合成路线1

The reaction of ethanolimine (I) with m-methoxyphenylacetone (II) gives the corresponding Schiff base (III), which is reduced with H2 over Pd/C to the corresponding secondary amine (IV). Methylation of (IV) with HCHO-HCOOH yields 1-(m-methoxyphenyl)-2-(N-(2-hydroxyethyl)-N-methylaminoipropane (V), which is treated with SOCl2 to afford the 2-chloroethyl derivative (VI). Finally, this compound is condensed with benzhydrol (VII) by means of NaNH2 in refluxing benzene, and treated with HCl.

合成路线2

The synthesis of GYKI-13504 is as follows: Trifluoroacetophenone (I) is reacted with triphenylbenzyl phosphonium chloride (II) in the presence of sodium methylate and this reaction yields stilbene (III). Stilbene (III) is then hydrogenized in the presence of charcoal palladium catalyzer and the yielded propane derivative (IV) is brominated with 1,2-dibromoethane. The brominated compound (V) is reacted with anizole (A) according to the Friedel Crafts' reaction. The yield (VI) is treated with pyridine hydrochloride and the phenol derivative (VII) is reacted with 2-chloroethanol tosylate (VIII) in the presence of potassium hydroxide. The chloroethoxy (IX) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the (E)-isomer (X) is obtained with fractionated crystallization. This latter product is reacted with 2-aminoethanol (B) to obtain the end product GYKI-13504.

合成路线3

Elimoclavine (I) obtained by fermentation is first O-mesylated and then the mesyl group in the product (II) displaced by 2-aminoethanol to give the hydroxyethylamino derivative (III). Repeated acylation of (III) with mesyl chloride affords the N,O-dimesylate (IV), which exchanges the O-mesyl group for an azido group on treatment with sodium azide to give the base (VI). Salt formation with maleic acid gives RGH-7825 (1,2).

合成路线4

The condensation of dimethylacetone-1,3-dicarboxylate (X) with ethanolamine (XI) yields methyl 3-(methoxycarbonylmethyl)-3-(2-hydroxyethylamino)acrylate (XII), which is cyclized with bromoacetaldehyde diethylacetal (XIII) affording methyl 1-(2-hydroxyethyl)-3-methoxycarbonylpyrrol-2-acetate (XIV). Acylation of (XIV) with methanesulfonyl chloride (XV) and triethylamine in CH2Cl2 yields the corresponding mesylate (XVI), which by treatment with methyl iodide in refluxing acetonitrile is converted into methyl 1-(2-iodoethyl)-3-methoxycarbonylpyrrole-2-acetate (XVII). The cyclization of (XVII) with NaH in DMF yields dimethyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1,7-dicarboxylate (XVIII), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding diacid (XIX). Partial esterification of (XIX) with isopropanol and HCl gives isopropyl 1,2-dihydro-3H-7-carboxypyrrolo[1,2-a]pyrrole-1-carboxylate (XX), which is decarboxylated by heating at 270 C affording isopropyl 1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXI). Benzoylation of (XXI) with N,N-dimethylbenzamide (XXII) and POCl3 in refluxing CH2Cl2 yields isopropyl 5-benzoyl-1,2-dihydro-3H-pyrrolo[1,2-a]pyrrole-1-carboxylate (XXIII), which is finally hydrolyzed with K2CO3 or NaOH in methanol - water.

合成路线5

The condensation of 2-nitroimidazole (I) with methyl chloroacetate (II) by means of sodium methoxide in hot DMF gives methyl (2-nitro-1-imidazolyl)acetate (III), which is then treated with ethanolamine (IV) in methanol.

合成路线6

The reaction of maleopimaric acid (I) with aqueous ammonia and heating at 170 C gives maleopimarimide (II), which by reaction with oxalyl chloride in benzene is converted into the corresponding acyl chloride (III). The reaction of (III) with morpholine (A) in benzene yields maleopimarimidyl morpholide (IV), which is finally condensed with ethanolamine (B) in refluxing methanol.

合成路线7

The reaction of maleopimaric acid (I) with SOCl2 in benzene produces the corresponding acyl chloride (V), which is then condensed with morpholine (A) by means of Et3N in benzene yielding maleopimaryl morpholide (VI). Finally, (VI) is condensed with ethanolamine (B) in refluxing ethanol.

