合成路线1

The cyclization of trifluoroacetylmethylpyridinium bromide (I) with 3-(4-trifluoromethylbenzoyl)acrylic acid (II) by means of ammonium acetate in refluxing methanol gives 2-trifluoromethyl-6-(4-trifluoromethylphenyl)isonicotinic acid (III), which by condensation with 2-bromopyridine (IV) by means of butyllithium in ethyl ether yields 2-trifluoromethyl-6-(4-trifluoromethylphenyl)4-pyridyl-2'-pyridyl ketone (V). Finally, this compound is reduced with H2 over Pt in aqueous concentrated HCl. The starting products are prepared as follows: 1) The acrylic acid (II) is obtained by condensation of maleic anhydride (VI) with 4-trifluoromethylphenylmagnesium bromide (VII) by means of ZnCl2 in refluxing ethyl ether. An alternative method is the condensation of 4-trifluoromethylacetophenone (VIII) with glyoxylic acid (IX) by means of triethylamine at 135 C. 2) The pyridinium salt (I) is prepared by bromination of 1,1,1-trifluoroacetone (X) giving 1,1,1-trifluoro-3-bromoacetone (XI), which is then condensed with pyridine.

合成路线2

The reaction of N-(2-oxo-2-phenylethyl)acetamide (I) with glyoxylic acid (II) by means of NaHCO3 in water gives threo-(2RS)-3-acetylamino-2-hydroxy-4-oxo-4-phenylbutanoic acid (III), which is reduced with H2 over Pd/C in acetic acid yielding threo-(2RS)-3-acetylamino-2-hydroxy-4-phenylbutanoic acid (IV). The treatment of (IV) with (S)-1-phenylethylamine followed by a fractionated crystallization affords (2S,3R)-3-acetyl-amino-2-hydroxy-4-phenylbutanoic acid (IV), which is hydrolyzed with HCl in refluxing water to afford (2R,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid (V). The protection of (V) with benzyl S-4,6-dimethylpyrimidin-2-ylthiolcarbonate (VI) by means of triethylamine in dioxane - water gives (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoic acid (VII), which is condensed whh benzyl (S)-leucinate (VIII) by means of di-cyclohexylcarbodiimide and p-toluenesulfonic acid yielding benzyl (2S,3R)-3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutanoyl-(S)-leucinate (IX). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in acetic acid.

合成路线3

This compound can be prepared by two related ways: 1) The condensation of methoxyacetaldehyde (I) with isopropylamine (II) gives methoxyacetaldehyde isopropylimine (III), which is treated with 4-benzyloxyindole (IV) in acetic acid yielding 4-benzyloxy-3-(1-isopropylamino-2-ethoxyethyl)indole (V). The reaction of (V) with ethyl nitroacetate (VI) in hot toluene affords ethyl 3-(4-benzyloxyindol-3-yl)-2-nitro-5-oxahexanoate (VII), which is reduced with H2 over Raney-Ni in ethanol giving ethyl 3-(4-benzyloxyindol-3-yl)-2-amino-5-oxahexanoate (VIII). Finally, this compound is cyclized with paraformaldehyde (IX) in refluxing benzene. 2) Compound (VIII) can also be cyclized with glyoxylic acid (X) yielding a mixture of the tetrahydrocarboline (XI) and the dihydrocarboline (XII), which, without separation, are decarboxylated and dehydrogenated with sulfur at 140 C.

合成路线4

The reaction of 3-ethoxycarbonyl-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido [1,2-a]pyrimidine (I) with glyoxilic acid (II) in ethanolic HCl gives 3-ethoxycarbonyl-6-methyl-4-oxo-9-carboxymethylen-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine (IIIa-b), which is reduced with H2 over Pd/C in ethanol.

合成路线5

The condensation of 2-pyrrolidinone (I) with 2-oxoacetic acid (II) in ethyl ether gives 2-hydroxy-2-(2-oxopyrrolidin-1-yl)acetic acid (III), which is fully methylated with methanol and conc. sulfuric acid to yield 2-methoxy-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (IV). The reaction of (IV) with PCl3 in hot toluene affords 2-chloro-2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (V), which is condensed with triethyl phosphite (VI), also in hot toluene, to provide the dimethyl phosphonate (VII). The condensation of (VII) with acetaldehyde (VIII) in THF by means of tetramethylguanidine gives 2-(2-oxopyrrolidin-1-yl)-2-butenoic acid methyl ester (IX), which is reduced with H2 and a chiral Rhodium catalyst in THF to yield 2(S)-(2-oxopyrrolidin-1-yl)butyric acid methyl ester (X). Finally, this ester is treated with ammonia in methanol to afford the target chiral amide.

合成路线6

The cyclization of glyoxylic acid (I) with cyclopentadiene (II) gives the racemic hydroxylactone (III), which is acylated with Ac2O to yield acetoxy compound (rac)-(IV). The enzymatic optical resolution of (rac)-(IV) by means of Pseudomonas fluorescens affords the chiral hydroxylactone (-)-(V), which is reduced with LiAlH4 in refluxing THF to provide the lactol (VI). The oxidation of (VI) with NaIO4 in ethyl ether/water gives the chiral carbaldehyde (VII), which is reduced with NaBH4 in ethanol to afford the diol (VIII). The reaction of (VIII) with triphosgene by means of TEA in dichloromethane affords the cyclic carbonate (IX), which is condensed with chloropurine (X) by means of Pd(PPh3)4 in DMSO/THF to provide the adduct (XI). Finally, this compound is hydrolyzed with NaOH to afford the target (-)-carbovir.

合成路线7

Aldol condensation between 1-indanone (I) and glyoxylic acid (II) in the presence of H2SO4 afforded keto acid (III). Catalytic hydrogenation of (III) over Pd/C furnished 2-indanylacetic acid (IV).

合成路线8

The Grignard condensation of phenylethynylmagnesium bromide with acetic anhydride in THF gives 4-phenyl-3-butyn-2-one (II), which is cyclized with 1-aminopyridinium iodide (III) by means of KOH in dichloromethane yielding the pyrazolopyridine (IV). The reaction of (IV) with 2-oxoacetic acid (V) by means of acetic acid in dimethoxyethane (DME) affords the butyric acid derivative (VI), which is cyclized with hydrazine in hot DMA to give the pyridazinone (VII). The condensation of (VII) with 4-bromobutyric acid ethyl ester (VIII) by means of benzyltriethylammonium chloride in hot DME/methanol provides the butyric ester intermediate (IX), which is finally hydrolyzed with NaOH.

合成路线9

5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII), which is acetylated with acetic anhydride to the acetate (XXXVIII). The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX), which is reduced with LiAlH4 in refluxing THF, affording triol (XL). The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI), which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). This compound, by reaction with triphosgene and triethylamine in dichloromethane, results in the cyclic carbonate intermediate (XXXII), already reported.

合成路线10

The second general approach to synthesis of lamivudine does not involve intermediacy of the racemic nucleoside. A variety of routes are available for preparing chiral oxathiolane intermediates which may be coupled to the cytosine base under appropriate conditions where the chirality of the oxathiolane is maintained. Various natural carbohydrate precursors have utility in the synthesis of lamivudine; for example, a synthesis from L-gulose has recently been reported. (+)-Thiolactic acid (XI) has served as a starting material for chiral oxathiolane (XII), which is coupled to silylated cytosine in the presence of TMS-iodide to afford (XIII). Separation of the pure beta-anomer and deprotection affords lamivudine. Alternatively, racemic acid (XV) may be prepared from glyoxylic acid (XIV) and resolution using a suitable chiral base such as norephedrine would afford the chiral acid (XVI), which may be esterified prior to coupling with cytosine to give (XVII) followed by final reduction to lamivudine.

