合成路线1

By cyclization of 2-(2,3-dichlorobenzylidene)acetyl acetic acid methyl ester (IV) with acetylacetic acid ethyl ester (V) and ammonia (VI) in tert-butanol.

合成路线2

The condensation of 6-methoxy-2-naphthaldehyde (I) with ethyl aceto-acetate (II) gives ethyl 2-(6-methoxy-2-naphthylmethylene)acetoacetate (III), which is reduced to ethyl 2-(6-methoxy-2-naphthylmethyl)acetoacetate (IV). Finally, this compound is hydrolyzed and decarboxylated in acidic medium.

合成路线3

The bromination of beta-naphthol (I) gives the 1,6-dibromo-beta-naphthol (II), which is partially debrominated with Sn and BrH, yielding 1-bromo-beta-naphthol (III). The methylation of (III) with methanol/sulfuric acid affords the corresponding methyl ether (IV), which is treated with Mg and DMF to provide 6-methoxynaphthalene-2-carbaldehyde (V). The condensation of (V) with ethyl acetoacetate (VI) gives the expected adduct (VII), which is reduced with H2 over Pd/C to provide 2-acetyl-3-(6-methoxy-2-naphthyl)propionic acid ethyl ester (VIII). Finally, this compound is decarboxylated with aqueous HCl.

合成路线4

Compound can be prepared in three different ways: 1) By cyclization of 2-(2-naphthyloxy)ethylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol. 2) By cyclization of 2-(2-naphthyloxy)ethylhydrazine (I) with tetrolic acid ethyl ester (III) in refluxing n-butanol. 3) By condensation of 3-methylpyrazol-5-one (IV) with 2-(2-naphthyloxy)ethyl bromide (V) by means of NaH in DMF or by heating at 110 C.

合成路线5

The reaction of 2,5-dimethoxybenzaldehyde (I) with ethyl acetoacetate (II) in a mixture of piperidine and glacial acetic acid in refluxing benzene gives ethyl alpha-acetyl-beta-(2,5-dimethoxyphenyl)acrylate (III), which is hydrogenated in a Parr low-pressure apparatus using 5% palladium on charcoal catalyst in ethyl acetate to yield ethyl alpha-acetyl-(2,5-dimethoxyphenyl)propionate (IV). The condensation of the propionate (IV) with 2,4.6-triaminopyrimidine in diphenylether at 195-230 C provides 2,4-diamino-7,8-dihydro-6-(2,5-dimethoxybenzyl)-5-methyl-7-oxopyrido[2,3-d]pyrimidine (VI). The key intermediate (VI) is converted to the 7-chloro compound (VII) by treatment with a 1:1 complex of N,N-dimethylformamide thionyl chloride, and finally (VII) is hydrogenolyzed with palladium on charcoal in the presence of potassium hydroxide to yield BW-301 U.

合成路线6

By cyclization of ethyl acetoacetate (I), 2,1,3-benzoxadiazole-4-carboxaldehyde (II) and concentrated NH3 in refluxing ethanol.

合成路线7

3) The reaction of the 7-aminocephem derivative (VI) with ethyl acetoacetate (IX) at room temperature gives the 3-aminocrotonate derivative (X), which is esterified with dioxolone (II) as before yielding the ester derivative (XI). The acidic (HCl) hydrolysis of (XI) in methanol-dichloromethane affords the 7-aminocephem derivative (XII) , which is finally condensed with 2-O-(tert-butoxycarbonyl-L-alanyl)mandelic acid (VII) by means of dicyclohexylcarbodiimide (DCC) in dichloromethane to yield the protected product (V), already obtained.

合成路线8

Hydrazine hydrate (I) is added dropwise under stirring to ethyl acetoacetate (II), which has been heated to 140 C, water and ethanol formed in the reaction are distilled off, and the mixture is heated at reflux. Upon completion of the reaction, the mixture is allowed to stand at room temperature, and the solid thus separated is collected and recrystallized from ethanol to obtain the title compound.