合成路线8

HECNU can be prepared as follows (2): The reaction of 2-chloroethylisocyanate (I) with activated sodium azide yields 2-chloroethylcarbamoylazide (II). The preparation of N-(2-chloroethyl)-N-nitrosocarbamoylazide (III) was performed by adding 2-chloroethylcarbamoyiazide (III) to a suspension of anhydrous sodium acetate and nitrogen tetroxide in carbon tetrachloride. Reaction of N-(2-chloroethyl)-N-nitrosocarbamoylazide (III) with ethanolamine (IV) in isopropanol yields elmustine. The described synthetic approach offers a useful means to get the nitroso group attached to the required position.

合成路线9

A new synthesis of miglitol has been reported: Reaction of the bromoglycoside (I) with ethanolamine (II) by means of Zn and NaBH3CN in refluxing propanol/water gives the adduct (III), which is benzylated with benzyl chloride and NaH in DMF yielding compound (IV). The cyclization of (IV) by means of mercury trifluoroacetate in THF, followed by a treatment with KHCO3 and KBr affords a mixture of the diastereomeric organomercuric piperidines (V) and (VI) which are separated by chromatography. The desired diastereomer (VI) was treated with O2 and NaBH4 in DMF to give the protected piperidinemethanol (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in ethanol. The undesired diastereomer (V) can be recovered by Swern oxidation giving aldehyde (VIII), isomerization of (VIII) with DBU to provide aldehyde (IX) and reduction of (IX) to the already reported piperidinemethanol (VII).

合成路线10

Ethyleneimine is reacted with tetrafluoro-1.4-benzoquinone (I) in the cold to form 2,5-diaziridinyl-3,6-difluoro-1-4-benzoquinone (II). The reaction with ethanolamine at room temperature results in BZQ, which is recrystallized from ethanol.

合成路线11

The protection of ethanolamine (I) with trityl chloride (II) in isopropanol gives N-tritylethanolamine (III), which is condensed with ethyl 4-chloroacetoacetate (IV) by means of NaH in THF to yield ethyl 4-[2-(tritylamino)ethoxy]acetoacetate (V). The cyclization of (V) with 2-chlorobenzaldehyde (VI) and methyl 3-aminocrotonate (VII) in refluxing methanol affords the protected dihydropyridine (VIII), which, without isolation, is finally detritylated by a treatment with aqueous benzenesulfonic acid.

合成路线12

By reaction of 4-(p-fluorobenzoyl)piperidine (I) with 3-(2-chloroethyl)-2,4-(1H,3H)-quinazolinedione (II) by means of Na2CO3 in refluxing 4-methyl-2-pentanone. The starting compounds are prepared as follows: 1) The Grignard reaction of N-benzyl-4-cyanopiperidine (III) with p-fluorophenylmagnesium bromide (IV) ethyl ether gives N-benzyl-4-p-fluorobenzoyl)piperidine (V), which by reaction with Na2CO3 and ethyl chloroformate (A) is converted into N-ethoxycarbonyl-4-(p-fluorobenzoyl)piperidine (VI). Finally, this compound is hydrolyzed with 48% HBr to give (I). 2) The reaction of ethyl anthranilate (VII) with ethyl chloroformate (A) in refluxing xylene gives ethyl 2-(ethoxycarbonylamino)benzoate (VIII), which is cyclized with 2-aminoethanol (B) at 170 C to afford 3-(2-hydroxyethyl)-2,4-(1H,3H)-quinazolinedione (IX). Finally, this compound is treated with SOCl2 in refluxing chloroform to afford (II).

合成路线13

The reaction of 3-acetyl-6-methyl-3,4-dihydro-2H-pyran-2,4-dione (I) with ammonia gives 2,6-dimethylpyridin-4-ol (II), which is nitrated with HNO3/H2SO4 and treated with SOCl2 to yield 4-chloro-2,6-dimethyl-3-nitropyridine (III). The condensation of (III) with ethanolamine (IV) affords N-(2,6-dimethyl-3-nitropyridin-4-yl)ethanolamine (V), which is finally condensed with 1-(diphenylmethyl)piperazine (VI) by means of SOCl2 and treated with HCl to furnish the target trihydrochloride.

