合成路线1

The enantiocontrolled addition of phthalimide (I) to 1,3-butadiene monoepoxide (II) with a chiral palladium catalyst and Na2CO3 in dichloromethane gives N-(2-hydroxy-1(S)-vinylethyl)phthalimide (III), which is treated with triflic anhydride and TEA in dichloromethane to yield the triflate (IV). The condensation of (IV) with dimethyl malonate (V) by means of NaH in THF affords the alkylated malonate (VI), which is finally decarboxylated and deprotected by a treatment with aqueous refluxing HCl. Note that the synthesis of the biologically active (S)-enantiomer simply requires a change in the chirality of the Pd catalyst used in the first step of the synthesis.

合成路线2

The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.

合成路线3

The addition reaction of 2,6-dimethylphenol (II) to (S)-2-methyloxirane (I) by means of NaOH in acetonitrile gives (S)-1-(2,6-dimethylphenoxy)-2-propanol (III), which is condensed with phthalimide (IV) by means of DEAD and PPh3 (with inversion of configuration) yielding N-[2-(2,6-dimethylphenoxy)-1(R)-methylethyl]phthalimide (V). Finally, this compound is treated with hydrazine and acetic acid in methanol to eliminate the phthalimido group.

合成路线4

The addition reaction of 2,6-dimethylphenol (II) to (R)-2-methyloxirane (I) by means of NaOH in acetonitrile gives (R)-1-(2,6-dimethylphenoxy)-2-propanol (III), which is condensed with phthalimide (IV) by means of DEAD and PPh3 (with inversion of configuration) yielding N-[2-(2,6-dimethylphenoxy)-1(S)-methylethyl]phthalimide (V). Finally, this compound is treated with hydrazine and acetic acid in methanol to eliminate the phthalimido group.

合成路线5

The synthesis of deuterated mosapride citrate has been reported: The cyclization of N-(4-fluorobenzyl)ethanolamine (I) with 2-chloroacrylonitrile (II) in ethyl ether gives 4-(4-fluorobenzyl)morpholine-2-carbonitrile (III), which is submitted to alcoholysis with ethanol and H2SO4, yielding the corresponding ethyl ester (IV). The reduction of (IV) with deuterated sodium borohydride (NaBD4) in THF affords the deuterated hydroxymethyl derivative (V), which is condensed with phthalimide (VI) by means of triphenylphosphine and dimethyl azodicarboxylate (AZDC) in THF to give the N-substituted phthalimide (VII). The cleavage of (VII) with hydrazine hydrate in refluxing ethanol yields the deuterated methylamine derivative (VIII), which is finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (IX) by means of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (EDCD) in dichloromethane, and treated with citric acid in the usual way.

合成路线6

The synthesis of the key chiral amine component (VII) is outlined: Conversion of 4,4,4-trifluorobutyric acid (XI) to the corresponding acid chloride and subsequent reaction with the anion derived from the Evans oxazolidinone (XII) yielded the acyloxazolidinone (XIII). Treatment of (XIII) with a strong base such as sodium hexamethyldisilazide and alkylation of the resultant enolate with iodomethane at -35 C afforded a mixture of the diastereomeric acyloxazolidinones (XIV). The desired diastereomer was obtained by crystallization of the crude product. Reductive cleavage of the chiral auxiliary gave the enantiomerically pure alcohol (XV), which was converted in two steps to the desired enantiomerically pure amine hydrochloride (VII). Alternative routes to the amine, such as resolution of racemic 4,4,4-trifluoro-2-methylbutyric acid followed by amide formation and reduction to (VII) could also be utilized.

合成路线7

The condensation of 13C-labelled methyl phenyl sulfone (I) with 2-(tert-butyldimethylsilyloxy)acetic acid ethyl ester (II) by means of BuLi in THF gives the labelled propanone derivative (III), which is condensed with ethyl 2-bromoacetate (IV) by means of NaH in THF to yield the gamma-oxo ester (V). Desulfurization of (V) by means of Al/Hg in THF/water affords the silylated 5-hydroxy-4-oxopentanoic acid ethyl ester (VI), which is desilylated by means of AcOH in THF/water to provide the free hydroxyester (VII). The condensation of (VII) with phthalimide (VIII) by means of DEAD and PPh3 in toluene gives the phthalimido derivative (IX), which is finally treated with refluxing 6N HCl to provide the target labelled aminolevulinic acid.

