt, S .; M. J. et al. Antibiotics, Vol. 41 (6): 780-787 (1 988), the teachings of which are incorporated herein by reference. The carboxylic acid group at C-3 of carbapenem is usually p-nitrobenzyl (P NB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylc Protected as a carboxyl protecting group such as rilethyl and the like. Furthermore, 6- (hi The hydroxyl group of the (droxyethyl) side chain may optionally be trimethylsilyl (TMS ), Triethylsilyl (TES), tert-butyldimethylsilyl (TBDM S), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxy Sicarbonyl, 2-trimethylsilylethoxycarbonyl, 2-trichloroeth Protected with hydroxyl protecting groups such as xyloxycarbonyl and the like.   The addition of the naphthosultam side group (SCG) to carbapenem is Tetrahydrofuran (THF), ether, acetonitrile, dimethylforma Suitable such as amide (DMF), benzene, dimethyl sulfoxide (DMSO), etc. Containing hydroxymethyl-carbapenem and naphthosultam side groups in a suitable solvent With a suitable activator (premixed) such as diethylazodicarboxylate (DEAD) / triphenylphosphine, diisopropylazodicarboxy Rate (DIAD) / tributylphosphine etc. at a temperature of about -20 ° C to 35 ° C. For about 5 to 90 minutes.   Also, naphthosultam and carbapenem together in a suitable solvent, Can be mixed with azodicarboxylate or phosphine reagents, The other components of the drug (phosphine or azodicarboxylate, respectively) are You can drown in the compound. Naphthosultam, carbapenem and activating reagent Once mixed, the reaction proceeds at a temperature of about -20C to 35C for about 5 to about 90 minutes. Is performed.   The resulting mixture is then purified according to standard operating procedures to the crude 2-naphthosultam-methyl To obtain substituted carbapenems, if necessary, by recrystallization or on silica gel. Chromatography Hexane, ethyl acetate, ether, benzene, dichloromethane, chloropho A suitable solvent such as lume, acetone, methanol, etc. or a mixture of two or more solvents And purified by elution.   Modification of the naphthosultam side chain of the compound, which is usually required for the introduction of a charged substituent, Best before removal of the protecting groups. For compounds containing a hydroxyl group in the side chain First, triflate, mesylate, tosylate, iodide, chloride, broth Activating the hydroxyl group by converting it to a suitable leaving group such as a amide, Next, the resulting leaving group is converted to an N-methyl containing a nitrogen atom capable of acting as a nucleophile. Imidazole, N- (2-hydroxyethyl) -imidazole, N-methyl-di Azabicyclooctane, 1- (carbamoylmethyl) -4-aza-1-azonia Bicyclo- [2.2.2] -octane, 1- (3-hydroxyprop-1-yl ) -4-aza-1-azoniabicyclo- [2.2.2] -octane, pyridine, Positively charged substituent on the side chain by substitution with a quaternized compound such as morpholine Can be introduced.   Also, charged substituents can be added before naphthosultam is added to the carbapenem. Can be incorporated into the fosultam side chain, Alternatively, it can be introduced after deprotection. Introduction of charged substituents before deprotection Is highly preferred.   Conversion of the hydroxyl group to a suitable leaving group can convert the hydroxyl-substituted compound In a suitable solvent such as dichloromethane, tetrahydrofuran, ether, benzene, etc. , Triethylamine, tributylamine, diisopropylethylamine In the presence of a suitable base such as trifluoromethanesulfonic anhydride, meta Sulfonic anhydride, toluenesulfonic anhydride, methanesulfonyl chloride, chloride With an activator such as benzenesulfonyl, toluenesulfonyl chloride and the like, about- This is achieved by treating at a temperature of 100 ° C to 0 ° C for about 5 to 120 minutes. this The resulting intermediate contains a leaving group, such as acetone, methyl ethyl ketone A solution containing the intermediate in a suitable solvent such as, for example, at a temperature of about -10 ° C to 50 ° C. For about 0.25 to 24 hours with excess sodium or potassium iodide By doing so, it can be converted into another leaving group, iodide.   