合成路线1

The condensation of 1-methyl-4-piperidone (I) with ethyl cyanoacetate (II) in refluxing acetic acid gives ethyl (1-methyl-4-piperidylidene)cyanoacetate (III), which by reaction with KCN in ethanol is converted to ethyl (1-methyl-4-cyano-4-piperidyl)cyanoacetate (IV). The decarboxylative hydrolysis of (IV) with refluxing aqueous HCl affords (1-methyl-4-carboxy-4-piperidyl)acetic acid (V), which is esterified with ethanol - HCl to its diethyl ester (VI). Finally, this compound is treated with ethylamine at 200 C.

合成路线2

The condensation of diethylgermanium dihydride (I) with methyl acrylate (II) gives diethyldi-(beta-carbomethoxyethyl)germane (III), which is cyclized by treatment with potassium tert-butoxide in refluxing toluene yielding carbomethoxy-4,4-diethyl-4-germacyclohexanone (IV). The decarboxylative hydrolysis of (IV) with refluxing 20% aqueous H2SO4 affords 4,4-diethyl-4-germacyclohexanone (V), which is condensed with ethyl cyanoacetate (VI) by means of ammonium acetate acetic acid in refluxing benzene giving ethyl alpha-cyano-alpha-(4,4-diethyl-4-germacyclohexylidene)acetate (VII). The treatment of (VII) with KCN in ethanol-water, and then with refluxing aqueous HCl yields 4,4-diethyl-4-germacyclohexane-1-carboxy-1-acetic acid (VIII), which is then converted into its cyclic anhydride (IX) by reaction with refluxing acetic anhydride. The reaction of (IX) with 3-dimethylaminopropylamine (X) at 180 C gives N-(3-dimethylaminopropyl)-2-aza-8,8-diethyl-8-germaspiro[4.5]decane-1,3-dione (XI), which is finally reduced with LiAlH4 in benzene-ether.

合成路线3

The reaction of 6-isopropyl-4-oxo-4H-1-benzopyran-3-carbonitrile (I) with morpholine (A) and DMF in hot water gives 2-amino-6-isopropyl-4-oxo-4H-1-benzopyran-3-carboxaldehyde (II), which is cyclized with ethyl cyanoacetate (III) by means of piperidine (B) in refluxing ethanol yielding ethyl 2-amino-7-isopropyl-1-azaxanthone-3-carboxylate (IV). Finally, this compound is saponified by a treatment with sulfuric acid in refluxing acetic acid water.

合成路线4

The Sandmeyer reaction of 4-trifluoromethylanthranilic acid (I) with NaNO2, HBr and Cu2Br2 gives 2-bromo-4-trifluoromethylbenzoic acid (II), which by reaction with SOCl2 is converted into 2-bromo-4-trifluoromethylbenzoyl chloride (III). The Rosemind reduction of (III) with H2 over Pd/BaSO4/S yields 2-bromo-4-trifluoromethylbenzaldehyde (IV), which is condensed with ethyl cyanacetate (V) in refluxing toluene affording ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]propenoate (VI). The addition of 4-fluorophenylmagnesium bromide (VII) to (VI) in toluene ether gives ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoate (VIII), which is hydrolyzed and decarboxylated partially with H2SO4 in refluxing acetic acid water to yield 3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoic acid (IX). Cyclization of (IX) with butyllithium in ether affords 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-one (X), which is reducted with NaBH4 in methanol giving 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-ol (XI). The reaction of (XI) with SOCl2 in hot toluene yields 1-chloro-3-(4-fluorophenyl)-6-(trifluoromethyl)indan (XII).

合成路线5

Reaction of cyclohexenone (I) with ethyl cyanoacetate (A) in the presence of ammonia affords the Guareschi salt (II), which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid (III). The anhydride (IV) can be treated either with methanol to yield the halfester (V), or with hydroxylamine to afford the N-hydroxyimide (VII). The halfester (V) is subjected to a Curtius type rearrangement to give the isocyanate (VI), which is hydrolyzed to the amino acid hydrochloride (Xl).