合成路线8

Reaction of furylandrostanediol (I) (J Chem Soc (C) 1966, 377) with bromoacetaldehyde diethylacetal (II) in the presence of NaH in refluxing tetahydrofuran provided ether (III). Subsequent acid hydrolysis of ethyl acetal of (III) gave aldehyde (IV), which was reduced to alcohol (V) with NaBH4. Coupling of (V) with phthalimide (VI) under Mitsunobu conditions produced the N-alkylated phthalimide (VII), and further hydrazinolysis yielded primary amine (VIII). The required guanidine function was finally introduced by treatment of (VIII) with 3,5-dimethyl-1-pyrazolylformamidinium nitrate (IX) in boiling EtOH.

合成路线9

The intermediate amine (XIV) was prepared by several synthetic routes. Condensation of methylene cyclohexane (I) with chlorosulfonyl isocyanate produced b-lactam (II). Treatment of (II) with H2SO4 in boiling MeOH gave ester (III), and subsequent reductive alkylation with formaldehyde and formic acid afforded dimethylamino compound (IV). Ester reduction with LiAlH4 in THF provided alcohol (V), which was condensed with phthalimide (VI) under Mitsunobu conditions to yield N-alkylated phthalimide (VII). Then, phthalimide hydrolysis with methylamine in MeOH provided amine (XIV). Alternatively, cyclohexylideneacetate (VIII) was treated with methanolic NH3 at 140 C in a sealed tube to give aminoacetamide (IX). This compound could also be obtained by heating b-lactam (II) with aqueous ammonia at 150 C. Subsequent alkylation of (IX) with iodomethane provided dimethylamino compound (X), which was reduced with vitride in refluxing toluene to give (XIV). Starting from cyclohexylideneacetonitrile (XI), treatment with NH3 at 100 C in a sealed tube gave aminonitrile (XII). This nitrile could also be prepared by dehydration of amide (X) with POCl3. Reductive alkylation of the primary amine of (XII) with HCHO in the presence of NaBH3CN gave dimethylamino nitrile (XIII). Then, hydrogenation of nitrile (XIII) in the presence of PtO2 provided amine (XIV). Finally, condensation of amine (XIV) with 1-benzotriazolyl ester (XVI), obtained by treatment of benzoic acid (XV) with 1-hydroxybenzotriazole and DCC, gave the title benzamide.

合成路线10

The reaction of 4(R)-hydroxy-L-proline (I) with allyl chloroformate (II) and NaOH gives the protected proline (III), which is esterified with MeOH and sulfuric acid to yield the methyl prolinate (IV). The reaction of (IV) with Ms-Cl and TEA affords the mesylate (V), which is reduced with NaBH4 to provide the prolinol derivative (VI). The Swern oxidation of alcohol (VI) gives the carbaldehyde (VII), which is condensed with the phosphorane (VIII) by means of NaOMe, yielding the acrylate (IX). The reduction of (IX) with DIBAL affords the substituted allyl alcohol (X), which is condensed with phthalimide (XI) by means of PPh3 and DIAD to provide the adduct (XII). The cleavage of the phthalimido group of (XII) with hydrazine gives the amino derivative (XIII), which is treated with Ms-Cl and TEA to yield the sulfonamide (XIV). The reaction of (XIV) with potassium thioacetate affords the acetylsulfanyl pyrrolidine (XV), which is hydrolyzed with HCl to provide the thiol (XVI). The condensation of the thiol (XVI) with the carbapenem derivative (XVII) by means of DIEA gives the protected adduct (XVIII), which is finally treated with Pd(II) and Bu3SnH in order to eliminate the allyl protecting groups. The intermediate carbapenem derivative (XVII) has been obtained from azetidinone (XIX) by known methods as indicated in the scheme.

合成路线11

The condensation of the formyl pyrrolidine (I) with ethyl (triphenylphosphoranylidene)acetate (II) in dichloromethane gives acrylate (III), which is reduced with DIBAL in THF to yield the substituted allyl alcohol (IV). The condensation of (IV) with phthalimide (V) by means of PPh3 and DEAD in THF affords the adduct (VI), which is treated with hydrazine ethanol to provide the amino derivative (VII). The reaction of (VII) with Ms-Cl and TEA in dichloromethane gives the sulfonamide (VIII), which is desilylated by means of TBAF in THF, yielding the pyrrolidinol (IX). The reaction of (IX) with Ms-Cl and TEA in dichloromethane affords the sulfonate (X), which is treated with potassium thioacetate in refluxing acetonitrile to provide the acetylsulfanylpyrrolidine (XI). The hydrolysis of (XI) with NaOH in methanol gives the thiol (XII), which is condensed with the carbapenem derivative (XIII) by means of DIEA in acetonitrile to yield the protected adduct (XIV). Finally, this compound is treated with PdCl2(PPh3)2 and Bu3SnH in dichloromethane in order to eliminate the allyl protecting groups.