In many cases, iodide is sufficiently pure that it can be used without further purification. Obtained in a pure state. For ease of handling, if iodide is not crystalline, Lyophilized from benzene An amorphous, easy-to-handle solid can be obtained.   Activated hydroxyl groups or iodides react the activating intermediate with the activating reagent. To be replaced. In some cases, activation and displacement are accomplished in a single step. Can be achieved. Activating reagents include dichloromethane, tetrahydrofuran, In a suitable solvent such as ether, DMF, benzene, acetonitrile, DMSO, etc. , Is added to the solution of the hydroxy-substituted compound in the presence of a suitable base. The resulting activated intermediate is prepared at about −78 ° C. with 1-3 molar equivalents of naphthosultam. Treated at a temperature of ５０50 ° C. for about 15-20 minutes. In some cases, in a kind of solvent Form an activated intermediate, isolate the activated intermediate, and perform the displacement reaction in different solvents It is desirable. In other cases, substitutions can be made without isolating the intermediate. Yes, when Q * is also used as the base, it is performed in parallel with the formation of the activated intermediate You can also.   If the displacement reaction is best achieved by using iodide, Solution is combined with approximately equivalents (0.9 to 1.05 molar equivalents) of naphthosultam Is done. Such as silver trifluoromethanesulfonate, silver tetrafluoroborate, etc. Non-nucleophilic Can be added. The reaction proceeds in the absence of silver salt, but the reaction is Proceeds more rapidly in the presence of the appropriate salt. In addition, the salt Aid in the removal of these substituted iodides, which in turn increases the efficiency of the next step Can be. The resulting mixture is then subjected to standard working procedures familiar to those skilled in the art. To provide the crude product, which may be recrystallized or chromatographed if necessary. Purified by   Other methods for introducing a positive charge into the side chain include methyl iodide, methyl bromide, Diltrichloroacetimidate, methyl trifluoromethanesulfonate, tet With a suitable alkylating reagent such as triethyloxonium lafluoroborate, etc. It can be applied to side chains containing nitrogen atoms which can be quaternized by the reaction. In the side chain Quaternization of the nitrogen atom results in a slight excess (1.05 to 1.2 molar equivalents) of the compound solution. )).   The synthesis of the target compound typically employs standard techniques well known to those skilled in the art. The protecting group present in the intermediate having the second substituent from the terminal Is completed by The deprotected end product can then be ion-exchanged, if necessary. Romatog Raffy, HPLC on reversed-phase silica gel, MPLC on reversed-phase polystyrene gel, etc. Purified using standard techniques such as, or by recrystallization.   The final product is structured by standard techniques such as NMR, IR, MS and UV Can be characterized. The final product is crystallized for ease of handling. If not, freeze-dry from water to obtain amorphous, easy-to-handle solids. it can.   Preferred values of R include halo, methyl, ethyl and propyl, which are Is substituted or unsubstituted by the hydroxyl protecting group OP is there.   Representative examples of the protecting group P include trimethylsilyl (TMS), triethylsilyl (TE S), tert-butyldimethylsilyl (TBDMS), tert-butyldiph Enylsilyl (TBDPS), acetyl, allyloxycarbonyl, 2-trimethyl It includes lucylylethoxycarbonyl, 2-trichloroethoxycarbonyl and the like.   Preferred R^aAnd R^bValues include H, methyl, ethyl and propyl. most Preferably, each represents ethyl. That is, preferably, NHR^aR^bIs Represents tylamine, diethylamine or dipropylamine.   As used herein, the term “reducing agent” refers to the position at position 8 when reacted with compound V. It means a compound that converts a nitrogen group into an amino group. Examples of suitable reducing agents include metals H combined_TwoFor example, Pd / C, formic acid combined with metal, combined with metal Combined trialkyl ammonium formate, cyclohexane and metal, tin chloride, etc. Including.                                 