合成路线6

The same product can be obtained from reaction of cyclohexenone (I) with ethyl cyanoacetate (A) in the presence of ammonia affords the Guareschi salt (II), which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid (III). The anhydride (IV) can be treated with the N-hydroxyimide (VII) via a Lossen type rearrangement by conversion of (VII) to N-benzenesulfonyloxylmide (VIII) and subsequent reaction with triethylamine in methanol followed by hydrolysis of the urethanester (IX). The free amino acid is finally obtained from the hydrochloride (X) via anion exchange.

合成路线7

The condensation of ethyl cyanoacetate (I) with farnesylacetone (II) by means of acetic acid ammonium acetate in refluxing benzene gives ethyl 2-cyano-3,7,11,15-tetramethyl-6,10,14-hexadecatrienoate (III), which is decarbo-xylated with NaOH in propylene glycol at room temperature yielding 3,7,11,15-tetramethyl-6,10,14-hexadecatrienonitrile (IV). The hydrolysis of (IV) with KOH in propylene glycol water at 130 C affords 3,7,11,15-tetramethyl-6,10,14-hexa-decatrienoic acid (V), which is finally condensed with morpholine (VI) by means of ethyl chlorocarbonate (VII) and triethylamine in THF.

合成路线8

The oxidation of 2-nitro-5-fluorotoluene (I) with KMnO4 in water gives 2-nitro-5-fluorobenzoic acid (II), which by reduction with H2 over Pd/C in methanol - aqueous HCl yields 2-amino-5-fluorobenzoic acid (III). The reaction of (III) with phosgene in THF aqueous HCl affords 5-fluoroisatoic acid anhydride (IV), which by cyclization with N-methylglycine (V) in OMS at 100 C affords 7-fluoro-4-methyl-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (VI). Finally, this compound is cyclized again with ethyl isocyanacetate (VII) by means of potassium tert-butylate and diethyl chlorophosphate in DMF.

合成路线9

The cyclization of anhydride (IV) with N-(2,4-dimethoxybenzyl)glycine (VIII) as before gives 7-fluoro-4-(2,4dimethoxybenzyl)-3,4-dihydro-2H-1,4-benzodiazepin-2,5(1H)-dione (IX), which by a new cyclization with (VII) as before is converted into ethyl-8-fluoro-5-(2,4dimethoxybenzyl)-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (X). The deprotection of (X) with trifluoroacetic acid yields ethyl-8-fluoro-5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate (XI), which is finally methylated with methyl iodide and NaH in DMF.

合成路线10

This compound has been obtained by two different ways: 1) The reaction of dipropylcarbinol (I) with HBr gives 4-bromoheptane (II), which is treated with KCN to yield 2-propylpentanenitrile (III). Finally, this compound is hydrolyzed to the target compound with NaOH or with H2SO4. 2) The condensation of cyanacetic acid ethyl ester (IV) with propyl bromide (V) by means of sodium propoxide in propanol gives crude dipropylcyanaacetic acid ethyl ester, which, without isolation, is hydrolyzed with NaOH in hot water yielding dipropylcyanacetic acid (VI). The decarboxylation of (VI) at 140-190 C affords the previously reported 2-propylpentanenitrile (III).

合成路线11

The condensation of 4-fluorocinnamic acid ethyl ester (I) with cyanacetic acid ethyl ester (II) by means of NaOEt in ethanol gives 2-cyano-3-(4-fluorophenyl)glutaric acid diethyl ester (III). Alternatively, glutarate (III) can also be obtained by condensation of 4-fluorobenzaldehyde (V) with cyanacetic ester (II) and acetic acid ethyl ester (VI). The reduction of the cyano group of (III) with H2 over PtO2 in ethanol, followed by cyclization in refluxing toluene, yields 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) as a mixture of the cis- and trans-isomers. The reaction of the mixture (IV) with EtONa in refluxing toluene causes isomerization of the cis-isomer, affording (rac)-trans-4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (VII), which is reduced with LiAlH4 or borane (NaBH4/BF3) to provide the (rac)-(trans)-hydroxymethylpiperidine (VIII). Finally, this compound is reductively methylated by treatment with formaldehyde and H2 over Pd/C in ethanol to furnish (rac)-(trans)-4-(4-fluorophenyl)-3-(hydroxymethyl)-1-methylpiperidine (IX), the desired intermediate. Alternatively, the cis/trans mixture 4-(4-fluorophenyl)-6-oxopiperidine-3-carboxylic acid ethyl ester (IV) can be methylated first with formaldehyde as before to give 4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (X), also as a cis/trans mixture. This mixture is treated with EtONa in refluxing toluene to yield (rac)-(trans)-4-(4-fluorophenyl)-1-methyl-6-oxopiperidine-3-carboxylic acid ethyl ester (XI). Finally, this compound is reduced with LiAlH4 in THF/toluene to afford the previously described target intermediate (IX).

