合成路线1

The reaction of pregnenolone (I) with I2 and pyridine at 90 C gives (3beta-hydroxypregn-5-en-20-one-21-yl)pyridinium iodide (II), which by treatment with sodium methoxide in refluxing methanol is converted into methyl 5-androsten-3beta-ol-17beta-carboxylate (III). The Meerwein-Poundorf oxidation of (III) with cyclohexanone (A) and aluminum isopropoxide in refluxing toluene yields methyl 4-androsten-3-one-17beta-carboxylate (IV), which is hydrolyzed with KOH in refluxing methanol - water to the corresponding free acid (3-oxo-4-etienic acid) (V). The reaction of (V) with oxalyl chloride (B) and diethylamine in refluxing toluene affords 17beta-(N,N-diethylcarbamoyl)-4-androstene-3-one (VI), which is oxidized with O3 or with NaIO4 and KMnO4 giving 17beta-(N,N-diethylcarbamoyl)-5-oxo-3,5-secoandrostan-3-oic acid (VII). The cyclization of (VII) with methylamine ethylene glycol at 180 C in a pressure vessel affords 17beta-(N,N-diethylcarbamoyl)-4-methyl-4-aza-5-androsten-3-one (VIII), which is finally reduced with H2 over Pt in acetic acid. The cyclization of the acid (VII) with NH3 in ethanol at 180 C in a pressure vessel gives 17beta-(N,N-diethylcarbamoyl)-4-aza-5-androsten-3-one (IX), which is reduced with H2 over Pt in acetic acid yielding 17beta-(N,N-diethylcarbamoyl)-4-aza-5alpha-androstan-3-one (X). Finally, this compound is methylated with CH3I by means of NaH in toluene.

合成路线2

The condensation of 4-[2-(acetylamino)ethyl]benzenesulfonyl chloride (I) with 1-cyclohexyl-2-iminoimidazolidine (III) by means of NaOH in refluxing acetone gives 1-[[4-(2-acetamidoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (III), which is hydrolyzed with refluxing 2N HCl yielding 1-[[4-(2-aminoethyl)phenyl]sulfonyl]-3-cyclohexyl-2-iminoimidazolidine (IV). Finally, this compound is acylated with crotonic anhydride (V) in dioxane. The starting products (I) and (II) are obtained as follows: 1) The acetylation of 2-phenylethylamine (VI) with acetic anhydride gives N-(2-phenylethyl)acetamide (VII), which is sulfonated with chlorosulfonic acid yielding compound (I). 2) The reductocondensation of cyclohexanone (IX) with ethylenediamine (VIII) gives N-cyclohexylethylenediamine (X), which is then cyclized with cyanogen chloride to compound (II).

合成路线3

The condensation of m-methoxybenzaldehyde (I) with cyclohexanone (II) by means of KOH in refluxing water gives m-methoxybenzalcyclohexanone (III), which by reaction first with dimethylamine (A) in ether and then reduction with LiAlH4 in the same solvent affords cis-2-(alpha-dimethylamino-m-methoxybenzyl)cyclohexanol (IV). The hydrolysis of (IV) with HCl in isopropanol yields the racemic product, which is finally resolved into the corresponding optical isomers with tartaric acid.

合成路线4

Reaction of cyclohexenone (I) with ethyl cyanoacetate (A) in the presence of ammonia affords the Guareschi salt (II), which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid (III). The anhydride (IV) can be treated either with methanol to yield the halfester (V), or with hydroxylamine to afford the N-hydroxyimide (VII). The halfester (V) is subjected to a Curtius type rearrangement to give the isocyanate (VI), which is hydrolyzed to the amino acid hydrochloride (Xl).

合成路线5

The same product can be obtained from reaction of cyclohexenone (I) with ethyl cyanoacetate (A) in the presence of ammonia affords the Guareschi salt (II), which is hydrolyzed and decarboxylated to give 1,1-cyclohexanediacetic acid (III). The anhydride (IV) can be treated with the N-hydroxyimide (VII) via a Lossen type rearrangement by conversion of (VII) to N-benzenesulfonyloxylmide (VIII) and subsequent reaction with triethylamine in methanol followed by hydrolysis of the urethanester (IX). The free amino acid is finally obtained from the hydrochloride (X) via anion exchange.

