合成路线1

The condensation of 2-(N-methylcarbamoylmethoxy)phenol (I) with 3-benzyloxy-1-(p-toluenesulfonyloxy)-2-propanol (II) by means of Na in refluxing methoxyethanol gives 3 benzyloxy-1-[2-(N-methylcarbamoylmethoxy)phenoxy]-2-propanol (III), which is debenzylated by hydrogenolysis with H2 over Pd/C in methanol yielding 1-[2-(N-methylcarbamoylmethoxy)phenoxy]-2,3-propanediol (IV). The tosylation of (IV) with tosyl chloride in pyridine affords 1-[2-(N-methylcarbamoylmethoxy)phenoxy]-3-tosyloxy-2-propanol (V), which by treatment with NaOH in water is converted into 1-[2-(N-methylcarbamoylmethoxy)phenoxy]-2,3-epoxypropane (VI). Finally, this compound is treated with tertbutylamine in refluxing tert-butanol.

合成路线2

The condensation of tert-butylamine (II) with 2-(2-chloro-1-hydroxyethyl)-7-ethylbenzofuran (I) or with 2-epoxyehtyl-7-ethylbenzofuran (III) in refluxing ethanol.

合成路线3

It can be prepared in two different ways: 1) The reaction of 1-chloro-2,3-propylene oxide (I) with tert-butylamine (II) in ether yields 1-chloro-3-tert-butylamino-2-propanol (III), which is condensed with 2,3-xylenol (IV) by means of KOH in ether-water. 2) By heating a mixture of 1-tert-butyl-3-azetidinol (V) and 2,3-xylenol (IV) at 155 C with KOH.

合成路线4

This compound can be obtained in two different ways: 1) The reaction of cyclopropylmethyl ketone oxime (II) with epibromohydrin (A) in THF containing NaH gives O-[2,3-epoxypropyl]cyclopropylmethyl ketone oxime (III), which is treated with excess tert-butylamine (C) in ethanol yielding the final compound. 2) By condensation of cyclopropylmethyl ketone (I) with 3-(aminooxy)-N-tert-butyl-2-hydroxypropanamine (B) in ethanol.

合成路线5

The condensation of N-methyl-4-hydroxyisocarbostyril (I) with epichlorohydrin (II) by means of sodium methoxide in hot methanol gives 4-(2,3-epoxypropoxy)-N-methylisocarbostyril (III), which is then treated with tert-butylamine (IV) in methanol, and with HCl.

合成路线6

The oxidation of 2-chloroacetophenone (I) with SeO2 in dioxane-water gives 2-chlorophenylglyoxal (II), b.p. 87-90 C/1 mm, which is then reductocondensed with tert-butylamine (III) and NaSH4 in ethanol.

合成路线7

The reaction of aminomethansulfonic acid (I) with phthalic anhydride (II) by means of potassium acetate in refluxing acetic acid gives phthalimidomethansulfonic acid (III), which by reaction with PCl5 in refluxing benzene is converted into its acyl chloride (IV). The condensation of (IV) with tert-butylamine (A) in CHCl3 affords N-tert-butylphthalimidomethansulfonamide (V), which by reaction with hydrazine hydrate in refluxing ethanol yields 2-aminomethan-N-tert-butylsulfonamide (VI). The reaction of (VI) with CS2 and MeI by means of triethylamine in ethanol gives N-tert-butylsulfamoylmethyldithiocarbamic acid methyl ester (VII), which is cyclized with NaN3 in hot water to afford 1-(N-tert-butylsulfamoylmethyl)tetrazol-5-thiol (VIII). The hydrolysis of (VIII) with trifluoroacetic acid yields compound 1-sulfamoylmethyltetrazol-5-thiol (IX).

合成路线8

The esterification of 5,8-dihydro-1-naphthol (I) with acetic anhydride gives the corresponding acetate (II), which is oxidized with silver acetate and I2 in acetic acid to yield 2,3-cis-1,2,3,4-tetrahydro-2,3,5-naphthalenetriol (III). The treatment of this product with sodium methylate and epichlorhydrin (A) in methanol gives 2,3-cis-1,2,3,4-tetrahydro-5-(2,3-epoxypropoxy)-2,3-naphthalenediol (IV), which is finally treated with tertbutylamine (B) in chloroform-methanol.