合成路线12

The reaction of acid (I) with SOCl2 in ethyl ether containing triethylamine gives the corresponding acyl chloride (VII), which is condensed with ethyl cyanacetate (VIII) by means of NaH in glyme yielding ethyl 2-cyano-3-(1-methyl-2-pyrrolyl)-3-oxopropanoate (IX). The reaction of (IX) with aniline (X) in refluxing xylene affords the corresponding anilide (V) already obtained.

合成路线13

For the synthesis of umespirone the following synthesis pathway was chosen: Acetone is condensed with ethyl cyanoethanoate (I) to yield ethylisopropylidenecyanoacetate (II). This product is reacted with N-butylcyanoacetamide (III) in sodium methoxide solution to give N-butyl-2,4-dicyano-3,3-dimethylglutarimide (IV). The glutarimide (IV) is cyclized with phosphoric acid to yield 3-butyl-9,9-dimethyl-3,7-diazabicyclo[3.3.1]nonane-2,4,6,8-tetraone (V). The quaternary salt (VIII) (R = CH3), prepared from 1-(2-methoxyphenyl)piperazine (VI) and 1,4-dibromobutane (VII), undergoes reaction with (V) in the presence of potassium carbonate to afford the free base KC-9172 (IX) (R = CH3).

合成路线14

The cyclization of ethyl cyanoacetate (I) with urea (II) in ethanolic NaOEt provided 6-aminouracil (III). Nitrosation of (III) with NaNO2 in aqueous AcOH, followed by reduction of the resulting nitroso compound (IV) using sodium hydrosulfite gave 5,6-diaminouracil, which was purified by conversion to its hydrochloride salt (V). Condensation of this diamine with melted oxalic acid produced tetrahydroxypteridine (VI). Subsequent reaction of (VI) with PCl5 and POCl3 afforded tetrachlorocompound (VII). The reaction of (VII) with pyrrolidine (VIII) in aqueous KHCO3/CHCl3 resulted in a mixture of 2-, 4-, 7- and 4,7-substituted compounds, from which the desired 4-pyrrolidino-2,6,7-trichloropteridine (IX) was isolated by column chromatography. Further treatment of (IX) with benzylamine (X) in dioxan at r.t. provided diamine (XI). Finally, substitution of the third chlorine atom for piperazine (XII) was accomplished in boiling dioxan.

合成路线15

1) The nitrosation of 3-chlorophenol (I) with NaNO2 and H2SO4 in water gives 3-chloro-4-nitrophenol (III), which is methylated with SO4(Me)2 and NaH in THF to yield 3-chloro-4-nitroanisole (IV). The condensation of (IV) with ethyl cyanoacetate (V) by means of NaH in DMF affords ethyl 2-(5-methoxy-2-nitrophenyl)cyanoacetate (VI), which is submitted to ethanolysis with ethanol/HCl affording the malonic ester derivative (VII). The hydrogenation of (VII) with H2 over PtO2 in toluene/ethanol gives the corresponding amino derivative (VIII), which is condensed with methyl 3-formylacrylate (IX) in ethanol yielding the intermediate imine (X). This imine (X), without isolation, is cyclized with zinc acetate in methanol affording 3-[3,3-bis(ethoxycarbonyl)-5-methoxy-2,3-dihydro-1H-indol-2-yl]acrylic acid methyl ester (XI), which is acetylated with acetic anhydride to the N-acetyl derivative (XII). The decarboxylative hydrolysis of (XII) with KOH in ethanol gives 3-(1-acetyl-3-carboxy-5-methoxy-2,3-dihydro-1H-indol-2-yl)acrylic acid (XIII), which is converted into its dimethyl ester (XIV) with SO4(Me)2 and K2CO3. The dehydrogenation of (XIV) with dichlorodicyanobenzoquinone (DDQ) in refluxing toluene yields 3-[1-acetyl-5-methoxy-3-(methoxycarbonyl)-1H-indol-2-yl]acrylic acid methyl ester (XV), which is deacetylated to (XVI) by column chromatography over basic alumina in dichloromethane/acetone. The nitration of (XVI) with fuming nitric acid in acetic acid affords the 4-nitro derivative (XVII), which is methylated with NaH and methyl iodide to the N-methyl derivative (XVIII). The reduction of (XVIII) with Sn and 3N HCl in ethanol/water yields the corresponding 4-amino derivative (XIX), which is oxidized with Fremy's salt (nitrodisulfonic acid potassium salt) to afford 3-[5-methoxy-3-(methoxycarbonyl)-1-methyl-4,7-dioxo-4,7-dihydro-1H-indo l -2-yl]acrylic acid methyl ester (XX). The reduction of (XX) with Na2S2O4 in CHCl3/ethanol/water gives the corresponding hydroquinone (XXI), which is first reduced with DIBAL (diisobutylaluminum hydride) in toluene/dichloromethane and then oxidized again with FeCl3 to afford 3-(hydroxymethyl)-2-(3-hydroxy-1-propenyl)-5-methoxy-1-methyl-4,7-dihydro-1H-indole-4,7-dione (XXII). Finally, this compound is treated with aziridine (XXIII) in hot methanol.

合成路线16

This compound can be obtained by two related ways: The reaction of cyclopentanone (I) with ethyl cyanoacetate (II) by means of HOAc/NH4OAc gives the cyclopentylidene derivative (III), which by reaction with KCN yields 1-(cyanomethyl)cyclopentanecarbonitrile (IV). The hydrolysis of (IV) with HCl affords the dicarboxylic acid (V), which by reaction with Ac2O affords the corresponding cyclic anhydride (VI). Finally, the reaction of (VI) with O-benzyl hydroxylamine hydrochloride and NaHCO3 provides the target compound. Alternatively, the cyclic anhydride (VI) is treated with hydroxylamine hydrochloride and Na2CO3 to gives the N-hydroxyimide (VIII), which is converted into its sodium salt (IX) by means of NaOEt in EtOH, and finally alkylated with benzyl chloride (X) to provide the target compound.

合成路线17

1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.

合成路线18

2) The reaction of 4-(2-formylethyl)benzoic acid ethyl ester (XIV) with paraformaldehyde (XV) by means of N-ethylbenzothiazolium bromide (XVI) and triethylamine gives the 4-hydroxy-3-oxobutyl derivative (XVII), which is condensed with ethyl cyanoacetate (I) by means of triethylamine in ethanol yielding the furancarboxylate derivative (XVIII). The cyclization of (XVIII) with guanidine (IV) by means of sodium ethoxide in ethanol affords 4-[2-(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl] benzoic acid ethyl ester (XIX), which is saponified with NaOH to the corresponding free acid (XX). The condensation of (XX) with L-glutamic acid diethyl ester (XXI) in the usual way affords the diethyl ester of LY-231514 (XXII), which is finally saponified with NaOH.

合成路线19

5) The condensation of 3-methylbutanal (XIX) with cyanoacetic acid ethyl ester (XXXII) or cyanoacetamide (XXXIII) by means of dipropylamine in refluxing hexane, followed by treatment with refluxing 6N HCl, gives 3-isobutylglutaric acid (XXXIV). This compound is converted into the corresponding anhydride (XXXV) by treatment with refluxing acetic anhydride. The reaction of the anhydride (XXXV) with NH4OH affords the glutaramic amide (XXXVI), which is submitted to optical resolution with (R)-(+)-1-phenylethylamine, yielding the (S)-enantiomer (XXXVII). Finally, this compound is submitted to a Hoffmann degradation with Br2/NaOH.

合成路线20

Conjugated addition of 2-nitroaniline (I) to acrylonitrile (II) in the presence of Triton B in dioxane yielded propionitrile (III), which was hydrogenated to the phenylenediamine (IV). Treatment of ethyl cyanoacetate (V) with a cold saturated solution of HCl in absolute ethanol gave ethyl ethoxycarbonylacetimidate hydrochloride (VI). Reaction of this acetimidate (VI) with phenylenediamine (IV) in refluxing ethanol afforded the benzimidazole (VII), which was converted to the diester (VIII) on treatment with ethanolic HCl. Dieckmann condensation of diester (VIII) in the presence of sodium ethoxide furnished the tricyclic ketoester (IX), which was finally condensed with 2,6-difluoroaniline (X) in refluxing xilene to afford the target carboxamide.

