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CN1268129A - The preparation method of cyanophthalofluoroaniline - Google Patents

The preparation method of cyanophthalofluoroaniline Download PDF

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CN1268129A
CN1268129A CN98806945A CN98806945A CN1268129A CN 1268129 A CN1268129 A CN 1268129A CN 98806945 A CN98806945 A CN 98806945A CN 98806945 A CN98806945 A CN 98806945A CN 1268129 A CN1268129 A CN 1268129A
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formula
acid
compound
reaction
cyanophthalofluoroaniline
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CN1138768C (en
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H·彼得森
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H Lundbeck AS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/38—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention discloses a method for preparing cyanophthalamide, which comprises the following steps of mixing a compound shown as the following formula (IV)1Is C1－6Alkyl, and X is O or NH) with a Grignard reagent of 4-halo-fluorophenyl and a Grignard reagent of 3-halo-N, N-dimethyl-propylamine in that order, to effect ring closure of the resulting compound of formula (V) (wherein R is1And X is as defined above), and will give 1, 3-dihydroisobenzo [ c)]The furan compound is converted into the corresponding 5-cyano derivative, namely cyanophthalfluoroaniline.

Description

The preparation method of nitalapram
The present invention relates to known thymoleptic nitalapram 1-[3-(dimethylamino) propyl group]-1-(4-fluorophenyl)-1, the preparation method of 3-dihydro-5-isobenzofurancarboniderivatives and the intermediate that is used for this method.
Background of invention
Nitalapram is known thymoleptic, goes on the market several years, and it has following structure: It is optionally, maincenter active serum element (serotonin; Therefore 5-HT) reuptake inhibitor has antidepressant activity.The antidepressant activity of this compound is described in many publications, J.Hyttel for example, Prog.Neuro-Psychopharmacol.﹠amp; Biol.Psychiat., 1982,6,277-295 and A.Gravem, Acta Psychiatr.Scand., 1987,75,478-486.EP-A-474580 has also disclosed the effect that this compound has treatment dementia and cerebrovascular disease.
Nitalapram is at first open in corresponding to the DE2657271 of US4136193, and this patent specification has been described the method for preparing nitalapram, and summary description can be used for preparing other method of nitalapram.
According to described method; corresponding 1-(4-fluorophenyl)-1; 3-dihydro-5-isobenzofurancarboniderivatives and 3-(N, N-dimethylamino) propyl chloride is being used as reaction in the presence of the methylsulfinyl methide of condensing agent, and starting material is by corresponding 5-br-derivatives and cupric cyanide prepared in reaction.
According to this method of general description only, nitalapram can be by carrying out the ring closure of following compound in the presence of dewatering agent: Formula II obtains with cupric cyanide exchange 5-bromine group subsequently.The starting material of formula II by 5-bromo-2-benzo [c] furanone by two continuous Grignard reactions, promptly respectively with 4-fluorophenyl magnesium chloride and N, N-dimethylaminopropyl magnesium chloride obtains.
US4650884 has described a kind of new and unexpected method and the intermediate for preparing nitalapram, according to this method, and the intermediate of following formula: Formula III obtains nitalapram by encircling closed reaction with the strength sulfuric acid dehydration.The intermediate of formula III by 5-cyano group-2-benzo [c] furanone by two continuous Grignard reactions, promptly respectively with 4-fluorophenyl magnesium halide and N, the reaction of N-dimethylaminopropyl magnesium halide obtains.
At last, the method for the single enantiomorph of preparation nitalapram is open in US4943590, and it also discloses the ring closure of formula III intermediate and can carry out under alkaline condition.
We are surprised to find the starting material that nitalapram can be easy to use now and prepare by method favourable and safety.
Summary of the invention
Therefore, the present invention relates to prepare the novel method of nitalapram, it comprises the steps: as shown in the formula the IV compound:
Figure A9880694500081
Formula IV is R wherein 1Be C 1-6Alkyl and X are O or NH, and the Grignard reagent with 4-halogen-fluorophenyl reacts successively, obtains formula IVa compound:
Figure A9880694500082
Formula IVa is R wherein 1With X be as defined above, with 3-halogen-N, the Grignard reagent of N-dimethyl-propyl group amine reaction, carry out ring closure as shown in the formula the V compound:
Figure A9880694500083
Formula V is R wherein 1With X be as defined above and will obtain be converted into corresponding 5-cyano derivative as shown in the formula the VI compound, i.e. nitalapram,
Figure A9880694500091
Formula VI is R wherein 1With X be as defined above, it separates as alkali or pharmaceutically useful salt.
On the other hand, the present invention provides the new intermediate of formula IVa and V respectively.
On the other hand, the invention provides the new intermediate of formula VI.