合成路线12

The chiral pyrrolidinethiol (XII), a key intermediate in the synthesis of 235904 (see scheme 23590401a intermediate (XVI) and scheme 23590402a intermediate (XII)), has been obtained as follows: The reaction of the N-protected hydroxyproline (I) with Ms-Cl and TEA in dichloromethane gives the mesylate (II), which is reduced with DIBAL in toluene to yield the carbaldehyde (III). The Horner-Emmons-Wadsworth condensation of (III) with triethyl phosphonoacetate (IV) by means of Na-OEt in THF affords the unsaturated ester (V), which is reduced with DIBAL in THF to provide the allyl alcohol derivative (VI) (1). The condensation of (VI) with phthalimide (VII) by means of PPh3 and DIAD furnishes the adduct (VIII). The cleavage of the phthalimido group of (VIII) with hydrazine gives the allylamino derivative (IX), which is treated with Ms-Cl and TEA to yield the methanesulfonamide (X). The reaction of (X) with potassium thioacetate yields the acetylsulfanyl pyrrolidine (XI), which is hydrolyzed with HCl to provide the target thiol intermediate (XII).

合成路线13

Pyrroline (III) was prepared by Favorskii rearrangement of 3,5-dibromo-2,2,6,6-tetramethylpiperidinone (I) in the presence of 1,3-diaminopropane (II). Acylation at the primary amino group of (III) with phthalic anhydride (IV) gave the 2-carboxybenzamide (VI), which was cyclized to the target phthalimide (VII) by refluxing in toluene in the presence of Et3N. Alternatively, the phthalimido derivative (VII) was obtained by condensation of amine (III) with phthalimide (V) at 150 C. The target compound was then isolated as the hydrochloride salt upon treatment with HCl in EtOH-Et2O.

合成路线14

The condensation of 2-amino-2-methylglutaric acid (I) with phthalimide (II) by means of TEA in refluxing toluene gives 2-methyl-2-phthalimidoglutaric acid (II), which is partially reduced with Zn and acetic acid yielding the racemic indolinone derivative (IV). The esterification of (IV) affords the dimethyl ester (V), which is enantioselectively monohydrolyzed by means of ChiroCLEC-BL catalyst affording a mixture of the (S)-monoester (VI) and unchanged (R)-diester (R)-(V), which is separated by flash chromatography. Finally, the chiral monoester (VI) is hydrolyzed with HCl/AcOH.

合成路线15

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,4,5-Trimethoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

合成路线16

Michael addition of methyl vinyl ketone (II) to phthalimide (I) in the presence of NaOEt afforded phthalimido ketone (III). Bromination of (III) in MeOH, followed by acid hydrolysis of the resulting dimethyl ketal provided bromo ketone (IV). Cyclization of bromo ketone (IV) with thiourea (V) yielded the amino thiazole (VI) and further deprotection of the phthalimido group of (VI) in refluxing HBr furnished diamine (VII). 3,5-Diiodo-4-methoxyphenylacetic acid (VIII) was converted to the corresponding acid chloride (IX) using oxalyl chloride, and subsequently coupled with amine (VII) under Schotten-Baumann conditions to give amide (X). Cyclization of (X) to the thiazolopyridine (XI) was effected by the Bischler-Napieralski procedure employing POCl3 in acetonitrile. The imine double bond of (XI) was then reduced by means of NaBH4, and the resulting compound was finally converted to the dihydrochloride salt.

合成路线17

Reduction of ethyl ester (I) with LiAlH4 provides primary carbinol (II), which is then converted into amine (III) by Mitsunobu reaction with phthalimide (A) in the presence of PPh3 and DEAD in THF, followed by an hydrazine mediated deprotection in EtOH. Reaction of amine (III) with 2-nitrophenyl isocyanate (IV) in CHCl3/THF or CH2Cl2, followed by reduction of the nitro group by hydrogenation over Pd/C in EtOH, affords aniline (V). Finally, aniline (V) is condensed with acid chloride (VI) in CHCl3 in the presence of pyridine to furnish the target compound.

合成路线18

Conversion of 10-undecen-1-ol (I) into the primary amine (IV) was effected by Mitsunobu coupling of (I) with phthalimide (II), followed by hydrazinolysis of the resulting N-(10-undecenyl)phthalimide (III). Amine (IV) was then acylated with O-acetylsalicyloyl chloride (V) to give salicylamide (VI). Oxidative cleavage of the terminal olefin to the carboxylic acid (VII) was achieved using potassium permanganate under phase-transfer conditions. The O-acetyl group was finally removed by treatment with NaOH.