合成路线9

Suspension of 3-methyl-2-pyrazolin-5-one (I) is added dropwise under stirring to ethyl acetoacetate (II), which has been heated to 140 C, water and ethanol formed in the reaction are distilled off, and the mixture is heated at reflux. Upon completion of the reaction, the mixture is allowed to stand at room temperature, and the solid thus separated is collected and recrystallized from ethanol to obtain the title compound.

合成路线10

The condensation of 4-fluorobenzaldehyde (I) with ethyl acetoacetate (II) by means of piperidine, followed by a treatment with hot NaOH and esterification with methanol in acid medium, gives 3-(4-fluorophenyl)glutaric acid dimethyl ester (III), which is stereoselectively hydrolyzed with liver esterase in aqueous acetone, yielding the monoester (IV) with a 95% ee. The selective reduction of the ester group of (IV) with LiH and LiBH4 in THF affords the chiral 5-hydroxypentanoic acid (V), which is esterified with dimethyl sulfate in methanol to the corresponding methyl ester (VI). The reaction of (VI) with MsCl and TEA in toluene gives the mesylate (VII), which is cyclized with benzylamine (VIII) and TEA in toluene, affording the chiral piperidone (IX).The reaction of (IX) with dimethyl carbonate (X) and NaH in hot toluene yields the chiral carboxylate (XI), which is reduced at the carboxylate and ketonic groups with LiAlH4 or BH3 in DMSO, providing the chiral piperidine methanol derivative (XII). The reaction of (XII) with MsCl and TEA in toluene yields the mesylate (XIII), which is condensed with the phenol derivative (XIV) by means of NaH in hot DMF, affording the adduct (XV). Finally, this compound is debenzylated by hydrogenation with H2 over Pd/C.

合成路线11

The cyclization of 2,3-dihydroxybenzaldehyde (I) with dibromomethane by means of KF in hot DMF gives 2,3-methylenedioxybenzaldehyde (II), which is condensed with ethyl acetoacetate (III) by means of piperidine and acetic acid in refluxing benzene to afford ethyl 2-acetyl-3-(2,3-methylenedioxyphenyl)acrylate (IV). Finally, this compound is cyclized with methyl 3-aminocrotonate (V) in hot isopropanol.

合成路线12

1) The condensation of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) in toluene gives ethyl 2-(3-nitrobenzylidene)acetoacetate (III), which is then cyclized with methyl 3-aminocrotonate (IV) [prepared from methyl acetoacetate (V) with NH3 and p-toluenesulfonic acid]; the reaction is carried out in refluxing ethanol.

合成路线13

2) This compound can also be obtained by direct cyclization of ethyl acetoacetate (I) with 3-nitrobenzaldehyde (II) and 3-aminocrotonate (IV) in refluxing ethanol.

合成路线14

Leflunomide can be obtained by several related ways: 1) The reaction of diketene (I) with 4-(trifluoromethyl)-aniline (II) in hot acetonitrile gives N-[4-(trifluoro-methyl) phenyl]acetoacetamide (III) , which by reaction with triethyl orthoformate (IV) in refluxing acetic anhydride yields the corresponding ethoxymethylene derivative (V). Finally, this compound is cyclized with hydroxylamine in refluxing ethanol/water. 2) The reaction of ethyl acetoacetate (VI) with triethyl orthoformate (IV) as before gives the corresponding ethoxymethylene derivative (VII), which by cyclization with hydroxylamine as before affords 5-methylisoxazole-4-carboxylic acid ethyl ester (VIII). The hydrolysis of (VIII) under acidic conditions yields the free acid (IX), which is converted into the acid chloride (X) by standard methods. Finally, this compound is condensed with 4-(trifluoro-methyl)aniline (II) by means of triethylamine in acetonitrile. 3) The formation of leflunomide from acid (IX) or its derivatives such as ethyl (VIII) or other esters can also be performed through other standard procedures of amide formation. 4) The N-[4-(trifluoromethyl)phenyl]acetoacetamide (III) can also be obtained by reaction of 4-(trifluoro-methyl) aniline (II) with 2,2,6-trimethyl-4H-1,3-dioxin-4-one (XI) in refluxing xylene.