合成路线9

By reaction of 5,8-dihydro-1-(2,3-epoxypropoxy)naphthalene (V) with tertbutylamine (B) to give 5,8-dihydro-1-[2-hydroxy-3-(tertbutylamino)propoxy]naphthalene (VI), followed by oxidation of the double bond with silver acetate and I2 in acetic acid.

合成路线10

A new method for the synthesis of pirbuterol hydrochloride has been described: By reaction of 2-phenyl-4H-1,3-dioxino[5,4-b]pyridine-6-carbaldehyde (I) with methyltriphenylphosphonium bromide (II) and NaOH in toluene to give 2-phenyl-6-vinyl-4H-1,3-dioxino[5,4-b]pyridine (III), which is treated with m-chloroperbenzoic acid (IV) in methylene chloride to give 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (V). Compound (V) can also be obtained from 6-(1,2-epoxyethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine (VI) by reaction with m-chloroperbenzoic acid (IV) as before. The reaction of (V) with tert-butylamine (VII) in methanol affords 6-(1-hydroxy-2-tert-butylaminoethyl)-2-phenyl-4H-1,3-dioxino[5,4-b]pyridine N-oxide (VIII), which is first treated with H2 over Pd/C in methanol and then with HCl in ethyl acetate to give pirbuterol hydrochloride.

合成路线11

The reaction of 2-cyclopentylphenol (I) with epichlorhydrin (II) in a basic medium yields 1,2-epoxy-3-(2'-cyclopentylphenoxy)propane (III), which is the condensed with tert-butylamine (IV) in hot ethanol.

合成路线12

The reaction of cyclohexane-1,3-dione (I) with ammonia gives 3-amino-2-cyclohexen-1-one (II), which is cyclized with acrylic acid (III) by heating at 140 C yielding 1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione (IV). The dehydrogenation of (IV) by means of Pd/C in refluxing decaline affords 5-hydroxy-1,2,3,4-tetrahydroquinolin-2-one (V), which is condensed with epichlorohydrin (VI) by means of NaOMe or NaOH in methanol giving 5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroquinolin-2-one (VII). Finally, this compound is treated with tert-butylamine in methanol.

合成路线13

The condensation of 3-acetyl-4-hydroxyaniline (I) with N,N-diethylcarbamoyl chloride (II) in pyridine gives the urea (II), which is treated with epichlorohydrin (IV) and NaOH to yield N-[3-acetyl-4-(2,3-epoxypropoxy)phenyl]-N',N'-diethylurea (V). Finally, the epoxy ring of (V) is opened with tert-butylamine (VI).

合成路线14

The reaction of 3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy)aniline (VII) with phenyl carbamate (VIII) in pyridine gives the N-[3-acetyl-4-[3-(tert-butylamino)-2-hydroxypropoxy]phenylcarbamic acid phenyl ester (IX), which is tretated with diethylamine (X) in ethanol/water. By reaction of N-[3-acetyl-4-(3-chloro-2-hydroxypropoxy)phenyl]-N',N'-diethylurea (XI) with tert-butylamine (VI).

合成路线15

There are several pathways for the preparation of the title compound according to the patent literature.

合成路线16

The condensation of 4-ethoxyaniline (II) with N,N-diethylcarbamoyl chloride (II) by means of KHCO3 gives the urea (III), which is acylated with acetyl chloride and AlCl3 to yield N-(3-acetyl-4-hydroxyphenyl)-N',N'-diethylurea (IV). The alkylation of (IV) with epichlorohydrin (V) affords the adduct (VI), which is treated with HBr providing the bromoalcohol (VII). Finally this compound is treated with tert-butylamine to furnish the target urea.

合成路线17

The reaction of D-mannitol (I) with acetone and ZnCl2 gives the diacetonide (II), which is oxidized with Pb(OAc)4 to yield the acetonide of (R)-glyceraldehyde (III). The reduction of (III) with H2 over Pd/C affords the (S)-glycerin acetonide (IV), which is treated with TsCl in pyridine to provide the corresponding tosylate (V). The condensation of (V) with the urea derivative (VI) by means of KOH in DMSO gives the adduct (VII), which is deprotected with HCl in acetone to yield the diol (VIII). Monotosylation of (VIII) with TsCl in pyridine affords the primary tosylate (IX), which is treated with Na in methanol to provide the epoxide (X). Finally this compound is treated with tert-butylamine to furnish the target (R)-enantiomer.

