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药物详细合成路线

Name Nitalapram;Citalopram hydrobromide;Lu-10-171B;ZD-211;Lu-10-171(free base);Sepram;Apertia;Lupram;Cipram;Prisdal;Celexa;Elopram;Seropram;Cipramil
Chemical Name 1-(3-Dimethylaminopropyl)-1-(p-fluorophenyl)-5-phthalancarbonitrile monohydrobromide;1-(3-Dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile monohydrobromide
CAS 59729-32-7
Related CAS 59729-33-8 (free base)
Formula C20H22BrFN2O
Structure
Formula Weight 405.31354
Stage 上市-1989
Company Lundbeck (Originator), Janssen-Cilag (Marketer), Almirall Prodesfarma (Licensee), Amersham (Licensee), Bayer (Licensee), Forest (Licensee), Mitsui Pharmaceuticals (Licensee), Recordati (Licensee)
Activity/Mechanism Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors
Syn. Route 14
Route 1
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.
List of intermediates No.
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (ii)
diethyl 2,2,5,5-tetramethylhexanedioate (a)
1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone (i)
(e)-2-chloro-3-hydroxy-2-propenal (iii)
(e)-2,3-dichloro-2-propenal (iv)
(e)-3-anilino-2-chloro-2-propenal (v)
(e)-2-chloro-3-isopropoxy-2-propenal (vi)
Reference 1:
    bigler, a.j.; et al.; quantitative structure-activity relationships in a series of selective 5-ht uptake inhibitors. eur j med chem - chim ther 1977, 12, 3, 289-295.
Reference 2:
    bogeso, k.p.; toft, a.s. (kefalas a/s); anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. de 2657013; fr 2338271; gb 1526331; jp 52105162; us 4136193 .
Reference 3:
    muddasani, p.r.; nannapaneni, w.c. (natco pharma ltd.); process for the preparation of high purity citalopram and its pharmaceutically acceptable salts. wo 0416602 .
Reference 4:
    roberts, p.j.; castaner, j.; serradell, m.n.; blancafort, p.; citalopram. drugs fut 1979, 4, 6, 407.

Route 2
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.
List of intermediates No.
1-(2-cyclohexylphenoxy)-3-[isopropyl(methyl)amino]-2-propanol (viii)
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (vi)
4-[(3r,4r)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2h-chromen-4-yl]phenyl acetate (iii)
4-(dimethylamino)butyric acid (i)
n-acetyl-3,4-xylidine; 3,4-dimethylacetanilide (ii)
4,5-dimethyl-2-nitroacetanilide (iv)
2-nitro-4,5-dimethylaniline; 6-nitro-3,4-xylidine; 4,5-dimethyl-2-nitroaniline (v)
1-azido-4,5-dimethyl-2-nitrobenzene (vii)
5,6-dimethyl-2,1,3-benzoxadiazol-1-ium-1-olate (ix)
2-amino-3-cyano-6,7-dimethyl-1,4-quinoxalinediiumdiolate (x)
Reference 1:
    dallasta, l.; casazza, u.; petersen, h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0023431 .

Route 3
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.
List of intermediates No.
3-sulfanyl-1-propanol (iv)
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (ii)
2-chloro-3-cyano-6,7-dimethyl-1,4-quinoxalinediiumdiolate (i)
(2s,3r,4r,5r)-2,3,4,6-tetrakis(benzyloxy)-5-hydroxyhexanal o-benzyloxime (iii)
o-phenyl o-[(1r,2s,3r,4s)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)imino]-1-[(benzyloxy)methyl]pentyl] carbonothioate (v)
1-[([(1r,2r,3s,4s,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)amino]cyclopentyl]methoxy)methyl]benzene; o-benzyl-n-[(1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentyl]hydroxylamine (vi)
Reference 1:
    ellegaard, p.; petersen, h.; rock, m.h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0012044 .

Route 4
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.
List of intermediates No.
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (ii)
1-(6-methyl-3-pyridinyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone (i)
1-[([(1r,2r,3s,4s,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)amino]cyclopentyl]methoxy)methyl]benzene; o-benzyl-n-[(1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentyl]hydroxylamine (iii)
(1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentylamine; (1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentanamine (iv)
n-[(1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentyl]acetamide (v)
n-[(1r,2s,3s,4r,5r)-2,3,4-trihydroxy-5-(hydroxymethyl)cyclopentyl]acetamide (vi)
(3r,4s,5s,6r)-3,4,5-tris(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2h-pyran-2-ol (vii)
Reference 1:
    rock, m.h.; petersen, h.; svane, h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0013648 .