Example 1 Chlorosulfonation   In a three-necked flask, add methylnaphthalene (2.63 kg) and trifluoroacetic acid (13.2 L) was charged. The two-phase mixture is stirred and cooled to 5 ° C. using an ice-water bath. Was. Chlorosulfonic acid (2.93 L) was added while maintaining the reaction temperature below 20 ° C. The addition took 30 minutes. The reaction solution is treated with deionized water at 15 It took a minute and stopped.   The product crystallized on addition of water to give a white slurry.   The reaction vessel was washed with TFA / water (1: 1, 1.0 L), and the washing solution was added to the stop vessel. Added. The cake was filtered on a polypropylene filter cloth and washed with water. cake Was dried in a stream of nitrogen overnight.                                 Example 2 Sulfonamide   Fill the flask with methylnaphthalenesulfonyl chloride (4.0 kg) and isopropa Noll (12.0 L) was charged. Diethylamine (3.73 L) in 10 minutes Was added to the slurry.   An exotherm to about 65 ° C. occurred and the starting material dissolved. The progress of the reaction is monitored by HPLC Monitored.   The solution was cooled to 20 ° C. and water (4 L) was added. Mix the raw sulfonamide The product (2 gm) was added and aged at 20 ° C. for 20 minutes. 1 ml of remaining water (32L) Added over time. The obtained slurry was aged at 20 ° C. for 20 minutes.   Filter the slurry over a 23 "polypropylene filter cloth And washed with water (12 L). The cake was dried overnight under a stream of nitrogen.                                 Example 3 Nitration   In a 2 L flask equipped with a nitrogen inlet, stirrer, addition funnel and temperature probe, N, N-diethyl-1-methyl-4-naphthalenesulfonamide (30 g) and And trifluoroacetic acid (TFA) (150 mL). The resulting solution is Cooled to ° C. Concentrated sulfuric acid (30 mL) was added over 2 minutes. Cool solution to -3 ° C Rejected.   The reaction temperature was raised to -3 ° C to + 5 ° C while rapidly stirring fuming nitric acid (6.2 mL). It was added to the solution over about 30 minutes while maintaining.   The progress of the reaction was monitored by HPLC. The reaction was carried out with a residual amount of HP starting material. LC analysis <1% (by area for product at 200 nm) Is considered complete when You.   While maintaining the reaction stop temperature below 25 ° C. using an ice water bath, add water (375 m L) was added over 60 minutes. The obtained slurry was aged at 20 ° C. for 30 minutes. , Filtered and the cake was washed with water (100 mL).   The cake was dried in a stream of nitrogen until the residual water content was less than 35% by weight.   The partially dried solid is taken up in ethyl acetate (75 mL) at 30 ° C. for 30 minutes A slurry was formed. Hexane (150 mL) was added over 20 minutes and the slurry was And aged at 20 ° C. for 30 minutes. Filter the slurry and wash with hexane (100 mL) And dried overnight in a stream of nitrogen.                                 Example 4 Reduction-cyclization   In a 72L round bottom flask, add N_TwoInlets, thermocouples, and overhead stirrers Was installed. Add 1-methyl-4-diethanol with ethanol (20 L) to the flask. 2.20 kg of ethylsulfonamido-5-nitronaphthalene was charged.   10% by weight of Pd / C (50% by weight in water, 0.17 kg) was slurried in water And rinsed off with water (80 mL) and ethanol (6 L). Get Potassium formate (1.74 kg) was added to the slurry at once. The slurry , Warmed to 60 ° C for 1 hour and then refluxed for 1 hour.   The reaction was determined by HPLC analysis with a residual SM of 0.2% relative to the starting material. When it is less than%, it is considered completed.   Upon completion of the reaction, the mixture was cooled to 20 ° C. and concentrated hydrochloric acid (2.73 L) was added for about 20 minutes. It was added.   The resulting slurry is solka-floc^TMFilter through a pad of The ki was washed with 10% hydrochloric acid in ethanol (13 L total). Clean the combined filtrates And heated at reflux temperature (81 ° C.) for 3-4 hours. Cyclization was achieved.   