合成路线1

The condensation of 2-methyl-3-(1H-imidazol-1-ylmethyl)indole (III) with acrylonitrile (IV) by means of benzyltrimethylammonium hydroxide (B) in dioxane gives 1-(2-cyanoethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (V), which is then hydrolyzed with KOH in water. The reaction of compound (III) with methyl acrylate (VI) in the same conditions as before gives 1-(2-methoxy-carbonylethyl)-2-methyl-3-(1H-imidazol-1-ylmethyl)indole (VII), which is also hydrolyzed. Compound (III) can be obtained from 2-methylindole (I).

合成路线2

1) The condensation of 3,4-diphenylpyrazole (I) with acrylonitrile (II) by means of benzyl-trimethyl-ammonium hydroxide (Triton B) in dioxane gives 1-(2-cyanoethyl)-3,4-diphenylpyrazole (III), which is then reductocondensed with dimethylamine by means of H2 over Pd/C in ethanol.

合成路线3

7-Chloro-3-hydroxy-5-(2'-fluorophenyl)-1,3-(dihydro-2H-1,4-benzodiazepin-2-one (I) is mixed with acrylonitrile (II), and after dropwise addition of triethylbenzylammonium chloride (A) and benzyl trimethylammonium hydroxide (B), stirring is continued for 8 hours. The crude material was recrystallized from acetonitrile.

合成路线4

1) The reaction of 4-(chloromethyl)pyridine (I) with KCN in refluxing methanol gives 2-(4-pyridyl)acetonitrile (II), which is alkylated with ethyl iodide and sodium hydride in DMF, yielding 2-(4-pyridyl)butyronitrile (III). The condensation of (III) with acrylonitrile (IV) by means of Triton B in tert-butanol affords 2-cyano-2-(4-pyridyl)hexanenitrile (V), which is finally cyclized with concentrated H2SO4 in refluxing acetic acid. 2) The alkylation of 2-(4-pyridyl)acetic acid ethyl ester (VI) with ethyl iodide and potassium tert-butoxide gives 2-(4-pyridyl)butanoic acid ethyl ester (VII), which is condensed with acrylamide (VIII) by means of potassium tert-butoxide, yielding 4-carbamoyl-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (IX). Finally, this compound is cyclized in the presence of potassium tert-butoxide. 3) The condensation of ester (VI) with acrylonitrile (IV) in the presence of Triton B gives 4-cyano-2-(4-pyridyl)butanoic acid ethyl ester (X), which is alkylated with ethyl iodide and lithium diisopropylamide yielding 4-cyano-2-ethyl-2-(4-pyridyl)butanoic acid ethyl ester (XI). Finally, this compound is cyclized with concentrated H2SO4 in refluxing acetic acid.

合成路线5

4) The (R)- and (S)-enantiomers of title product are obtained as follows: the trans-esterification of 2-(4-pyridyl)acetic acid methyl ester (XII) with the chiral alcohol (Oppolzer's camphor) (XIII) by means of butyllithium in THF gives the corresponding ester (XIV), which is alkylated with ethyl iodide and potassium hydride in THF yielding a mixture of the corresponding alkylated esters (XVR) and (XVS). The condensation of this mixture with acrylonitrile (IV) by means of potassium tert-butoxide in tert-butanol affords a mixture of the two diastereomeric nitriles (XVIR) and (XVIS), which are easily separable by column chromatography in silica gel. Both isolated compounds are then cyclized with sulfuric acid in refluxing acetic acid.

合成路线6

The reaction of 2-piperidineethanol (I) with acrylonitrile (II) gives N-(2-cyanoethyl)piperidine-2-ethanol (III), which by treatment with SOCl2 is converted into the chloronitrile (IV). The cyclization of (IV) with NaH affords 3-cyanoquinolizidine (V), which by hydrolysis with ethanol and HCl yields ethyl quinolizidine-3-carboxylate (VI). The Grignard reaction of (VI) with 2-thienylmagnesium bromide gives thienyl-3-quinolizidinyl methanol (VIII), which is dehydrated with HCl ethanol to afford 3-(di-2-thienylmethylene)quinolizidine (IX). Finally, this compound is quaternirzed with methyl bromide in acetone.

合成路线7

The cyclization of diphenyldiazomethane (I) with acrylonitrile (II) in CHCl3 gives cyano-2,2-diphenylcyclopropane (III), which is then cyclized with ethylenediamine tosylate (IV) by heating at 200 C.