合成路线15

The cyclization of ethyl acetoacetate (I) with 3-amino-2-butenenitrile (II) gives 4-hydroxy-2,6-dimethylpyridine-3-carbonitrile (III), which is treated with SOCl2 and oxidized with MCPBA to yield 4-chloro-2,6-dimethylpyridine-3-carbonitrile N-oxide (IV). Finally, this compound is condensed with thiomorpholine (V) to afford the target compound.

合成路线16

By direct cyclization of phenylhydrazine (I) with ethyl acetoacetate (II) in refluxing ethanol.

合成路线17

Reaction of 4-methoxyaniline (XXI) with ethyl acetoacetate (XXII) by means of triethanolamine in refluxing xylene gives the acetoacetanilide (XXIII), which is cyclized by means of hot triethanolamine and H2SO4 to yield 6-methoxy-4-methylquinolin-2(1H)-one (I), which is treated with refluxing POCl3 to provide 2-chloro-6-methoxy-4-methylquinoline (XXIV). Reaction of compound (XXIV) with SO2Cl2 in hot AcOH affords 2,5-dichloro-6-methoxy-4-methylquinoline (XXV), which is treated with MeONa in refluxing methanol to furnish 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Alternatively, the reaction of compound (XXIV) with MeONa as before gives 2,6-dimethoxy-4-methylquinoline (XXVII), which is treated with SO2Cl2 in hot AcOH to give the already described 5-chloro-2,6-dimethoxy-4-methylquinoline (XXVI). Nitration of compound (XXVI) with KNO3 and P2O5 gives the 8-nitroquinoline derivative (XXVIII), which is condensed with 3-(trifluoromethyl)phenol (IV) by means of KOH in hot NMP to yield the diaryl ether (VII). Finally, the nitro group of compound (VII) is reduced with hydrazine over Pd/C.

合成路线18

b) The intermediate 7(S)-(tert-Butoxycarbonylamino)-5-azaspiro[2.4]heptane (VII) can also be obtained as follows: 1) The cyclopropanation of ethyl acetoacetate (XXXI) with 1,2-dibromoethane (XXXII) by means of K2CO3 in DMF gives 1-acetylcyclopropane-1-carboxylic acid ethyl ester (XXXIII), which is brominated with Br2 in ethanol yielding the bromoacetyl derivative (XXXIV). The cyclization of (XXXI) with (R)-alpha-methylbenzylamine (XIII) by means of triethylamine affords 5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane-4,7-dione (XXXV), which by reaction with hydroxylamine is converted into the monooxime (XXXVI). The reduction of (XXXVI) with H2 over RaNi in methanol affords 7-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptan-4-one as a diastereomeric mixture (XXXVII) + (XXXVIII), which is separated by column chromatography. The reduction of the (7S)-isomer (XXXVIII) with LiAlH4 in THF gives 7(S)-amino-5-[1(R)-phenylethyl]-5-azaspiro[2.4]heptane (XXXIX), which is protected in the usual way to the tert-butoxycarbonyl derivative (XL). Finally, this compound is debenzylated to (VII) by hydrogenation with H2 over Pd/C in ethanol.

