合成路线1

The Sandmeyer reaction of 4-trifluoromethylanthranilic acid (I) with NaNO2, HBr and Cu2Br2 gives 2-bromo-4-trifluoromethylbenzoic acid (II), which by reaction with SOCl2 is converted into 2-bromo-4-trifluoromethylbenzoyl chloride (III). The Rosemind reduction of (III) with H2 over Pd/BaSO4/S yields 2-bromo-4-trifluoromethylbenzaldehyde (IV), which is condensed with ethyl cyanacetate (V) in refluxing toluene affording ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]propenoate (VI). The addition of 4-fluorophenylmagnesium bromide (VII) to (VI) in toluene ether gives ethyl 2-cyano-3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoate (VIII), which is hydrolyzed and decarboxylated partially with H2SO4 in refluxing acetic acid water to yield 3-[2-bromo-4-(trifluoromethyl)phenyl]-3-(4-fluorophenyl)propanoic acid (IX). Cyclization of (IX) with butyllithium in ether affords 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-one (X), which is reducted with NaBH4 in methanol giving 3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-ol (XI). The reaction of (XI) with SOCl2 in hot toluene yields 1-chloro-3-(4-fluorophenyl)-6-(trifluoromethyl)indan (XII).

合成路线2

The reaction of 5-bromophthalide (I) with 4-fluorophenylmagnesium bromide (II) in ether gives 4-bromo-4'-fluoro-2-(hydroxymethyl)benzophenone (III), which is reduced with LiAlH4 or NaBH4 in ether to afford 4-bromo-4'-fluoro-2-(hydroxymethyl)benzhydrol (IV). The cyclization of (IV) with 60% H3PO4 or TsOH or H2SO4 at 100 C yields 5-bromo-1-(4-fluoropheny)phthalan (V), which by reaction with cuprous cyanide in refluxing DMF is converted into 1-(4-fluorophenyl)-5-phtalancarbonitrile (VI). Finally, this compound is condensed with 3-(dimethylamino)propyl chloride (A) by means of NaH in hot DMSO.

合成路线3

A new method for the preparation of citalopram has been developed: The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (I) with refluxing SOCl2 gives the acyl chloride (II), which is condensed with 2-amino-2-methyl-1-propanol (III) in THF yielding the corresponding amide (IV). The cyclization of (IV) by means of SOCl2 affords the oxazoline (V), which is treated with 4-fluorophenylmagnesium bromide (VI) in THF giving the benzophenone (VII). This compound (VII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (VIII) in the same solvent, providing the cabinol (IX), which is cyclized by means of methanesulfonyl chloride and Et3N in CH2Cl2 yielding the isobenzofuran (X). Finally, this compound is treated with POCl3 in refluxing pyridine to generate the 5-cyano substituent of citalopram.

合成路线4

A new method for the preparation of citalopram has been reported: The Grignard reaction of 1-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the hydroxymethyl benzophenone (III), which is esterified with pivaloyl chloride in ethyl ether/THF to yield the ester (V). A new Grignard reaction of (V) with 3-(dimethylamino)propylmagnesium bromide in THF affords citalopram.

合成路线5

Two new methods for the preparation of citalopram have been developed: 1) The Grignard condensation of 5-bromoisobenzofuran-1(3H)-one (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethyiamino)propylmagnesium bromide (III) in THF yields N-[3-[5-bromo-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (IV). Finally, this compound is treated with Zn(CN) and Pd(PPh3)4 with or without NaCN in refluxing THF. 2) The Grignard condensation of 5-hydroxyisobenzofuran-1(3H)-one (V) with 4-fluorophenylmagnesium bromide (II) in THF gives a nonisolated intermediate, which by a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (III) in THF yields N-[3-[5-hydroxy-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-1-yl]propyl-N,N-dimethylamine (VI). The sulfonation of the hydroxy group of (VI) with trifluromethanesulfonyl chloride affords the triflate (VII), which is finally treated with NaCN, Cul and Pd(PPh3)4 in refluxing acetonitrile.

合成路线6

The Grignard reaction of 5-aminophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives the methanone (III), which is submitted to a new Grignard reaction with 3-(dimethylamino)propylmagnesium chloride (IV) in the same solvent to yield 1-[4-amino-2-(hydroxymethyl)phenyl]-4-(dimethylamino)-1-(4-fluorophenyl)-1-butanol (V). The cyclization of (V) by heating in H3PO4 affords the isobenzofuran derivative (VI), which is finally submitted to diazotation with NaNO2 and H2SO4 , followed by reaction with NaCN.

