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药物详细合成路线

Name Sertraline;CP-51974-1;CP-5197401(hydrochloride)
Chemical Name (1S-cis)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine;(1S,4S)-4-(3,4-Dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine
CAS 79617-96-2
Related CAS 79559-97-0 (HCl)
Formula C17H17Cl2N
Structure
Formula Weight 306.23774
Stage 未确定
Company Pfizer (Originator)
Activity/Mechanism Antidepressants, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, 5-HT Reuptake Inhibitors
Syn. Route 8
Route 1
a new synthesis of [7-3h]-sertraline has been described:the optical resolution of 7-bromo-1-(methylamino)tetraline (i) with n-acetyl-d-phenylalanine gives the (r)-isomer (ii), which is acylated with formic acid - acetic anhydride to the formamide (iii). the oxidation of (iii) with kmno4 in acetone - water yields 6-bromo-4(r)-(methylamino)-1,2,3,4-tetrahydronaphthalen-1-one (iv), which, by a grignard condensation with 3,4-dichlorophenylmagnesium bromide (v) in ether - toluene, affords 6-bromo-1(s)-(3,4-dichlorophenyl)-4(r)-(n-methylformamido)-1,2,3,4-tetrahydronaphthalen-1-ol (vi). the reduction of (vi) with triethylsilane tetrafluoroborate in dichloromethane gives 6-bromo-1(s)-(3,4-dichlorophenyl)-4(r)-(n-methylformamido)tetraline (vii), which is hydrolyzed with hcl in isopropanol to the corresponding methylamine (viii). oxidation of (viii) with naclo naoch3 in methanol - water yields the imine (ix), which is reduced with nabh4 in thf - methanol to 6-bromo-1(s)-(3,4-dichlorophenyl)-4(s)-(methylamino)tetraline (x), along with starting (viii). after separation by column chromatography, (x) is reduced with h2 over pd/c or with t2 over pd/c in thf containing triethylamine.
List of intermediates No.
4-[[2-(acetoxy)benzoyl]amino]-3-hydroxybenzyl acetate (i)
2-hydroxy-n-[2-hydroxy-4-(hydroxymethyl)phenyl]benzamide (ii)
2-hydroxy-n-[4-(hydroxymethyl)-3,6-dioxo-1,4-cyclohexadien-1-yl]benzamide (iii)
5-indanamine; 2,3-dihydro-1h-inden-5-ylamine (iv)
n-(2,3-dihydro-1h-inden-5-yl)acetamide (v)
n-(6-nitro-2,3-dihydro-1h-inden-5-yl)acetamide (vi)
n-(4-nitro-2,3-dihydro-1h-inden-5-yl)acetamide (vii)
6-nitro-2,3-dihydro-1h-inden-5-ylamine; 6-nitro-5-indanamine (viii)
5-bromo-6-nitroindane (ix)
5-(2,4-difluorophenoxy)-6-nitroindane (x)
Reference 1:
    williams, m.t.; welch, w.m.; synthesis of 7-3h-(is,4s)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-n-methyl-i-naphthalenamine hydrochloride (7-3h-sertraline). j label compd radiopharm 1993, 33, 2, 119.

Route 2
the friedel-krafts reaction of benzene (i) and 3,4-dichlorobenzoyl chloride (ii) by means of alcl3 in dichloromethane gives 3,4-dichlorobenzophenone (iii), which is condensed with diethyl succinate (iv) by means of potassium tert-butoxide in tert-butyl alcohol yielding ethyl 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenylbut-3-enoate (v). hydrolysis of (v) with hbr in refluxing acetic acid affords 4-(3,4-dichlorophenyl)-4-phenylbut-3-enoic acid (vi), which is hydrogenated with h2 over pd/c in ethyl acetate giving 4-(3,4-dichlorophenyl)-4-phenylbutanoic acid (vii), which is converted into the corresponding acyl chloride (viii) with refluxing socl2. cyclization of (viii) with alcl3 in cs2 yields 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2h)-naphthalenone (ix), which is treated with methylamine and ticl4 in thf affording the corresponding schiff base (x). finally, this compound is reduced with h2 over pd/c in thf.
List of intermediates No.
propylene oxide; 2-methyloxirane (iv)
ethyl 2-[(1s,2s,13s,21r)-16-(benzyloxy)-22-(cyclopropylmethyl)-2-hydroxy-14-oxa-22-azaheptacyclo[13.9.1.0(1,13).0(2,21).0(4,12).0(5,10).0(19,25)]pentacosa-4(12),5,7,9,15(25),16,18-heptaen-11-yl]acetate (i)
(2r)-2-[[(benzyloxy)carbonyl]amino]-3-methoxypropionic acid (ii)
methyl (3s)-2-[[(4r)-3-(tert-butoxycarbonyl)-2-oxo-1,3-oxazolidin-4-yl]carbonyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (iii)
methyl (3s)-2-[(2r)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (v)
(e)-2-butenyl (3s)-2-[(2r)-2-[(tert-butoxycarbonyl)amino]-3-hydroxypropanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (vi)
allyl (2s,3s)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoate (vii)
(2s,3s)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoic acid (viii)
(e)-2-butenyl (3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (ix)
(3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid (x)
Reference 1:
    kraska, a.r.; welch, w.m. jr.; koe, b.k.; harbert, c.a. (pfizer inc.); antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphtalenamine. ep 0030081; jp 1981086137; us 4536518 .
Reference 2:
    castaner, j.; serradell, m.n.; sertraline. drugs fut 1984, 9, 4, 277.

Route 3
a stereoselective synthesis of sertraline has been described:the silylation of 1,2-dihydronaphthalen-1(r)-ol (i) with tert-butyldiphenylsilyl chloride (tbdps-cl) gives the corresponding silyl ether (ii), which is brominated with br2 and triethylamine (tea) in dichloromethane yielding the 4-bromo-compound (iii). the condensation of (iii) with 3,4-dichlorophenyltrimethyltin (iv), by means of a palladium catalyst affords the silylated phenylnaphthalenol (v), which is deprotected with tbaf and acetic acid to provide 4-(3,4-dichlorophenyl)-1,2-dihydronaphthalen-1(r)-ol (vi). the regioselective hydrogenation with h2 over chiral iridium or rhodium catalysts gives the (1r-trans)-tetrahydronaphthol (vii), which is treated with diphenylphosphoryl azide (dppa) and dbu in thf yielding the (1s-cis)-azide (viii). the reduction of (viii) with h2 over pd/c in ethanol affords the corresponding amine (ix), which is treated with ethyl chloroformate to give the expected carbamate (x). finally, this compound is reduced with lialh(ome)3 in thf.2,4-dichlorophenyltrimethyltin (iv) is prepared by reaction of 3,4-dichlorophenol (xi) with triflic anhydride in pyridine/ch2cl2 to give triflate (xii), which is converted to (iv) by reaction with hexamethylditin and pd(pph3)4 in thf.the silylated naphthalenol (v) can also be obtained by condensation of (iii) with the phenylboronic acid (xiii) in the presence of a palladium catalyst.
List of intermediates No.
tert-butyl 4-(cyclooctylamino)-1-piperidinecarboxylate (i)
tert-butyl 4-[cyclooctyl(propionyl)amino]-1-piperidinecarboxylate (ii)
n-cyclooctyl-n-(4-piperidinyl)propanamide (iii)
methyl (2r)-2-(dibenzylamino)-2-phenylethanoate (xiii)
(2r)-2-(dibenzylamino)-2-phenyl-1-ethanol (v)
(2r)-2-(dibenzylamino)-2-phenylethanal (iv)
ethyl (e,4s)-4-(dibenzylamino)-4-phenyl-2-butenoate (xii)
methyl (4s)-4-(dibenzylamino)-4-phenylbutanoate (xi)
(4s)-4-(dibenzylamino)-4-phenyl-1-butanol (vi)
(4s)-4-(dibenzylamino)-4-phenylbutanal (vii)
(4s)-4-(dibenzylamino)-1-(3,4-dichlorophenyl)-4-phenyl-1-butanol (viii)
n,n-dibenzyl-n-[(1s,4s)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenyl]amine; (1s,4s)-n,n-dibenzyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenamine (ix)
tert-butyl (1s,4s)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate (x)
Reference 1:
    rovis, t.; lautens, m.; selective functionalization of 1,2-dihydronaphthalenols leads to a concise, stereoselective synthesis of sertraline. tetrahedron 1999, 55, 29, 8967.