合成路线19

A synthesis of pitavastatin has been reported: Cyclization of 2-amino-4'-fluorobenzophenone (I) with 3-cyclopropyl-3-oxopropionic acid methyl ester (II) by means of H2SO4 in refluxing acetic acid or methanesulfonic acid in refluxing benzene gives 2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-carboxylic acid methyl ester (III), which is reduced with DIBAL in toluene to yield the carbinol (IV). Oxidation of compound (IV) with PCC and AcONa in dichloromethane affords carbaldehyde (V), which is condensed with tributylstannane (VI) by means of BuLi in THF to provide the enol ether (VII). Hydrolysis of (VII) by means of TsOH in THF/water gives the unsaturated carbaldehyde (VIII), which is condensed with acetoacetic ester (IX) by means of NaH and BuLi in THF to yield the 5-hydroxy-3-oxoheptenoic ester derivative (X). Stereoselective reduction of the oxo group of (X) by means of diethylmethoxyborane and NaBH4 in THF/methanol gives the racemic syn-dihydroxy compound (XI) in a syn/anti ratio of 98:2. Finally, compound (XI) is hydrolyzed with NaOH in aqueous ethanol to yield racemic pitavastatin sodium. Alternatively, the unsaturated carbaldehyde (VIII) can also be obtained by reaction of carbaldehyde (V) with phosphonate (XII) by means of NaOH in toluene/water to give the unsaturated nitrile (XIII), which is finally reduced with DIBAL in toluene to afford the target carbaldehyde (VIII).

合成路线20

A further procedure employed the chiral keto acid (XXII) as the key intermediate. The cyclohexenone carboxylic acid (XXI) was synthesized via aldol condensation between 3-benzoylacrylic acid (XIX) and ethyl acetoacetate (XX), followed by cyclization and decarboxylation under Robinson annulation reaction conditions. Resolution of (XXI) to furnish the desired (S)-enantiomer (XXII) was accomplished either via formation of the diastereomeric salts with cinchonidine or, alternatively, by esterification of (XXI) with n-butanol --yielding the isomeric mixture (XXIII)--, followed by enantioselective hydrolysis of the (S)-butyl ester from in the presence of alpha-chymotrypsin. Coupling of keto acid (XXII) with tetrahydropyridine (V) provided keto amide (XXIV). The keto group of (XXIV) was then reduced with NaBH4 to form a diastereomeric mixture of allylic alcohols (XXV), which were further reduced employing NaBH3CN in the presence of ZnCl2 to furnish the target (R)-cyclohexenecarboxamide (XXVI). The amide function of (XXVI) was finally reduced to the title amine by means of LiAlH4 in methyl tert-butyl ether.

合成路线21

Chloroacetaldehyde (VII), prepared by acid hydrolysis of the dimethyl ketal (VI), was condensed with ethyl acetoacetate (VIII) to produce ethyl 2-methyl-3-furoate (IX). Basic hydrolysis of ester (IX), followed by chlorination of the resultant carboxylic acid (X) with SOCl2, gave acid chloride (XI). Then, condensation of amine (V) with acid chloride (XI) yielded amide (XII), which was finally converted to the title thioamide by treatment with Lawesson's reagent in hot toluene.

合成路线22

The target compound can be obtained by heating benzaldehyde (I) with ethyl acetoacetate (II) in HOAc in the presence of ZnCl2 and Ac2O.

合成路线23

The condensation of 2-[6-(dimethylamino)pyridin-3-yl]acetonitrile (I) with ethyl acetate (II) by means of NaH in THF gives 2-[6-(dimethylamino)pyridin-3-yl]-3-oxobutyronitrile (III), which is treated with hydrazine in refluxing ethanol/water to yield the corresponding hydrazone (IV). The cyclization of (IV) with ethyl acetoacetate (V) in refluxing dioxane affords 3-[6-(dimethylamino)pyridin-3-yl]-2,5-dimethylpyrazolo[2,3-a]pyrimidin-7-ol (VI), which is treated with refluxing POCl3 to provide the expected 7-chloro derivative (VII). Finally, this compound is treated with dipropylamine (VIII) in refluxing acetonitrile to furnish the target dipropylamino derivative.