The solution was cooled to 40 ° C. to a concentrated slurry. slurry Was cooled to 20 ° C. and water (7.5 L) was added over 30 minutes. 5 slurry C. and aged for 15 minutes.   The slurry was filtered and washed with water (5L). Dry crystalline solids overnight under nitrogen flow did.                                 Example 5 Dilithiation-carboxylation   2.0 L flask with nitrogen inlet, stirrer, temperature probe, and addition funnel Sco was charged with THF (5L). Add diisopropylamine (1.34 L) Added. The solution was cooled to −15 ° C., and n- Butyl lithium (6.0 L) was added dropwise to lithium diisopropylamide (LDA). ) Got.   In another 50L flask equipped with a stirrer and nitrogen inlet, Charge THF (10 L) and 1-Me NH naphthosultam (1.0 kg). It is. The solution was degassed by vacuum / replacement with nitrogen, cooled to −15 ° C., The LDA solution was added dropwise while maintaining the temperature at 5 ° C. to −5 ° C. to form a dianion solution.   The dianine solution was aged at −15 ° C. for 30 minutes.   In another 100 L flask equipped with a stirrer, nitrogen inlet and temperature probe, THF (10 L) was charged and degassed by reduced pressure / substitution with nitrogen. Bring the solution to -20 ° C Cool, absolutely dry grade CO_TwoWas blown into THF until saturated. Next, The carbonated solution while ensuring that the resulting slurry is well mixed. Was slowly added. After warming to 10 ° C., 10 L of 2N HCl was added to the solution. And aged for 30 minutes.   The solution was concentrated under atmospheric pressure to about 10 L to remove THF and initiate crystallization. Was. The resulting slurry was aged at 15 ° C. for 30 minutes, filtered and the cake was washed with water (10 L) and dried in a stream of nitrogen.Example 6 Borane reduction   In a 50L round bottom flask, add N_TwoInlets, thermocouples, addition funnels and overheads A thaler was installed. In a flask, dry NH-sultamcarboxylic acid (1. 14 kg) and THF (18 L). The slurry was cooled to 15 ° C . NaBH is added to this slurry._Four(327 g) was added followed by BF_ThreeEtherate (1.42 L) was added slowly.   The slurry was aged at 15-20 ° C and the progress of the reaction was monitored by HPLC. Was.   Cool the slurry to 10 ° C and slowly add methanol (1.2 L) Excess borane was quenched. Slowly add 2N HCl (11 L) for 30 minutes Matured. Termination reaction mixture Was distilled at atmospheric pressure to remove volatiles. The resulting solution is cooled to 55 ° C. The crystallization was started by adding the material and cooled to 15 ° C. over 1 hour. After aging for 30 minutes The slurry was filtered, washed with 10 L of water and dried under a stream of nitrogen.                                 Example 7 Dilithiation-hydroxymethylation   In a 10 mL flask equipped with a nitrogen inlet, stirrer, and temperature probe, add T HF (2 mL) was charged.   Diisopropylamine (0.14 mL) was added. Cool the solution to -15 ° C N-Butyllithium (0.66 mL) while maintaining the reaction temperature at -15 ° C to 0 ° C Was added dropwise to obtain lithium diisopropylamide (LDA).   In a separate 20 mL flask equipped with a stirrer and nitrogen inlet, THF (2 mL) ) And 1-MeNHNaphthosultam (0.07 g). Reduce the solution Degas by pressure / nitrogen displacement, cool to -15 ° C and bring solution temperature to -15 ° C to -5 ° C. The LDA solution was added dropwise while maintaining to produce a dianion solution.   The dianine solution was aged at −15 ° C. for 30 minutes.   Another 20 with stirrer, nitrogen inlet and temperature probe In a mL flask, THF (2 mL) and paraformaldehyde (0.12 g) And deaerated by vacuum / replacement with nitrogen. The solution was cooled to -20 <0> C. next, Add the dianine solution to this paraformaldehyde solution while ensuring thorough mixing. It was added very well. After warming to 10 ° C., 10 mL of 2N HCl was added to the solution, Aged for 30 minutes.   The solution was concentrated under atmospheric pressure to about 10 mL to remove THF and initiate crystallization. I let you. The resulting slurry was aged at 15 ° C for 30 minutes, filtered and the cake was washed with water (1 0 mL) and dried in a stream of nitrogen.