合成路线6

The reaction of 3beta-hydroxy-15beta,16beta-methylene-5-androsten-17-one (I) with 1-bromo-3,3 dimethoxypropane (II) by means of Li in THF gives the corresponding 3,3-dimethoxypropyl derivative (III), which by cyclization with acetic acid is converted to the lactol (IV). Oxidation of (IV) with cyclohexanone and aluminum isopropoxide in refluxing toluene yields 15beta,16beta-methylene-4-androstene[17(beta-1')-spiro)-5']perhydrofuran-2',3-dione (V), which is dehydrogenated with chloranil in refluxing tert-butanol to the 4,6-androstadiene (VI). Cyclopropanation of (VI) with trimethylsolfoxoniurn iodide (A) and NaH in DMSO affords the 6beta,7beta:15beta,16beta-dimethylene compound (VII), which is finally dehydrogenated by means of 2,3-dichloro-5,6-dicyanobenzoquinone in refluxing dioxane.

合成路线7

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

合成路线8

The condensation of cyclohexanone (I) with 4 methoxyphenylacetonitrile (II) by means of n-butyllithium in THF gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl) acetonitrile (III), which is reduced with H2 over Rh/A12O3 in ethanol-ammonia yielding 1-[2-amino-1-(4 methoxyphenyl)ethyl]cyclohexanol (IV). Finally, this compound is methylated with formaldehyde and formic acid in refluxing water.

合成路线9

The condensation of 2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (I) with cyclohexanone (II) by means of isopropylmagnesium bromide in toluene/methyl tert-butyl ether gives 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylthioacetamide (III), which is finally desulfurized by means of Raney-nickel in dioxane/acetic acid.

合成路线10

1) The condensation of (S)-L-malic acid (I) and cyclohexanone (II) by means of boron trifluoride etherate gives the cyclic lactone (III), which is reduced by borane and treated with tert-butyldiphenylchlorosilane yielding the silyl ether (IV). The transesterification of (IV) with sodium methoxide in methanol affords 4-(tert-butyldiphenylsilyloxy)-2(S)-hydroxybutyric acid methyl ester (V), which is reduced with borane as before and esterified with naphthalenesufonyl chloride to give the sulfonate (VI). The treatment of (VI) with sodium methoxide affords the epoxide (VII), which is alkylated with decyllithium yielding 1-(tert-butyldiphenylsilyloxy)tetradecan-3(R)-ol (VIII). The benzylation of (VIII) with benzyl trichloroacetimidate (BTA) gives the benzyl ether (IX), which is desilylated with HF in acetonitrile yielding 3(R)-benzyloxytetradecan-1-ol (X). The oxidation of (X) with PDC gives 3(R)-benzyloxytetradecanal (XI), which is condensed with 1-(trimethylsilyl)-2(E)-nonene (XII) by means of a titanium dichloride complex yielding the diastereoisomeric mixture of alcohols (3R,4S,6R)- (XIII) and (3S,4S,6R)- (XIV), which are separated by column chromatography. The silylation of both isomers with tert-butyldimethylsilyl chloride affords both isomers (XV) and (XVI), which are ozonolyzed with O3 and oxidized with NaClO2 to yield the corresponding acids (XVII) and (XVIII). The desilylation of (XVII) and (XVIII) with HF in acetonitrile gives the hydroxy acids (XIX) and (XX), which are cyclized by means of benzenesulfonyl chloride and pyridine to the isomeric oxetanones (XXI) and (XXII). The unwanted isomer (XXII) can be isomerized by means of lithium diisopropylamide in THF to the correct isomer (XXI). The debenzylation of (XXI) by hydrogenation with H2 over Pd/C affords (3S,4S)-3-hexyl-4-[2(R)-hydroxytridecyl]oxetan-2-one (XXIII), which is finally condensed with N-formyl-L-leucine (XXIV) by means of diethyl azodicarboxylate (DEAD) in THF.