合成路线11

This compound has been obtained by two related ways: 1) The sulfonation of 3,5-dichloroaniline (I) with chlorosulfonic acid gives 2-amino-4,6-dichlorobenzenesulfonyl chloride (II), which is condensed with 3-bromobenzylamine (III) by means of TEA yielding the corresponding sulfonamide (IV). The cyclization of (IV) with glyoxylic acid (A) in ethanol/sulfuric acid affords the esterified benzothiadiazine-3-carboxylate (V), which is finally hydrolyzed with aqueous NaOH. 2) The reaction of sulfonyl chloride (II) with liquid ammonia gives the corresponding sulfonamide (VI), which is cyclized with glyoxylic acid (A) as before yielding the benzothiadiazine (VII). Finally the alkylation of (VII) with 3-bromobenzyl bromide (VIII) by means of NaH affords the already reported benzothiadiazine-3-carboxylate (V). 3) The enantiomers of the title compound have been obtained in optically pure form by preparative liquid chromatography on a Pirkle-type chiral phase column.

合成路线12

The cyclization of 4-chlorophenylene-1,2-diamine (I) with glyoxylic acid (II) in isopropanol gives a mixture of 7-chloroquinoxalin-2-ol (III) and 6-chloroquinoxalin-2-ol (IV), which, without isolation is treated with refluxing POCl3, and the resulting mixture of dichloro compounds is submitted to flash chromatography to obtain the desired 2,7-dichloroquinoxaline (V). The condensation of (V) with 2-(4-hydroxyphenoxy)propionic acid methyl ester (VI) by means of K2CO3 in refluxing acetone affords the ester precursor (VII), which is hydrolyzed with KOH in THF/water and acidified with HCl to provide the racemic 2-[4-(7-chloroquinoxalin-2-yloxy)phenoxy]propionic acid (VIII). Finally, this compound is converted into its sodium salt with NaOH in water.

合成路线13

The chiral piperidine (2S,4R)(VI) has been obtained as follows: The cyclization of 3-buten-1-ol (XXII) with (S)-1-phenylethylamine (XXIII) and glyoxylic acid (XXIV) by means of tosyl chloride in THF gives a mixture of the (2S,4R) and (2R,4S) lactones (XXV), which is resolved by fractional crystallyzation of their salts with the chiral camphorsulfonic acid (XXVI), followed by elimination of the acid with ammonia to afford (2S,4R)(XXVII). The reaction of lactone (XXVII) with isopropylmagnesium chloride and tert-butylamine in THF gives (2S,4R)-N-tert-butyl-4-hydroxy-1-(1(S)-phenylethyl)piperidine-2-carboxamide (XXVIII), which is debenzylated by hydrogenation and protected with tert-butoxycarbonyl anhydride yielding (2S,4R)-N-(tert-butoxycarbonyl)-4-hydroxypiperidine-2-carboxamide (2S,4R)(XI), which is finally condensed with 4-(chloromethyl)pyridine (XII) as before to obtain the chiral piperidine (2S,4R)(VI), already reported.

合成路线14

Dehydroxylation of compound (I) by hydrogenation over Pd/C in MeOH provides tetralinecarboxylic acid methyl ester (II), which is then reduced by means of LiAlH4 in THF to afford tetralinemethanol as a mixture of enantiomers (III). Separation of isomers in (III) is then achieved by first acylation of the alcohol with (-)-menthyl chloroformate (IV) in pyridine, followed by the separation of the two resulting diastereomers by recrystallization to give (-)-menthyl carbonate (V) and its subsequent hydrolysis with NaOH in THF/H2O to furnish compound (VI).

合成路线15

Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished the target amidine, which was isolated as the hydrochloride salt.

合成路线16

Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished amidine (XII). Finally, basic hydrolysis of the ester function provided the target amidinoacid, which was isolated as the hydrochloride salt.