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] May 20, 1999 (May 20, 1999) [Details of Amendment] Claims 1. Formula I: (Wherein, R halo are presented or,. Representing a C _{1 to 6} alkyl P is not been or substituted substituted with OP is a protecting group) A method of synthesizing a compound represented by, (a ) Formula II: (Wherein R is defined as above) by reacting a compound of formula III with chlorosulfonic acid In that to produce a compound represented, (b) (. Wherein, R ^a and R ^b representing H or C _{1 to 6} alkyl) Compound III NHR ^a R ^b is reacted with the formula IV: (C) reacting compound IV with HNO ₃ to form a compound of formula V (D) reacting compound V with a reducing agent to form a compound of formula VI: And (e) reacting compound VI with an acid to produce a compound of formula I. 2. 2. The method according to claim 1, wherein R represents methyl. 3. 2. The method according to claim 1, wherein R represents halo. 4. One of R ^a and R ^b represents H or C _{1 to 6} alkyl, The method of claim 1 the other is C _{1 to 6} alkyl. 5. The method of claim 4, R ^a and R ^b represents C _{1 to 6} alkyl. 6. 6. The method according to claim 5, wherein ^Ra and ^Rb represent ethyl. 7. The method of claim 1, wherein step (a) is performed in a solvent selected from the group consisting of nitromethane, nitrobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and trifluoroacetic acid. 8. The method according to claim 7, wherein the solvent is trifluoroacetic acid. 9. The method of claim 7, wherein step (a) is performed at a temperature from about -40C to about 100C. 10. The method of claim 1, wherein step (b) is performed in a substantially non-reactive organic solvent. 11. The method according to claim 10, wherein the solvent is selected from isopropanol, tertiary butanol, toluene, xylene, hexane, ether, ester, tetrahydrofuran, and many chlorinated solvents as described above. 12. The method according to claim 11, wherein the reaction temperature of step (b) is from about -50C to reflux temperature. 13. The method according to claim 1, wherein step (c) is performed in a solvent selected from trifluoroacetic acid, sulfuric acid, nitrobenzene and chlorinated organic solvents. 14． 14. The method of claim 13, wherein step (c) is performed at about -30C to about 60C. 15. 15. The method of claim 14, wherein step (c) is performed at about 0C to about 20C. 16. 2. The method of claim 1, wherein step (d) is performed at a temperature from about -40 <0> C to reflux. 17． Step a (d), hydrogen gas, formic acid or formic acid derivative [ammonium formate, metal formate metal (sodium, potassium, is selected from lithium and calcium), it is selected from formic acid tri -C _{1 to 6} alkylammonium, 17. The method according to claim 16, which is performed using a reducing agent selected from the group consisting of sodium borohydride, cyclohexene, and tin chloride. 18. The method according to claim 1, wherein step (e) is performed using an acid selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid and methanesulfonic acid. 19. The method according to claim 19, wherein the acid is hydrochloric acid. 20. Formula X: Or a compound of the formula XI: Is reacted with a lithiating agent to give a compound of formula XII: By reacting the lithiated compound with CO ₂ to form a compound of formula XIV: And reacting the compound with a reducing agent to produce a compound of formula X. 21. Formula X: Or a compound of the formula XI: Is reacted with a lithiating agent to give a compound of formula XII: And reacting the lithiated compound with HCHO to form a compound of formula X: Producing a compound represented by the formula: 22. Formula XII: A compound represented by the formula: 23. Formula XIV: A compound represented by the formula:

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AU, AZ, BA, BB, BG, BR, BY, CA, CN, CU, CZ, EE, GE, GW, HU, ID, IL, IS, JP, KG, KR, KZ, LC, LK, LR, LT, LV, MD, MG, MK, MN, MX , NO, NZ, PL, RO, RU, SG, SI, SK, SL, TJ, TM, TR, TT, UA, US, UZ, VN, YU (72) Inventor Miller, Ross A United States of America, New Jersey 07065, Lowway, East Lincoln Avenue 126 (72) Inventor Lieberman, David Earl United States, New Jersey 07065, Lowway, East Lincoln Avenue 126 [continued abstract]