合成路线24

The cyclization of 5-amino-4-(4-methoxy-2-methylphenyl)-3-methylpyrazole with ethyl acetoacetate (II) in refluxing acetic acid gives 7-hydroxy-3-(4-methoxy-2-methylphenyl)-5-methylpyrazolo[1,5-a]pyrimidine (III), which is treated with POCl3 and diethylaniline in refluxing toluene yielding the corresponding chloro derivative (IV). Finally, this compound is treated with pentyl-3-amine in DMSO at 150 C.

合成路线25

The cyclization of 5-aminopyrazole (I) with ethyl acetoacetate (II) by means of p-tolulenesulfonic acid in refluxing toluene gives the pyrazolo-pyrimidinone (III), along with its undesired isomer that is separated by crystallization or chromatography. The reaction of (III) with POCl3 gives the chloro derivative (IV), which is finally condensed with butylethylamine (V).

合成路线26

The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). Finally, this compound is deprotected and hydrolyzed to the target compound with LiOH in ethanol.

合成路线27

The cyclopropanation of ethyl acetoacetate (I) with 1,2-dibromoethane and K2CO3 in DMF, followed by hydrolysis with NaOH gives 1-acetylcyclopropane-1-carboxylic acid (II), which is condensed with 1(R)-phenylethylamine (A) by means of butyl chloroformate in dichloromethane yielding the chiral amide (III). The protection of the acetyl group with ethylene glycol and p-toluenesulfonic acid affords the cyclic acetal (IV), which is brominated with Br2 in dioxane to give the bromomethyl compound (V). The cyclization of (V) by means of NaH in THF affords the spirocyclopropane derivative (VI), which is deprotected with HCl providing the spiro pyrrolidinedione (VII). The reaction of (VII) with hydroxylamine affords the oxime (VIII), which is reduced with H2 over RaNi in methanol and crystallized with l-tartaric acid to give the desired chiral 7(R)-amino-5-(1(R)-phenylethyl)-5-azaspiro[2.4]heptan-4-one (IX). The reduction of the ketonic group of (IX) with LiAlH4 yields the chiral amine (X), which is protected with tert-butoxycarbonyl anhydride to the carbamate (XI). The hydrogenation of (XI) with H 2 over Pd/C affords the spiropyrrolidine (XII) with its NH group free, which is condensed with the quinolizine (XIII) by means of triethylamine in DMF providing intermediate (XIV). This compound is methylated by means of methyl iodide and sodium bis(trimethylsilyl)amide yielding the methylamino derivative (XV), which is finally deprotected and hydrolyzed to the target compound with LiOH in ethanol.

合成路线28

Claisen condensation of ethyl acetoacetate (I) with ethyl nicotinate (II) using 2.5 equivalents of LDA produced the corresponding diketoester, which was isolated as the enol form (III). Subsequent cyclization of (III) at 150 C with removal of EtOH under reduced pressure afforded pyrone (IV). This was finally coupled with 1-cyclohexene-carboxaldehyde (V) in the presence of L-proline to give the target pyranochromene.

合成路线29

Claisen condensation of ethyl acetoacetate (I) with ethyl nicotinate (II) using 2.5 equivalents of LDA produced the corresponding diketoester, which was isolated as the enol form (III). Subsequent cyclization of (III) at 150 C with removal of EtOH under reduced pressure afforded pyrone (IV). This was finally coupled with (S)-perillaldehyde (V) in the presence of L-proline to give the target pyranochromene.

合成路线30

The intermediate fluoropyrrolidine (XIV) was obtained as follows: Alkylation of ethyl acetoacetate (I) with 1,2-dibromoethane (II) led to the cyclopropane derivative (III). Bromination of (III) provided bromo ketone (IV), which was condensed with (S)-1-phenylethylamine (V), yielding amino ketone (VI). Acylation of amine (VI) with (diethylfosfonyl)fluoroacetyl chloride (VII) gave amide (VIII). Intramolecular Wadsworth-Emmons condensation of keto phosphonate (VIII) in the presence of potassium tert-butoxide produced the pyrrolinone (IX). Catalytic hydrogenation of the pyrroline double bond of (IX), followed by separation of the resultant diastereomeric mixture, furnished pyrrolidinone (X). After saponification of the ethyl ester group of (X), the resulting acid (XI) was subjected to Curtius rearrangement in the presence of DPPA and t-BuOH, giving rise to carbamate (XII). Lactam (XII) reduction by means of borane in THF afforded pyrrolidine (XIII). The N-phenylethyl group of (XIII) was then removed by hydrogenation over Pd/C to furnish the required intermediate pyrrolidine (XIV) (See scheme no. 27170201a, intermediate (IX)).

合成路线31

Aminopyrazole (I) was cyclized to pyrazolopyrimidine (III) by means of ethyl acetoacetate (II) in refluxing dioxan. Chlorination of (II) with POCl3 produced the corresponding chloro derivative (IV). This was then heated with an excess of amine (V) in a sealed vessel at 100 C to afford the target compound, which was isolated as the hydrochloride salt.

合成路线32

Suzuki coupling of 2-bromoaniline (I) with boronic acid (II) in the presence of a palladium catalyst gave biphenyl (III). Subsequent condensation of (III) with ethyl acetoacetate (IV) afforded enamine (V), which was cyclized to hydroxyquinoline (VI) in refluxing diphenyl ether. Chlorination of (VI) in boiling POCl3 produced the corresponding 4-chloroquinoline (VII). This was finally condensed with N-(cyclopropylmethyl)-N--propylamine (VIII) to provide the target aminoquinoline.

合成路线33

The reaction of ethyl acetoacetate (I) with NaNO2 in acetic acid-water gives ethyl 2-(hydroxyimino)-3-oxobutyrate (II), which is cyclized with thiourea (III) by means of SO2Cl2 in methylene chloride yielding ethyl 2-(2-aminothiazol-4-yl)-2-(hydroxyimino)acetate (IV). The treatment of (IV) with trityl chloride (V) and triethylamine in DMF affords ethyl 2-(hydroxyimino)-2-(2-tritylaminothiazol-4-yl)acetate (VI), which by condensation with tert-butyl 2-bromo-2-methylpropionate (VII) by means of K2CO3 in DMSO is converted into ethyl 2-(2-tert-butoxycarbonyl-2-propyloxymino)-2-(2-tritylaminothiazol-4-yl)acetate (VIII). The hydrolysis of (VIII) with NaOH in refluxing methanol gives 2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (IX), which by condensation with tert-butyl 7-aminocephalosporanate (X) by means of 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in DMF yields tert-butyl 7-[2-(2-tert-butoxycarbonyl-2-propyloxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]cephalosporanate (XI). The hydrolysis of (XI) with trifluoroacetic acid in anisole affords 7-[2-(2-aminothiazol-4-yl)-2-(2-carboxy-2-propyloxyimino)acetamido]cephalosporanic acid (XII), which is finally treated with pyridine (A) and NaI.

合成路线34

7-Aminoquinolin-2-one (III) was prepared by Knorr cyclization of m-phenylenediamine (I) with ethyl acetoacetate (II). Subsequent diazotization of (II), followed by acid hydrolysis gave rise to the 7-hydroxyquinolinone (IV). Alkylation of (IV) with 3-chloro-3-methylbut-1-yne (V), followed by Claisen rearrangement of the resulting propargyl ether (V) afforded the pyranoquinolinone (VII). This was protected as the N-Boc derivative (VIII) by treatment with Boc2O and Et3N. Sharpless asymmetric dihydroxylation of (VIII) using dihydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst furnished the (R,R)-diol (IX), which was esterified with (-)-(S)-camphanoyl chloride (X) to produce diester (XI). The Boc protecting group of (XI) was finally removed by treatment with trifluoroacetic acid.

合成路线35

Friedel Crafts' condensation of phloroglucinol (I) with 3,3-dimethylacrylic acid (II) in the presence of boron trifluoride etherate gave the dihydroxy chromanone (III). Selective alkylation of the 7-hydroxyl group of (III) with iodomethane in the presence of K2CO3 furnished the methyl ether (IV). The carbonyl group of (IV) was subsequently reduced with NaBH4 in refluxing THF under basic conditions to produce chroman (V). The lactone ring of (VII) was then formed by a Pechmann reaction of (V) using ethyl acetoacetate (VI) and boron trifluoride to afford the tricyclic compound (VII). Dehydrogenation of (VII) employing DDQ in refluxing dioxan gave (VIII). The target 3'R,4'R-dihydroxylated derivative (IX) was obtained by Sharpless asymmetric dihydroxylation of (VIII) with hydroquinine 2,5-diphenyl-4,6-pyrimidinediyl diether ((DHQ)2-PYR) as the chiral catalyst. Diol (IX) was finally esterified with (-)-S-camphanoyl chloride (X) to afford the title diester.

合成路线36

By cyclization of ethyl acetoacetate (I) with 2-trifluoromethylbenzaldehyde (II) and N-(2-aminoethyl)morpholine (III) in refluxing ethanol

合成路线37

The reaction of 2,6-dichloro-4-methoxybenzyl chloride (I) with tetraethylammonium cyanide in refluxing dichloromethane gives 2-(2,6-dichloro-4-methoxyphenyl)acetonitrile (II), which is condensed with ethyl acetate (III) by means of sodium ethoxide in refluxing ethanol to yield the 3-oxobutyronitrile (IV). The cyclization of (IV) with hydrazine (V) by means of HOAc in refluxing benzene affords the aminopyrazole (VI), which is further cyclized with ethyl acetoacetate (VII) in refluxing acetic acid to provide 3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-ol (VIII). The reaction of (VIII) with refluxing POCl3 furnishes the corresponding chloro derivative (IX), which is allowed to react with ethylenediamine (X) in hot acetonitrile to give 7-(2-aminoethylamino)-3-(2,6-dichloro-4-methoxyphenyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidine (XI). Finally, this compound is reductocondensed with tetrahydropyran-4-one (XII) by means of sodium cyanoborohydride in methanol/HOAc to yield the target CP-671906-01.

合成路线38

Nitrosation of tert-butyl acetoacetate (I) with NaNO2/AcOH produces the oximino ester (II). Reductive cyclization of (II) with ethyl acetoacetate (III) in the presence of Zn/AcOH leads to the pyrrole dicarboxylate (IV). Selective decarboxylation of the t-butyl ester of (IV) under acidic conditions, followed by Vilsmeier formylation of the intermediate ethyl 2,4-dimethylpyrrole-3-carboxylate furnishes the pyrrole aldehyde (V). Alternatively, this compound is directly obtained from (IV) upon treatment with trimethyl orthoformate and trifluoroacetic acid. Basic hydrolysis of the ethyl ester group of (V) yields the pyrrolecarboxylic acid (VI). This is coupled to 2-(diethylamino)ethylamine (VII) to afford the corresponding amide (VIII).

合成路线39

Treatment of anacardic acid (I) with diethyl sulfate produces the dialkylated derivative (II). Ester group reduction in (II) employing LiAlH4 then yields the benzylic alcohol (III), which is further oxidized to aldehyde (IV) with pyridinium chlorochromate. Condensation of aldehyde (IV) with ethyl acetoacetate (V) in the presence of piperidine and AcOH gives the benzylidene acetoacetate (VI). This is finally condensed with enamino ester (VII) under modified Hantzsh conditions to furnish the target dihydropyridine compound.