合成路线11

In an alternative method, condensation of semicarbazide hydrochloride (I) with cyclohexanone (II) yields the semicarbazone (III). Subsequent reaction of (III) with ethyl chloroacetate (IV) in the presence of NaOMe gives rise to the cyclohexylidene aminohydantoin (V). Treatment of (V) with 5-(p-nitrophenyl)furfural (VI) under acidic conditions affords the furfurylidene aminohydantoin (VII). This is finally converted into the corresponding sodium salt employing methanolic NaOMe (3).

合成路线12

By reaction of 2-aminocyclopent-1-ene-1-carbonitrile (I) with cyclohexanone (II) in presence of polyphosphoric acid in benzene followed by treatment with hydrochloric acid in ethanol.

合成路线13

By reaction of 2-aminocyclopent-1-ene-1-carbonitrile (I) with cyclohexanone (II) in presence of polyphosphoric acid in benzene followed by treatment with hydrochloric acid in ethanol.

合成路线14

By cyclocondensation of 2-aminobenzonitrile (I) with cyclohexanone (II) by means of ZnCl2 at high temperature.

合成路线15

By cyclocondensation of isatine (V) with cyclohexanone (II) and aqueous concentrated NH3 at 150 C in a pressure vessel to acridine-9-carboxamide (VI), followed by a Hoffman degradation with Br2 and sodium methoxide in methanol

合成路线16

This compound can be prepared by two different methods: 1) By cyclocondensation of p-anisidine (I) with 2-oxocyclohexanecarboxylate (II) to 7-methoxy-1,2,3,4-tetrahydroacridone (III), which by treatment with refluxing POCl3 is converted to 9-chloro-7-methoxy-1,2,3,4-tetrahydroacridine (IV). This compound is converted to final product by treatment with NH3 in refluxing p-cresol. 2) By cyclocondensation of 5-methoxyisatin (V) and cyclohexanone (VI) in concentrated aqueous ammonia at 150 C to 7-methoxy-1,2,3,4-tetrahydroacridine-9-carboxamide (VII), followed by a Hoffman degradation with potassium hypobromite.

合成路线17

The intermediate 2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-amine (IV) has been obtained by two different ways: The cyclization of the bicyclic isatin (I) with cyclohexanone, NH4OH and NH4OAc in methanol gives 2,3-dimethyl-5,6,7,8-tetrahydrofuro[2,3-b]quinolin-4-carboxamide (III), which is submitted to a Hofmann rearrangement by means of Br2 and NaOH in water to yield the intermediate amine (IV). The cyclization of 2-amino-4,5-dimethylfuran-3-carbonitrile (V) with cyclohexanone (II) by means of ZnCl2 in hot xylene or nitrobenzene gives directly the intermediate amine (IV). Finally, amine (IV) is condensed with 2-(2-oxopyrrolidin-1-yl)acetic acid methyl ester (VI) by means of NaH in NMP to provide the target amide.

合成路线18

Treatment of carboxylic acid (I) with refluxing cyclohexanone (II) and H2SO4 affords derivative (III), which is then condensed with propargyl bromide (IV) by means of NaH in DMF to yield propargyl ether (V). Treatment of (V) with Et3N in toluene followed by condensation with 4-cloro-iodobenzene (VI) by means of PdCl2, PPh3 and CuI provides propinyloxy derivative (VII), which is then converted into propenyloxy derivative (VIII) by hydrogenation over Pd/ BaSO4 in pyridine. Opening of the lactone ring of (VIII) by means of NaH in MeOH and THF affords methyl ester (IX), which is then condensed with benzoyl chloride (X) by means of DMAP and Et3N in CH2Cl2 to give benzoate (XI). Treatment of (XI) with Et2Zn and chloroiodomethane in dichloroethane (or alternatively in CH2Cl2 or THF) followed by recrystallization from isopropanol furnishes cyclopropane derivative (XII), which is then hydrolyzed by treatment with NaOH in dioxane to yield alcohol (XIII). Finally, (XIII) is condensed with intermediate (XIV) by means of NaH in DMF and then deprotected by treatment with HCl in dioxane to afford the target compound.