Claims (1)

[Claims] 1. Formula I: (Wherein, R halo are presented or,. Representing a C _{1 to 6} alkyl P is not been or substituted substituted with OP is a protecting group) A method of synthesizing a compound represented by, (a ) Formula II: (Wherein R is defined as above) by reacting a compound of formula III with chlorosulfonic acid In that to produce a compound represented, (b) (. Wherein, R ^a and R ^b representing H or C _{1 to 6} alkyl) Compound III NHR ^a R ^b is reacted with the formula IV: (C) reacting compound IV with HNO ₃ to form a compound of formula V (D) reacting compound V with a reducing agent to form a compound of formula VI: And (e) reacting compound VI with an acid to produce a compound of formula I. 2. 2. The method according to claim 1, wherein R represents methyl. 3. 2. The method according to claim 1, wherein R represents halo. 4. One of R ^a and R ^b represents H or C _{1 to 6} alkyl, The method of claim 1 the other is C _{1 to 6} alkyl. 5. The method of claim 4, R ^a and R ^b represents C _{1 to 6} alkyl. 6. 6. The method according to claim 5, wherein ^Ra and ^Rb represent ethyl. 7. The method of claim 1, wherein step (a) is performed in a solvent selected from the group consisting of nitromethane, nitrobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, and trifluoroacetic acid. 8. The method according to claim 7, wherein the solvent is trifluoroacetic acid. 9. The method of claim 7, wherein step (a) is performed at a temperature from about -40C to about 100C. 10. The method of claim 1, wherein step (b) is performed in a substantially non-reactive organic solvent. 11. The method according to claim 10, wherein the solvent is selected from isopropanol, tertiary butanol, toluene, xylene, hexane, ether, ester, tetrahydrofuran, and many chlorinated solvents as described above. 12. The method according to claim 11, wherein the reaction temperature of step (b) is from about -50C to reflux temperature. 13. The method according to claim 1, wherein step (c) is performed in a solvent selected from trifluoroacetic acid, sulfuric acid, nitrobenzene and chlorinated organic solvents. 14． 14. The method of claim 13, wherein step (c) is performed at about -30C to about 60C. 15. 15. The method of claim 14, wherein step (c) is performed at about 0C to about 20C. 16. 2. The method of claim 1, wherein step (d) is performed at a temperature from about -40 <0> C to reflux. 17． Step a (d), hydrogen gas, formic acid or formic acid derivative [ammonium formate, metal formate metal (sodium, potassium, is selected from lithium and calcium), it is selected from formic acid tri -C _{1 to 6} alkylammonium, 17. The method according to claim 16, which is performed using a reducing agent selected from the group consisting of sodium borohydride, cyclohexene, and tin chloride. 18. The method according to claim 1, wherein step (e) is performed using an acid selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid and methanesulfonic acid. 19. The method according to claim 19, wherein the acid is hydrochloric acid. 20. Formula X: Or a compound of the formula XI: Is reacted with a lithiating agent to give a compound of formula XII: By reacting the lithiated compound with CO ₂ to form a compound of formula XIV: And reacting the compound with a reducing agent to produce a compound of formula X. 21. Formula X: Or a compound of the formula XI: Is reacted with a lithiating agent to give a compound of formula XII: And reacting the lithiated compound with HCHO to form a compound of formula X: Producing a compound represented by the formula: 22. Formula I: (Wherein, R or represents halo, represents. A C _{1 to 6} alkyl P is not the or substituted substituted with OP is a protecting group), a compound represented by. 23. Formula V: (Wherein, R or represents halo, represents C _{1 to 6} alkyl P is not been or substituted substituted with OP is a protective group; R ^a and R ^b represents H or C _{1 to 6} alkyl ). 24. Formula XI: A compound represented by the formula: 25. Formula XII: A compound represented by the formula: 26. Formula X or XIV: A compound represented by the formula: