CN1268621C - Preparation of citalopram - Google Patents
Preparation of citalopram Download PDFInfo
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- CN1268621C CN1268621C CN 03165033 CN03165033A CN1268621C CN 1268621 C CN1268621 C CN 1268621C CN 03165033 CN03165033 CN 03165033 CN 03165033 A CN03165033 A CN 03165033A CN 1268621 C CN1268621 C CN 1268621C
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Abstract
The present invention relates to a method for preparing citalopram, which comprises a reaction of a compound disclosed as a formula (IV) and 3-(N, N-dimethylamino)propyl magnesium halide to prepare citalopram, wherein R is C1-6 alkyl, acyl, C1-6 alkyl-sulfonyl or aryl-sulfonyl.
Description
The application is the dividing an application of PCT/DK99/00581 application for a patent for invention of the same title submitted on October 25th, 1999, and original application enters the China national stage June 22 calendar year 2001, and obtains Chinese patent application numbers 99814896.2.
Technical field
The antidepressant drug citalopram that the present invention relates to know, be 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation method of 3-dihydro-5-isobenzofurancarboniderivatives.
Background of invention
Citalopram is the thymoleptic of knowing, and has gone on the market for many years, has following array structure:
Formula I
It is a selectivity central action thrombotonin (serotonin; Therefore 5-HT) reuptake inhibitor has antidepressant activity.The antidepressant activity of this compound is existing report in many pieces of documents, J.Hyttel for example, Prog.Neuro-Psychopharmcol.﹠amp; Biol.Psychiat. (" nerve-psychopharmacology and biological psychiatry progress ") 1982,6,277-295 and A.Gravem, Acta Psychiatr.Scand. (" Scandinavia psychiatry journal ") 1987,75,478-486.It is effective to the treatment of dull-witted and cerebrovascular disease that EP-A 474580 further discloses this compound.
Citalopram is disclosed in DE 2,657 for the first time, in 271, is equivalent to US 4,136,193.This patent gazette has been described a kind of preparation method of citalopram, has summarized the another kind of method that can be used for preparing citalopram.
According to described method, in the presence of methanesulfinyl methide condensing agent, make corresponding 1-(4-fluorophenyl)-1, the reaction of 3-dihydro-5-isobenzofurancarboniderivatives and 3-(N, N-dimethylamino) propyl chloride.Raw material is from the prepared in reaction of corresponding 5-br-derivatives and cuprous cyanide.
According to the method for only doing general general introduction, in the presence of dewatering agent, by the ring closure of following compounds
Formula II
With cuprous cyanide exchange 5-bromine group, can obtain citalopram subsequently.Formula II raw material obtains by two step successive Grignard reactions from 5-bromo-2-benzo [c] furanone, just respectively with 4-fluorophenyl magnesium chloride and N, N-dimethylamino-propyl magnesium chloride.
US Patent No 4,650,884 have described preparation method and intermediate novel and surprising citalopram, according to this method, the following formula intermediate
By with the strength sulfuric acid dehydration, carry out ring-closure reaction, to obtain citalopram.The formula III intermediate prepares by two step successive Grignard reactions from 5-cyano group-2-benzo [c] furanone, just respectively with 4-fluorophenyl magnesium halide and N, the reaction of N-dimethylamino-propyl magnesium halide.
Further method is disclosed among international patent application Nos.WO 98019511, WO 98019512 and the WO 98019513.WO 98019512 and WO 98019513 relate to such method, make 5-amino-, the 5-carboxyl-or 5-(secondary amino group carbonyl)-2-benzo [c] furanone carries out two step successive Grignard reactions, ring closure and with gained 1,3-dihydroisobenzofuran derivative is converted into corresponding 5-cyano compound, i.e. citalopram.International patent application No.WO 98019511 discloses a kind of preparation method of citalopram, wherein make (4-replaces-and 2-hydroxymethyl phenyl-(4-fluorophenyl) carbinol compound carries out ring closure, the 1-(4-fluorophenyl)-1 that gained 5-replaces, the 3-dihydroisobenzofuran is converted into corresponding 5-cyano derivative, the latter is with the alkylation of (3-dimethylamino) propyl group halogenide, to obtain citalopram.
At last, the method for indivedual enantiomers of preparation citalopram is disclosed in US Patent No 4,943, in 590, can also find out obviously that therefrom the ring closure of formula III intermediate can be undertaken by unsettled ester and alkali.
Find shockingly that now utilize suitable raw material, citalopram can be prepared by novel, smooth and safe method.
Summary of the invention
Therefore, the present invention relates to the preparation method of novel citalopram, comprise formula IV compound
Wherein R is C
1-6Alkyl, acyl group, C
1-6Alkyl sulphonyl or aryl sulfonyl,
With 3-(N, N-dimethylamino) propyl group magnesium halide, be preferably 3-(N, N-dimethylamino) propyl group magnesium chloride, obtain citalopram
Formula I
Separate and obtain alkali or its pharmacy acceptable salt.
The present invention provides novel formula IV intermediate on the other hand.
The present invention relates to the method for preparation formula IV intermediate aspect further.
The present invention also has another aspect, and formula IV compound is used for the preparation of formula III racemic compound.
Formula III
The present invention relates to medicine composition for treating depression on the other hand, wherein comprises the citalopram according to the inventive method preparation.
According to method of the present invention, citalopram obtains from formula IV compound by the single step Grignard reaction, and R is C among the formula IV
1-6Alkyl, acyl group, C
1-6Alkyl sulphonyl or aryl sulfonyl
Surprisingly, the Grignard reaction product spontaneously carries out ring closure, directly obtains citalopram, and therefore, being reflected in the step of formula IV compound and Grignard reagent generates citalopram.
And according to the present invention, formula IV compound can be prepared by three kinds of diverse ways.
One of these methods comprise the protection of the methylol alcohol of formula VI's (4-cyano group-2-hydroxymethyl phenyl) (4-fluorophenyl) methyl alcohol:
Oxidation then obtains formula IV compound, and wherein R is C
1-6Alkyl, acyl group, C
1-6Alkyl sulphonyl or aryl sulfonyl.
The oxidation of formula V compound can be carried out with any conventional oxidant, preferably uses Na
2WO
4Carry out.
Formula VI raw materials of compound can be prepared as described in international patent application No.PCT/DK97/00511.
The method of another kind of preparation formula IV compound comprises 5-cyano group-2-benzo [c] furanone and 4-fluorophenyl magnesium halide, is preferably the reaction of 4-fluorophenyl magnesium bromide, react with R-X then, wherein R is as defined above, X is a leavings group, preferably R-X is a pivalyl chloride, 3,5-dimethoxy-benzoyl chloride, methyl-iodide, monobromoethane, toluene sulfonyl chloride, Me
2SO
4Or MeSO
2Cl.
This reaction is described below:
Raw material 5-cyano group-2-benzo [c] furanone can be as Tirouflet J., 26,1959,35 described preparations of Bull.Soc.Sci. (" section association circular ") Bretagne.
According to the method for the third preparation formula IV compound, a kind of enantiomer of formula III compound, be that the R-enantiomer is protected and dehydration, obtain formula VII compound, latter's oxidation obtains the ketone of formula IV.
In this manner, the R-enantiomer of formula III can be used for the preparation of racemize citalopram.
The oxicracking of formula VII compound is undertaken by oxygenizement, preferably uses MnO
4 -(permanganate) or ozone, RuCl
3, OsO
4Carry out.
Citalopram as the thymoleptic listing is the form of racemoid.But, in the near future, the active S-enantiomer of citalopram also plans to introduce market.
The active S-enantiomer of citalopram can prepare like this, from the formula III compound, separates S-enantiomer and R-enantiomer, carries out the ring closure of S-enantiomer then, as described in US Patent No 4943590.The R-enantiomer of formula III compound was not used after separation in the past
And according to further aspect of the present invention, after the R-of formula III enantiomer was converted into the photoactive formula IV compound of irrotationality, the racemic compound of formula III can as described belowly be prepared:
The racemic compound of formula III can be separated into the enantiomer of optically active according to US Patent No 4943590 described operations, thereby obtains the S-enantiomer of formula III compound, and the latter is used for the preparation of S-citalopram.The R-enantiomer of formula III compound can reclaim in above-mentioned circulation means once more.
In this manner, the R-enantiomer of formula III can be converted into the S-citalopram.
Other reaction conditionss, solvent etc. that are used for above-mentioned reaction are the normal conditions of this class reaction, are easily determined by those skilled in the art.
Embodiment
The term C that spreads all over specification sheets and claims
1-6Alkyl refers to have a branch or a unbranched alkyl to six carbon atom, for example comprises methyl, ethyl, 1-propyl group, 2-propyl group, 1-butyl, 2-butyl, 2-methyl-2-propyl group, 2,2-dimethyl-1-ethyl and 2-methyl 1-propyl group.
Term aryl refers to list or bicyclic carbocyclic aromatic group, for example phenyl and naphthyl, particularly phenyl or cyclosubstituted phenyl.
The term heteroaryl refers to list or bicyclic heterocyclic aromatic group, for example indyl, thienyl, pyrimidyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzofuryl, benzothienyl, pyridyl and furyl, particularly pyrimidyl, indyl and thienyl.
Acyl group is used in C
1-6Alkyl-or aryl-or the implication of heteroaryl carbonyl in, C wherein
1-6Alkyl and aryl and heteroaryl are as defined above.
Halogen refers to chlorine, bromine or iodine.
Preferably, leavings group refers to halogenide or sulfonate.
In preferred implementation of the present invention, R is an acyl group, is preferably valeryl, ethanoyl or optional substituted benzoyl.
Compound of Formula I can be used its free alkali or pharmaceutically-acceptable acid addition.As acid salt, can use and the formed salt of organic or inorganic acid.The example of organic salt be with following acid formed those: toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethionic acid, acetate, propionic acid, tartrate, Whitfield's ointment, citric acid, glyconic acid, lactic acid, oxysuccinic acid, mandelic acid, styracin, citraconic acid, aspartic acid, stearic acid, palmitinic acid, methylene-succinic acid, oxyacetic acid, para-amino benzoic acid, L-glutamic acid, Phenylsulfonic acid and theophylline acetate, and 8-halogen theophylline, for example 8-bromine theophylline.The example of inorganic salt be with hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid formed those.
The acid salt of compound can be prepared according to methods known in the art.The acid of alkali and calculated amount is reacted in water miscible solvent, and acetone or alcohol for example by concentrating and refrigerated separation salt, perhaps reacts in water immiscible solvent with excessive acid subsequently, for example ether, ethyl acetate or methylene dichloride, and salt spontaneously separates.
Pharmaceutical composition of the present invention can be in any suitable manner, with any suitable form administration, for example with the form oral administration of tablet, capsule, powder agent or syrup, perhaps with the form administered parenterally of common aseptic injectable solution.
Pharmaceutical preparation of the present invention can be prepared according to the ordinary method of this area.For example, tablet can prepare like this, and is with activeconstituents and ordinary adjuvants and/or mixing diluents, in conventional tabletting machine that the mixture compacting is in blocks subsequently.The example of auxiliary agent or thinner comprises: W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Can use any other auxiliary agent or additive, for example tinting material, spices, sanitas etc. are as long as they can be compatible with activeconstituents.
Injection solution can prepare like this, and activeconstituents and possible additive are dissolved in a part of injection solvent, and preferred sterilized water is adjusted solution to volume required, and with solution sterilization, can is in ampoule that is fit to or bottle.Can add this area any suitable additive commonly used, for example opening property agent, sanitas, antioxidant etc.
Embodiment
The following example is further set forth the present invention.
Embodiment 1
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-1-hydroxyl-methyl]-benzyl ester
To (4-cyano group-2-hydroxymethyl phenyl) (4-fluorophenyl) methyl alcohol that is stirring (9.2g, 0.037mol) with triethylamine (4.0g, add in solution 0.04mol) pivalyl chloride (4.2g, 0.39mol).Stir after 60 minutes, reaction mixture be poured on ice, with diethyl ether extraction (2 * 75ml), dry (MgSO
4), concentrating under reduced pressure obtains colourless oil (12.0g).Compound is through chromatogram purification, and (eluent is hexane/ethyl acetate 1: 9) obtains title compound (8.2g, 70%).
1H?NMR(DMSO-D
6)：1.1(s，9H)，5.15(m，2H)，6(bs，1H)，6.25(d，J＝6Hz，1H)，7.1-7.2(m，2H)，7.3-7.4(m，2H)，7.7-7.9(m，3H).
Embodiment 2
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
To stirring 2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-1-hydroxyl-methyl]-benzyl ester (8.0g, add in ethyl acetate 0.025mol) (20ml) solution 30%wt superoxol (10g, 0.079mol), Na
2WO
4.2H
2(0.15g is 0.0005mol) with (n-octyl) 3NCH for O
3HSO
4(0.23g, 0.0005mol).Mixture heating 4 hours under refluxing then is cooled to room temperature, pour among rare HCl, with the diethyl ether extraction (2 * 50ml), dry (MgSO
4), concentrating under reduced pressure obtains title ketone compound (7.8g, 97.5%).
Embodiment 3
Acetate 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and oxalate thereof
Method 3A under 20 ℃, with diacetyl oxide (103g 1mol) is added drop-wise to 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(72g is in acetonitrile 0.21mol) (438g) solution for 3-methylol-benzonitrile.In case add fully, (stirring is spent the night for 5.5g, 0.05mol) (cause thermopositive reaction, temperature rises to 28 ℃ from 20 ℃) to drip trimethylsilyl chloride.Then with dense H
2SO
4(14.5g 0.14mol) joins in the reaction mixture, and reaction mixture heats 30 minutes (the HPLC Indicator Reaction is complete) down at 50 ℃ then.After the cooling, the reaction mixture concentrating under reduced pressure is with ammonia soln (23%) neutralization, with toluene extraction (2 times).Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is light orange oil (69.5g, 85%).
Be called oxalate.(1g, methyl alcohol 0.0177mol) (50ml) solution join the title ene compound that is stirring, and (6.63g is in methyl alcohol 0.0173mol) (50ml) solution with warm oxalic acid.After the cooling, filtering separation crystal (7.4g) is with cold methanol (10ml) washing.M.p.168℃
1H?NMR(DMSO-D
6)：1.9(s，3H)，2.2(m，2H)，2.62(s，6H)，3.1(t，J＝6.2Hz，2H)，4.8(s，2H)，6.35(t，J＝7Hz，1H)7.1-7.25(m，4H)，7.42(d，J＝7Hz，1H)，7.9-8(m，2H).
13C；NMR(DMSO-D6)：20.35，24.98，42.16，55.54，62.51，111.17，115.25，115.59，118.51，124.85，128.0，128.18，131.32，132.43，132.73，135.65，135.99，138.68，142.9，164.72，169.96.
Calculate C
24H
25N
2O
6F C, 63.14; H, 5.53; N, 6.14. actual measurement, C, 63.1; H, 5.58; N, 6.12
Acetate 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-Ding-1 thiazolinyl]-benzyl ester
Method 3B. is under 20 ℃, with diacetyl oxide (1112g, 10.8mol) be added drop-wise to 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-3-methylol-benzonitrile (1000g, 2.9mol) acetonitrile (1000g) solution in (cause thermopositive reaction, temperature rises to 50 ℃ from 20 ℃), stirred 2 hours.With dense H
2SO
4(300g 3mol) joins in the reaction mixture, and reaction mixture heats 3 hours (the HPLC Indicator Reaction is complete) down at 50 ℃ then.After the cooling, reaction mixture is with ammonia soln (25%) neutralization, with toluene extraction (2 times).Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is light orange oil (1023g, 92%).
Embodiment 4
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and oxalate thereof
Method 4A. is under 20 ℃, with pivalyl chloride solution (26.0g, 0.215mol) join 4-[4-dimethylamino-1-(fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(72g, 0.21mol) (25.0g is in acetonitrile 0.247mol) (438g) solution with triethylamine for 3-methylol-benzonitrile.After 60 minutes, drip dense H
2SO
4(40ml), reaction mixture heated 180 minutes down at 70 ℃.Reaction mixture is cooled to room temperature, with ammoniacal liquor (25%) neutralization, extracts with diethyl ether.Organic phase drying (MgSO
4), concentrating under reduced pressure obtains title compound, is xanchromatic oil (82g, 96%).
Be called oxalate.(acetone) M.p.188 ℃
1H?NMR(DMSO-D
6)：1.07(s，9H)，2.2(m，2H)，2.6(s，6H)，3.05(t，J＝6.2Hz，2H)，4.725(d，J＝12Hz，1H)，4.85(d，J＝12Hz，1H)，6.3(t，J＝6.3Hz，1H)7.1-7.3(m，4H)，7.42(d，J＝7Hz，1H)，7.9-8(m，2H).
13C；NMR(DMSO-D
6)：25.1，26.71，42.3；55.67，62.55，111.21，115.3，115.64，128.17，131.33，132.28，136.13，138.58，142.76，164.4
Calculate C
27H
31N
2O
6F:C, 65.04; H, 6.28; N, 5.62. actual measurement, C, 64.86; H, 6.63; N, 5.6
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester and hydrogen chloride salt thereof
Method 4B. under 0 ℃, with pivalyl chloride solution (30.1g 0.25mol) joins 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(85.5g is in acetonitrile 0.21mol) (290ml) solution for 3-methylol-benzonitrile.Reaction mixture stirred 60 minutes, added dense H then
2SO
4(32.5g, 0.33mol).In case add fully, be reflected at 70 ℃ and heated 180 minutes down.Reaction mixture is cooled to room temperature, under reduced pressure removes acetonitrile (220ml), uses ammoniacal liquor (23%) neutralization then, extracts with diethyl ether.Organic phase drying (MgSO
4), concentrating under reduced pressure obtains the pink oil (102.1g) of title compound.
(50.0g, methanol solution 0.11mol) join in the methanol solution (200ml) of the anhydrous HCl that is stirring with title ene compound II.After at room temperature stirring 30 minutes, under reduced pressure remove and desolvate, add diethyl ether, filter the gained white solid,, obtain HCl salt (48.1g) with the diethyl ether washing.Mp＝165℃
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, hydrosulfate
Method 4C. under 0 ℃, with pivalyl chloride solution (29g 0.24mol) joins 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(5.5g is in acetonitrile 0.21mol) (290ml) solution for 3-methylol-benzonitrile.Reaction mixture stirred 60 minutes, added dense H then
2SO
4(32.5g, 0.33mol).In case add fully, be reflected at 70 ℃ and heated 180 minutes down.Reaction mixture is cooled to room temperature, under reduced pressure removes acetonitrile, adds toluene (200ml) and also under reduced pressure removes, and obtains title compound, is rose pink oil (112.4g).
2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, hydrogen chloride salt
Method 4D. at room temperature is added drop-wise to pivalyl chloride (7.6g 0.63mol) 4-[4-dimethylamino-1-(4-fluoro-the phenyl)-1-hydroxyl-butyl that is stirring]-(21.35g is in acetonitrile 0.052mol) (21.35g) solution for 3-methylol-benzonitrile.In case add fully, add methylsulfonyl chloride (6.1g, CH 0.053mol)
2Cl
2(50ml) solution, add then triethylamine (10.6g, 0.105mol).Reaction mixture further stirred 30 minutes, poured in the water, used CH
2Cl
2Extraction, organic phase drying (MgSO
4), concentrating under reduced pressure.Oil with gained is dissolved in dehydrated alcohol HCl then, and concentrating under reduced pressure is handled with diethyl ether, filters, and obtains the HCl salt (22.6g, 98%) of alkene.
Embodiment 5
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5A. is to the alkene 2 that is stirring, 2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-HCl salt (165g, H 0.337mol) of benzyl ester
2So that remaining on 45-50 ℃ of a kind of like this speed, temperature of reaction adds NaMnO in O (1100ml) solution
4H
2O solution (40%vv) (3.7mol).In case add fully, reaction mixture is cooled to room temperature, filter.Solid filtering thing cold water washing (3 * 150ml), solid residue is stirred in acetone (2000ml), filter, evaporation obtains thick ketone, and (eluent is a hexane: ethyl acetate 8: 2) to filter purifying by the silicon-dioxide plug, obtain title ketone, be pure compound 82g (75%).MP＝81℃
1H?NMR(DMSO-D
6)：0.9(s，9H)，5.1(s，2H)，7.35-7.5(m，3H)，7.65(d，J＝7Hz，1H)，7.8-7.9(m，2H)，8.0(m，1H)，8.1(s，1H)
13C；NMR(DMSO-D6)：26.5，63.01，113.183，116.0，116.36，118.02，129.35，132.19，132.58，133.03，133.18，133.34，135.98，141.7，163.62，167.65，176.87，193.94
Calculate C
20H
18NO
3F:C, 70.79; H, 5.35; N, 4.13. actual measurement, C, 70.49; H, 5.30; N, 4.07
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5B. will contain the O of ozone
2The alkene 2 that feeding is being stirred, 2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester (38.0g, H 0.093mol)
2In O (1300ml) and dense HCl (70ml) solution, carry out HPLC after the reaction.Between the reaction period, the adularescent precipitation generates, and when reaction finishes white solid is filtered, and washes with water, and drying under reduced pressure obtains protected title ketone, is pure compound (22.5g, 72%).
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Method 5C. is to alkene 2,2-dimethyl-propionic acid 5-cyano group-2-[4-dimethylamino-1-(4-fluoro-phenyl)-but-1-ene base]-benzyl ester, H
2SO
4(11.0g adds NalO in water 0.022mol) (250ml) and ethyl acetate (100ml) suspension
4(30g, 0.14mol) and RuCl
3Hydrate (0.35g).Suspension is vigorous stirring 16 hours at ambient temperature.The gained suspension filters by the silicon-dioxide plug.Separate organic phase, water (50ml) washing.Evaporating solvent obtains title compound in a vacuum, is a kind of oil, places post crystallization.Yield: 7.4g (99%).
Embodiment 6
2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-benzyl ester
Will (19.2g, 0.11mol) (3.2g, 0.13mol) anhydrous THF (100ml) drips of solution of Zhi Bei 4-fluorophenyl magnesium bromide be added to 5-cyano group-2-benzo [c] furanone (15.9g is in anhydrous THF (150ml) suspension 0.1mol) with magnesium chips from the 4-bromofluorobenzene.Temperature remains on below 5 ℃.After adding fully, reaction mixture at room temperature stirs and spends the night.
(13.3g 0.11mol) joins in the reaction mixture, temperature is elevated to 60 ℃ reaches 2 hours with pivalyl chloride.Gained solution is joined NH
4Cl (100ml, aq) with ice (50g) saturated solution in.Add diethyl ether (100ml), separate each phase.Organic phase with 0.1N NaOH (2 * 100ml) and water (100ml) wash organic phase MgSO
4(20g) drying.Evaporating solvent obtains thick title compound (29.8g, 88%), is a kind of oil, is enough pure to further reaction.
Crystallization from EtOAc/ normal heptane (1: 9) obtains pure sample.The gained title compound is the yellow-white crystal.
Embodiment 7
1-(3-dimethylamino-propyl group)-1-(4-fluoro-phenyl)-1,3-dihydro-isobenzofuran-5-formonitrile HCN and oxalate thereof
Under 0 ℃; to 2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-(28.5g adds 3-(N in anhydrous THF (150ml) solution 0.084mol) to benzyl ester; the N-dimethylamino) propyl group magnesium chloride solution (2.2 equivalent) carries out HPLC after the reaction.At 0 ℃ after following 1 hour, add saturated ammonium chloride, mixture ethyl acetate extraction, drying (Na
2SO
4), concentrating under reduced pressure obtains title compound, is a kind of oil.(28.0g, (purity 87%, HPLC)).Crystallization obtains oxalate from acetone.
Embodiment 8
4-[1-(4-fluoro-phenyl)-formyl radical]-3-methylol-benzonitrile
With ketone 2,2-dimethyl-propionic acid 5-cyano group-2-[1-(4-fluoro-phenyl)-formyl radical]-(20g 0.061mol) joins in the freshly prepd sodium methylate (0.25g sodium, 100ml methanol solution) benzyl ester, at room temperature stirs (protection is gone in the HPLC indication fully).Under reduced pressure remove methyl alcohol then, be dissolved in MTBE, with the saturated ammonium chloride washing, dry (MgSO
4), concentrating under reduced pressure obtains the de-protected ketone (14.6g) of title compound.
Embodiment 9
4-[4-dimethylamino-1-(4-fluoro-phenyl)-1-hydroxyl-butyl]-3-methylol-benzonitrile
Under 0 ℃, to ketone 4-[1-(4-fluoro-phenyl)-formyl radical]-(15.0g adds 3-(N, N-dimethylamino) propyl group magnesium chloride solution (2.2 equivalent) to 3-methylol-benzonitrile in anhydrous THF solution 0.046mol), carry out HPLC after the reaction.At 0 ℃ after following 1 hour, add saturated ammonium chloride, mixture extracts with MTBE, dry (MgSO
4), concentrating under reduced pressure obtains title compound, is a kind of oil.(16.7g, (purity 85%)).
Claims (8)
1. prepare the method for S-citalopram or its salt, comprise the following steps:
A) the R-enantiomorph of formula III compound is protected, dehydration forms formula VII compound then
Formula III formula VII
Wherein R is an acyl group;
B) oxicracking formula VII compound forms formula IV compound
Formula IV
Wherein R as above defines;
C), and make formula VIII compound and 3-(N, N-dimethylamino) the propyl group halogenation reactive magnesium that obtains to formula IV compound deprotection, the racemic compound of preparation formula III,
Formula VIII formula III
Then
D) R and the S enantiomorph of separation formula III compound;
E) make the S-enantiomorph closed loop of formula III compound, and separate S-citalopram or its salt.
2. according to the process of claim 1 wherein that the R-enantiomorph of the formula III compound that step d) obtains is converted into formula IV compound by following manner:
F) the R-enantiomorph of formula III compound is protected, dehydration forms formula VII compound then
Formula VII
Wherein R such as claim 1 definition;
G) oxicracking formula VII compound forms formula IV compound; Optional as required then repeating step c) to g).
3. according to the method for claim 2, the described oxicracking of wherein said formula VII compound is by adopting permanganate, ozone, RuCl
3Or OsO
4The oxidation of carrying out realizes.
4. prepare the method for citalopram or its salt, comprise the following steps:
A) the R-enantiomorph of formula III compound is protected, dehydration forms formula VII compound then,
Formula III formula VII
Wherein R is an acyl group;
B) oxicracking formula VII compound forms formula IV compound,
Formula IV
Wherein R as above defines;
C), and make formula VIII compound and 3-(N, N-dimethylamino) the propyl group halogenation reactive magnesium that obtains to formula IV compound deprotection, the racemic compound of preparation formula III,
Formula VIII formula III
Make the racemic compound closed loop of formula III compound then, and separation of racemic citalopram or its salt.
5. according to the method for one of claim 1-4, wherein R is valeryl, ethanoyl or optional substituted benzoyl.
6. according to the method for one of claim 1-4, wherein 3-(N, N-dimethylamino) propyl group magnesium halide is 3-(N, a N-dimethylamino) propyl group magnesium chloride.
7. formula IV compound,
Formula IV
Wherein R is an acyl group.
8. the compound of claim 7, wherein R is valeryl, ethanoyl or optional substituted benzoyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03165033 CN1268621C (en) | 1999-10-25 | 1999-10-25 | Preparation of citalopram |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 03165033 CN1268621C (en) | 1999-10-25 | 1999-10-25 | Preparation of citalopram |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB998148962A Division CN1133633C (en) | 1999-10-25 | 1999-10-25 | Method for preph. of citalopram |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1550497A CN1550497A (en) | 2004-12-01 |
| CN1268621C true CN1268621C (en) | 2006-08-09 |
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ID=34324124
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 03165033 Expired - Fee Related CN1268621C (en) | 1999-10-25 | 1999-10-25 | Preparation of citalopram |
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| Country | Link |
|---|---|
| CN (1) | CN1268621C (en) |
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1999
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| CN1550497A (en) | 2004-12-01 |
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