合成路线21

Thiophene (III) was obtained by condensation of (4-methoxyphenyl)acetone (I) with ethyl cyanoacetate (II) in the presence of NH4OAc and AcOH, followed by treatment with sulfur and diethylamine. Subsequent reaction of (III) with ethyl isocyanato-acetate (IV) in pyridine at 45 C and further cyclization with ethanolic NaOEt provided the thienopyrimidine (V). Cleavage of the methyl ether was performed by treatment with AlCl3 and dimethyl disulfide in CH2Cl2 at r.t. to afford phenol (VI), which was then acetylated with Ac2O in pyridine to give ester (VII). N-Alkylation with 2-(methylsulfanyl)benzyl chloride (VIII) in the presence of K2CO3 in DMF yielded (IX), and then the acetate ester was hydrolyzed with K2CO3 in a mixture of H2O/MeOH/THF. The resulting phenol (X) was alkylated with chloromethyl methyl ether (XI) in the presence of NaH to provide (XII).

合成路线22

Aminothiophene (III) was prepared by condensation of phenylacetone (I) with ethyl cyanoacetate (II), followed by treatment with sulfur and diethylamine. Subsequent condensation of (III) with diethyl ethoxymethylenemalonate (IV) at 120 C provided the enaminomalonate (V). the partial hydrolysis of (V) with KOH in EtOH-dioxan provided monoacid (VI), which was cyclized by means of PPE to the thienopyridine (VII). Alkylation of (VII) with 2,6-difluorobenzyl chloride (VIII) and K2CO3 yielded predominantly the N-benzylated compound (IX), which was selectively nitrated at the phenyl ring to produce (X) (2). Radical bromination of the 3-methyl group of (X) gave bromomethyl compound (XI).

合成路线23

By condensation of 3-methoxybenzaldehyde (I) with ethyl cyanoacetate (II) by means of NaOH in ethanol.

合成路线24

The condensation of 4-hydroxy-3-methoxybenzaldehyde (I) with ethyl cyanoacetate (II) by means of NaOH in ethanol gives the 2-cyanopropenoate (III), which is then alkylated at the OH group with ethyl 2-bromoacetate (IV) by means of K2CO3 and tetrabutylammonium bromide in THF.

合成路线25

Knoevenagel condensation of ketone (I) with ethyl cyanoacetate followed by Michael addition of cyanoacetamide to the resulting alpha-cyanocinnamate (IIa-b) yields cyclic imide (III). Hydrolysis and decarboxylation of (III) with H2SO4 gives diacid (IV), which is cyclized by means of hot H2SO4 to provide indanone (V). Treatment of (V) with oxalyl chloride in CH2Cl2 and catalytic DMF followed by addition of EtOH affords ethyl ester (VI), which is then converted into oxime (VII) by means of t-BuONO in Et2O and HCl. Hydrogenolysis of (VII) with H2 over Pd/C in HOAc/HCl provides alpha-amino derivative (VIII). By reacting (VIII) with ethyl oxalyl chloride (A), in CH2Cl2 in presence of Et3N, (IX) was obtained and then cyclized in presence of NH4OAc in refluxing HOAc to yield pyrazino derivative (X). Finally (X) is hydrolyzed with HCl in dioxane.

合成路线26

The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II), which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V). The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI), which is esterified with methanol/HCl giving the methyl ester (VII). The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII), which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX). The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b). The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer. Finally, this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.

合成路线27

The cyclization of ethyl cyanoacetate (I) with carbon disulfide gives 5-sulfanylthiazole-4-carboxylic acid ethyl ester (II), which is reduced with LiAlH4 in THF to the corresponding carbinol (III). The condensation of (III) with 2-iodoethyl phenyl sulfone (IV) affords the thioether (V), which is treated with SOCl2 in DMF to afford the chloromethyl derivative (VI). The condensation of (VI) with 2-aminoethanethiol (A) by means of NaI in dioxane/water gives the bis thioether (VII), which is protected at the amino group with Boc2 to afford the carbamate (VIII), and treated with NaOMe in methanol to provide the sodium thiolate (IX). The condensation of (IX) with the cephem derivative (X) in ethyl acetate/aqueous NaHCO3 gives the expected addition product (XI), which is further condensed with 2-(tert-butoxycarbonylamino)-2-(trityloxyimino)acetic acid (XII) by means of POCl3 in THF yielding the fully protected target compound (XIII). Finally, this compound is deprotected by treatment with TFA and triethylsilane.

合成路线28

Knoevenagel condensation of 4-fluorobenzaldehyde (I) with ethyl cyanoacetate (A) gave adduct (II). Subsequent conjugate addition of NaCN to (II), followed by alkylation with ethyl 3-chloropropionate (B) furnished the dicyano diester (III). Acid hydrolysis of (III), with concomitant decarboxylation, afforded tricarboxylic acid (IV), which was further esterified with methanolic HCl to give ester (V). Dieckmann cyclization of (V) using NaOMe, and then hydrolysis and decarboxylation gave rise to the racemic trans ketoacid (VI). Esterification of (VI), and reduction of the resulting keto ester (VII) with NaBH4 produced a mixture of diastereomeric alcohols. The desired trans,trans-isomer (VIII) was then isolated by column chromatography. Ester hydrolysis of (VIII) and re-solution as the corresponding salt with (R)-alpha-methylbenzylamine furnished the (-)-hydroxy acid (IX) that was esterified to (X) with methanolic HCl.

合成路线29

The reduction of 3,4-dinitrobenzoic acid amide (I) with H2 over Pd/C in methanol gives 3,4-diaminobenzoic acid (II), which is cyclized with 3-ethoxy-3-iminopropionic acid ethyl ester (IV) (obtained by reaction of cyanacetic acid ethyl ester (III) with ethanolic HCl) in hot acetic acid to yield 2-(5-carbamoyl-1H-benzimidazol-2-yl)acetic acid ethyl ester (V). The reaction of 3-methoxy-4-nitrobenzoic acid (VII) with aqueous methylamine in a sealed tube at 100 C gives 3-(methylamino)-4-nitrobenzoic acid (VIII), which is reduced with H2 over Pd/C in methanol/THF to yield 4-amino-3-(methylamino)benzoic acid (VI). The cyclization of (VI) with (V) by means of 1,3-dimethylperhydropyrimidin-2-one (DMPU) at 190 C affords the substituted bis-benzimidazolylmethyl (IX). The reaction of (IX) with 2-amino-3-phosponopropionic acid tris-trimethylsilyl ester (X) (prepared by esterification of 2-amino-3-phosphonopropionic acid (XI) with N-methyl-N-(trimethylsilyl)trifluoroacetamide (XII)) by means of (PyBroP) in DMF provides the carboxamide (XIII). Finally, the cleavage of the trimethylsilyl ester groups by means of TFA furnishes the target phosphonic acid.

合成路线30

Cyclization of 1-(4-nitrophenyl)acetone (I) with ethyl 2-cyanoacetate (II) by means of NH4OAc, HOAc, S and diethylamine gives 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (III), which is cyclized with phenyl isocyanate (IV) in pyridine to yield the thieno[2,3-d]pyrimidinedione derivative (V). Alkylation of compound (V) with 2,6-difluorobenzyl chloride (VI) by means of K2CO3 and KI in DMF affords the adduct (VII), which is brominated with NBS and AIBN in chlorobenzene to provide the bromomethyl derivative (VIII). Reaction of compound (VIII) with N-benzyl-N-methylamine (IX) by means of DIEA in DMF gives the tertiary amine (X), which by reduction of the nitro group with H2 over Pd/C in ethyl ether/formic acid yields the primary amine (XI). Finally, this compound is treated with CDI, O-methylhydroxylamine (XII) and TEA in dichloromethane.