合成路线8

The synthesis of baogongteng A has been published: The alkylation of 3-hydroxypyridine (I) with benzylbromide (II) gives 1-benzyl-3-hydropyridinium bromide (III), which is condensed with acrylonitrile (IV) by means of triethylamine at reflux temperature, yielding the bicyclic nitrile (V). The reduction of (V) with LiAlH4 gives the bicyclic hydroxy nitrile (VII), also obtained by stepwise reduction of (V) with H2 over Pd/C to (VI) and posterior reduction to (VII) with NaBH4. The protection of (VII) with trimethylsilyl chloride and triethylamine affords the silyloxy derivative (VIII), which is treated with methylmagnesium iodide to yield the acetyl derivative (IX). Oxidation of (IX) with m-chloroperbenzoic acid (MCPBA) in CHCl3 affords the acetoxy compound (X), which is finally debenzylated by hydrogenation with H2 and Pd/C in ethanol to give the free base (XI). This is then treated with benzoic acid.

合成路线9

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.

合成路线10

Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .

合成路线11

An asymmetric synthesis of pregabalin has been reported: Condensation of isobutyraldehyde (I) with acrylonitrile (II) by means of DBU and 2,6-di-tert-butyl-4- methylphenol (DBP) gives 3-hydroxy-4-methyl-2-methylenepentanenitrile (III), which is acylated with AcCl or Ac2O and pyridine to yield the acetate (IV). The carboxylation of (IV) by means of Pd(OAc)2, PPh3, CO and EtOH affords 3-cyano-4-methyl-3-hexenoic acid ethyl ester (Va-b), which is hydrolyzed with KOH in THF/water to provide the corresponding carboxylic acid potassium salt (VIa-b). Acidification of (VIa-b) with HCl, followed by reaction with tert-butylamine gives the corresponding salt (VIIa-b), which is reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid butylammonium salt (VIII). Finally, the CN group of (VIII) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol. Alternatively, intermediate (VIa-b) can be reduced with H2 over a chiral (R,R)-rhodium catalyst [(R,R)-Rh] in THF/water to yield (S)-3-cyano-5-methylhexanoic acid potassium salt (IX). Finally, the CN group of (IX) is reduced with H2 over a sponge-Ni catalyst in basic (KOH) ethanol.

合成路线12

Treatment of a benzenic solution of 4-piperidone hydrate (I) with anhydrous AlCl3 provided 4,4-diphenylpiperidine (II). Then, conjugate addition of acrylonitrile (III) in the presence of triethylamine in ethanol gave the cyanoethylpiperidine (IV), which was reduced with borane in THF to afford the intermediate primary amine (V). Dihydropyridine (IX) was prepared by Hantzsch synthesis by condensation of 3-aminocrotonamide (VI), 4-nitrobenzaldehyde (VII) and cyanoethyl acetoacetate (VIII) in refluxing ethanol. Cyanoethyl ester was then cleaved with dilute KOH at 0 C to give acid (X), which was finally coupled with amine (V) by treatment with DEC to yield the target amide.

合成路线13

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14

The addition of glycine ethyl ester (I) to 2-propenenitrile (II) by means of KOH in water gives N-(2-cyanoethyl)glycine ethyl ester (III), which is cyclized by means of di-tert-butyl dicarbonate yielding the protected pyrrolidinone (IV). The reduction of (IV) with NaBH4 in ethanol affords the pyrrolidinol (V), which is further reduced with LiAlH4 in THF and protected with di-tert-butyl dicarbonate to give the fully N-protected compound (VI). The oxidation of (VI) with pyridine/SO3 complex yields the pyrrolidinone (VII), which is treated with O-methylhydroxylamine (VIII) to afford the correponding oxime (IX). The deprotection of (IX) with acetyl chloride in cool methanol gives 4-(aminomethyl)pyrrolidin-3-one O-methyloxime (X), which is finally condensed with 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (XI) by means of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in acetonitrile.

合成路线15

The condensation of 3-amino-1-(2-fluorophenyl)-6-methoxyindolin-2-one (I) with acrylonitrile (II) by means of K2CO3 in DMSO gives the propionitrile derivative (III), which was submitted to optical resolution with (+)-dibenzoyl tartaric acid to yield enantiomer (IV). The condensation of (IV) with isoquinoline-3-carboxylic acid (V) by means of DEC and HOBt in DMF affords the carboxamide (VI), which is treated with HCl in methanol to provide the propionic ester (VII). Finally, this compound is hydrolyzed with NaOH in methanol/water to furnish the target sodium propionate derivative as a pure enantiomer.