合成路线18

The reaction of 4-nitrophenol (I) with acetic anhydride in aqueous NaOH gives the corresponding acetate (II), which is submitted to a Fries migration with AlCl3 in nitrobenzene at 140 C to yield the acetophenone (III). The condensation of (III) with epichlorohydrin (IV) by means of K2CO3 affords the adduct (V), which is treated with tert-butylamine (VI) in water to obtain the aminoisopropanol derivative (VII). The reduction of the nitro group of (VII) with H2 over Pd/C in methanol gives the corresponding amino derivative (VIII), which is finally condensed with N,N-diethylcarbamoyl chloride (IX) by means of TEA in THF to yield the target urea.

合成路线19

The reaction of 5-hydroxy-7-tetralone (I) with epichlorohydrin (I) at reflux temperature gives 5-(3-chloro-2-hydroxypropoxy)-7-tetralone (III), which is then condensed with butylamine (IV) in refluxlng alcohol.

合成路线20

It can be obtained in two different ways both starting from the sodium salt of 5-hydroxy-3,4-dihydro-1(2H)-naphthalenone (I): 1) Its condensation with epichlorhydrine (A) in ethanol gives 5-(2,3-epoxypropoxy)-3,4-dihydro-1(2H)-naphthalenone (II), which is then condensed with tert-butylamine (B) in refluxing ethanol. 2) Its condensation with 3-chloro-1,2-propanediol (C) gives 5-(2,3-dihydroxy-propoxy)-3,4-dihydro-1(2H)-naphthalenone (III), which is esterified with tosyl chloride to the sulfonic ester (IV), and finally condensed with tert-butylamine.

合成路线21

By reaction of alpha,m-(dichloropropiophenone (I) with tert-butylamine (B) in refluxing acetonitrile or by reaction of alpha-bromo-m-chloropropiophenone (VI) with tert-butylamine (B) in acetonitrile at room temperature. The starting product (I) can be obtained in two different ways: 1) The Grignard condensation of m-chlorobenzonitrile (II) with ethyl magnesium bromide (A) in refluxing ether gives m-chloropropiophenone (III), which is then treated with SO2Cl2 in tetrachloroethane. 2) The reaction of propiophenone (IV) with SO2Cl2 in tetrachloroethane gives alpha-chloropropiophenone (V), which is then chlorinated in the ring by means of SO2Cl2 and AlCl3 in tetrachloroethane. The starting product (VI) is obtained by bromination of m-chloropropiophenone (III) with Br2 in methylene chloride

合成路线22

The nitration of 8-hydroxy-3,4-dihydrocarbostyril (I) with HNO3 in acetic acid-acetic anhydride gives 5-nitro-8-hydroxy-3,4-dihydrocarbostyril (II), which is reduced with SnCl2 in concentrated HCl yielding 5-amino-8-hydroxy-3,4-dihydrocarbostyril (III). The oxidation of (III) with FeCl3 in aqueous HCl affords 5,8-dioxo-3,4,5,8-tetrahydrocarbostyril (IV), which by treatment with SO2 in water is converted into 5,8-dihydroxy-3,4-dihydrocarbostyril (V). The treatment of (V) with benzyl chloride (A) and potassium carbonate in acetone gives 5-hydroxy-8-benzyloxy-3,4-dihydrocarbostyril (VII), which by reaction with epichlorohydrin (B) by means of piperidine affords 8-benzyloxy-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril (VII). The opening of the epoxide ring of (VII) with tert-butylamine (C) in methanol yields 8-benzyloxy-5-(3-tert-butylamino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (VIII) (1,2), which is finally hydrogenated with H2 over Pd/C.

合成路线23

By bromination of 4-amino-3,5-dichloroacetophenone (I) with Br2 in CHCl3 to give 4-amino-3,5-dichloro-alpha-bromoacetophenone (II), m.p. 140-5 C, which is condensed with tert-butylamine (III) in CHCl3 to 4-amino-3,5-dichloro-alpha-tertbutylaminoacetophenone hydrochloride (IV), m.p. 252-7 C; this product is finally reduced with NaBH4 in methanol.

合成路线24

The formylation of 5-hydroxy-1,2,3,4-tetrahydroisoquinoline (I) with formamide (II) at 140 C gives N-formyl-5-hydroxy-1,2,3,4-tetrahydroisoquinoline (III), which is condensed with epichlorohydrin (IV) by means of NaOH in water yielding N-formyl-5-(2,3-epoxypropoxy)-1,2,3,4-tetrahydroisoquinoline (V). Finally, this compound is condensed with tert-butylamine (VI).