合成路线31

The condensation between 3-methoxybenzaldehyde (I), S-methylisothiourea (II) and ethyl cyanoacetate (III) in the presence of K2CO3 in hot EtOH leads to pyrimidine (IV). Subsequent chlorination of (IV) by means of POCl3 and dimethylaniline furnishes the 6-chloropyrimidine (V). Reaction of (V) with ethyl mercaptoacetate (VI) and potassium tert-butoxide gives rise to the thienopyrimidine (VII). The ethyl ester group of (VII) is then hydrolyzed to the carboxylic acid (VIII) employing LiOH. Finally, coupling of acid (VIII) with tert-butylamine by means of TBTU produces the target N-tert-butyl amide

合成路线32

The condensation of tert-butoxycarbonylproline (I) with methylamine (II), isovaleraldehyde (III) and ethyl isocyanoacetate (IV) in methanol gives Boc-Pro-Me-Leu-Gly-OEt (V), which is separated from its diastereoisomer by chromatography over silica gel. The reaction of (V) with ammonia in cold methanol yields the corresponding amide (VI). Finally this compound is deprotected by treatment with dry HCl in ethyl acetate

合成路线33

Knoevenagel condensation between N-Boc-4-piperidinone (I) and ethyl cyanoacetate (II) produced the piperidinylidene cyanoacetate (III), which was further converted to the thienopyridine derivative (IV) upon treatment with sulfur and morpholine. Acylation of amine (IV) with ethyl oxalyl chloride (V) furnished the oxalamide (VI). Subsequent hydrolysis of the ester groups of (VI) under basic conditions led to diacid (VII). The title compound was finally obtained by trifluoroacetic acid-promoted Boc group cleavage.

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The cyclization of phenylacetone (I) with ethyl cyanoacetate (II) by means of HOAc and AcONH4 in refluxing benzene, followed by a treatment with sulfur in hot ethanol gives 2-amino-4-methyl-5-phenylthiophene-3-carboxylic acid ethyl ester (III). The condensation of (III) with diethyl ethoxymethylene malonate (IV) by heating at 120 C yields the adduct (V), which is submitted to a selective hydrolysis with KOH in hot ethanol to afford the carboxylic acid (VI). The cyclization of (VI) by means of PPE at 120 C provides the thienopyridine (VII), which is nitrated with NaNO3 and H2SO4 to give the 4-nitrophenyl derivative (VIII). The alkylation of the hydroxy-thienopyridine (VIII) with 2,6-difluorobenzyl chloride (IX) by means of NaH in DMF yields the benzylated thienopyridinone (X), which is brominated with NBS and AIBN in refluxing CCl4 to afford the bromomethyl derivative (XI). The condensation of (XI) with N-benzyl-N-methylamine (XII) by means of TEA in DMF provides the tertiary amine (XIII). The reduction of the nitro group of (XIII) by means of Fe and HCl in ethanol gives the 4-aminophenyl derivative (XIV), which is acylated with trifluoroacetic anhydride and TEA to yield the acetamide (XV). The reaction of (XV) with N,O-dimethylhydroxylamine (XVI) and TEA in CH2Cl2 affords the methoxyamide (XVII).

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Methoxycarbonylation of 5-bromo-2,2-difluoro-1,3-benzodioxole (I) under CO atmosphere in the presence of Pd(PPh3)4 and Et3N in MeOH/acetonitrile at 75 °C produces the benzodioxole carboxylate (II), which is reduced to primary alcohol (III) using LiAlH4 in THF . Similarly, alcohol (III) can be obtained by reduction of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (IV) with Red-Al in toluene . Chlorination of alcohol (III) with SOCl2, optionally in the presence of DMAP, in CH2Cl2 or MTBE affords 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (V), which upon cyanation with NaCN in DMSO produces nitrile (VI) . In an alternative procedure, coupling of bromo benzodioxole (I) with ethyl cyanoacetate (VII) by means of Pd(dba)2, t-Bu3P and Na3PO4 in toluene/H2O at 70 °C yields the 2-cyanoacetate derivative (VIII), which undergoes decarboethoxylation to compound (VI) by means of HCl in DMSO/H2O at 75 °C . Dialkylation of nitrile (VI) with 1-bromo-2-chloroethane (IX) in the presence of either NaOH and BnNEt3Cl or KOH and Oct4NBr at 70 °C yields 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonitrile (X). After hydrolysis of nitrile (X) with NaOH in boiling H2O or EtOH, the resulting carboxylic acid (XI) is chlorinated with SOCl2 in the presence of DMF toluene at 60 °C to provide the acid chloride (XII) . Condensation of the cyclopropanecarbonyl chloride (XII) with 6-amino-2-chloro-3-methylpyridine (XIII) in pyridine at 110 °C affords the N-pyridyl amide (XIV), which finally undergoes Suzuki coupling with pinacol 3-carboxyphenylboronate (XV) by means of Pd(dppf)Cl2 and K2CO3 in hot DMF/H2O to furnish lumacaftor .
Alternatively, condensation of acid chloride (XII) with the biaryl amine (XVI) in the presence of Et3N and DMAP in toluene generates the tert-butyl ester (XVII), which is finally hydrolized by treatment with HCl in acetonitrile/water , followed by dissolving the obtained amino acid hydrochloride salt in aqueous NaOH or H2O, or by direct hydrolysis of ester (XVII) with HCOOH at 60-80 °C .