合成路线14

The synthesis of the optical enantiomers of mosapride has been described: The reductocondensation of 4-fluorobenzaldehyde (I) with ethanolamine (II) by means of NaBH4 and NaHCO3 in refluxing methanol gives 2-(4-fluorobenzylamino)ethanol (III), which is condensed with epichlorohydrin (IV) to yield the diol (V). Compound (V), without isolation, is cyclized with conc. H2SO4 to afford 2-(chloromethyl)-4-(4-fluorobenzyl)morpholine (VI), which is treated with refluxing water-formamide to afford the corresponding methanol derivative (VII). Tosylation of (VII) with tosyl chloride and triethylamine/4-(dimethylamino)pyridine in dichloromethane gives the tosylate (VIII) as a racemic mixture. The optical resolution of (VIII) with N-(p-toluenesulfonyl)-L-glutamic acid in methanol affords the (S)-tosylate [(S)-IX] and the (R)-tosylate [(R)-IX]. The reaction of both [(S)-IX] and [(R)-IX] with sodium azide followed by reduction with bis(2-methoxyethoxy)aluminum hydride (vitride) gives the chiral amines [(S)-X] and [(R)-X], which are finally condensed with 4-amino-5-chloro-2-ethoxybenzoic acid (XI) by means of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (WSC) in dichloromethane, yielding the (S)- and (R)-enantiomers of mosapride.

合成路线15

The esteritication of nicotinic acid (I) with methanol and HCl or H2SO4 yields the corresponding methyl ester (II), which is treated with ethanolamine (A) to afford N-(beta-hydroxyethyl)nicotinamide (III). Finally, this compound is transformed into the nitrate ester by the usual methods.

合成路线16

In scheme 14476001a hexadecanol is reacted with phosphoroxy chloride in the presence of triethylamine in tetrahydrofuran with subsequent condensation with ethanolamine in dioxane/triethylamine. Hydrolysis with aqueous hydrochloric acid and methylation with dimethyl sulfate in the presence of potassium carbonate yields hexadecyl phosphocholine.

合成路线17

By condensation of N-(2-hydroxyethyl)-N-[3-(4-nitrophenyl)propyl]amine (I) with 1,3-dimethyl-6-[2-(p-toluenesulfonyloxy)ethylamino]pyrimidine-2,4(1H,3H)-dione (II) by means of NaOH in hot ethanol or methanol. The starting materials are obtained as follows: 1) The esterification of 3-(4-nitrophenyl)propanol (III) with p-toluenesulfonyl chloride (IV) by means of pyridine in chloroform gives the corresponding p-toluenesulfonate (V), which is then condensed with ethanolamine (VI) by heating at 100 C to afford amine (I). 2) The condensation of ethanolamine (VI) with 6-chloro-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (VII) by heating at 90 C, or by means of triethylamine in refluxing isopropanol, gives 6-(2-hydroxyethylamino)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (VIII), which is then esterified with p-toluenesulfonyl chloride (IV) as before yielding pyrimidine (II).

合成路线18

The starting products are prepared as follows: The reaction of pyridine-3-carboxylic acid methyl ester (I) with ethanolamine (II) gives the 2-hydroxyethylamide (III), which by reaction with diketene in THF yields the corresponding acetoacetic ester (V). The reaction of (V) with ammonia in THF affords the expected 3-aminocrotonate ester (VI).

合成路线19

Protection of the amino group of 2-aminoethanol (I) with di-tert-butyldicarbonate, followed by reaction with phenylchlorocarbonate, gives 2-(tert-butoxycarbonylamino)ethylphenylcarbonate (II), which on reaction in refluxing 1,2,3,4-tetrahydroisoquinoline (III) yields 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-(tert-butoxycarbonylamino)ethyl ester (IV). Compound (IV) is deprotected with HCl in methanol to give 1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid 2-aminoethyl ester (V), which is coupled with 3-(N-tert-butoxycarbonyl-N-phenylamino)propanoic acid (VI) in the presence of dicyclohexylcarbodiimide to afford N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(N'-tert-butoxycarbonyl-N'-phenylamino)propanamide (VII). Deprotection of (VII) with HCl in methanol gives N-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethyl]-3-(phenylamino)propanamide (VIII), which is acylated with 5-bromonicotinoyl chloride hydrochloride (IX) in the presence of triethylamine to yield 3-bromo-5-[N-phenyl-N-[2-[2-(1,2,3,4-tetrahydroisoquinolin-2-ylcarbonyloxy)ethylcarbamoyl]ethyl]carbamoyl]pyridine (X). Compound (X) is finally reacted with iodopropane and iodide anion exchanged by nitrate with IRA-410 (NO3-).