合成路线19

The reaction of 2-hydroxybenzamide (XI) with cyclohexanone (XII) by means of Ts-OH in toluene gives the spiranic benzoxazine (XIII), which is condensed with 2-bromopropionyl bromide (XIV) by means of pyridine in toluene, yielding the corresponding acylated benzoxazine (XV). The condensation of (XV) with chiral azetidinone (XVI) by means of Zn in refluxing THF affords the adduct (XVII), which is finally hydrolyzed with LiOH and H2O2 to furnish the target azetidinonepropionic acid (I).

合成路线20

Racemic cyclohexylphenyl glycolic acid (CHPGA) (I) is dissolved with (L)-tyrosine methyl ester (II) in refluxing acetonitrile/water to yield a mixture of diastereomeric salts, which is resolved by crystallization to afford the desired diastereomeric salt [(S)-CHPGA-(L)-TME] (III). Finally, the hydrolysis of salt (III) with HCl or H2SO4 at 40-50ºC in toluene yields the enantiomer (IV). Alternatively intermediate (IV) can be obtained as follows: acetalization of (S)-mandelic acid (V) with pivaldehyde (VI) in pentane and catalytic TfOH provides derivative (VII), which is then treated with LHMDS and then condensed with cyclohexanone (VIII) in THF to furnish aldol adduct (IX). Elimination of tertiary alcohol in (IX) with SOCl2 and pyridine in THF gives derivative (X), which is then converted into intermediate (IV) either by first hydrolysis of lactone (X) with KOH in MeOH and subsequent hydrogenation of the obtained derivative (XI) over Pd/C in MeOH, or by first hydrogenation of (X) over Pd/C in MeOH to give (XII), followed by hydrolysis with KOH in MeOH. On turn, derivative (XII) can alternatively be synthesized by treatment of derivative (VII) with LHMDS, followed by reaction with 3-bromocyclohexene (XIII) in THF to provide derivative (XIV), which is then hydrogenated over Pd/C.

合成路线21

Reaction of 4,6-dimethylpyridin-2-amine (I) with isoamyl nitrite and HCl gives 2-chloro-4,6-dimethylpyridine (II), which is treated with hydrazine in diethylene glycol at 140 C yielding 2-hydrazino-4,6-dimethylpyridine (III). Cyclization of (III) with cyclohexanone (IV) in refluxing diethylene glycol affords the tetrahydro-alpha-carboline (V), which is dehydrogenated with Pd in refluxing diethylene glycol, giving the alpha-carboline (VI). The alkylation of (VI) with the benzyl bromide (VII) by means of potassium tert-butoxide in DMF yields the adduct (VIII), which is hydrolyzed with concentrated H2SO4 to provide the carboxylic acid (IX). Finally, this acid is condensed with (R)-2-hydroxy-1-phenylethylamine (X) by means of HOBT and EDC in CH2Cl2, giving a diastereomeric mixture of the corresponding amides that is resolved by column chromatography. The benzyl bromide intermediate (VII) has been obtained as follows: Esterification of 2-(4-methylphenyl)acetic acid (XI) with tert-butanol and DCC and DMAP in CH2Cl2 gives the corresponding tert-butyl ester (XII), which is condensed with cyclopentyl bromide (XIII) by means of t-BuOK in DMF to yield racemic 2-cyclopentyl-2-(4-methylphenyl)acetic acid tert-butyl ester (XIV). Finally, this compound is brominated with NBS and AIBN in refluxing CCl4.

合成路线22

Reaction of quinic acid (I) with boiling cyclohexanone (II) and a trace of H2SO4 under azeotropical removal of water gave lactone-ketal (III). Subsequent alkylation with bromide (IV) and NaH in DMF at r.t. provided ether (V), which was hydrolyzed with NaOH in aqueous dioxan to produce the sodium carboxylate (VI). Protected 4-hydroxycinnamic acid (VII) was converted to the imidazolide (VIII) on treatment with carbonyl diimidazole (CDI) in DMF, and this was subsequently condensed with (VI) in the presence of NaH in DMF to afford ester (IX). Finally, deprotection of acetal and silylethoxymethyl groups with HCl in aqueous dioxan at r.t. provided the target compound.