合成路线25

The reaction of (E)-6-(3-aminophenyl)-6-(3-pyridyl)-5-hexenoic acid methyl ester (I) with diphenyl N-cyanocarbinimidate (II) in isopropanol gives the N-cyanoisourea (III), which is condensed with tert-butylamine (IV) in refluxing isopropanol yielding the guanidine derivative (IV). Finally, hydrolysis of the ester group of (IV) with NaOH affords the target compound.

合成路线26

Finally, the target compound has been obtained as follows: The selective esterification of the phosphono group of intermediate (IX) with iodomethyl pivalate (XVIII) by means of triethylamine in DMF gives the sulfonic acid (XIX), which was purified through its calcium salt. Finally, this compound is treated with tert-butylamine in methanol to afford the target salt.

合成路线27

Nitration of minocycline (I) with KNO3 and H2SO4 gives the 9-nitro derivative (II), which is reduced with H2 over Pd/C in 2-methoxyethanol/2N H2SO4 to provide 9-aminominocycline (III). Acylation of compound (III) with 2-bromoacetyl bromide (IV) in N,N-dimethylpropyleneurea (DMPU) affords 9-(2-bromoacetamido)minocycline (V). Finally, this compound is treated with tert-butylamine (VI) to yield, after purification, GAR-936.

合成路线28

The reacion of 3-(trifluoromethyl) benzoic acid (I) first with SOCl2 (or oxalyl chloride) and then with NH4OH in dioxane given the corresponding amide (II), which is treated with SOCl2 giving 3-(trifluoromethyl)benzonitrile (III) was condensed with ethylmagnesium bromide to afford ketone (IV), which was brominated in either methanol or dioxane to yield bromoketone (V). Alkylation of tert-butylamine (VI) with bromoketone (V) provided the aminoketone (VII). Reduction of this ketone to the aminoalcohol was performed with several reagents, among them, borane in THF afforded the most favourable ratio for the desired treo diastereoisomer (80:20). Finally, the diastereomeric mixture was separated by preparative HPLC.

合成路线29

Reaction of 2,3,5,6-tetrafluoropyridine (I) with ammonia in formamide gives the 2-aminopyridine derivative (IV), which is condensed with tert-butylamine (XIII) in N-methylpyrrolidone to yield 6-(tert-butylamino)-3,5-di- fluoropyridine-2-amine (XIV). Condensation of amine (XIV) with 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylic acid ethyl ester (VII) gives the adduct (XV), which is cyclized by means of K2CO3 in DMF to afford the quinolone derivative (XVI). Treatment of quinolone (XVI) with HCl in AcOH produces simultaneous ester hydrolysis and tert-butyl group removal, providing 4-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (XI). Finally, this compound is condensed with 3-hydroxyazetidine (XII) by means of N-methylpyrrolidine in DMF.

合成路线30

NXY-059 is synthesized by condensation of N-tert-butylhydroxylamine (I) or its acetate or hydrochloride salts and disodium benzaldehyde-2,4-disulfonate (II) directly in refluxing MeOH or mixtures of MeOH/water or i-PrOH/MeOH/water or by means of MeONa in refluxing MeOH/water or i-PrOH/MeOH/water. N-tert-butylhydroxylamine (I) can be prepared as follows: a) Reduction of 2-methyl-2-nitropropane (III) with either Zn in HOAc/EtOH or aluminum foil and HgCl2 in EtOH/ether/H2O. b) Condensation of benzaldehyde (IV) with tert-butyl-amine (V) in refluxing toluene provides N-benzylidene-N-tert-butylamine (VI), which is oxidized with meta-chloroperbenzoic acid and Na2CO3 in water/toluene/ EtOH to furnish the phenyloxaziridine derivative (VII). Finally, the oxaziridine ring of (VII) is opened by treatment with H2SO4/HOAc in EtOH/H2O. c) Heating of the phenyloxaziridine derivative (VII) at 130 C gives N-tert-butylphenylnitrone (VIII), which is finally treated with H2SO4/HOAc in toluene. Disodium benzaldehyde-2,4-disulfonate (II) can be obtained as follows: a) Heating of 2,4-dichlorobenzaldehyde (IX) with sodium sulfite at 170 °C in water in water, followed by oxidation with sodium hypochlorite. b) Reaction of 2,4-dichlorobenzal chloride (X) with sodium sulfite and Na2CO3 or NaHCO3 at 170 C in water, followed by oxidation with sodium hypochlorite.