合成路线20

Displacement of the benzylic bromide (XIII) with concomitant hydrolysis of the phenolic acetate with ethanolamine (XIV) gave amine (XV). A further aromatic bromide of (XV) was displaced with hot 1,3-propanediamine (XVI), yielding adduct (XVII). Hydrogenolysis of the remaining bromide of (XVII) using Pd/C furnished (XVIII). Finally, methyl ether cleavage in (XVIII) with hot HCl provided the title compound

合成路线21

The synthesis of BBR-3438 has been described: The cyclization of 6-chloro-9-fluorobenz[g]isoquinoline-5,10-quinone (I) with 2-hydroxyethylhydrazine (II) in hot pyridine gives 2-(2-hydroxyethyl)-5-chloroindazolo[4,3-gh]isoquinolin-6(2H)-one (III), which is condensed with N-(2-aminoethyl)-N-methylcarbamic acid tert-butyl ester (IV) in hot pyridine yielding the corresponding 5-[2-[N-(tert-butoxycarbonyl)-N-methylamino]ethylamino] derivative (V). The mesylation of the OH group of (V) with mesyl chloride and triethylamine in dichloromethane affords the mesylate (VI), which is condensed with hot ethanolamine (VII) to give the protected compound (VIII). Finally, this compound is deprotected with HCl yielding BBR-3438.

合成路线22

The synthesis of BBR-3409 has been described: The cyclization of 6-chloro-9-fluorobenz[g]isoquinoline-5,10-quinone (I) with 2-hydroxyethylhydrazine (II) in hot pyridine gives 2-(2-hydroxyethyl)-5-chloroindazolo[4,3-gh]isoquinolin-6(2H)-one (III), which is condensed with N-(2-aminoethyl)-N,N-dimethylamine (IV) in hot pyridine yielding the corresponding compound (V). The mesylation of the OH group of (V) with mesyl chloride and triethylamine in dichloromethane affords the mesylate (VI), which is condensed with hot ethanolamine (VII) to give BBR-3409.

合成路线23

The reductocondensation of ethanolamine (I) with 3-methylbenzaldehyde (II) by means of NaBH4 gives N-(3-methylbenzyl)ethanolamine (III), which is treated with SOCl2 to yield the 2-chloroethyl derivative (IV). The reaction of (IV) with methylamine (V) affords N-methyl-N'-(3-methylbenzyl)ethane-1,2-diamine (VI), which is condensed with the pyrazole-carboxamide derivative (VII) to provide the unstable compound (VIII)?? (IX). The reduction of (IX) with NaBH4 gives the racemic amide (X), which is submitted to optical resolution by preferential crystallization to yield the (R)-isomer (XI) (1,2). The hydrogenation of (XI) with H2 over Pd/C in ethanol affords the debenzylated compound (XII), which is alkylated by reductocondensation with acetaldehyde (XIII) and NaBH4 in methanol to provide the chiral N-(1-ethyl-4'-methylperhydro-1,4-diazepin-6-(R)-yl)-1H-pyrazole-3-carboxamide (XIV). Finally, this compound is treated with refluxing aqueous HCl to give the corresponding 6(R)-amino derivative (XV).

合成路线24

In an alternative procedure, 3-chloroaniline (I) was acylated with chloroacetyl chloride (V) to produce chloroacetamide (IX). Displacement of the chloride group of (IX) with ethanolamine (X) gave rise to the amide alcohol (XI), which was then cyclized to the piperazinone (VIII) under Mitsunobu conditions.

合成路线25

The acetylation of 5-bromopyridine-2-amine (I) with acetic anhydride in AcOH gives the expected amide (II), which is alkylated with ethylene by means of palladium acetate, tri p-tolylphosphine and triethylamine in hot acetonitrile to yield N-(5-vinylpyridin-2-yl)acetamide (III). The regioselective dihydroxylation of the vinyl group of (III) with AD-Mix-B in tert-butanol affords N-[5-(1(R),2-dihydroxyethyl)pyridin-2-yl]acetamide (IV), which is monotosylated with Ts-Cl in cool pyridine to give the tosylate (V). The reaction of (V) with potassium tert.-butoxide in THF yields the epoxide (VI), which is condensed with 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) in hot toluene/DMSO to provide the expected addition product (VIII). Finally, this compound is treated with 6N HCl on a steam bath. The intermediate 2-[4-(2-aminoethoxy)phenyl]-N-methylacetamide (VII) has been obtained as follows: The reaction of benzyl chloroformate (IX) with ethanolamine (X) by means of NaHCO3 in water gives the carbamate (XI), which is condensed with 2-(4-hydroxyphenyl)-N-methylacetamide (XII) (obtained by reaction of the corresponding methyl ester (XIII) with methylamine), by means of PPh3 and diisopropyl azodicarboxylate (DIAD) in THF yielding the intermediate (XIV). Finally, this compound is submitted to elimination of the carbamate protecting group by hydrogenation with H2 over Pd/C in methanol to provide the target intermediate (VII).