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3-Chloro-4-(2-pyridylmethoxy)aniline (I) is condensed with ethyl cyanoacetate (II) at 100-115 °C to give the N-aryl 2-cyanoacetamide (III). Reduction of 3-ethoxy-4-phthalimido-1-nitrobenzene (IV) with H2 over Pd/C in THF at 50 °C followed by coupling of the resulting aniline with the cyano amide (III) by means of triethyl orthoformate in refluxing propanol affords the 3-amino-2-cyanopropenamide derivative (V). After intramolecular cyclization of propenamide (V) by means of POCl3 in acetonitrile at 60-70 °C, the obtained 6-phthalimidoquinoline derivative is hydrolyzed by means of NH4OH in EtOH at 62-68 °C to give the 6-aminoquinoline (VI) (1). Alternatively, the aminoquinoline (VI) can be obtained by condensation of the aniline derivative (I) with 6-acetamido-4-chloro-7-ethoxyquinoline-3-carbonitrile (VII) in the presence of methanesulfonic acid at 70-75 °C, affording the diarylamine (VIII), which is then deacetylated to the aminoquinoline (VI) by hydrolysis with HCl . Finally, compound (VI) is acylated with 4-(dimethylamino)-2-butenoyl chloride (IX) , obtained by chlorination of the corresponding free acid (X) or its hydrochloride salt with either (COCl)2 by means of DMF in THF or DMF/i-PrOAc , POCl3 in DMAc, or SOCl2 in DMAc , in the presence of NMP .
In a related strategy, 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (XI) is reduced to the corresponding amine (XII) by means of Fe and acetic acid in refluxing methanol. Subsequent acylation of (XII) with 4-(dimethylamino)-2-butenoyl chloride (IX) in the presence of NMP in acetonitrile or DMF yields carboxamide (XIII), which is finally coupled with 3-chloro-4-(2-pyridylmethoxy)aniline (I) by means of pyridinium chloride in refluxing isopropanol or 2-methoxyethanol .

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N-Protection of 2-amino-5-nitrophenol (XVII) with Ac2O in the presence of AcOH gives N-(2-hydroxy-4-nitrophenyl)acetamide (XXI), which upon O-alkylation with ethyl bromide (XX) in the presence of K2CO3 in DMF at 60 °C affords N-(2-ethoxy-4-nitrophenyl) acetamide (XXII). Reduction of the nitro derivative (XXII) with H2 over Pd/C in THF furnishes the corresponding aniline (XXIII), which by condensation with ethyl 2-cyano-3-ethoxy-2-propenoate (XXIV) at reflux produces enamine (XXV). Thermal cyclization of enamino ester (XXV) in Dowtherm at 250 °C then yields 4-hydroxyquinoline derivative (XXVI) , which upon chlorination with POCl3 in 1,2-diethoxyethane at 80-85 °C affords N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (VII) . Alternatively, condensation of ethyl cyanoacetate (II) with morpholine (XXVII) at 100-110 °C gives 4-(cyanoacetyl)morpholine (XXVIII), which after coupling with 4-acetamido-3-ethoxyaniline (XXIII) in the presence of triethyl orthoformate in i-PrOH at 50-60 °C produces the arylamino propenamide (XXIX). Finally, cyclization of (XXIX) in the presence of POCl3 in acetonitrile at 60-65 °C then leads to the target intermediate (VII) .