合成路线1

The reaction of p-chlorobenzoic acid (I) with SOCl2 gives p-chlorobenzoyl chloride (II), which is esterified with 4-fluorophenol (III) affording 4-fluorophenyl-4-chlorobenzoate (IV). The isomerization of (IV) with AlCl3 yields 4-chloro-2'-hydroxy-5'-fluorobenzophenone (V), which is condensed with 4-aminobutyric acid (VI) by means of sodium methoxide in ethanol giving 4-[[alpha-(p-chlorophenyl)-5-fluoro-2-hydroxybenzylidene]amino]butyric acid (VII). The reaction of (VII) with SOCl2 in THF affords the corresponding acyl chloride (VIII), which is then treated with NH3. An alternative way of converting the acid (VII) into its amide is by treatment with carbonyldiimidazole (A) and liquid NH3 in THF.

合成路线2

2) By direct cyclization of (I) with N,N'- carbonyldiimidazole (III) in refluxing benzene.

合成路线3

3) The treatment of indomethacin (III) with 1,1'-carbonyldiimidazole (A) at room temperature in dichloromethane affords the imidazolide (IVa), which is reacted with tropic acid (V) under the same mild conditions to afford title compound.

合成路线4

Antineopleston A10 (A10) can be obtained by two different ways: 1) A10 has been synthesized in two steps: Condensation of phenylacetic acid (I) with L-glutamine (V) to give phenylacetyl-L-glutamine (VI), followed by intramolecular cyclization of the latter. In the first step (I) is activated by reacting with various reagents such as HOSu (N-hydroxysuccinimide) (II) in the presence of DCC, DCC (N,N-dicyclohexylcarbodiimide) or 2-mercaptothiazoline (III) in the presence of DCC to afford the intermediates (IVa), (IVb) and (IVc), respectively. Without isolation, the intermediate (IVa), (IVb) or (IVc) is treated with a solution of L-glutamine in CH3CN:H2O (2:1) containing NaHCO3 to give (VI) in 60, 87 and 82% yields, respectively. In the second step (VI) is converted to the activated intermediate (IXa) or (IXb) by treatment with CDI (1,1'-carbonydiimidazole) (VII) or HOSu (VIII) in the presence of DCC. Finally, intramolecular cyclization of (IXa) or (IXb) is effected by treating the latter at 80 C to yield A10 in 85 or 82% yield, respectively. 2) Reaction of phenylacetyl chloride with L-glutamine in aqueous solution containing NaHCO3 affords phenylacetyl-L-glutamine (VI), which is heated at 160 C to give A10.

合成路线5

4) The reaction of phenyl thiobutyrate (XIX) with 9-borabicyclo[3.3.1]nonane (9-BBN) gives the enol ester (XX), which is condensed with the optically active imine (XXI) [prepared from 3-(trimethylsilyl)propynal (XXIII) and (S)-alpha-methylbenzylamine (XXII)] to afford the adduct (XXIV). The cyclization of (XXIV) by means of tert-butylmagnesium chloride in ether yields 3alpha-ethyl-1-(alpha-methylbenzyl)-4beta-[2-(trimethylsilyl)ethynyl]azetidin-2-one (XXV), which is deprotected with tetrabutylammonium fluoride giving the free acetylene derivative (XXVI). The partial reduction of (XXVI) with H2 over Pd-CaCO3-PbO yields the corresponding ethylene compound (XXVII), which is hydroxylated with disiamylborane (DSB) to give the 2-hydroxyethylazetidinone (XXVIII). The protection of (XXVIII) with tert-butyldimethylsilyl chloride yields the silylated compound (XXIX), which is treated with Na-NH3 to afford 3alpha-ethyl-4beta-[2-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (XXX). The protection of (XXX) with tert-butyldimethylsilyl chloride as before gives the fully silylated compound (XXXI), which is submitted to a controlled hydrolysis yielding 3alpha-ethyl-4beta-(2-hydroxyethyl)-1-(tert-butyldimethylsilyl)azetidin-2-one (XXXII). The oxidation of (XXXII) with CrO3 - pyridine gives the acetic acid derivative (XXXIII), which is deprotected to afford 2-(3alpha-ethyl-2-oxoazetidin-4beta-yl)acetic acid (XXXIV). The reaction of (XXXIV) with carbonyldiimidazole (XXXV) gives the corresponding imidazolide (XXXVI), which is condensed with magnesium 4-nitrobenzyl malonate (XXXVII) yielding 4-nitrobenzyl 4-(3alpha-ethyl-2-oxoazetidin-4beta-yl)-3-oxobutanoate (XXXVIII). The diazotation of (XXXVIII) with 4-azidobenzoic acid (XXXIX) gives the 2-diazo-3-oxobutanoate derivative (XL), which is finally cyclized to carbapen derivative (XII) in the presence of rhodium acetate. The reaction of (XII) with diphenyl chlorophosphate affords the enol phosphate (XIII), which is condensed with N-acetylcysteamine (XIV) to give 4-nitrobenzyl ester of PS-5 (XV). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C.