合成路线7

The reaction of terephthalic acid (I) with trioxane and oleum at 140-150 C gives 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (II), which is treated with SOCl2 in refluxing toluene to yield the acyl chloride (III). The condensation of (III) with 2-hydroxy-1,1-dimethylethylamine (IV) in the same solvent affords the amide (V), which is cyclized by means of SOCl2 in dichloromethane to provide the oxazoline (VI). The Grignard condensation of (VI) with 4-fluorophenylmagnesium bromide (VII) in THF gives the benzophenone (VIII), which is submitted to a new Grignard condensation with 3-(dimethylamino)propylmagnesium bromide (IX) in the same solvent to yield the diol (X). Finally, this compound is treated with POCl3 or SOCl2 and POCl3 in hot pyridine to afford the target citalopram. Alternatively, the cleavage of the oxazoline ring of (X) with H2SO4 and then with NaOH gives the sodium carboxylate (XI), which is treated with SOCl2 in dichloromethane to yield the corresponding acyl chloride (XII). The reaction of (XII) with dry ammonia in the same solvent affords the carboxamide (XIII), which is finally dehydrated with POCl3 in refluxing acetonitrile to provide the target citalopram.

合成路线8

The Grignard condensation of ethyl 1-benzyl-piperidine-4-carboxylate (I) with 4-fluorophenylmagnesium bromide (II) in THF gives a-bis(4-fluorophenyl)-1-benzylpiperidine-4-methanol (III), which is dehydrated with HCl in refluxing acetic acid yielding 1-benzyl-4-[bis(4 fluorophenyl)methylene]piperidine (IV). Elimination of the benzyl group of (IV) by hydrogenation with H2 over rhodium/carbon in methanol affords 4-[bis(4 fluorophenyl)metlylene] piperidine (V), which is finally condensed with 6-(2-chloroethyl)-7-methyl 5H thiazolo[3,2-a]pyrimidin-5-one (VI) by means of Na2CO3 and KI lo refluxing 4-methyl-2-pentanone. Compound (VI) is obtained by cyclocondensation of 2-thiazolylamine (VII) with 3 acetyl 4,5 dihydro-2(3H)furanone (VIII) by means of aqueous concentrated HCl in refluxing toluene.

合成路线9

The condensation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) with 4-fluorophenylmagnesium bromide (II) in toluene, ether/toluene or ether/dichloromethane gives 1-methyl-4-(4-fluorophenyl)piperidine-3-carboxylic acid methyl ester (III) / (IV), which are an intermediates in the synthesis of paroxetine.(Scheme 10786008a).

合成路线10

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11

AHR-53338 is synthesized in an overall yield of 62% from ethyl isonipecotate (I): Ethyl isonipecotate (I) is protected with benzyl bromide (II) to give (III), which is then treated with 2.5 moles of 4-fluorophenylmagnesium bromide to give the tertiary alcohol (IV). The benzyl group is removed by catalytic hydrogenolysis to give the secondary piperidine (V). The reaction of 1-bromo-3-chloropropane (VI) with acetovanillone (VII) gives 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (VIII) in excellent yield. A mixture of (V) and (VIII) in 1-butanol and triethylamine heated at reflux yields AHR-53338 isolated as the mandelic acid salt.

合成路线12

The Grignard condensation of 5-cyanophthalide (I) with 4-fluorophenylmagnesium bromide (II) in THF gives 1-(4-fluorophenyl)-1-hydroxy-1,3-dihydroisobenzofuran-5-carbonitrile bromomagnesium salt (III), which slowly rearranges to the benzophenone (IV). A new Grignard condensation of (IV) with 3-(dimethylamino)propylmagnesium chloride (V) in THF affords the expected bis(magnesium) salt (VI), which is hydrolyzed with acetic acid to provide the diol (VII) as a racemic mixture. Selective esterification of the primary alcohol of (VII) with (+)-3,3,3-trifluoro-2-methoxy-2-phenylacetyl chloride (VIII) gives the monoester (IX) as a mixture of diastereomers. This mixture is separated by HPLC and the desired diastereomer (X) is treated with potassium tert-butoxide in toluene.