合成路线16

The 2-chloroethylation of ethyl homovanillate (I) with 1-bromo-2-chloroethane and K2CO3 in acetone gives ethyl 2-[4-(2-chloroethoxy)-3-methoxyphenyl]acetate (II), which is treated with sodium azide in toluene followed by hydrolysis with aqueous NaOH in MeOH, yielding 2-[4-(2-azidoethoxy)-3-methoxyphenyl]acetic acid (IV). The reaction of (IV) with SOCl2 and Et3N affords the acyl chloride (V). The reaction of 3-iodo-o-xylene (VI) and acrylonitrile under the Heck reaction conditions [Pd(OAc)2, tri-o-tolylphosphine and Et3N in MeCN] gives an isomeric mixture of 3-(3,4-dimethyl-phenyl)-2-propenenitrile (VII), which is hydrogenated with Pd/C followed by Raney-Ni to provide 3-(3,4-dimethylphenyl)propylamine (IX). The coupling reaction between the acyl chloride (V) and amine (IX) with Et3N in CH2Cl2 gives the amide (X). Finally, Pd/C catalyzed hydrogenation of this compound affords 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-N-[3-(3,4-dimethylphenyl)propyl]acetamide.

合成路线17

The Hantzsch cyclization of 3-nitrobenzaldehyde (I), methyl acetoacetate (II) and NH4OAc in refluxing ethanol or isopropanol gives 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester (III), which is reduced with H2 over sulfided carbon in ethanol or with Fe/NH4Cl in methanol/water to yield the corresponding amino derivative (IV). The reaction of (IV) with methyl chloroformate and pyridine in acetonitrile/dichloromethane affords the carbamate (V), which is treated with B-chlorocatecholborane in refluxing THF to provide the corresponding isocyanate (VI). Finally, this compound is condensed with 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) in dichloromethane to furnish the target urea. The intermediate 3-[4-(3-methoxyphenyl)piperidin-1-yl]propylamine (VII) is obtained by condensation of 4-(3-methoxyphenyl)piperidine (VIII) with acrylonitrile (IX) in refluxing acetonitrile to give 3-[4-(3-methoxyphenyl)piperidin-1-yl]propionitrile (X), which is reduced with H2 over Raney-Ni in methanol/aq. NH3.

合成路线18

1) The reaction of diethyl-2-benzylmalonate (I) with acrylonitrile (II) by means of sodium ethoxide in methyl-tert-butyl ether gives diethyl 2-benzyl-2-(2-cyanoethyl)malonate (III), which is reduced with H2 over Pd/C in ethanol/aq. HCl yielding diethyl 2-(3-aminopropyl-2-benzylmalonate (IV). The protection of (IV) with tert-butoxycarbonyl anhydride affords carbamate (V), which is regioselectively hydrolyzed with porcine liver estearase giving 2(S)-benzyl-5-(tert-butoxycarbonylamino)-2-(ethoxycarbonyl)pentanoic acid (VI). The deprotection of the amino group of (VI) with trifluoroacetic acid, followed by cyclization by means of dicyclohexylcarbodiimide (DCC) and hydroxybenzotriazole (HOBT) in methyl-tert-butyl ether gives piperidone (VII), which is protected with tert-butoxycarbonyl anhydride yielding 3(S)-benzyl-1-(tert-butoxycarbonyl)-2-oxopiperidine-3-carboxylic acid ethyl ester (VIII). The reduction of (VIII) with lithium triethylborohydride gives the 2-hydroxy deerivative (IX), which is dehydroxylated with triethylsilane in dichloromethane and deprotected with boron trifluoride ethearate to yield 2(S)-benzylpiperidine-2-carboxylic acid ethyl ester (X). 2) The reduction of the piperidone (VII) to the piperidine (X) can also be performed by reaction of (VII) with Lawesson's reagent [2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide] in refluxing toluene to give the corresponding piperidinethione (XIV), which is then desulfurized by means of Raney Nickel and NaBH4 in THF/water yielding the desired piperidine (X).

合成路线19

The title compound was synthesized through Baylis-Hillman reaction of p-nitrobenzaldehyde (I) with acrylonitrile (II) in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) and NaI.

合成路线20

3-(Carbomethoxy)propionyl chloride (XV) is condensed with the chiral oxazolidine (XVI) to provide (XVII). Titanium-catalyzed Michael addition of acrylonitrile to the N-acyl oxazolidine (XVII) affords nitrile (XVIII), which is reduced to the primary amine (XIX) by catalytic hydrogenation in the presence of PtO2. Reductive alkylation of amine (XIX) with N-Boc-4-piperidone (XX) gives rise to the aminopiperidine (XXI). This is then cyclized to the piperidinyl piperidone (XXII) upon heating in acetonitrile. After alkaline hydrolysis of the methyl ester group of (XXII), coupling of the resultant acid (XXIII) with methylamine gives rise to the corresponding amide (XXIV). The N-Boc protecting group of (XXIV) is then removed by treatment with trifluoroacetic acid to furnish piperidine (XXV)

合成路线21

Addition of acrylonitrile (II) to 3,4-difluoro-2-nitroaniline (I) gave the anilinopropionitrile (III). Subsequent hydrogenation of the nitro group of (III) over Pd/C led to the phenylenediamine (IV), which was condensed with carbethoxyacetimidate-HCl (V) to produce the benzimidazole (VI). After conversion of the nitrile group of (VI) to ester (VII) with ethanolic HCl, Dieckmann condensation using NaOEt furnished the cyclic ketoester (VIII). Finally, reaction of (VIII) with 2,6-difluoroaniline (IX) in xylene yielded the target carboxamide.