合成路线6

The reaction of 4-(3-indolyl)butyric acid (I) with 4-phenyl-3,4-dehydropiperidine (II) by means of carbonyldiimidazole (A) in THF gives 3-[4-oxo-4-(4-phenyl-3,4-dehydro-1-piperidyl)butyl]indole (III), which is reduced with LiAlH4 in THF.

合成路线7

The reaction of N-(cyclohexanecarbonyl)-D-alanine (I) with 3-mercapto-2-methylpropanoic acid (II) by means of carbonyldiimidazole (III) in THF gives 3-[N-(cyclohexanecarbonyl)-D alanilthio]-2-methyl-propanoic acid (IV), which is then condensed with L-protine (V) by means of triethylamine and ethyl chloroformate (VI) o THF.

合成路线8

The reaction for preparing the esters is shown schematically by the condensation of 1-methyl-5-(4-methylbenzoyl)pyrrol-2-acetic acid and 7-(2-oxyethyl)theophylline as a general example, giving rise to the formation of the 1-methyl-5-(4-methylbenzoyl)pyrrol-2-acetate of 7-(2-oxyethyl)theophylline.

合成路线9

The cyclization of 2-(methylaminomethyl)aniline (I) with 1,1'-carbonyldiimidazole (II) in refluxing THF gives 3-methyl-1,2,3,4-tetrahydroquinazolin-2-one (III), which is condensed with methyl succinyl chloride (IV) by means of anhydrous AlCl3 in refluxing carbon disulfide to yield 6-[3-(methoxycarbonyl)propionyl]-3-methyl-1,2,3,4-tetrahydroquinazolin-2-one (V). Finally, this compound is cyclocondensed with hydrazine in refluxing ethanol.

合成路线10

The condensation of cyclohexene-epoxide (I) with pyrrolidine (II) gives trans-2-(1-pyrrolidinyl)cyclohexanol (III), which by reaction with NaH and methanesulfonyl chloride, and then with benzylamine is converted into trans-2-(1-pyrrolidinyl)-N-benzylcyclohexylamine (IV). The debenzylation of (IV) by hydrogenolysis with H2 over Pd/C affords trans-2-(1-pyrrolidinyl)cyclohexylamine (V), which is formylated with ethyl formate to the corresponding N-formyl-trans-2-(1-pyrrolidinyl)cyclohexylamine (VI). The reduction of (VI) with LiAlH4 in refluxing ether gives trans-N-methyl-2-(1-pyrrolidinyl)cyclohexylamine (VII), which is finally condensed with 3,4-dichlorophenylacetic acid (VIII) by means of carbonyl diimidazole (IX) in THF.

合成路线11

Morpholine (VI) was treated with carbonyl diimidazole (VII), and the resulting imidazolide (VIII) was further condensed with ethylenediamine (IX) to give urea (X). Reaction of epoxide (V) with amine (X) furnished the title compound.

合成路线12

Separation of the Enantiomer: The enantiomers are separated from the racemic carboxylic acid (IV). After activation of the carboxylic acid group as imidazolide (V), this compound reacts with L-phenylglycinol and toluene sulfonic acid in DMF forming the diastereomeric mixture of L-phenylglycinolamides. These diastereomers can be separated by fractionated crystallization using ethanol (diastereomer VI) or a mixture of diethylether and isopropanol (diastereomer VII) as solvents. The release of enantiomerically pure carboxylic acids (VIII) and (IX) takes place by cleavage of the amide bond with sulfuric acid, neutralization and recrystallization from ethanol. The (R)-(-)-enantiomer is the active leukotriene synthesis inhibitor BAY X 1005.

合成路线13

Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2'-amino-5'-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.