合成路线31

Treatment of 3,4-dibutoxy-3-cyclobutene-1,2-dione (VI) with tert-butylamine (VII) yielded the amino cyclobutenedione (VIII). Subsequent condensation of (VIII) with 3-chloro-4-(aminomethyl)benzonitrile (V) in THF provided the target diamino derivative.

合成路线32

Coupling of carboxylic acid (I) with tert-butylamine (II) by means of EDC-HOBt in CH2Cl2 affords carboxamide (III), whose Boc group is removed by treatment with HCl/dioxane to provide compound (IV). Coupling of thiazolidine (IV) to Boc-protected allophenylnorstatine (V) by means of DCC and HOBt in EtOAc provides derivative (VI), whose is deprotected by treatment with HCl/dioxane to yield (VII), which is then coupled to Boc-Val-OH (VIII) with EDC-HOBt in DMF to furnish compound (IX). On the other hand, aminophenol derivative (XI) is condensed with benzyl chloroacetate (XII) in DMF in the presence of K2CO3 to furnish derivative (XIII), which is then debenzylated by hydrogenation over Pd/C in MeOH to yield acetic acid derivative (XIV). Finally, the Boc group of (IX) is removed with HCl/dioxane and the resulting amine (X) is coupled to carboxylic acid (XIV) by first treatment with N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) and DCC in CH2Cl2 followed by treatment with Et3N in DMF. Alternatively, the coupling can be performed by means of EDC and HOBt in DMF.

合成路线33

The condensation of vanillin (I) with epichlorohydrin (II) in ethanolic NaOH produced the glycidyl ether (III). Epoxide ring opening in (III) by means of tert-butylamine (IV) in EtOH furnished amino alcohol (V). The title dihydropyridine derivative was then obtained by reaction between aldehyde (V), methyl acetoacetate (VI), ammonia under Hantzsch condensation conditions, and was isolated after conversion to the hydrochloride salt.

合成路线34

It can be prepared in several different ways: 1) By reaction of the 1-(2-cyanophenoxy)-2-hydroxy-3-bromopropane (I) with N,N'-di-tert-butylurea (A) in tetralin at 200 C. 2) By condensation of the 1-(2-cyanophenoxy)-2-hydroxy-3-bromopropane (I) with dihydropyrane (B) to the corresponding tetrahydropyranyl ether (III), which is condensed with tert-butylamine (C) in benzene to 1-(2-cyanophenoxy)-3-tert-butylaminopropanol-2-tetrahydropyranyl ether (IV) (oxalate, m.p. 102-5 C), which is finally hydrolyzed with diluted HCl at 100 C.

合成路线35

It can be prepared in several different ways: 3) By hydrolysis of 1-(2-cyanophenoxy)-2-hydroxy-3-(N-acetyl-N-tert-butylamino)propane (V) with KOH in refluxing ethanol. 4) By heating N,N'-di-tert-butyl-N-[(2-hydroxy-3-O-cyanophenoxy)propyl]urea (VI) at 200 C in tetralin. 5) By condensation of the 1-(2-cyanophenoxy)-2,3-epoxypropane (II) with tert-butylamine (C) in ethanol.

合成路线36

The selective methylation of 5,6,7,8-tetrahydro-5,8-ethanonaphthalene-1,4-diol (I) with dimethylsulfate in a two phase system gives 4-methoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (II), which is condensed with epichlorohydrin (III) by means of piperidine at 100 C yielding 1-methoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (IV). The reaction of (IV) with tert-butylamine (V) at 100 C affords 1-methoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VI), which is finally demethylated by treatment with pyridine hydrochloride at 160 C

合成路线37

The selective hydrolysis of 1,4-diacetoxy-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII) with diethylamine in methanol gives 4-acetoxy-5,6,7,8-tetrahydro-5,8-ethano-1-naphthol (VIII), which is condensed with epichlorohydrin (III) by means of piperidine at 90 C to afford 1-acetoxy-4-(2,3-epoxypropoxy)-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (VII). The reaction of (IX) with tert-butylamine (V) in refluxing toluene gives 1-acetoxy-4-[3-(tert-butylamino)-2-hydroxypropoxy]-5,6,7,8-tetrahydro-5,8-ethanonaphthalene (X), which is finally hydrolyzed with dry HCl in refluxing methanol

合成路线38

合成路线39