合成路线26

The cyclization of 5,6-diamino-1-propylpyrimidine-2,4(1H,3H)-dione (I) with 4-bromobenzoic acid (II) by means of EDC and HOBT in DMF gives 8-(4-bromophenyl)-3-propylxanthine (III), which is treated with P2S5 in refluxing pyridine to yield the 6-thioxanthine (IV). The reaction of (IV) with Me-I and NaOH in ethanol affords the methylsulfanylpurin-2-one (V), which is treated with ethanolamine (VI) in DMSO at 150 C to provide the 2-hydroxyethylamino derivative (VII). Finally, this compound is cyclized by means of SOCl2 in refluxing chloroform to provide the target imidazopurine.

合成路线27

Acid-catalyzed condensation of ethanolamine (I) with urea (II) produced oxazolidinone (III). Subsequent reaction of (III) with triethyloxonium fluoborate yielded ethoxyoxazoline (IV). This was finally condensed with 2-(3,4-dimethoxyphenyl)- ethylamine to afford the title compound, which was isolated as the hydrochloride salt.

合成路线28

Asymmetric dihydroxylation of intermeddiate silylated olefin (XII) employing potassium ferricyanide in the presence of osmium tetraoxide and the chiral auxiliary hydroquinidine 1,4-phthalazindiyl diether produced diol (XVIII). After conversion of the primary hydroxyl group of (XVIII) to the corresponding tosylate (XIX), displacement with ethanolamine yielded hydroxy amine (XX). Protection of (XX) as the Boc derivative (XXI), followed by cyclization under Mitsunobu conditions gave rise to morpholine (XXII). The Boc and silyl groups of (XXII) were then deprotected with HCl in dioxan, and the deprotected morpholine (XXIII) was acylated with 3,4,5-trimethoxybenzoyl chloride (XXIV) to produce amide (XXV). The alcohol group of (XXV) was then converted to mesylate (XXVI) using methanesulfonyl chloride and triethylamine. Optionally, the alchohol group was subjected to Swern oxidation, affording aldehyde (XXVII).

合成路线29

The reaction of 3-chloroaniline (I) with ethanolamine (II) by means of 47% HBr by heating at 170 C gives N-(3-chlorophenyl)ethylenediamine (III), which is condensed with ethyl 2-bromopropionate (IV) by means of triethylamine in refluxing toluene yielding the alanine derivative (V). The cyclization of (V) with refluxing 2N HCl affords the piperazinone (VI), which is reduced with LiAlH4 in ethyl ether providing 1-(3-chlorophenyl)-3-methylpiperazine (VII). The alkylation of (VII) with 1-bromo-3-chloropropane (VIII) by means of NaOH in acetone/water gives 4-(3-chlorophenyl)-1-(3-chloropropyl)-2-methylpiperazine (IX), which is condensed with the sodium salt of 1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (X) in refluxing xylene/isobutanol yielding the target compound as a racemic mixture (XI). Finally, this compound is submitted to optical resolution with L-(+)-tartaric acid (XII).

合成路线30

Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) in the presence of NaOEt to provide diethyl 2-(ethoxyethyl)malonate (III). Treatment of 2-chloronitrobenzene (IV) with 2,2,2-trifluoroethanol (V) afforded the trifluoroethyl ether (VI). Subsequent reduction of the nitro group of (VI) by means of iron in acetic acid gave aniline (VII), which was condensed with malonate (III) in refluxing diphenyl ether, yielding furoquinoline (VIII). Further reaction of (VIII) with o-toluidine (IX) in boiling diethylene glycol produced the tetrahydropyrroloquinoline (X). Aromatization of the pyrrole ring of (X) to give (XI) was achieved by dehydrogenation in diphenyl ether in the presence of Pd/C. Chloroquinoline (XII) was then obtained by chlorination of (XI) with POCl3. Finally, displacement of the chlorine atom of (XII) by means of ethanolamine at 180 C furnished the title compound.