合成路线14

The selective mesylation of 2'-O-acetyl-3-des(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyloxy)-6-O-methyl-3-oxoerythromycin A (I) with methanesulfonic anhydride in pyridine gives the expected 11-O-methanesulfonyl derivative (II), which is treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetone to yield the 10,11-didehydro derivative (III). The acylation of (III) with carbonyl diimidazole (IV) by means of NaH in THF affords the 12-O-acyl derivative (V), which is finally cyclocondensed with 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) in hot acetonitrile. The intermediate compound 4-[4-(3-pyridyl)imidazol-1-yl]butylamine (VI) is obtained as follows: The condensation of N-(4-bromobutyl)phthalimide (VII) with 4-(3-pyridyl)imidazole (VIII) by means of NaH in DMF gives N-[4-[4-(3-pyridyl)imidazol-1-yl]butyl]phthalimide (IX), which is then treated with hydrazine in refluxing ethanol.

合成路线15

OP C-33509 has been obtained by coupling imidazolecarboxamide (VI) with amine (IX) in refluxing CHCl3. The intermediates (VI) and (IX) have been obtained as follows: 1) Alkylation of 6-hydroxycarbostyril (I) with N-(3-bromopropyl)- phthalimide (II) in the presence of K2CO3 in DMF furnished the phthalimidopropyl ether (III). Subsequent hydrazinolysis of the phthalimide in refluxing EtOH provided the primary amine (IV). Then, the imidazolecarboxamide (VI) was obtained by treating amine (IV) with 1,1'-carbonyldiimidazole (V) and two equivalents of imidazole in DMSO. 2) Ring opening of 1,2 epoxycyclohexane (VII) with cyclopropylamine (VIII) gave the racemic trans aminoalcohol. Resolution of enantiomers (IX) and (X) was accomplished by esterification with (S)-mandelic acid (XI), followed by chromatographic separation of the diastereomeric esters. Hydrolysis of the desired ester (XII) then provided optically pure aminoalcohol (IX). Finally, the target urea derivative was obtained by coupling imidazolyl urea (VI) with amine (IX) in refluxing chloroform.

合成路线16

Treatment of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline dihydrochloride (I) with 1,1'-carbonyldiimidazole (II) gave the intermediate imidazolide (III) which, upon treatment with 4-(5-fluoro-1H-indol-3-yl)piperidine (IV) afforded the unsymmetrical urea. Finally, treatment with HCl in acetone yielded the title hydrochloride salt.

合成路线17

The reaction of 4-fluorobenzoyl chloride (I) with N,O-dimethylhydroxylamine (II) in pyridine gives the N-methylhydroxamate (III), which is condensed with 5-bromo-1H-indole (IV) by means of KH and t-BuLi yielding the ketone (V). The alkylation of (V) with ethyl iodide and NaH in DMF affords (1-ethylindol-5-yl)(4-fluorophenyl)methanone (VI), which is reduced with NaBH4 in methanol to the corresponding carbinol (VII). Finally, this compound is treated with carbonyl diimidazole in THF.

合成路线18

The acylation of indole (I) with 4-fluorobenzoyl chloride (II) by means of AlCl3 in dichloromethane gives 3-(4-fluorobenzoyl)indole (III), which is N-alkylated with ethyl iodide and K2CO3 in acetone yielding 1-ethyl-3-(4-fluorobenzoyl)indole (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.

合成路线19

The methylation of 5-bromo-1H-indole (I) with methyl iodide and NaH in DMSO gives the 1-methyl derivative (II), which is acylated with 4-fluorobenzoyl chloride (III) and AlCl3 in dichloromethane yielding the 3-acyl derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the corresponding carbinol (V), which is finally treated with carbonyl diimidazole (VI) in THF.

合成路线20

The known 7,8-dihydro-8-methyl-5-(4-nitrophenyl)-9H-1,3-dioxolo-[4,5-h]-2,3-benzodiazepine (I) was condensed with 1,1'-carbonyldiimidazole (II) in refluxing THF to produce imidazolide (III). Subsequent reaction of (III) with boiling cyclopropylamine (IV) gave rise to the cyclopropylcarbamoyl derivative (V). The nitro group of (V) was then reduced to the corresponding amine by hydrogenation over Pd/C.

合成路线21

The compound was prepared by solid-phase synthesis. Condensation of tert-butyl carbazate (I) with 1,1'-carbonyldiimidazole (II) afforded the acyl imidazole (III). Coupling of (III) with amino resin produced the Boc-protected semicarbazide-linked resin (IV), which was deprotected with trifluoroacetic acid to give (V). Condensation of (V) with protected L-argininal (VI) provided the semicarbazone resin (VII). Further solid-phase peptide synthesis by means of sequential coupling with L-alanine, D-serine and phenethylsulfonyl chloride yielded the peptide-resin (VIII). Finally, deprotection of both Boc groups of (VIII) with concomitant resin cleavage by means of aqueous trifluoroacetic acid furnished the target compound.