合成路线17

The cyclization of 2-(3,5-dimethoxyphenyl)glyoxal monohydrate (I) with methyl glyoxylic acid (II) and ammonium acetate in acetonitrile gives the aryl imidazole (III), which is protected with dihydrofuran (IV) and Ts-OH, yielding compound (V). The regioselective lithiation of (V) with n-BuLi, followed by reaction with labeled 14CO2 provides the carboxylic acid (VI), which is esterified with MeI and CaO in DMSO to furnish the methyl ester (VII). The reduction of the ester group of (VII) with LiBH4 affords the carbinol (VIII), which is esterified with trichloroacetonitrile (IX) to provide the trichloroacetimidate (X).

合成路线18

This compound has been obtained by several related ways: 1.- The Sam and Thompson cyclization of 3-(2-thienyl)acrylic acid (I) gives the thienocyclopentanone (II), which is condensed with oxoacetic acid (III) yielding 2-(4-oxo-5,6-dihydro-4H-cyclopenteno[b]furan-5-ylidene)acetic acid (IV). The reduction of (IV) with Zn and acetic acid affords the corresponding saturated compound (V), which is condensed with 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (VI) by means of DCC and HOBt in dichloromethane to give the corresponding piperidide (VII). The protection of the ketonic group of (VII) with ethylene glycol and TsOH yields the ethylene ketal (VIII), which is reduced at the piperidide group with LiAlH4 in ethyl ether yielding the final intermediate (IX). Finally, this compound is treated with HCl to eliminate the ethylene ketal protecting group. 2.- The condensation of the thienocyclopentanone (II) with ethyl bromoacetate (X) by means of LDA gives the acetate (XI), which is hydrolyzed with KOH in ethanol affording the previously reported saturated acetic acid derivative (V). 3.- The condensation of acetate (XI) with piperidine (VI) by means of Me3Al gives also the previously reported piperidide (VII).

合成路线19

Glyoxylic acid (II), generated in situ by oxidative cleavage of tartaric acid (I) with sodium periodate, was condensed with deoxyanisoin (III) to provide the aldol adduct (IV). Cyclization of hydroxyacid (IV) with hydrazine gave rise to the hydroxy dihydropyridazinone (V), which was further dehydrated to (VI) upon treatment with p-toluenesulfonic acid in refluxing benzene. Finally, alkylation of pyridazinone (VI) with 4-chlorocinnamyl chloride (VII) in the presence of potassium carbonate furnished the title compound.

合成路线20

In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).

合成路线21

Reductive condensation of 1,4-butanediamine (I) with glyoxylic acid (II) affords 3,8-diazaoctanoic acid (III). Subsequent acylation of diamino acid (III) with 2,3-diacetoxybenzoyl chloride (IV) provides diamide (V). After activation of (V) as the corresponding mixed anhydride with either methyl or isobutyl chloroformate, condensation with ampicillin (VI) yields the title compound.

合成路线22

The condensation of 1-tetralone (I) with 2-oxoacetic acid (II) by means of KOH gives 2-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-ylidene)acetic acid (III), which is cyclized with hydrazine in hot butanol to yield the tricyclic pyridazinone (IV). The treatment of (IV) with hot POCl3 gives the chloropyridazine derivative (V), which is treated with hydrazine in boiling water to provide the hydrazino derivative (VI). The hydrogenation of (VI) with H2 over Ni in methanol gives the aminopyridazine derivative (VII), which is condensed with ethyl 11-bromoundecanoate (VIII) (prepared by esterification of the corresponding acid (IX) with Et-OH/HCl) in hot DMF to yield the adduct (X). The hydrolysis of (X) with HCl in hot HOAc affords the corresponding acid (XI), which is finally condensed with 1-(2-pyrimidinyl)piperazine (XII) by means of HOBt and EDC in DMF to provide the target amide.