合成路线13

The chlorination of 1-oxo-1,3-dihydroisobenzofuran-5-carboxylic acid (XII) with refluxing SOCl2 gives the acyl chloride (XIII), which is condensed with 2-amino-2-methyl-1-propanol (XIV) in THF to yield the corresponding amide (XV). The cyclization of (XV) by means of SOCl2 affords the oxazoline (XVI), which is treated with 4-fluorophenylmagnesium bromide (XVII) in THF to give the benzophenone (XVIII). This compound (XVIII), without isolation, is treated with 3-(dimethylamino)propylmagnesium chloride (XIX) in the same solvent to provide the carbinol (XX), which is submitted to optical resolution with (+)- or (-)-tartaric acid, or (+)- or (-)-camphor-10-sulfonic acid (CSA) to give the desired (S)-enantiomer (XXI). Cyclization of (XXI) by means of methanesulfonyl chloride and TEA in dichloromethane yields the chiral isobenzofuran (XXII), which is finally treated with POCl3 in refluxing pyridine.

合成路线14

A new synthesis for flutrimazole has been reported: The Grignard condensation of 2-fluorobenzophenone (I) with 4-fluorophenylmagnesium bromide (II) gives the corresponding triphenylcarbinol (III), which by reaction with refluxing SOCl2 is converted to the trityl chloride (IV). Finally, this compound is condensed with imidazole (V) in acetonitrile.

合成路线15

The synthesis of bervastatin is outlined: Heating of 2-hydroxyacetophenone (A) with cyclopentanone (B) and pyrrolidine in toluene gave 3,4-dihydrospiro[1-benzopyran-2(2H),1'-cyclopentan]-4-one (I). 1,2-Addition of 4-fluorophenylmagnesium bromide (D) on (I) followed by dehydration of the intermediate alcohol (II) upon treatment with p-toluenesulfonic acid yielded 4-(4-fluorophenyl)spiro[1-benzopyran-2(2H),1'-cyclopentane] (III). Vilsmeier reaction on (III) using 3-morpholinoacrolein (E) gave the corresponding prop-2-enal (IV). Addition of the dianion of ethyl acetoacetate to aldehyde (IV) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (V) with diethylmethoxyborane and sodium borohydride yielded bervastatin.

合成路线16

N-Benzyl-4-piperidone (I) was reacted with a Grignard reagent prepared from 4-fluorobromobenzene (II) to give the carbinol (III). The benzyl group was removed by catalytic hydrogenation and the resulting amine (IV) was alkylated with 3-bromopropionaldehyde ethylene acetal (V) to the alcohol (VI). Ring closure in hydrochloric acid gave the bicyclic endo-alcohol [(±)-VII] along with some of the exo-isomer removed by crystallization. [(±)-VII] was resolved by crystallization with (R,R)-tartaric acid mono-4-chloroanilide (VIII) to give [(+)-VII] of yet unknown absolute configuration. The latter was acylated with propionic anhydride followed by crystallization with hydrogen chloride in ether to furnish the end product.

合成路线17

By condensation of (-)-anhydroecgonine methyl ester (I) with 4-fluorophenylmagnesium bromide (II) by means of cuprous chloride in refluxing ether.

合成路线18

3) The reaction of 4-hydroxybenzaldehyde (XII) with benzyl bromide and K2CO3 in acetone gives 4-(benzyloxy)benzaldehyde (XIII), which is condensed with 4-fluoroaniline (XIV) in isopropanol, yielding the imine (II). Cyclization of (II) with methyl 4-(chloroformyl)butyrate (XV) by means of tributylamine in toluene affords the trans-azetidinone (XVI), which is hydrolyzed with LiOH in THF/water to provide the propionic acid derivative (XVII). The reaction of (XVII) with oxalyl chloride in dichloromethane gives the corresponding acyl chloride (XVIII), which is condensed with 4-fluorophenylmagnesium bromide (XIX) by means of ZnCl2 and Pd(PPh3)4 in THF to yield a racemic mixture of saturated trans-azetidinones that was resolved by chiral HPLC to the trans-(3R,4S)-enantiomer (XX). The enantioselective reduction of (XX) with BH3 and the chiral oxaborole catalyst CBS gives the benzylated alcohol (XI), which is finally debenzylated as before with H2 over Pd/C in ethanol.