Route 5
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.
List of intermediates No.
1-(2-cyclohexylphenoxy)-3-[isopropyl(methyl)amino]-2-propanol (iv)
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (ii)
Reference 1:
    bregnedal, p.; petersen, h.; bogeso, k.p. (h. lundbeck a/s); method for the preparation of citalopram. us 6258842; wo 9819512 .

Route 6
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.
List of intermediates No.
2-[(e)-(dimethylamino)methylidene]-1-(3-methoxyphenyl)-1,3-butanedione (vii)
4-[(3r,4r)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2h-chromen-4-yl]phenyl acetate (iv)
4-(dimethylamino)butyric acid (ii)
n-acetyl-3,4-xylidine; 3,4-dimethylacetanilide (iii)
4,5-dimethyl-2-nitroacetanilide (v)
2-nitro-4,5-dimethylaniline; 6-nitro-3,4-xylidine; 4,5-dimethyl-2-nitroaniline (vi)
1-azido-4,5-dimethyl-2-nitrobenzene (viii)
5,6-dimethyl-2,1,3-benzoxadiazol-1-ium-1-olate (x)
1-[([(1r,2r,3s,4s,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)amino]cyclopentyl]methoxy)methyl]benzene; o-benzyl-n-[(1r,2s,3s,4r,5r)-2,3,4-tris(benzyloxy)-5-[(benzyloxy)methyl]cyclopentyl]hydroxylamine (ix)
Reference 1:
    greenwood, a.k.; mchattie, d.; rechka, j.a.; hedger, p.c.m.; gamble, m.p. (resolution chemicals ltd.); process for the preparation of citalopram. wo 0166536 .

Route 7
the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with n,n-dimethyl-2-propenamide (ii) by means of lda in thf gives the addition compound (iii), which is then reduced to the target citalopram by means of red-al in toluene.
List of intermediates No.
(2s,3s)-2-[(tert-butoxycarbonyl)amino]-3-[((2r)-2-[[(9h-fluoren-9-ylmethoxy)carbonyl]amino]propanoyl)oxy]butyric acid (ii)
(e)-2-chloro-3-isopropoxy-2-propenal (i)
Reference 1:
    petersen, h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0168630 .

Route 8
the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with n-(2,3-epoxypropyl)-n,n-dimethylamine (ii) by means of lda in thf gives the addition compound (iii), which is then reduced to the target citalopram by means of h2 over pd/c, pt/c or rh/c.alternatively, the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with 3-(dimethylamino)propionaldehyde (iv) by means of lda in thf also gives the intermediate addition compound (iii).
List of intermediates No.
(e)-2-chloro-3-isopropoxy-2-propenal (i)
Reference 1:
    petersen, h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0168628 .

Route 9
the reduction of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (i) with lialh4 in thf/ethyl ether gives 5-(aminomethyl)-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (ii), which is finally oxidized with cu2cl2 and oxygen in hot pyridine, or with k2s2o8 and niso4 in dichloromethane/water to yield the target compound.
List of intermediates No.
Reference 1:
    petersen, h.; dancer, r. (h. lundbeck a/s); method for the preparation of citalopram. wo 0185712 .

Route 10
the reaction of 5-carboxyphthalide (i) with 4-fluorophenylmagnesium bromide (ii) in thf gives the lactol (iii), which is treated with 3-(dimethylamino)propylmagnesium chloride in the same solvent to yield the dihydroxylated intermediate (v). the cyclization of (v) by means of conc. hcl affords the isobenzofuran derivative (vi), which is finally treated with sulfamide and thionyl chloride in sulfolane at 130 c in order to convert the carboxy group of (vi) into the target 5-cyano group of citalopram.
List of intermediates No.
1-(2-cyclohexylphenoxy)-3-[isopropyl(methyl)amino]-2-propanol (iv)
(1s,3r,4r,5s,6r)-8-methyl-3-(4-methylphenyl)-6-[(4-methylphenyl)sulfinyl]-4-phenyl-8-azabicyclo[3.2.1]octan-2-ol (ii)
4-(dimethylamino)butyric acid (i)
Reference 1:
    petersen, h.; dancer, r.; ahmadian, h. (h. lundbeck a/s); method for the preparation of citalopram. wo 0216341; wo 0216342 .

Route 11
the reaction of 5-chloro-1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran (i) with nacn catalyzed by nicl2, pph3 and zn in refluxing acetonitrile gives the target citalopram.
List of intermediates No.
Reference 1:
    petersen, h.; rock, m.h. (h. lundbeck a/s); method for the preparation of citalopram. us 2002061925; wo 0011926 .