合成路线31

Ethanolamine (I) was protected as the N-benzyloxycarbonyl derivative (II) and subsequently converted to tosylate (III). Alkylation of N,N,N'-trimethylethylenediamine (IV) with tosylate (III) produced triamine (V). The benzyloxycarbonyl protecting group was then removed by transfer hydrogenolysis with ammonium formate and Pd/C to yield triamine (VI).

合成路线32

Reaction of 2-chloronitrobenzene (I) with the sodium alkoxide of 2,2,2-trifluoroethanol (II) in cold THF afforded trifluoroethyl ether (III). The nitro group of (III) was then reduced by means of iron and AcOH to produce 2-(trifluoroethoxy)aniline (IV). Condensation of (IV) with diethyl (2-ethoxyethyl)malonate (V) in boiling diphenyl ether led to the furoquinolinone system (VI), and subsequent reaction of (VI) with 2-methyl-4-methoxyaniline (VII) in refluxing diethylene glycol generated the pyrroloquinolinone (VIII). Chlorination of (VIII) with POCl3 gave chloropyrroloquinoline (IX). Finally, displacement of the chlorine of (IX) by ethanolamine at 180 C yielded the title compound.

合成路线33

In a further procedure, epoxide (XXXII) was condensed with ethanolamine (XXXIX) to afford amino diol (XL). Coupling of (XL) with carbamate (IX) produced the N-(hydroxyethyl)urea (XLI). Chlorination of the primary hydroxyl group of (XLI) with POCl3, followed by cyclization in the presence of Et3N, gave rise to the title imidazolidinone. Alternatively, amino diol (XL) was coupled with 4-nitrophenyl isocyanate (XXXV) to give urea (XLII). Chlorination of (XLII), followed by cyclization in the presence of Et3N, produced imidazolidinone (XLIII). The tetrazolyl group of the target compound was then introduced by catalytic hydrogenation of the nitro group of (XLIII), followed by treatment with NaN3 and triethyl orthoformate.

合成路线34

Treatment of benzoylacetate derivative (I) with triethyl orthoformate and Ac2O yields derivative (II), which is then subjected to cyclization with N-tert-buxoxycarbonyl-2,4-difluoro-m-phenylenediamine (III) in EtOH, followed by treatment with K2CO3 in DMF, to afford dihydroquinoline ethyl carboxylate derivative (IV). Simultaneous hydrolysis and Boc removal of (IV) with HCl gives carboxylic acid (V), which is then treated with an aqueous solution of methylamine in the presence of pyridine to provide derivative (VI). Finally, the ethanolamine salt of the compound is formed by treatment of (VI) with ethanolamine and pyridine.

合成路线35

Condensation of 4-fluorobenzenesulfonyl chloride (I) with anthranilic acid derivative (II) by means of pyridine yields sulfonamide derivative (III), which is then N-alkylated by reaction with benzyl bromide (IV) by means of NaH in DMF to furnish compound (V). Saponification of the methyl ester group of (V) by treatment with NaOH in refluxing MeOH affords carboxylic acid (VI) (1), which is then converted into compound (X) by condensation with hydroxy derivative (IX) by means of NaH in DMF. (In turn, compound (IX) can be obtained by coupling of 2-benzofurancarboxylic acid (VII) with ethanolamine (VIII) by means of HOBt/EDC and NMM in DMF. Finally, the target product is obtained by derivatization of the carboxylic acid moiety of (X) with hydroxylamine hydrochloride by means of HOBt/EDC and Et3N in DMF.

合成路线36

3-Chloroaniline (I) was acylated with chloroacetyl chloride (II) in isopropyl acetate. The resulting chloroacetanilide (III) was condensed with ethanolamine (IV) to yield the (hydroxyethyl)glycinamide (V). Cyclization of (V) to produce the piperazinone (VI) was then effected by treatment with di-tert-butyl azodicarboxylate and tributylphosphine.

合成路线37

By reaction of 2-aminobenzophenones (I) with bromoacetyl halide (II) or tosyloxyacetyl halide (VI) to give, respectively, 2-(bromoacetylamino)benzophenones (III) or 2-(tosyloxyacetylamino)benzophenones (VII), which are treated with ethanolamine (IV) to give the compounds (V), which with acetic acid in ethanol give the desired compounds. These compounds can also be obtained from (III) and (VI) without isolation of (V)

合成路线38

Formation in anhydrous medium of the acyl halide (II) of dl-2-(4'-isobutylphenyl)propionic acid (I) with phosphorous or sulfur halides or oxyhalides, and the subsequent reaction in anhydrous medium with beta-hydroxyethylamine (III) to give N-(beta-hydroxyethyl)-dl-2-(4’-isobutylphenyl)propionamide.

合成路线39

Diethyl malonate (I) was alkylated with 2-bromoethyl ethyl ether (II) to provide diethyl (2-ethoxyethyl)malonate (III). Subsequent condensation of malonate (III) with 2-(trifluoromethoxy)aniline (IV) in boiling diphenyl ether generated the furoquinoline derivative (V). This was then condensed with 2-methyl-4-methoxyaniline (VI) in refluxing diethylene glycol to furnish adduct (VII). Chlorination of pyrroloquinolone (VII) with phosphoryl chloride gave rise to the chloro pyrroloquinoline (VIII). The chloro group of (VIII) was finally displaced with ethanolamine (IX) at 190 C, yielding the title compound.

合成路线40

It can be prepared in several different ways: 1) By condensation of (I) with ethanolamine (II) by means of triethylamine in dioxane that gives 2-(2-hydroxyethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (III), which is then esterified with methanesulfonyl chloride and triethylamine in dioxane. (1,2) 2) By condensation of 2-chloro-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (I) with 2-(methylsulfonyloxy)ethylamine by means of triethylamine (IV) in CH2Cl2. (1,2) 3) By condensation of (I) with 2-chloroethylamine (V) by means of triethylamine in CH2Cl2 that gives 2-(2-chloroethylamino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (VI), which is then transformed into the ester by means of silver methanesulfonate in refluxing acetonitrile. (1,2) 4) By cyclization at N-(3-hydroxypropyl)-2-chloroethylamine (VII) with N-(2-methylsulfonyl-oxyethyl)dichlorophosphoramide (VIII) by means of triethylamine in CH2Cl2. (1,2) 5) By mesylation of 2-(ethyleneimino)-3-(2-chloroethyl)tetrahydro-2H-1,3,2-oxaza-phosphorine-2-oxide (IX) with methanesulfonic acid in ethyl ether. (1,2)

合成路线41

The reaction of 2-benzoylbenzoic acid (I) with SOCl2 in CHCl3, benzene or DMF gives the corresponding acyl chloride (II), which is condensed with ethanolamine (III) by means of TEA in CHCl3 to yield the amide (IV). The reduction of (IV) with LiAlH4 in THF affords the diol (V), which is cyclized by means of Ts-OH in refluxing benzene to provide 1-phenyl-3,4,5,6-tetrahydro-1H-2,5-benzoxazocine (VI). Finally, this compound is methylated by means of dimethyl sulfate in refluxing benzene, or by means of formaldehyde in hot dioxane/water. Alternatively, the cyclization of N-[2-[1-[2-(chloromethyl)phenyl]-1-phenylmethoxy]ethyl]-N-methylamine (VII) by means of pyridine in refluxing acetonitrile gives also the target benzoxazocine.

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The precursor triamine (VI) is prepared as follows. Ethanolamine (I) is protected as the N-Cbz derivative (II) upon treatment with N-(benzyloxycarbonyloxy)succinimide. Subsequent tosylation of (II) to yield (III), followed by displacement of the tosylate of (III) with trimethyl propanediamine (IV) furnishes the protected triamine (V). Then, Cbz group hydrogenolysis in (V) in the presence of Pd/C gives rise to triamine (VI).

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Esterification of ethanolamine hydrochloride (I) by means of acetyl chloride in HOAc yields 2-aminoethyl acetate (II). The carboxyl groups of folic acid (III) are protected by coupling with amino ester (II) in the presence of EDC, to produce diamide (IV). Subsequent condensation of (IV)with dimethylformamide diethylacetal (DMF-DEA) gives formamidine (V). The 4-carbonyl group of (V) is then protected as the phenethyl ether (VII) by treatment with 4-nitrophenethyl alcohol (VI) under Mitsunobu coupling conditions.