合成路线19

4) The reaction of methyl 4-(chloroformyl)butyrate (XV) with the chiral oxazolidinone (XXI) by means of DMAP and TEA in dichloromethane gives the acylated oxazolidinone (XXII), which is cyclized with the benzylideneimine (II) by means of TiCl4, titanium isopropoxide and TBAF in dichloromethane, yielding trans-(3R,4S)-azetidinone (XXIII). This chiral compound (XXIII) is worked up to give ezetimibe by the same reaction sequence used for its racemic analogue (XVI) but without optical resolution. 5) Racemic trans-azetidinone (XVI) can be submitted to chiral chromatography (Chiracel OD column), microbial or enzymatic subtractive resolution to provide the trans-(3R,4S)-azetidinone (XXIII) or direct microbial or enzymatic hydrolytic resolution to directly provide the trans-(3R,4S)-azetidinone-propionic acid (XXIV), the compound also obtained by hydrolysis of (XXIII) with LiOH. This (3R,4S)-free acid (XXIV) is treated with oxalyl chloride giving the (3R,4S)-acyl chloride (XXV), which by condensation with 4-fluorophenylmagnesium bromide (XIX) yields the (3R,4S)-azetidinone (XX). Reduction of (XX) with borane-dimethylsulfide complex in THF affords an equal mixture of diasteromeric alcohols that was submitted to chiral chromatography on a Chiracel OD column providing the benzylated (3'S)-alcohol (XI).

合成路线20

Ethyl isonipecotate (I) was protected as the N-trityl derivative (II) using triphenylmethyl chloride and triethylamine. Addition of Grignard reagent (IV) (prepared from 1-bromo-4-fluorobenzene (III) and magnesium in Et2O) to (II) produced the diaryl carbinol (V). Alcohol dehydration with simultaneous trityl group cleavage under acidic conditions yielded 4-[bis(4-fluorophenyl)methylene]piperidine (VI). 4-Chlorobutyrylpyrrolidine (IX), prepared by coupling of 4-chlorobutyryl chloride (VII) and pyrrolidine (VIII), was then condensed with piperidine (VI) to yield the target compound.

合成路线21

Addition of 4-fluorophenylmagnesium bromide (XIII) to 1-benzyl-4-piperidinone (XII) afforded carbinol (XIV), which was dehydrated to the tetrahydropyridine (XV) by treatment with p-toluenesulfonic acid in refluxing toluene. Hydrogenation of the olefin (XV) with concomitant benzyl group hydrogenolysis gave 4-(4-fluorophenyl)piperidine (XVI) (1). This compound was also obtained by catalytic hydrogenation of the commercially available 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine (XVII). Alkylation of piperidine (XVI) with N-(3-bromopropyl)phthalimide (XVIII) provided adduct (XIX), which was subjected to hydrazinolysis in refluxing MeOH to furnish the primary amine (XX). Deprotonation of oxazolidine (IX) with n-butyllithium in THF at -78 C, followed by condensation with p-nitrophenyl chloroformate, gave the p-nitrophenoxycarbonyl derivative (XXI). This was finally coupled with amine (XX) to furnish the title carboxamide.

合成路线22

The bicyclic nitrile (III) was prepared by reaction of 1,7-dichloroheptan-4-one (I) with 2-aminoisobutyronitrile (II) in the presence of methanolic ammonia (1). Addition of 2-adamantyllithium (IV) to nitrile (III) in Et2O at -50 C furnished ketone (V). Subsequent addition of 4-fluorophenylmagnesium bromide (VI) to ketone (V) in cold THF provided the desired carbinol, which was isolated as the corresponding hydrochloride salt by lyophilization of its solution in aqueous HCl.

合成路线23

In an alternative route to morpholine (XVIII), bromination of 1,3-bis(trifluoromethyl)benzene (XX) by means of 1,3-dibromo-5,5-dimethylhydantoin (XXI) yielded bromide (XXII). The Grignard reagent prepared from aryl bromide (XXII) was acylated with acetic anhydride at -15 C to produce acetophenone (XXIII). Enantioselective reduction of ketone (XXIII) with ruthenium(II) chloride in the presence of (1S,2R)-cis-1-amino-2-indanol furnished the (R)-alcohol (XXIV). N-Benzyl ethanolamine (XXV) was condensed with glyoxylic acid (XXVI) to give the hydroxy oxazinone (XXVII). This was coupled with the chiral alcohol (XXIV) using trifluoroacetic anhydride and boron trifluoride etherate to afford the target (R,R)-adduct (XXVIII) as the main diastereoisomer. Addition of 4-fluorophenylmagnesium bromide (XXIX) to the lactam function of (XXVIII), followed by catalytic hydrogenation of the intermediate (XXX), provided the required disubstituted morpholine (XVIII).