合成路线23

The reaction of 5(R)-(azidomethyl)-3-phenyloxazolidin-2-one (I) with Ac2O and MsOH gives the 4-acetylphenyl derivative (II), which is cyclized with glyoxylic acid (III) and hydrazine (IV) in hot acetic acid to yield the pyridazinone derivative (V). The reduction of the azido group of (V) by means of PPh3 in THF/water affords the aminomethyl compound (VI), which is finally condensed with ethyl dithioacetate (VII) by means of TEA in DMF to provide the target thioacetamide.

合成路线24

The reaction of 5(R)-(azidomethyl)-3-phenyloxazolidin-2-one (I) with Ac2O and MsOH gives the 4-acetylphenyl derivative (II), which is cyclized with glyoxylic acid (III) and hydrazine (IV) in hot acetic acid to yield the pyridazinone derivative (V). The reduction of the azido group of (V) by means of PPh3 in THF/water affords the aminomethyl compound (VI), which is condensed with acetic anhydride and pyridine to provide the acetamide (VII). Finally, this compound is treated with Lawesson's reagent in hot dioxane to furnish the target pyridazinethione.

合成路线25

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线26

The cyclization of 4-(benzyloxycarbonylamino)acetophenone (I) with glyoxylic acid (II) and hydrazine (III) in hot acetic acid gives the pyridazinone (IV), which is treated first with Lawesson's reagent in hot dioxane and then with MeI and TEA in DMF to yield the methylsulfanyl pyridazine (V). The cyclization of (V) with acetamide (VI) by means of t-BuOLi in methanol/DMF affords the oxazolidinone (VII), which is finally treated with Lawesson's reagent in hot dioxane to provide the target thioacetamide.

合成路线27

合成路线28

合成路线29

5-Hydroxy-4-propyl-2-furanone (V) is obtained by aldol condensation of glyoxylic acid (XXI) with valeraldehyde (XXII) in the presence of morpholine in heptane, followed by cyclization of the intermediate aldehyde acid under acidic conditions .
Preparation of iodoacyl chloride (VIII) starts with the conjugate addition of propylmagnesium bromide (XXIV) to 2-furanone (XXIII) in the presence of CuI and TMSCl in ethyl ether to produce 4-propylbutyrolactone (XXV), which undergoes lactone ring opening by means of iodotrimethylsilane in CH2Cl2, affording 3-(iodomethyl)hexanoic acid (XXVI), and finally, chlorination of acid (XXVI) with SOCl2 in benzene .

合成路线30

Oxidation of cyclobutanemethanol (XXVIII) with NaOCl and catalytic TEMPO by means of KBr and NaHCO3 in CH2Cl2/H2O gives cyclobutanecarboxaldehyde (XXIX), which is then condensed with nitromethane in the presence of Et3N in toluene to yield the nitro alcohol (XXX). Subsequent treatment of alcohol (XXX) with acetic anhydride in the presence of DMAP furnishes a mixture of the acetate ester (XXXI) and the dehydration compound (2-nitrovinyl)cyclobutane (XXXII), which can also be obtained as the only reaction product by dehydration of nitro alcohol (XXX) with MsCl in the presence of Et3N. Reduction of the mixture of compounds (XXXI) and (XXXII) or the nitro olefin (XXXII) by catalytic hydrogenation over Pd/C in MeOH optionally in the presence of Et3N, or with NaBH4 in PEG-400/H2O or t-BuOH, affords (2-nitroethyl)cyclobutane (XXXIII), which is condensed with glyoxylic acid (XXXIV) in the presence of Et3N to yield the nitro hydroxy acid (XXXV). Then, compound (XXXV) is reduced with H2 over Pd/C in MeOH and esterified with MeOH and p-TsOH·H2O to give amino ester (XXXVI). Finally, aminolysis of methyl ester (XXXVI) with NH3 and NH4OH in MeOH followed by N-protection by means of Boc2O and K2CO3 in MeOH/H2O yields intermediate (XXVII) .