Route 4
a new total synthesis of sertraline has been described: the reduction of n,n-dibenzyl-d-phenylglycine methyl ester (i) with lialh4 in thf gives alcohol (ii), which is oxidized to aldehyde (iii) with oxalyl chloride in dichloromethane. the condensation of (iii) with the phosphorane (iv) in benzene yields the unsaturated ester (v), which is reduced with mg in methanol affording the saturated methyl ester (vi). reduction of (vi) with lialh4 in thf provides the corresponding butanol derivative (vii), which is oxidized to the aldehyde (viii) with pyridinium dichromate (pdc) in dichloromethane. the grignard reaction of (viii) with 3,4-dichlorophenylmagnesium bromide (ix) in thf affords the secondary alcohol (x), which is cyclized by means of alcl3 in dichloromethane yielding a mixture of the desired cis-isomer (xi) along with some trans-isomer separated by column chromatography. debenzylation of (xi) by h2 over pd(oh)2 in methanol, followed by protection with boc2o yields the carbamate (xii), which is methylated with methyl iodide and nah in thf to afford the protected intermediate (xiii). finally, compound (xiii) is deprotected with tfa in dichloromethane.
List of intermediates No.
n-(2,3-dihydro-1h-inden-5-yl)acetamide (ix)
2-chloro-1-(3-pyridinyl)-1-ethanone (iv)
6-amino-1,3-bis(cyclopropylmethyl)-2,4(1h,3h)-pyrimidinedione (i)
6-amino-1,3-bis(cyclopropylmethyl)-5-nitroso-2,4(1h,3h)-pyrimidinedione (ii)
5,6-diamino-1,3-bis(cyclopropylmethyl)-2,4(1h,3h)-pyrimidinedione (iii)
6-amino-1,3-bis(cyclopropylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylformamide (v)
1,3-bis(cyclopropylmethyl)-3,7-dihydro-1h-purine-2,6-dione (vi)
1,3-bis(cyclopropylmethyl)-8-nitro-3,7-dihydro-1h-purine-2,6-dione (vii)
2-[(2-amino-6-oxo-1,6-dihydro-9h-purin-9-yl)methoxy]ethyl (2s)-2-{[(benzyloxy)carbonyl]amino}-3-methylbutanoate (viii)
sodium (2s)-2-{[(e)-3-methoxy-1-methyl-3-oxo-1-propenyl]amino}-3-methylbutanoate (x)
2-[(2-amino-6-oxo-1,6-dihydro-9h-purin-9-yl)methoxy]ethyl 4-methylbenzenesulfonate (xi)
methyl (e)-3-{[(1s)-1-({2-[(2-amino-6-oxo-1,6-dihydro-9h-purin-9-yl)methoxy]ethoxy}carbonyl)-2-methylpropyl]amino}-2-butenoate (xii)
2-(1-adamantyl)-4-bromophenol (xiii)
Reference 1:
    chandrasekhar, s.; reddy, m.v.; an expedient total synthesis of cis-(+)-sertraline from d-phenylglycine. tetrahedron 2000, 56, 8, 1111.

Route 5
the reaction of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-one (i) with methylamine by means of ticl4 in toluene gives the corresponding imine (ii), which is reduced with h2 over 5% pd/graphite, yielding a 12:1 mixture of (??(cis)(iii) and (?)(trans)(iii). this mixture was resolved by a treatment with (d)-mandelic acid, crystallization of the resulting salt, and treatment with naoh in toluene/water to afford the target (+)(s,s)(cis)-sertraline.
List of intermediates No.
(e)-2-butenyl (3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (i)
(3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid (ii)
Reference 1:
    gershon, n.; nidam, t.; mendelovich, m.; pilarsky, g. (teva pharmaceutical industries ltd.; teva pharmaceuticals usa, inc.); novel process for preparing (+)-cis-sertraline. wo 0168566 .