合成路线19

The condensation of 2-(chloromethyl)-1,4-dioxaspiro[4,5]decane (I) with the sodium salt of phthalimide (II) in hot DMF affords the N-substituted phthalimide (III). Subsequent phthaloyl group hydrazinolysis gives the primary amine (IV). Finally, condensation of amine (IV) with S-methyl pseudothiourea sulfate (V) leads to the title guanidine derivative

合成路线20

The reaction of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (I) with SOCl2, followed by dechlorination with Zn/HCl, gives 5-hydroxy-2-methyl-4H-pyran-4-one (II), which is condensed with formaldehyde to yield 3-hydroxy-2-(hydroxymethyl)-6-methyl-4H-pyran-4-one (III). The protection of the aromatic OH group of (III) with Bn-Br affords the benzyl ether (IV), which is treated with methylamine to provide the corresponding 4-pyridone (V). The reaction of the OH group of (V) with phthalimide (VI) by means of DEAD and PPh3 gives the expected phthalimido derivative (VII), which is cleaved with hydrazine to yield the aminomethyl derivative (VIII). The condensation of the amino group of (VIII) with the activated amide (IX) (obtained by condensation of N-propylsuccinamic acid (X) with 2-thiazolidinone (XI) by means of DCC and DMAP) affords the adduct (XII), which is finally debenzylated by hydrogenation with H2 over Pd/C to provide the target succinamide derivative.

合成路线21

Condensation between (S)-alpha-methylbenzylamine (I) and ethyl glyoxylate (II) afforded imine (III), which was subjected to hetero-Diels-Alder cycloaddition with 2-(trimethylsilyloxy)-1,3-butadiene (IV) producing piperidinecarboxylate (V) as the major diastereoisomer. Ketalization of (V) with triethyl orthoformate gave the corresponding the diethyl acetal (VI). The ester group of (VI) was then reduced to alcohol (VII) employing LiAlH4. Mitsunobu condensation of alcohol (VII) with phthalimide (VIII) gave (IX) which, followed by acidic ketal hydrolysis, furnished (X). Condensation of piperidinone (X) with t-butyl cyanoacetate (XI) in the presence of sulfur and morpholine gave rise to two regioisomeric thienopyridine derivatives (XII) and (XIII), which were separated by column chromatography.

合成路线22

合成路线23

Esterification of 5-chlorothiophene-2-carboxylic acid (I) with MeOH in the presence of H2SO4 at 53 °C gives the corresponding methyl ester (II), which is either brominated using Br2 and AlCl3 in CHCl3 or iodinated by means of BTMA-ICl2 and ZnCl2 in AcOH at 70 °C, yielding the corresponding 4-bromo- or 4-iodo-thiophenecarboxylates (IIIa or IIIb). Metalation of 1-methylpyrazole (IV) with BuLi in THF, followed by condensation with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (V) affords the pyrazolylboronate (VI), which is then condensed with either thienyl bromide (IIIa) or iodide (IIIb) by means of Pd(t-Bu3P)2 and K2CO3 in 1,4-dioxane/water at 70 °C to produce methyl 5-chloro-4-(1-methylpyrazol-5-yl)-2-thiophenecarboxylate (VII). Treatment of compound (VII) with NCS in THF at 70 °C gives the chloropyrazole derivative (VIII), which by ester hydrolysis with NaOH in H2O/MeOH/THF provides the corresponding carboxylic acid (IX). Condensation of acid (IX) with amine (X) by means of PyBroP and DIEA in CH2Cl2 gives amide (XI), which is finally deprotected with NH2NH2 in THF/MeOH (1). Scheme 1.Amine intermediate (X) is prepared by reduction of N-Boc-(3-fluorophenyl) alanine (XII) with BH3·THF in THF to afford the primary alcohol (XIII), which is then subjected to Mitsunobu coupling with phthalimide (XIV) using PPh3 and DIAD in THF to provide compound (XV). Finally, compound (XV) is deprotected by cleavage of the N-Boc group with HCl in MeOH .

