合成路线1

The reaction of 2,6-dimethylaniline (I) with phosgene (II) in refluxing benzene gives 2,6-dimethylphenyl isocyanate (III), which is then condensed with methylguanidine carbonate (A) by means of K2CO3 in THF and treated with HCl to obtain the corresponding hydrochloride.

合成路线2

By condensation of 2,6-dimethylaniline (I) with 8-pyrrolizineacetlc acid (II) by means of NaH in refluxing dioxane.

合成路线3

The synthesis of EO 122 starts from quinuclidine-3-carboxylic acid (I), which is converted to the acid chloride (II) by oxalyl chloride. The addition of 2,6-dimethylaniline (III) to the acid chloride yields EO-122.

合成路线4

Compound can be prepared in two different ways both starting from 2,6-xylidine (I): 1) By condensation of (I) with N-carbobenzoxyalanine (B) by means of dicyclohexylcarbodiimide in methylenechloride giving N-(carbobenzoxyalanyl)xylidine (II), which is then hydrogenated over Pd/C in ethanol - methylene chloride. 2) By condensation of (I) with 2-bromopropionyl bromide (A) by means of sodium acetate in acetic acid giving 2-bromo-2',6'-propionoxylidide (III), which is then treated with NH3 in alcohol water.

合成路线5

1) The acylation of 2,6-dimethylaniline (II) with chloroacetyl chloride by means of triethylamine in dichloromethane gives N-(2,6-dimethylphenyl) chloroacetamide (III), which is condensed with piperidine (IV) in refluxing ethanol to yield N-(2,6-dimethylphenyl)-2-piperazinoacetamide IV). Finally, this compound is condensed with 3-(2-methoxyphenoxy)-12-epoxypropane (VI) in refluxing methanol toluene.

合成路线6

2) The condensation of epoxide (VI) with piperazine (IV) in refluxing isopropanol gives 1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]piperazine (VII), which is then condensed with chloroacetamide (III) in refluxing ethanol.

合成路线7

The hydrolysis of 1-benzyl-4-(methylamino)piperidine-4-carboxamide (I) with refluxing concentrated aqueous HCl gives the corresponding free acid (II), which is debenzylated with H2 over Pd/C in basic medium yielding 4-(methylamino)piperidine-4-carboxylic acid sodium salt (III). The protection of (III) with benzyl chloroformate (IV) in basic THF - water affords 1-(benzyloxycarbonyl)-4-(methylamino)piperidine 4 carboxylic acid (V), which by cyclization with phosgene in dioxane is converted to benzyl 1-methyl-2,4-dioxo 3-oxa-1,8-diazaspiro[4.5]decane-8 carboxylate (VI). The reaction of (VI) with 2,6-dimethylaniline (II) by heating at 160 C gives benzyl 4-(2,6-dimethylphenylaminocarbonyl)-4-(methylamino)piperidine-1-carboxylate (VIII), which is methylated with refluxing methyl iodide to the corresponding dimethylamino compound (IX). The deprotection of (IX) with H2 over Pd/C in methanol yields 4-(dimethylamino)-N-(2,6-dimethylphenyl)piperidine-4-carboxamide (X), which is finally condensed with 1,2-epoxycyclohexane (XI) in refluxing ethanol.

合成路线8

By condensation of 2-(2-oxopyrrolidino)acetic acid (I) with 2,6-dimethylaniline (II) by means of dicyclohexylcarbodiimide (DCC) in refluxing chloroform.

合成路线9

4-Nitrobenzoylchloride (I) is condensed with 2,6-dimethylaniline (II) in the presence of base (potassium carbonate or triethylamine) to provide the 4-nitrobenzamide (III). Reduction of the aromatic nitro group in (III) using catalytic hydrogenation produces the corresponding 4-aminobenzamide, ameltolide.

合成路线10

Optical resolution of DL-pipecolinic acid (I) with (+)-tartaric acid gives L-pipecolinic acid (II), which is treated with PCl5 to obtain acil chloride (III). This compound is condensed with 2,5-dimethylaniline (IV) by means N-methylpirrolidine (NMP) to afford amide (V). Finally, amide (V) is alkylated with 1-bromopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.

