合成路线1

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2

By reaction of 3-(2-methyl-2-aminopropyl)indole (I) and 2-(2,3-epoxypropoxy)benzonitrile (II) by heating at 120-40 C followed by a treatment with HCl in ethanol. The starting products are obtained as follows: 1) The reaction of 3-(dimethylaminomethyl)indole (III) with 2-nitropropane (IV) by means of KOH gives 3-(2-methyl-2-nitropropyl)indole (V), which is then reduced with hydrazine and Raney-Ni in ethanol to yield (I). 2) The reaction of 2-hydroxybenzonitrile (VI) with epichlorohydrin (VII) by means of piperidine affords 2-(3-chloro-2-hydroxypropoxy)benzonitrile (VIII), which is epoxidized again to (II) by treatment with NaOH in hot THF-water.

合成路线3

[2H]-Labeled pimonidazole is synthesized as follows: The condensation of 2-nitroimidazole (I) with 3-chloro-1,2-epoxypropane (II) gives 1-(3-chloro-2-hydroxypropyl)-2-nitroimidazole (III), which is oxidized with CrO3 - H2SO4 in acetone yielding 1-(3-chloro-2-oxopropyl)-2-nitroimidazole (IV). The reduction of (IV) with NaB[2H]4 in ethanol affords 1-(3-chloro-2-hydroxy-2(2H)-propyl)-2-nitroimidazole (V), which is cyclized with NaOH to the corresponding labeled epoxide (VI). Finally, this compound is condensed with piperidine (VII) in refluxing ethanol.

合成路线4

2) By condensation of 1-(3-chloro 2 hydroxypropyl)-2-nitroimidazole (III) with piperidine (IV) in refluxing methanol.

合成路线5

3) By condensation of 1-(2,3-epoxypropyl)-2 nitroimidazole (V) with (IV) in refluxing ethanol.

合成路线6

1) The cyclization of 6-chloro-3-hydrazino-4-methylpyridazine (I) with refluxing formic acid gives 6-chloro-8-methyl-1,2,4-triazolo[4,3-b]pyridazine (II), which is then condensed with piperidine (III) at reflux temperature.

合成路线7

Ethyl 4-bromobutyrate (I) is condensed with piperidine (II) in refluxing benzene to give ethyl 4-(1-piperidyl)butyrate (III), which is hydrolyzed with refluxing aqueous HCl to 4-(1-piperidyl)butyric acid (IV) . Finally, this acid is esterified with 5,5-dimethyl-8-(3-methyl-2-octyl)-10-hydroxy-2-(2-propynyl)-1,2,3,4-tetrahydro-5H[1]benzopyrano[3,4-d]pyridine (V) by means of dicyclohexylcarbodiimide (A) in methylene chloride.

合成路线8

The enol acylation of 5alpha-androst-2-en-17-one (I) with isopropenyl acetate (A) using H2SO4 as catalyst gives 17-acetoxyandrost-2,16-diene (II), which is epoxidized by treatment with m-chloroperbenzoic acid in ether yielding 2alpha,3alpha:16alpha,17alpha-diepoxy-17beta-acetoxy-5alpha-androstane (III). The hydrolytic rearrangement of (III) with KOH affords 2alpha,3alpha-epoxy-5alpha-androstan-17beta-ol-16-one (IV), which is condensed with refluxing aqueous piperidine (B) to give 2beta,16beta-dipiperidino-5alpha-androstan-3alpha-ol-17-one (V). The reduction of (V) with NaBH4 in methylene chloride - methanol yields 2beta,16beta-dipiperidino-5alpha-androstan-3alpha,17beta-diol (VI), which is acetylated by reaction with acetyl chloride as usual to afford the corresponding diacetate (VII). Finally, this compound is quaternized by reaction with methyl bromide in ether.

合成路线9

This compound can be obtained by several different ways: 1) By condensation of 4-ethylpropiophenone (I), formaldehyde (II) and piperidine (III) in refluxing isopropanol. 2) By reaction of 4-ethyl-alpha-methyl-beta-chloropropiophenone (IV) with (III) in refluxing ethanol. 3) By cyclization of 4-ethyl-alpha-methyl-beta-amino-propiophenone (V) with 1,5-dibromopentane (VI) in hot ethanol. 4) By a Friedel-Kraft's reaction of ethylbenzene (VII) with 3-piperidinoisobutyryl chloride (VIII) by means of AlCl3 at reflux temperature. 5) By condensation of 4-ethyl-alpha-methylenepropiophenone (IX) with (III) in ethanol.

合成路线10

The demethylation ot o-vanillin (I) with AlCl3 dissolved in pyridine gives 2,3 dihydroxybenzaldehyde (II). Subsequent alkylation by means of hexyl bromide with NaH gives 3-hexyloxy-2-hydroxybenzaldehyde (III), which is then condensed with malononitrile and piperidine, yielding 3-cyano-8-hexyloxycromen-2-one (IV), a needle-like yellow crystalline substance. Finally, compound (IV) is treated with sodium azide and AlCl3 in refluxing THF, yielding the formation of the tetrazole ring.

合成路线11

The reductocondensation of piperidine (I) with 3-hydroxybenzaldehyde (II) by means of sodium borohydride in ethanol gives 3-(1-piperidylmethyl)phenol (III), which is then condensed with N-(3-bromopropyl)phthalimide (IV) by means of NaH in DMF yielding N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]phthalimide (V). The hydrolysis of (V) with hydrazine in ethanol affords 3-[3-(1-piperidylmethyl)phenoxy]propylamine (VI), which is acylated with hydroxyacetic acid (VII) at 200 C giving N-[3-[3-(1-piperidylmethyl)phenoxy]propyl]hydroxyacetamide (VIII). Finally, this compound is acetylated with acetic anhydride at 100 C.

合成路线12

Compound can be prepared in tvvo different ways both starting from 2,4-diamino-6-chloropyrimidine (I): 1) The oxidation of (I) with m-chloroperbenzoic acid in alcohol gives 6-amino-4-chloro-1,2-dihydro-1-hydroxy-2-iminopyrimidine (II), which is then condensed with refluxing piperidine. 2) A mixture of (I), 2,4-dichlorophenol (A) and KOH was heated at 150 C to give 2,4-diamino-6-(2,4-dichlorophenoxy)pyrimidine (III), which is oxidized with m-chloroperbenzoic acid in alcohol giving 6-amino-4-(2,4-dichlorophenoxy)-1,2-dihydro-1-hydroxy-2-iminopyrimidine (IV). Finally, this product is treated with piperidine at 150 C.

合成路线13

3,4-Methylenedioxycinnamic acid (I) is transformed into the corresponding acid chloride (II) by treatment with oxalyl chloride in benzene. The acid chloride is then converted without purification into antiepilepsirine by treatment with piperidine in benzene.

合成路线14

This compound can be prepared by several different ways: 1) The reaction ot 4-(chloromethyl)pyridine (I) with NaCN in toluene - water gives 4-(cyanomethyl)pyridine (II), which is condensed with methyl acrylate (III) yielding dimethyl 4-cyano 4-(4-pyridyl)pimelate (IV). The hydrolysis and decarboxylation of (IV) atfords 4-(4-pyridyl)pimelic acid (V), which is cyclized by means of potassium tert-butoxide giving 4-(4-pyridyl)cyclohexanone (VI). The acetylation of (VI) with acetic anhydride or acetylimidazole affords 2-acetyl(4-4 pyridyl)cyclohexanone (VII), which is finally cyclized with acetylacetamide (VIII) by means of dimethylamine. 2) The cyclization of (VII) with cyanoacetamide (IX) by means of piperidine gives 4-cyano-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone (X), which is finally treated with methyl magnesium iodide in ether. 3) The condensation of 4 bromopyridine (XI) and cyclohexanedione monoethyleneketal (XII) by means of butyllithium in THF gives 4-hydroxy-4-(4-pyridyil)cyclohexanone ethyleneketal (XIII), which is dehydrated by treatment with SOCl2 and then with NaOH to afford 4-(4-pyridyl)-3-cyclohexenone ethyleneketal (XIV). Finally, this compound is hydrolyzed with HCl and reduced with H2 over Pd/C in 0.5 N HCl yielding cyclohexanone (VII), already obtained.

合成路线15

Intermediate (III) can be obtained as follows: The reaction of (I) with piperidine (B) by means of potassium tertbutoxide in refluxing tert-butanol gives 10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-one (XII), which by reaction with methyllithium in ether is converted into 5-hydroxy-5-methyl-10-(1-piperidyl)-5H-dibenzo[a,d]cycloheptene (XIII). Finally, the dehydration of (XIII) in refluxing ethanolic HCl yields (III), already obtained.

合成路线16

By condensation of D-pyroglutamic acid (I) with piperidine (II) by means of dicyclohexylcarbodiimide (DCC) in acetonitrile.

合成路线17

A new synthesis of lafutidine has been described: The condensation of 2-bromopyridine-4-carbaldehyde ethylene ketal (I) with 4-(tetrahydropyranyloxy)-2(Z)-buten-1-ol (II) by means of NaOH, K2CO3 and tetrabutylammonium bisulfate in refluxing toluene gives the corresponding substitution product (III), which by treatment with pyridinium p-toluenesulfonate (PPTS) in hot ethanol yields the 2(Z)-butenol (IV). The reaction of (IV) with SOCl2 and then with potassium phthalimide (V) affords the substituted phthalimide (VI), which by treatment with hydrazine hydrate in refluxing methanol gives the 2(Z)-butenamine (VII). The condensation of (VII) with 2-(2-furylmethylsulfinyl)acetic acid 4-nitrophenyl ester (VIII) in THF yields the expected amide (IX), which is treated with p-toluenesulfonic acid in refluxing acetone/water to eliminate the ethylene ketal protecting group yilding the aldehyde (X). Finally, this compound is reductocondensed with piperidine (XI) by means of NaBH4 in ethanol.

合成路线18

The chlorination of 2-phenyl-3-methyl-4-oxo-4H-1-benzopyran-8-carboxylic acid (I) with thionyl chloride gives the corresponding chloride (II), which is esterified with 1,1-dimethyl-2-(1-piperidinyl)ethanol (IV), obtained by alkylation of excess piperidine (III) with 1-chloro-2-methyl-2-propanol. Rec 15/2053 is obtained as the hydrochloride.

合成路线19

6-Quinoxalinecarboxylic acid (III) was prepared by condensation of 3,4-diaminobenzoic acid (I) with glyoxal (II). The title amide was then prepared by coupling of acid (III) with piperidine (VI) via formation of the mixed anhydride (IV) with pivaloyl chloride and Et3N or, alternatively, via activation of (III) as the imidazolide (V) by treatment with carbonyldiimidazole

合成路线20

The alkylation of 3-hydroxybenzaldehyde (I) with N-(3-bromopropyl)phthalimide (II) in the presence of NaOMe leads to 3-(phthalimidopropoxy)benzaldehyde (III). The reductive alkylation of piperidine with aldehyde (III) in the presence of formic acid gives N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]phthalimide (IV), which is converted to N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]amine (V) by treatment with 6N HCl. Condensation of (V) with glycolic acid in boiling xylene provides N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]-2-hydroxyacetamide (VI), which is complexed with bismuth (+3) citrate (VII) in boiling water.

合成路线21

The reaction of 2,4,6,8-tetrachloropyrimido[5,4-d]pyrimidine (I) with piperidine (A) at room temperature gives 2,6-dichloro-4,8-di(N-piperidino)pyrimido[5,4-d]pyrimidine (II), which is treated with diethanolamine (B) at 200 C to yield 2,6-bis(diethanolamino)-4,8-di(N-piperidino)pyrimido[5,4-d])pyrimidine (III) (1). The reduction of (III) with Zn in hot formic or acetic acid or in hot aqueous HCl gives 2,6-bis(diethanolamino)-8-(N-piperidino)-1,2,3,4-tetrahydropyrimido[5,4-d]pyrimidine (IV), which is then dehydrogenated with I2 - KI in water.

合成路线22

Synthesis of intermediate (XXX) of Scheme 25142902e: Alkylation of piperidine (XXVII) with ethyl 4-bromocrotonate (XXVIII) afforded tertiary amine (XXIX). Acid hydrolysis of the ethyl ester of (XXIX) then provided carboxylic acid (XXX).

合成路线23

Condensation of benzaldehyde (I) with hippuric acid (II) in the presence of NaOAc in boiling Ac2O furnished oxazolone (III). The title compound was then obtained by ring opening of (III) with piperidine (IV) in chloroform at 0 C, followed by chlorination with Cl2 gas.

合成路线24

Compound can be prepared in two ditferent ways both starting from 9,10-dibromo-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (II): 1) The reaction of compound (II) with refluxing methanol affords 9-bromo-10-methoxy-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (III), which is dehydrobrominated with KOH in refluxing methanol giving 10-methoxy-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (IV). The condensation of compound (IV) with the magnesium derivative of 4-chloro-1-methylpiperidine (A) in THF yields 10-methoxy-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-ol (V), which is finally dehydrated and demethylated with 3N HCl at 95-100 C. 2) The dehydrobromination of compound (II) with KOH in refluxing methanol affords 10-bromo-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (VI), which is then condensed with the magnesium derivative of 4-chloro-1-methylpiperidine in THF giving 10-bromo-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-ol (VII). This compound is dehydrated with 14% ethanolic HBr at 100 C giving 10-bromo-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (VIII) (2,3), which is finally hydrolyzed with 50% H2SO4 at 100 C. Compound (VIII) can be also be treated with piperidine and potassium terbutylate in dioxane at 130 C to give 10-piperidino-4-(1-methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophene (IX), which is finally hydrolyzed with refluxing 2N HCl. The starting material (II) is prepared by bromination of 9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-4-one (I) with N-bromosuccinimide (B) and benzoyl peroxide in carbon tetrachloride.

合成路线25

N-(2,3-Epoxypropyl)piperidine (III), prepared from piperidine (I) and epichlorhydrin (II), was condensed with nicotinic acid amidoxime (IV) in the presence of basic catalysts, such as NaOH, t-BuOK, Al2O3 or SnO2, in hot DMF to provide the title compound, which was finally converted to the dihydrochloride salt.

合成路线26

The intermediate amide (IV) can be obtained by two related methods. The homochiral methylenesuccinate (I) was coupled with piperidine (II) in the presence of EDC and HOBt to afford amide (III). Subsequent stereoselective conjugate addition of methylamine produced the (R,R)-amine (IV). In a related procedure, conjugate addition of methylamine to unsaturated ester (V) gave adduct (VI). Acid cleavage of the tert-butyl ester of (VI) generated carboxylic acid (VII), which was then coupled with piperidine (II) to provide (IV). Sulfonamide (VIII) was prepared by condensation of amine (IV) with methanesulfonyl chloride. Hydrogenolysis of the benzyl ester of (VIII) yielded acid (IX), which was finally coupled with hydroxylamine producing the title hydroxamic acid.

合成路线27

The title amide was prepared by coupling of 2,3-dihydrobenzodioxin-6-carboxylic acid (I) with piperidine (II). Carbonyldiimidazole or some chlorinating reagents, such as thionyl chloride or oxalyl chloride, were used as the carboxylate-activating reagents for the coupling reaction. Alternatively, acid (I) was previously converted to an activated mixed anhydride with either pivaloyl chloride or trifluoroacetic anhydride in the presence of triethylamine.

合成路线28

Isoniazid (I) was treated with carbon disulfide and KOH to give potassium 4-pyridyl dithiocarbazinate (II). Cyclization of (II) in the presence of hydrazine produced the amino triazole (III). This was condensed with 5-bromoisatin (IV), yielding the imino adduct (V). Finally, Mannich reaction of (V) with piperidine (VI) and formaldehyde furnished the title compound.

合成路线29

3-Formylchromen-4-one (II) was prepared by Vilsmeier formylation of 2'-hydroxyacetophenone (I) with POCl3 and DMF. Cyclization of (II) with guanidine carbonate (III) in refluxing EtOH gave rise to the benzopyranopyrimidine (IV). This was finally condensed with piperidine (V) in the presence of TiCl4 to furnish the title compound.

合成路线30

The reaction of 2-chloro-3-nitropyridine (I) with piperidine (II) in dichloromethane gives 3-nitro-2-(1-piperidinyl)pyridine (III), which is cyclized by means of anhydrous ZnCl2 in refluxing acetic acid yielding the acetoxy dipyridoimidazole (IV). The deacetylation of (IV) with NaOH in methanol affords the alcohol (V), which is oxidized with oxalyl chloride and DMSO in dichloromethane to give the ketone (VI). The bromination of (VI) with Br2 in hot aqueous HBr yields the alpha-bromoketone (VII), which is finally cyclized with N,N-dimethylthiourea (VIII) in refluxing ethanol.

合成路线31

Condensation of 16-alpha-bromo-3-beta-hydroxy-5-androsten-17-one (I) with piperidine (II) produced the 16-piperidino derivative (III). Oppenauer oxidation of alcohol (III) with concomitant double-bond migration afforded the unsaturated ketone (IV), which was subsequently condensed with pyrrolidine (V) to yield the dienamine (VI). Reduction of the enamine and ketone functions of (VI) with NaBH4 gave the pyrrolidino alcohol (VII). This was then esterified with acetic anhydride in hot pyridine, yielding acetate (VIII). Finally, quaternization of (VIII) with methyl iodide provided the title bis-ammonium salt.