Route 12
the intermediate 1-(4-fluorophenyl)-1-(3-hydroxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (iv) has been obtained by three related ways:1. the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with 3-(tert-butyldimethylsilyloxy)propyl bromide (ii) by means of lda in thf gives 1-[3-(tert-butyldimethylsilyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (iii), which is deprotected with hcl in methanol to yield the hydroxypropyl intermediate (iv).2. the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with 3-(benzyloxy)propyl bromide (v) by means of lda in thf gives 1-[3-(benzyloxy)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (vi), which is deprotected by treatment with 1,4-cyclohexadiene over pd/c in ethanol to yield the hydroxypropyl intermediate (iv).3. the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (i) with 3-(tetrahydropyranyloxy)propyl bromide (vii) by means of lda in thf gives 1-(4-fluorophenyl)-1-[3-(tetrahydropyranyloxy)propyl]-1,3-dihydroisobenzofuran-5-carbonitrile (viii), which is deprotected with ts-oh in methanol to yield the hydroxypropyl intermediate (iv).the reaction of the intermediate (iv) with ts-cl and tea in toluene gives the corresponding tosylate (ix), which is finally treated with dimethylamine in hot dmf to afford the target citalopram.the reaction of the intermediate (iv) with ms-cl and tea in thf gives the corresponding mesylate (x), which is finally treated with dimethylamine in hot ethanol/thf to afford the target citalopram.alternatively, the reaction of mesylate (x) with nan3 in hot dmf gives the corresponding azido compound (xi), which is hydrogenated with h2 over pd/c in etoh to yield the 3-aminopropyl derivative (xii). finally, this compound is methylated by means of formaldehyde and nacnbh3 in methanol to provide the target citalopram.
List of intermediates No.
(v)
2-bromo-n-(2-cyanophenyl)-2-methylpropanamide (ii)
(e)-2-chloro-3-isopropoxy-2-propenal (i)
tert-butyl 2-(benzylamino)acetate (vii)
Reference 1:
    petersen, h.; rock, m.h.; ahmadian, h. (h. lundbeck a/s); method for the preparation of citalopram. us 6420574 .

Route 13
the reaction of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-5-iodo-1,3-dihydroisobenzofuran (i) with cucn and pyridine in dmf at 140 c gives the target citalopram.
List of intermediates No.
Reference 1:
    biswas, s.; kumar, y.; sharma, t.k.; sathyanarayana, s.; vijayaraghavan, b. (ranbaxy laboratories ltd.); process for the preparation of citalopram. wo 0272565 .

Route 14
this compound has been obtained by several related ways.1.- the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (i) with 3-chloropropyl tosylate (ii) by means of lda in thf gives 1-(4-fluorophenyl)-1-(3-tosyloxypropyl)-1,3-dihydroisobenzofuran-5-carbonitrile (iii), which is then condensed with dimethylamine in hot dmf to yield the target citalopram.2.- the condensation of 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5- carbonitrile (i) with 3-chloropropyl mesylate (iv) by means of lda in thf gives 1-(4-fluorophenyl)-1-(3-mesyloxypropyl)-1,3-dihydroisobenzofuran-5- carbonitrile (v), which is then condensed with sodium azide in hot dmf to yield the corresponding azido derivative (vi). the reduction of (vi) with h2 over pd/c in ethanol affords the 3-aminopropyl derivative (vii), which is finally reductively methylated with formaldehyde and nabh3cn in methanol to provide the target citalopram.3.- the reaction of mesylate (v) with methylamine in thf gives the corresponding methylaminopropyl derivative (viii), which is finally methylated by means of hcho in refluxing hcooh to yield the target citalopram.4.- the direct condensation of mesylate (v) with dimethylamine in hot ethanol/thf also gives the target citalopram.
List of intermediates No.
(e)-2-chloro-3-isopropoxy-2-propenal (i)
Reference 1:
    rock, m.h.; ahmadian, h. (h. lundbeck a/s); method for the preparation of citalopram. ca 2401374; ep 1263750; fr 2805814; jp 2003519692; us 2003092761; wo 0151478 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名氢溴酸西酞普兰;英文名Nitalapram;Citalopram hydrobromide;Lu-10-171B;ZD-211;Lu-10-171(free base);Sepram;Apertia;Lupram;Cipram;Prisdal;Celexa;Elopram;Seropram;Cipramil;CAS[59729-32-7]

 
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