合成路线40

Suzuki coupling of 2-bromoaniline (I) with 2,4-dichlorophenylboronic acid (II) affords the biphenylyl amine (III). This is condensed with ethyl acetoacetate (IV) to produce enamine (V), which is further cyclized in hot diphenyl ether to furnish the hydroxyquinoline (VI). Treatment of the sodium salt of (VI) with N-phenyl trifluoromethanesulfonimide gives rise to the aryl triflate (VII). Finally, displacement of the sulfonate group of (VII) with 1,2,3,6-tetrahydropyridine-4-carboxamide (VIII) in hot DMF provides the title compound

合成路线41

The intermediate 4-fluoro-5-hydroxy-2-methylindole (X) can be prepared by three alternative methods. The condensation of 2-fluoro-4-nitroanisole (XI) with 4-chlorophenoxyacetonitrile (XII) by means of potassium tert-butoxide produces a regioisomeric mixture of ortho-nitroarylacetonitriles (XIIIa) and (XIIIb) which, without separation, are reductively cyclized to indoles (XIVa) and (XIVb) by catalytic hydrogenation over Pd/C. After protection of indoles (XIV) as the respective N-Boc derivatives (XVa) and (XVb), metalation with tert-butyllithium followed by treatment with iodomethane yields the corresponding 1-Boc-2-methylindoles, which are further deprotected to (XVIa) and (XVIb) utilizing TFA. Demethylation of the mixture of methoxyindoles (XVI) with BBr3 in cold CH2Cl2 leads to the analogous hydroxyindoles, which are separated by column chromatography to provide the target 4-fluoro-5-hydroxy-2-methylindole (X) (2). In a different method, 2,3,4-trifluoronitrobenzene (XVII) is condensed with ethyl acetoacetate (XVIII) by means of NaH in THF followed by chromatographic separation of the resulting regioisomeric mixture to provide the 2-aryl acetoacetate (XIX). After acidic decarboxylation of (XIX), the obtained arylacetone derivative (XX) is protected as the dimethyl ketal (XXI) with trimethyl orthoformate and montmorillonite K10. Selective displacement of one fluoride group in (XXI) with sodium methoxide in methanol affords 1-(2-fluoro-3-methoxy-6-nitrophenyl)acetone dimethyl ketal (XXII), which is hydrolyzed to ketone (XXIII) under acidic conditions. The reductive cyclization of (XXIII) by means of TiCl3 and ammonium acetate provides 4-fluoro-5-methoxy-2-methylindole (XVIa), which is demethylated to (X) by using BBr3 as above (1, 2). Alternatively, the difluorophenyl ketal (XXI) is displaced with benzyl alcohol in the presence of NaH to give the benzyl ether (XXIV), which undergoes further ketal hydrolysis to the ketone (XXV) under acidic conditions. Finally, simultaneous cyclization and deprotection of (XXV) with H2 and Pd/C furnishes the desired 4-fluoro-5-hydroxy-2-methylindole (X) (2). Scheme 2.

合成路线42

合成路线43

合成路线44

Condensation of ethyl 3-oxobutyrate (LVII) with N,N-dimethylformamide dimethylacetal (XXXII) in EtOAc affords ethyl 2-acetyl-3-(dimethylamino)-2-propenoate (LVIII), which by cyclocondensation with ethyl oxalyl chloride (XXI) by means of LiHMDS in THF provides diethyl 4-oxopyran-2,5-dicarboxylate (LIX). Condensation of pyranone derivative (LIX) with 2,2-dimethoxyethylamine (XXVI) in EtOH gives pyridone (LX), which is then brominated with NBS in DMF to yield the 3-bromopyridin-4-one derivative (LXI). Hydrolysis of acetal (LXI) using HCOOH and H2SO4 in CH2Cl2 yields the corresponding aldehyde (LXII), which is cyclized with 3(R)-aminobutan-1-ol (XI) in the presence of AcOH in refluxing MeOH/toluene to afford the hexahydropyrido[1’,2’:4,5]pyrazino[2,1-b][1,3]oxazine derivative (LXIII). Finally, bromo ester (LXIII) is submitted to treatment with KOSiMe3 in DME .

合成路线45

合成路线46