合成路线24

Addition of 4-fluorophenylmagnesium bromide (XXII) to dimethyl oxalate (XXIII) leads to methyl 4-fluorobenzoylformate (XXIV). Subsequent fluorination of (XXIV) employing diethylaminosulfur trifluoride affords the gem-difluoro ester (XXV). Reduction of ester (XXV) with NaBH4 in cold MeOH gives rise to the aldehyde hemiacetal (XXVI). Then, Wittig condensation of hemiacetal (XXVI) with the ylide generated from phosphonium salt (XXI) provides olefin (XXVII). This is partly reduced to the saturated compound (XXVIII) by treatment with in situ generated diimide, and completely reduced to (XXVIII) by catalytic hydrogenation over iridium black. Cleavage of the N-Boc protecting group of (XXVIII) to furnish piperidine (XXIX) is accomplished by means of iodotrimethylsilane in CHCl3.

合成路线25

The intermediate piperidine (XXIX) has been prepared by an alternative procedure. N-Boc-3-(4-Piperidinyl)propionic acid (XXX) is converted to the mixed anhydride (XXXI), which is further reacted with N,O-dimethylhydroxylamine producing the Weinreb amide (XXXII). Condensation of (XXXII) with 4-fluorophenylmagnesium bromide (XXII) leads to ketone (XXXIII). Acidic cleavage of the N-Boc group of (XXXIII), followed by treatment of the resultant piperidine (XXXIV) with benzyl chloroformate leads to the Cbz-protected analogue (XXXV). Difluorination of ketone (XXXV) is carried out by the method of Katzenellenbogen, consisting of formation of dithioketal (XXXVI), which is then reacted with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of HF-pyridine to afford the gem-difluoro compound (XXXVII), accompanied by an unseparable by-product. A new protecting group switch is required in order to achieve complete purification of (XXXVII), which is thus converted into the N-Boc derivative (XXVIII). Acidic cleavage of (XXVIII) as above leads to the piperidine (XXIX).

合成路线26

合成路线27

In one method, metalation of 1-bromo-4-fluorobenzene (XI) with Mg in 2-MeTHF at 90 °C gives 4-fluorophenyl magnesium bromide (XII), which then couples with 2-bromothiophene (XIII) in the presence of NiCl2·dppe and AcOH in 2-MeTHF at 22 °C or in the presence of Pd(OAc)2 and DPPP in THF to yield 2-(4-fluorophenyl)thiophene (XIV). Finally, this compound undergoes Friedel–Crafts acylation with 5-iodo-2-methylbenzoic acid (XV) (initially chlorinated with SOCl2 in CH2Cl2) using AlCl3 in CH2Cl2, and subsequent reduction with (Me2SiH)2O in refluxing acetonitrile .
In another method, hydrolysis of methyl 5-bromo-2-methylbenzoate (XVI) with NaOH in MeOH at 50 °C gives rise to the benzoic acid (XVII) , which is then chlorinated with (COCl)2 in the presence of DMF in CH2Cl2 to yield 5-bromo-2-methylbenzoyl chloride (XVIII). Friedel–Crafts reaction of acyl chloride (XVIII) with 2-(4-fluorophenyl) thiophene (XIV) in the presence of AlCl3 in CH2Cl2 affords ketone (XIX), which is then reduced by means of Et3SiH and BF3·Et2O in CH2Cl2/acetonitrile to afford 2-(5-bromo-2-methylbenzoyl)-5-(4-fluorophenyl)thiophene (III) . Finally, compound (III) is iodinated with NaI and CuI in the presence of (MeNHCH2)2 in refluxing toluene/diglyme (IV) .
Alternatively, coupling of 4-fluorophenylboronic acid (XX) with either 2-bromothiophene (XIII) in the presence of PdCl2(PPh3)2 and Na2CO3 in dimethoxyethane at 75-80 °C or with 2-iodothiophene (XXI) in the presence of PdCl2(PPh3)2 at 50 °C affords 2-(4-fluorophenyl) thiophene (XIV) .