合成路线23

Anthranitic acid (I) is reacted with cyclohexanone (II) to give 5-hydroxy-1,2,3,4-tetrahydroacridine (III). The hydroxy compound (III) is then reacted with phosphorous oxychloride to give 5-chloro-1,2,3,4-tetrahydroacridine (IV). Aminolysis of (IV) with n-butylamine affords centbucridine.

合成路线24

The condensation between cyclohexanone (I) and dimethyl itaconate (II) in the presence of NaOMe in cold Et2O afforded the spirobutenolide (III) together with some hydrolyzed product (IV). A further hydrolytic treatment with aqueous NaOH provided acid (IV), which was then converted to acid chloride (V) by treatment with PCl5 in refluxing cyclohexane. Reaction of this acid chloride with N-(2-methoxyphenyl)piperazine in CH2Cl2 at 0 C produced the title amide.

合成路线25

The condensation between cyclohexanone (I) and dimethyl itaconate (II) in the presence of NaOMe in cold Et2O afforded the spirobutenolide (III) together with some hydrolyzed product (IV). A further hydrolytic treatment with aqueous NaOH provided acid (IV), which was then converted to acid chloride (V) by treatment with PCl5 in refluxing cyclohexane. Reaction of this acid chloride with N-(4-fluorophenyl)piperazine in CH2Cl2 at 0 C produced the title amide.

合成路线26

The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II), which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V). The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI), which is esterified with methanol/HCl giving the methyl ester (VII). The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII), which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX). The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b). The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer. Finally, this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.

合成路线27

Lithiation of 1-cyano-5-methoxybenzocyclobutane (I), followed by addition of cyclohexanone (II), provided the 1-hydroxycyclohexyl adduct (III). The cyano group of (III) was then reduced to amine (IV) using LiAlH4. Reductive alkylation of amine (IV) with formaldehyde and NaBH3CN furnished the corresponding dimethylamino derivative, which was then converted to the corresponding hydrochloride salt with ethereal HCl.

合成路线28

The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (XLVIII) with cyclohexanone (XLIX) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (L), which was reduced with DIBAL in dichloromethane to yield the lactol (LI). The condensation of (LI) with the phosphonium chloride (LII) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LIII), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LIV). The condensation of (LIV) with the functionalized allyl silane (LV) by means of BF3/Et2O in acetonitrile gave the adduct (LVI), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LVII). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LVII) with hot AcOH/water afforded the diol (LVIII), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LIX). The coupling of (LIX) with the silylated vinyl iodide (LX), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXI), which was submitted to cleavage of the cyclohexylidene ketal by means of AcOH/TFA to yield the trihydroxy compound (LXII). The protection of the three OH groups of (LXII) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXIII), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).

合成路线29

The previously referenced vinyl iodide intermediate (XXXIV) was obtained as follows: The reaction of L-mannonic acid gamma-lactone (LI) with cyclohexanone (LII) by means of H2SO4 in toluene gave the bis-cyclohexylidene ketal (LIII), which was reduced with DIBAL in dichloromethane to yield the lactol (LIV). The condensation of (LIV) with the phosphonium chloride (LV) by means of t-Bu-OK in refluxing THF afforded the vinyl ether (LVI), which was hydroxylated with OsO4 and dihydroquinidine-4-chlorobenzoate as chiral ligand and acylated with acetic anhydride and pyridine to provide the diacetate (LVII). The condensation of (LVII) with the functionalized allyl silane (LVIII) by means of BF3/Et2O in acetonitrile gave the adduct (LIX), which was submitted to cyclization by means of Triton B(OMe) in THF/methyl acetate to yield the perhydropyrano[3,2-b]pyran derivative (LX). The selective hydrolysis of the exocyclic cyclohexylidene ketal of (LX) with hot HOAc/water afforded the diol (LXI), which by oxidative cleavage with NaIO4 in THF afforded the aldehyde (LXII). The coupling of (LXII) with the silylated vinyl iodide (LXIII), catalyzed by NiCl2 and CrCl2 in DMSO, gave the silylated allyl alcohol (LXIV), which was submitted to cleavage of the cyclohexylidene ketal by means of HOAc/TFA to yield the trihydroxy compound (LXV). The protection of the three OH groups of (LXV) with Tbdms-OTf and lutidine in dichloromethane afforded the tris-Tbdms protected vinyl silane (LXVI), which was finally iodinated with N-iodosuccinimide (NIS) in acetonitrile/chloroacetonitrile to provide the target vinyl iodide intermediate (XXXIV).