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Regioselective substitution of the 2-chloro group of 2,4-dichloroquinoline (I) with 1,2,3,4-tetrahydroisoquinoline (II) in refluxing toluene provides the 2-(tetrahydroisoquinolinyl)quinoline (III). Then, displacement of the remaining 4-chloro group by heating with ethanolamine (IV) furnishes the title compound

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The pyrrolo-oxazine fragments, the free base (II) or the Boc-protected (V) can be synthesized as follows. Butene-1,4-diol (XXIV) is subjected to either of the two following alternative procedures: 1) treatment with mesyl chloride in the presence of Et3N in CH2Cl2 and subsequent reaction with tosylamine, NaOH and tetrabutylammonium hydrogensulfate (TBAHS) in toluene/water at 40 °C (1, 2); or 2) chlorination with thionyl chloride followed by treatment with tosylamide by means of NaH in DMF (3) to afford 1-tosyl-2,5-dihydro-1H-pyrrole (XXV). Compound (XXV) is then epoxidated with meta-chloroperbenzoic acid (mCPBA) in refluxing dichloromethane to yield cis-N-tosyl-6-oxa-3-azabicyclo[3.1.0]hexane (XXVI) (1-3). Desymmetrization of intermediate (XXVI) is carried out by condensation with ethanolamine (XXVII) in refluxing dichloromethane to yield the racemic N-alkylated pyrrolidine derivative rac-(XXVIII), which by reaction with tosyl chloride in pyridine/THF at –10 °C affords the tosylate rac-(XXIX). Cyclization of the racemic (XXIX) by means of NaOH in THF/methanol at 0-3 °C gives the racemic pyrrolo-oxazine rac-(XXX), from which the desired enantiomer (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (XXX) is separated by chiral chromatography. Finally, compound (XXX) is detosylated by means of HBr/AcOH and anisole at 60 °C and the resulting dihydrobromide salt (XXXI) is treated with potassium hydroxide in isopropanol to afford the free base intermediate (II) (1). Scheme 3.
In an improved method for intermediate (II), compound (XXVI) is desymmetrized by coupling with (R)-phenylethylamine (XXXII) in water (2, 3), resulting in a mixture of diastereomers that is resolved by crystallization (2) or chromatography (3). The desired isomer (XXXIII) is N-acylated with chloroacetyl chloride (XXXIV) by means of triethylamine (2) or DIEA in THF (3) to afford the N-chloroacetyl amine (XXXV), which then cyclizes in the presence of sodium hydroxide (2) or potassium tert-butoxide in dichloromethane (3). The resulting bicyclic lactam (XXXVI) is reduced with LiAlH4 in THF (3) or NaBH4 in the presence of BF3.THF complex (2) to give the pyrrolooxazine derivative (XXXVII) (2, 3), which is detosylated by treatment with HCl and subsequently with NaOH, yielding the free amine (XXXVIII). Finally, compound (XXXVIII) is subjected to hydrogenolysis over Pd/C in methanol to afford the target (4aS,7aS)-octahydropyrrolo[3,4-b][1,4]oxazine (II) (2). Scheme 3.
The Boc-protected compound (V) is obtained by subjecting N-alkylated derivative (XXXVII) to hydrogenolysis over Pd/C in methanol followed by treatment with tert-butoxycarbonyl anhydride in dichloromethane. The resulting fully protected intermediate (XXXIX) is finally detosylated with sodium naphthalenide (3). Scheme 3.

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Enantioselective synthesis of suvorexant is based on enzymatic transamination and described as follows. Cyclization of 2-amino-4-chlorophenol (XVI) with trimethyl orthoformate HC(OMe)3 in the presence of p-TsOH in THF provides 5-chlorobenzoxazole (XVII), which subsequently reacts with LiHMDS in THF followed by bromination of the resulting anion with NBS to afford 2-bromo-5-chlorobenzoxazole (XVIII). Condensation of crude bromo derivative (XVIII) with ethanolamine (XIX) in acetonitrile gives 2-(5-chloro-2-benzoxazolylamino)ethanol (XX), which is subjected to aza-Michael addition with methyl vinyl ketone (II) in the presence of NaOH in DMF to yield the β-amino ketone (XXI). Activation of crude alcohol (XXI) with MsCl in the presence of Et3N in i-PrOAc provides keto mesylate (XXII), which by transamination and cyclization with i-PrNH2 in the presence of CDX-017 enzyme and pyridoxal phosphate in DMSO, and subsequent acidification with HCl, provides the (R)-azepane derivative (XXIII). Finally, Schotten-Baumann acylation of amine (XXIII) with 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride (XXIV) in the presence of K2CO3 in i-PrOAc/H2O affords suvorexant. Chloride (XXIV) was prepared from 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) by treatment with (COCl)2 in the presence of DMF in i-PrOAc .

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