合成路线32

The chlorination of 3-[5-(m-bromophenyl)-2H-tetrazol-2-yl]propionic acid (I) with thionyl chloride in refluxing chloroform gives the corresponding acyl chloride (II), which is then treated with dry piperidine (III) in THF

合成路线33

The esterification of vanillic acid (I) with benzyl bromide and K2CO3 in DMF gives the protected benzyl ester (II), which is nitrated with conc. HNO3 in acetic acid to yield 4-benzyloxy-5-methoxy-2-nitrobenzoic acid benzyl ester (III). The reduction of (III) with SnCl2 in ethyl acetate affords the corresponding 2-amino compound (IV), which is cyclized with ammonium formate in DMF at 150 C to provide the quinazolinone (V). The reaction of (V) with refluxing SOCl2 gives the chloro derivative (VI), which is condensed with 1-(tert-butoxycarbonyl)piperazine (VII) by means of DIEA in hot THF to give the 4-piperazinyl quinazoline (VIII). The reductive cleavage of the benzyl protecting group of (VIII) by means of H2 over Pd/C in ethanol yields the hydroxy compound (IX), which is condensed with 3-(tosyloxy)propyl chloride (X) by means of Cs2CO3 in DMF to afford the corresponding ether (XI). The reaction of the tosyloxy group of (XI) with piperidine (XII) in DMF provides the piperidinyl derivative (XIII), which is Boc deprotected by treatment with HCl in dioxane to give the piperazinyl precursor (XIV). Finally, this compound is condensed with 4-isopropoxyphenyl isocyanate (XV) in DMF to yield the target piperazine carboxamide.

合成路线34

The condensation of 4-hydroxy-3-methoxybenzoic acid ethyl ester (I) with 3-chloropropyl bromide (II) by means of K2CO3 in refluxing DMF gives the 4(3-chloropropoxy)-3-methoxybenzoic acid ethyl ester (III), which is nitrated by means of HNO3 and AcOH to yield the 2-nitro derivative (IV). The condensation of (IV) with piperidine (V) by means of K2CO3 in hot toluene affords 5-methoxy-2-nitro-4-[3-(1-piperidinyl)propoxy]benzoic acid ethyl ester (VI), which is reduced by means of Pd/C and HCO2K in ethanol/water to provide the 2-amino derivative (VII). The cyclization of (VII) with formamide and ammonium formate at 135 C gives the quinazoline (VIII), which is treated with SOCl2 in refluxing toluene to yield the chloro derivative (IX). Finally this compound is condensed with the piperazinecarboxamide (X) by means of K2CO3 in hot DMF/toluene to afford the target CT-53518.

合成路线35

Acetylation of the diarylamine (I) with Ac2O yields acetamide (II), which is reduced at the nitro group by means of H2 over Raney Ni in THF to give 6-aminoquinazoline derivative (III). Condensation of amine (III) with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA affords the butenamide derivative (V), which is then deacetylated with NaOH, yielding anhydrous dacomitinib (VI). Finally, crude dacomitinib (VI) is recrystallized in dichloroethane/water .
Anhydrous dacomitinib (VI) can also be obtained as follows: Reduction of the 6-nitroquinazoline derivative (I) with H2 over Raney Ni in THF yields the 6-aminoquinazoline derivative (VII), which is then condensed with 4-bromo-2-butenoyl chloride (VIII) in the presence of Et3N in THF to give the 4-bromo-2-butenamide derivative (IX). Finally, 4-bromoamide (IX) is condensed with piperidine (X) using Et3N in DMA .
4-Bromo-2-butenoyl chloride (VIII) is obtained by hydrolysis of methyl 4-bromocrotonate (XI) with Ba(OH)2 in EtOH/H2O to produce acid (XII), which is finally treated with (COCl)2 in the presence of DMF in CH2Cl2 .
Anhydrous dacomitinib (VI) is also obtained by N-deprotection of its 3,4-dimethoxybenzyl derivative (XIII) with TFA in THF .

合成路线36

Compound (XIII) can be obtained by reductocondensation of 3-chloro-4-fluoroaniline (XIX) with 3,4-dimethoxybenzaldehyde (XXI) using NaCNBH3 or NaBH(OAc)3 in AcOH/i-PrOH to yield the benzylaniline derivative (XXII), which by condensation with 4-chloro-7-fluoro-6-nitroquinazoline (XVIII) in i-PrOH gives the tertiary amine (XXIII) . Substitution of fluoroquinazoline (XXIII) with NaOMe in refluxing MeOH affords the 7-methoxyquinazoline derivative (XXIV), which is reduced to the quinazoline-4,6-diamine (XXV) by means of H2 over Raney Ni in THF. Finally, compound (XXV) is coupled with 4-(piperidin-1-yl)-2-butenoyl chloride (IV) in DMA .
4-(Piperidin-1-yl)-2-butenoyl chloride (IV) can be prepared by condensation of methyl 4-bromocrotonate (XI) with piperidine (X) to yield methyl 4-(piperidin-1-yl)-2-butenoate (XXVI), which is then hydrolyzed with HCl to give 4-(piperidin-1-yl)-2-butenoic acid (XXVII). Finally, acid (XXVII) is reacted with (COCl)2 in the presence of DMF in CH2Cl2 .

合成路线37