合成路线30

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31

In a different method, acetylation of 3-amino-1,2-propanediol (I) yields the amide diol (II). Ketalization of cyclohexanone (III) with diol (II) furnishes the spiro dioxolane (IV). The acetamide function of (IV) is then hydrolyzed to amine (V) employing aqueous hydrazine. Amine (V) is condensed with N,N'-di-(carbobenzoxy)-N''-(trifluoromethylsulfonyl)guanidine (VI) to produce the protected guanidine (VII). The N-carbobenzoxy groups of (VII) are finally removed by hydrogenolysis over Pd/C. Alternatively, amine (V) is condensed with cyanogen bromide to produce the cyanamide (VIII). Then, reaction of cyanamide (VIII) with ammonium chloride in aqueous ammonia furnishes the title guanidine compound

合成路线32

Michael addition of acrylonitrile to the enamine resultant from cyclohexanone (I) and pyrrolidine, followed by alkylation with ethyl bromoacetate, leads to the cyano ester (II). Subsequent Wittig reaction of (II) with methoxymethylene triphenylphosphorane affords the enol ether (III). The ester group of (III) is then reduced to alcohol (IV) using L-selectride. Further intramolecular cyclization of (IV) under acidic conditions gives rise to the bicyclic compound (V). Lithiation of p-bromostyrene (VI) with tert-butyllithium, followed by addition to nitrile (V) produces the ketone adduct (VII). Photooxygenation of (VII), followed by cyclization in the presence of trimethylsilyl triflate, furnishes the fused trioxane derivative (VIII). Finally, oxidative cleavage of the vinyl group of (VIII) with potassium permanganate yields the target carboxylic acid.

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The tosylate precursor (I) can be prepared by a number of different methods. Microbial dihydroxylation of chlorobenzene (XIII) gives (1S,2S)-3-chlorocyclohexa-3,5-diene-1,2-diol (XIV), which is further hydrogenated to (XV) in the presence of Rh/Al 2O3. Regioselective tosylation of (XV), followed by hydrogenation of the resulting monotosylate (XVI) over Pd/C, leads to (1S,2R)-2-hydroxycyclohexyl tosylate (XVII). Subsequent coupling of (XVII) with imidate (X) provides the target intermediate (I) (1). In a different method, ketalization of (S,S)-1,2-cyclohexanediol (XVIII) with 2,2-dimethoxypropane provides the acetonide (XIX), which is oxidized to 2(S)-hydroxycyclohexanone (XX) by treatment with bis(trifluoromethyl)-dioxirane (BTDO). Subsequent tosylation of (XX) furnishes 2(S)-tosyloxycyclohexanone (XXI). Alternatively, the chiral tosyl ketone (XXI) can be obtained by monotosylation of diol (XVIII) in the presence of Bu2SnO to afford the hydroxy tosylate (XXII), which is subjected to Jones oxidation, giving ketone (XXI). The diastereoselective reduction of ketone (XXI) then provides an alternative route to 2(R)-hydroxy tosylate (XVII). Alternatively, the chiral tosyl ketone (XXI) is condensed with the sodium alkoxide of 3,4-dimethoxyphenethyl alcohol (XI) to yield the 2(R)-ether (XXIIIa). Stereoselective reduction of ketone (XXIIIa) utilizing bulky reducing agents such as L-Selectride, LS-Selectride or alpine boranes gives the (S)-cyclohexanol (XXIV), which can be further converted to tosylate (I) under the usual conditions. Similarly, the phenethyl alcohol (XI) can be reacted with 2-chlorocyclohexanone (XXV) by means of NaH to yield the racemic ketone ether (XXIIIb), which is enantioselectively reduced to the (1S,2R)-phenethoxycyclohexanol (XXIV) under Noyori’s asymmetric hydrogenation conditions. A further route to the phenethoxy ketone (XXIIIa) consists of the enantioselective α-oxyamination of cyclohexanone (XXVI) with nitrosobenzene in the presence of L-proline to produce the chiral hydroxylamine derivative (XXVII), which is subsequently cleaved to 2(R)-hydroxycyclohexanone (XXVIII) by treatment with CuSO4, and then coupled with imidate (X) in the presence of boron trifluoride etherate. Optionally, 2(R)-hydroxycyclohexanone (XXVIII) can be obtained by oxidation of the (1R,2R)-cyclohexanediol acetonide (XXIX) with BTDO. Another method for obtaining the (1S,2R)-phenethoxy cyclohexanol (XXIV) is based on the asymmetric reduction of (3,4-dimethoxyphenyl)acetaldehyde cyclohexanediol acetal (XXX) by means of triethylsilane in the presence of chiral Lewis acids (2). Scheme 2.