Route 6
the condensation of 1-naphthol (i) with an excess of o-dichlorobenzene (ii) at 100 c by means of anhydrous alcl3 gives 4-(3,4-dichlorophenyl)-1-tetralone (iii), which is allowed to react with n-methylhydroxylamine (iv) and naoac in refluxing ethanol, yielding the nitrone (v). the reduction of (v) with h2 over rani in methanol affords a racemic cis/trans (9:1) mixture of methylamines, which by crystallization of its hydrochloride in ethanol provides pure (racemic)-(cis)-(vi). finally, the target (1s)-(cis)-compound is obtained by optical resolution of (vi) with (r)-(-)-mandelic acid.
List of intermediates No.
1-[[3-amino-2-(dibenzylamino)-4-quinolinyl]amino]-2-methyl-2-propanol (iv)
3-quinolinecarbaldehyde (i)
(e)-2-butenyl (3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (iii)
Reference 1:
    vukics, k.; et al.; improved industrial synthesis of antidepressant sertraline. org process res dev 2002, 6, 1, 82.

Route 7
the reaction of intermediate 4-(3,4-dichlorophenyl)-4-phenylbutyric acid (i) (see scheme number 09017202a intermediate (vii)) with (cocl)2 in dichloromethane gives the acyl chloride (ii), which is condensed with methyl carbamate (iii) in hot toluene to yield n-[4-(3,4-dichlorophenyl)-4-phenylbutyryl]carbamic acid methyl ester (iv). the reduction of (iv) with dibal in toluene/dichloromethane affords the hydroxybutyl derivative (v), which is cyclized by means of ticl4 in dichloromethane to provide n-[4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl]carbamic acid methyl ester as a mixture of the cis and trans isomers, easily separated by chromatography. finally, the desired cis isomer (vi) is reduced with lialh4 in thf to afford the target (rac)-sertraline.
List of intermediates No.
allyl (2s,3s)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoate (i)
(2s,3s)-5-[(2-azidoacetyl)(methyl)amino]-2-(1-hydroxy-1-methylethyl)-3-methyl-4-oxopentanoic acid (ii)
tert-butyl (1s,4s)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthalenylcarbamate (vi)
5-({2-bromo-9-[(triisopropylsilyl)oxy]-9h-fluoren-9-yl}amino)-2-(3,4-dimethoxyphenyl)-2-isopropylpentanenitrile (iii)
Reference 1:
    deninno, m.p.; et al.; the preparation and intra- and intermolecular addition reactions of acyclic n-acylimines: applications to the synthesis of (±)-sertraline. j org chem 2001, 66, 21, 6988.

Route 8
the reaction of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-one (i) with methylamine and formic acid in dmf gives the corresponding methylimine (ii), which is reduced with h2 over pd/c to yield (rac)(cis)-4-(3,4-dichlorophenyl)-n-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (rac)(cis)(iii). finally, this compound is submitted to optical resolution by means of mandelic acid to afford the target (1s)(cis)-sertraline.
List of intermediates No.
(e)-2-butenyl (3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylate (i)
(3s)-2-[(2r)-3-([(2s)-2-[[2-[(2-azidoacetyl)(methyl)amino]propanoyl](methyl)amino]-3-hydroxy-3-methylbutanoyl]oxy)-2-[(tert-butoxycarbonyl)amino]propanoyl]-2,3,4,5-tetrahydro-3-pyridazinecarboxylic acid (ii)
Reference 1:
    laitinen, i.; pietikaeinen, p. (orion corporation); process for the production of sertraline and intermediates useful therefor. us 2003013768 .

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舍曲林;英文名Sertraline;CP-51974-1;CP-5197401(hydrochloride);CAS[79617-96-2]

 
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