合成路线11

Compound (XII) is protected with benzyl chloroformiate (VII) to afford compound (XIII), which is condensed with 2,5-dimethylaniline (XIV) by means SOCl2/DMAP to yield amide (XIV). This compound (XIV) is deprotected by means trimethylsillyl chloride to yield compound (XV), which is hydrogenated by means Rh/Al2O3. Finally, this compound (V) is alkylated with 1-iodopropane by means potassium carbonate (K2CO3) to yield Ropivacaine.

合成路线12

1) The optical resolution of pipecolic acid (I) with (+)-tartaric acid in water-ethanol gives L-pipecolic acid (II), which by reaction with Cl5P in acetyl chloride is converted to the acyl chloride (III). The condensation of (III) with 2,6-xylidine (IV) by means of N-methylpyrrolidone (NMP) in acetone affords L-pipecolic acid 2,6-xylidide (V), which is finally alkylated with propyl bromide (VI) and K2CO3 in hot isopropanol.

合成路线13

3) The protection of 1,2,3,6-tetrahydropyridine-2(S)-carboxylic acid (XII) with benzyl chloroformate (VII) gives the benzyloxycarbonyl derivative (XIII), which is condensed with 2,6-xylidine (IV) with SOCl2 and DMAP as before yielding the amide (XIV). Deprotection of (XIV) with iodotrimethylsilane in dichloromethane affords N-(2,6-dimethylphenyl)-1,2,3,6-tetrahydropyridine-2(S)-carboxamide (XV), which is reduced with H2 over Rh/Al2O3 in DMF giving the saturated amide (V). Finally, this compound is alkylated with propyl iodide and K2CO3 as before.

合成路线14

Phthalimide (III) was prepared by condensation of 4-nitrophthalic anhydride (I) with 2,6-dimethylaniline (II) in refluxing AcOH. Reduction of the nitro group of (II) by transfer hydrogenation using cyclohexene and Pd/C provided the title aminophthalimide.

合成路线15

Levobupivacaine has been obtained by two different ways: 1) The deamination of N-benzoyloxycarbonyl-L-lysine (I) with NaNO2/acetic acid gives 6-acetoxy-2(S)-(benzyl-oxycarbonylamino)hexanoic acid (II), which is amidated with 2,6-dimethylaniline (III) and dicyclohexylcarbodiimide (DCC) to the expected amide (IV). The deacetylation of (IV) with K2CO3 in methanol affords compound (V), which is tosylated as usual with tosyl chloride giving intermediate (VI), which is stereospecifically cyclized by means of K2CO3 in ethanol yielding N-(2,6-dimethyl-phenyl)piperidine-2 (S)-carboxamide (VII). Finally, this compound is alkylated with butyl bromide and K2CO3 or by reductoalkylation with butyraldehyde. 2) The amidation of piperidine-2-carboxylic acid (VIII) with 2,6-dimethylaniline (III) by means of SOCl2 in toluene gives the corresponding amide (IX), which is alkylated with butyl bromide as before yielding racemic bupivacaine (X) (3). This compound is then submitted to optical resolution by treatment with (S,S)-(­)-tartaric acid followed by crystallization of the resulting tartrate and acidification with HCl in isopropanol.

合成路线16

Compound can be prepared in two related ways: 1) The acylation of 2,6-dimethylaniline (I) with chloroacetyl chloride (II) in acetic acid gives omega-chloro-2,6-dimethylacetanilide (III), which is then condensed with disodium salt of iminodiacetic acid (IV) in refluxing ethanol-water. 2) The reaction of (III) with ammonia in ethanol gives omega-amino-2,6-dimethylacetanilide (V), which is finally treated with chloroacetic acid (A) and NaOH in refluxing 95% ethanol.

合成路线17

A pyridine carboxylic acid anilide (III) can be produced by reacting a pyridine carboxylic acid chloride (I) with an aromatic amine (II). The pyridine carboxylic acid anilide (III) is hydrogenated to the corresponding piperidine carboxylic acid anilide (IV), which is thereafter hydroalkylated

合成路线18

合成路线19