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The pyrrolidine building blocks are in turn synthesized as shown in Scheme 5. 3(R)-Hydroxypyrrolidine (IV) is protected as the N-Boc derivative (LIV), followed by O-alkylation with benzyl bromide and acidic deprotection of the resulting benzyl ether (LV) to furnish 3(R)-benzyloxypyrrolidine (II). Condensation of pyrrolidine (II) with cyclohexene oxide (XXXI) gives the trans-pyrrolidinocyclohexanol (LVI) as a diastereomeric mixture, which is separated either by crystallization with di-p-toluoyl-L-tartaric acid (DTTA) or by diastereoselective N-oxidation of the undesired diastereoisomer to furnish the target isomer (IX). Alternatively, intermediate (IX) can be obtained by ring opening of epoxide (XXXI) with pyrrolidine (II) in the presence of chiral catalysts. In a different strategy, enantioselective ring opening of cyclohexene oxide (XXXI) with B-bromodiisopinocamphenylborane provides the optically enriched trans-bromohydrin (LVII), which is then condensed with benzyloxypyrrolidine (II) to yield the (1S,2R)-pyrrolidinocyclohexanol (LVIII). Inversion of the configuration of alcohol (LVIII) to produce (IX) is then accomplished by Mitsunobu coupling with formic acid, followed by acidic hydrolysis of the resulting (1R,2R)-formate ester (LIX). Further synthetic strategies leading to the pyrrolidinocyclohexanol (IX) involve cyclization of (R,R)-2-aminocyclohexanol (LX) with 2(R)-benzyloxy-1,4-butanediol ditosylate (LXI), and condensation of (LX) with cyclohexanone (XXVI), followed by asymmetric hydroboration and oxidative work-up of the resulting enamine (LXII) (2). Alternatively, (R,R)-2-aminocyclohexanol (LX) can be converted to the intermediate acetoxysuccinimide (XII) by condensation with 2(R)-acetoxysuccinic anhydride (VI) (prepared from L-malic acid [LXIII] and acetyl chloride) to produce a regioisomeric mixture of succinamic acids (LXIVa) and (LXIVb), which undergoes cyclization to imide (XII) upon heating with acetyl chloride (4). Similarly, racemic trans-2-benzyloxycyclohexylamine (LXV) is resolved by enantioselective N-acylation with isopropyl methoxyacetate in the presence of lipase, followed by hydrolysis of the resulting (R,R)-methoxyacetamide (LXVI) to provide (LXVII) (5). Acylation of (R,R)-2-benzyloxycyclohexylamine (LXVII) with O-acetylmalic anhydride (VI), followed by cyclization with acetyl chloride, yields the N-(2-benzyloxycyclohexyl)succinimide (LXVIII), which is then debenzylated to (XII) by catalytic hydrogenation over Pd/C (4). Scheme 5.

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