合成路线22

Acylation of 3,5-dimethoxyaniline (I) with 4-methoxyphenylacetyl chloride (II) afforded amide (III). Treatment of (III) with Vilsmeier reagent gave rise to 2-chloroquinoline derivative (IV), which was hydrolyzed to quinolinone (V) using aqueous HOAc. Conjugate addition to (V) of acrylonitrile (VI) produced the cyanoethyl quinolinone (VII). The title tetrazole was then obtained by reaction of nitrile (VII) with tributyltin azide in hot toluene.

合成路线23

The cyclization of 3,5-dimethoxyaniline (I) with 2-formyl-2-(4-methoxyphenyl)acetic acid ethyl ester (II) by means of polyphosphoric acid trimethylsilyl ester (PPSE) by heating at 110 C gives the quinolone (III), which is alkylated with vinyl cyanide (IV) by means of Triton B in DMF to yield the propionitrile derivative (V). Finally, the cyano group of (V) is converted into the target tetrazolyl derivative by cyclization with tri-tert-butylstannyl azide in refluxing toluene.

合成路线24

The reaction of cyclohexanone (I) with acrylonitrile (II) by means of pyrrolidine gives 3-(2-oxocyclohexyl)propionitrile (III), which is condensed with methoxymethyltriphenylphosphonium chloride (IV) in THF to yield the methoxymethylene derivative (V). The condensation of propionitrile (V) with 4-bromostyrene (VI) by means of n-BuLi ethyl ether affords the styryl ketone (VII), which is cyclized by means of triphenyl phosphite and O3 (or air, methylene blue and light) to provide trioxane (VIII) as a diastereomeric mixture that is separated by column chromatography. Finally, the vinyl group of the desired diastereomer (VIII) is oxidized with KMnO4 in acetone to afford the target compound.

合成路线25

The title compound was prepared by chemical modification of the natural macrocyclic depsipeptide RO-0093655 (I). Conjugate addition of acrylonitrile (II) to the side-chain amino group of (I) produced the aminopropionitrile derivative (III). Subsequent acylation of aminonitrile (III) with the di-Boc-protected L-ornithine (IV) gave amide (V).

合成路线26

Alkylation of ethyl 4-hydroxybenzoate (I) with 2-iodobenzyl bromide (II) affords the 4-benzyloxybenzoate (III). Subsequent reaction of ester (III) with hydrazine hydrate produces the hydrazide (IV), which is subjected to a Michael reaction with acrylonitrile (V), yielding (VI). Finally, cyclization of the hydrazide (VI) with triphosgene gives rise to the target ozadiazole derivative.

合成路线27

Conjugate addition of acrylonitrile (II) to 4-phenylpiperidine (I) affords the piperidinopropionitrile (III). Catalytic hydrogenation of the cyano group of (III) in the presence of Raney nickel and methanolic ammonia leads to diamine (IV). This is further converted into isothiocyanate (VI) by reaction with thiocarbonyl diimidazole (V). Subsequent addition of sodium cyanamide to isothiocyanate (VI) yields the intermediate N-cyano isothiourea sodium salt (VII).

合成路线28

Rilpivirine can be synthesized as follows. Chlorination of 2-(p-cyanophenylamino)-4-pyrimidinone (I) with refluxing POCl3 gives the chloropyrimidine (II), which is condensed with ethyl 4-amino-3,5-dimethylbenzoate (III) by heating at 150 °C to afford the diamino pyrimidine (IV). Reduction of ester (IV) with LiAlH4 in THF followed by reoxidation of the obtained alcohol (V) utilizing MnO2 in CH2Cl2 gives the aldehyde (VI). Then, Wittig reaction of aldehyde (VI) with cyanomethyl triphenylphosphonium chloride (VII) in the presence of t-BuOK provides the target cyanovinyl derivative (1, 2). In a related method, chloropyrimidine (II) is condensed with either 4-bromo-(VIIIa) or 4-iodo-2,6-dimethylaniline (VIIIb) at 150 °C to yield the corresponding diaminopyrimidines (IXa) and (IXb). Subsequent Heck coupling of aryl halides (IXa) and (IXb) with acrylonitrile (X) by means of palladium acetate and tri-o-tolylphosphine provides the title compound rilpivirine (1, 3). Scheme 1.

合成路线29