合成路线24

Bromination of 1,2-diethoxy-3-fluorobenzene (XIII) with NBS in acetonitrile gives 1-bromo-3,4-diethoxy-2-fluorobenzene (XVI), which undergoes bromide displacement with CuCN in DMF at 155 °C to yield 3,4-diethoxy-2-fluorobenzonitrile (XVII). Metalation of compound (XVII) with BuLi in the presence of tetramethylpiperidine (TMP) in THF at –10 °C followed by reaction with DMF and quenching with AcOH leads to 3,4-diethoxy-2-fluoro-6-formylbenzonitrile (XVIII). Reduction of aldehyde (XVIII) with NaBH(OAc)3 in EtOAc at 40 °C provides the benzylic alcohol (XIX), which is then activated as the mesylate (XX) by means of MsCl and Et3N in DME. Condensation of mesylate (XX) with phthalimide (XXI) by means of t-BuOK in DMF furnishes the N-substituted phthalimide (XXII), which is finally subsubjected to hydrazinolysis and subsequent cyclization in the presence of HCl in THF. Also, the isoindole (X) can be obtained by direct cyclization of the cyano mesylate (XX) with NH3 in toluene in a pressure vessel .
Alternatively, isoindole (X) can be prepared by metalation of 3,4-diethoxy-2-fluorobenzonitrile (XVII) with MeLi in the presence of TMP in THF, followed by alkylation with MeI to afford 3,4-diethoxy-2-fluoro-6-methylbenzonitrile (XXIII), which is then brominated with NBS by means of AIBN in refluxing CCl4 to yield 6-(bromomethyl)-3,4-diethoxy-2-fluorobenzonitrile (XXIV). Benzylic bromide (XXIV) can also be prepared by treatment of primary alcohol (XIX) with PBr3 in DME. Subsequent cyclization of the benzonitrile (XXIV) with NH3 in toluene affords 3-amino-5,6-diethoxy-4-fluoroisoindole (X) .

合成路线25

Reduction of methyl 4-formyl-3-nitrobenzoate (XIII) by means of Fe and HCl in EtOH, followed by Friedländer condensation of the resulting aminoaldehyde with acetophenone (XIV) in the presence of KOH at 95 °C, and treatment with HCl, yields 2-phenylquinoline-7-carboxylic acid hydrochloride (XV). Reduction of acid (XV) with LiAlH4 in THF gives alcohol (XVI), which is then oxidized by means of MnO2 in CHCl3 to give 2-phenylquinoline-7-carbaldehyde (XVII). Coupling of carbaldehyde (XVII) with the metalated derivative of 2-chloropyrazine (XVIII) in the presence LTMP (prepared from BuLi and TMP) in THF yields the diaryl carbinol (XIX), which is then subjected to Mitsunobu reaction with phthalimide (XX) in the presence of PS-PPh3 and DIAD in THF to provide the N-substituted phthalimide (XXI). Hydrazinolysis of phthalimide (XXI) with NH2NH2 in EtOH/CH2Cl2 then affords amine (I).
Alternatively, carbaldehyde (XVII) can be prepared by arylation of 7-methylquinoline (XXII) with phenyl lithium in THF, followed by air oxidation to produce 7-methyl-2-phenylquinoline (XXIII). Side chain oxidation of (XXIII) using SeO2 at 160 °C provides the target aldehyde (XVII) .

合成路线26

Metalation of 2-chloropyrazine (XVIII) with LTMP (prepared from BuLi and TMP) in THF, followed by formylation with DMF and subsequent reduction with NaBH4 yields (3-chloro-2-pyrazinyl)methanol (XXXI). Mitsunobu coupling of alcohol (XXXI) with phthalimide (XX) in the presence of PPh3 and DIAD in THF gives the N-substituted phthalimide (XXXII), which is then subjected to hydrazinolysis with NH2NH2 in CH2Cl2 to provide, after treatment with HCl, (3-chloro-2-pyrazinyl)methylamine dihydrochloride (XXXIII) . Coupling of amine (XXXIII) with succinimidyl ester (XXXIV) (prepared by condensation of 3-oxocyclobutanecarboxylic acid [XXXVI] with N-hydroxysuccinimide [XXXV] using DCC in isopropyl acetate [3]) in the presence of NaHCO3 in THF/H2O produces the 3-oxocyclobutanecarboxamide (XXXVII). Cyclization of amide (XXXVII) in the presence POCl3 and DMF in EtOAc affords 3-(8-chloroimidazo[1,5-a]pyrazin-3-yl)cyclobutanone (XXXVIII), which is then brominated by means of NBS in DMF to yield the 1-bromo derivative (XXXIX) . Addition of CH3MgI to ketone (XXXIX) in THF, followed by chloride substitution with NH3, gives rise to cis-3-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methylcyclobutanol (XII) .