合成路线22

The reaction of imidazole (I) with phosgene (II) in hot benzene gives carbonyldiimidazole (III), which is condensed with 5-sulfamoyl-2-methoxybenzoic acid (IV) in THF yielding 1-(5-sulfamoyl-2-methoxybenzoyl)imidazole (V). Finally this compound is condensed with 1-methyl-2-aminomethylpyrrolidine (VI) in THF at room temperature

合成路线23

合成路线24

Condensation of methyl 5-amino-4-fluoro-1-methylbenzimidazole-6-carboxylate (XVI) with 4-bromo-2-fluoro-1-iodobenzene (XVII) by means of Pd2dba3, Cs2CO3 and xantphos in toluene/dioxane gives the 5-phenylamino-benzimidazole derivative (IX), which is hydrolyzed with KOSiMe3 in DMF/THF to provide the potassium salt (XVIII). Compound (XVIII) is activated as its imidazolide (XIX) by treatment with carbonyl diimidazole (XX) in the presence of imidazole hydrochloride in THF/optionally DMF at 50 °C. Alternatively, hydrolysis of methyl ester (IX) by means of NaOH in H2O affords carboxylic acid (X), which is further activated as its imidazolide (XIX) under the same conditions mentioned above. Condensation of intermediate (XIX) with O-(2-tert-butoxyethyl)hydroxylamine (XXI) in H2O provides amide (XXII), which is finally O-deprotected by means of H3PO4 in aceto nitrile .

合成路线25

Chlorination of 3,3,3-trifluoro-2,2-dimethylpropanoic acid (I) using (COCl)2 in refluxing CHCl3 gives the corresponding acid chloride (II) , which by condensation with 4-methoxy-3-buten-2-one (III) by means of LiHMDS in THF at –78 °C affords the hepta-1,4-dien-3-one derivative (IV) . Cyclization of intermediate (IV) in the presence of TFA in toluene or benzene produces the pyranone (V) (1-5), which is treated with aqueous NH3 at 65 °C to provide pyridinone (VI). Bromination of compound (VI) with POBr3 in toluene at 80 °C or in dichloroethane at 85 °C leads to the 4-bromopyridine derivative (VII). Subsequent coupling of bromopyridine (VII) with 2-acetamido-4-methylthiazole (VIII) by means of Pd(OAc)2, t-Bu3P·HBF4 and Cs2CO3 in refluxing DMF yields the pyridylthiazole adduct (IX), which by deacetylation using HCl in refluxing EtOH affords the 2-aminothiazole derivative (X) . Acylation of amine (X) with phenyl chloroformate (XI), optionally in the presence of DIEA in THF gives the thiazolylcarbamate (XII), which is finally condensed with L-prolinamide (XIII), optionally in the presence of Et3N in H2O .
Similarly, reaction of amine (X) with carbonyldiimidazole (XIV) in refluxing CH2Cl2 gives the carbamoyl imidazolide (XV), which is finally coupled with L-prolinamide (XIII) in the presence of Et3N in DMF or in DMAc at 65°C .

合成路线26

6-O-Methylerythromycin A (I) is protected with benzoic anhydride in the presence of triethylamine and DMAP in ethyl acetate to afford 2’,4”-di-O-benzoyl-6-O-methylerythromycin A (II). Treatment of the protected intermediate (II) with 1,8 diazabicyclo[5.4.0]undec-7-ene (DBU) followed by 1,1-carbonyldiimidazole (CDI) (III) in DMF yields 10,11-anhydro-2’,4”-di-O-benzoyl-12-O-imidazolylcarbonyl-6-Omethylerythromycin A (IV), which is converted to the 2’,4”-di-O-benzoyl-11-N-(4-azidobutyl)-6-O-methylerythromycin A 11,12-cyclic carbamate (V) by treatment with 4-azidobutylamine (XIII) and DBU in DMF. The cladinose sugar is cleaved from carbamate (V) by hydrolysis with 1 N HCl in acetone to provide 11-N-(4-azidobutyl)-5-(2’-benzoyldesosaminyl)-3-hydroxy-6-O-methylerythronolide A 11,12-cyclic carbamate (VI). 1-N-(4-Azidobutyl)-5-(2’-benzoyldesosaminyl)-3-oxo-6-O-methylerythronolide A 11,12-cyclic carbamate (VII) is prepared by oxidation of the secondary alcohol of intermediate (VI) with Dess-Martin periodinane (DMP).