On the other hand, the present invention relates to contain the medicine composition for treating depression of the nitalapram of the inventive method preparation.
In whole specification sheets and claims, C 1-6Alkyl is meant the alkyl of side chain or straight chain, and it contains 1-6 carbon atom, for example 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 isophthalic acid-propyl group.
The Grignard reagent that can be used for the 4-halogen-fluorophenyl in the first step is a magnesium halide, and for example magnesium chloride, magnesium bromide or magnesium iodide preferably use magnesium bromide.Spendable 3-halogen-N, the Grignard reagent of N-dimethyl propyl amine is a magnesium halide, for example magnesium chloride, magnesium bromide or magnesium iodide preferably use magnesium bromide.Separable or separate type IVa intermediate not, preferred two reactions are carried out continuously and are not separated intermediate.
The ring closure of formula V compound is carried out through unstable ester by acid or with alkali.The closed mineral acid of using of acyclic acidic; for example sulfuric acid or phosphoric acid; or organic acid; for example methylsulfonic acid, tosic acid or trifluoroacetic acid carry out; the closed alkali of using of alkalescence ring; for example triethylamine, xylidine, pyridine etc. are through unsettled ester, and for example methylsulfonyl, p-toluenesulfonyl, 10-camphor sulfonyl, trifluoroacetyl group or trifyl ester carry out.Be reflected in the inert solvent and carry out, preferred adopt cooling, especially at about 0 ℃ and preferably by a still process, i.e. esterification and add alkali simultaneously and carry out.
When X is O, radicals R 1-X-CO-is converted into the process of cyano group preferably to carry out through the corresponding amide group, amide group subsequently with as wherein X be that the same procedure of the formula VI compound of NH is converted into cyano group.
R 1-X-CO-(X=O) to the reaction of acid amides by with acid or basic hydrolysis, subsequent transformation be acyl chlorides and by with ammonia or alkylamine, preferred tertiary butylamine reaction amination is carried out.Acidic hydrolysis can use any suitable acid, and for example Hydrogen bromide, hydrochloric acid, Hydrogen bromide/acetate carry out.Alkaline hydrolysis can be with any suitable alkali, and for example salt of wormwood, sodium hydroxide, potassium hydroxide etc. carry out.The conversion process of acid amides can also be reacted under pressure and heating with ammonia or alkylamine by ester (X=O) and be carried out.
By conventional nitrile synthesis acid amides is converted into cyano group.Therefore, the acid amides that obtains or wherein X be NH formula V acid amides preferably by with dewatering agent, most preferably reaction such as thionyl chloride, phosphorus pentachloride is converted into cyano compound, i.e. nitalapram.
In addition, hydrolyzable ester, promptly wherein X is the formula VI compound of O, reacts to form nitrile with chloro sulfonyl isocyanate subsequently.
Method of the present invention can be through separating or not separating intermediate and carry out.
Method of the present invention also can be used for preparing activity (the S)-enantiomorph of nitalapram.In this case, formula V compound is separated into optically active enantiomorph by the similar approach of describing in US4943590, thereby obtains (the S)-enantiomorph of formula V compound, and it is used to encircle closed reaction in step c).Therefore, the single enantiomorph that has comprised formula V and VI intermediate in the general formula respectively.
Other reaction conditions, solvent etc. are the normal conditions of this class reaction, can easily be determined by those skilled in the art.
The starting material of formula IV be commercial available or by 5-carboxyl-2-benzo [c] furanone by with thionyl chloride reaction, subsequently with C 1-6Alkanol or C 1-6The alkylamine preparation.5-carboxyl-2-benzo [c] furanone is commercial available and can pass through currently known methods (Tirouflet, J.; Bull.Soc.Sci.Bretagne 26,1959, and 35) preparation.
In an embodiment of the present invention, X is O and R 1Be ethyl, propyl group or butyl, preferred ethyl, 2-propyl group or the tertiary butyl.
In another embodiment of the present invention, X is NH, R 1Be ethyl, propyl group or butyl, preferred ethyl, 2-propyl group or the tertiary butyl, the most preferably tertiary butyl.
Compound of Formula I can be used as free alkali or its pharmaceutically useful acid salt.As acid salt, can use and the salt that forms of organic acid or mineral acid.The example of this class organic salt is and toxilic acid, fumaric acid, phenylformic acid, xitix, succsinic acid, oxalic acid, dimethylene Whitfield's ointment, methylsulfonic acid, ethane disulfonic 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 acetate tea alkali, and 8-halo tea alkali, for example salt of 8-bromine tea alkali formation.The example of these inorganic salt is the salt that forms with hydrochloric acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid and nitric acid.
The acid salt of compound can be by the currently known methods preparation of this area.Alkali or with the acid of calculated amount at the miscible solvent of water, for example react in the acetone or alcohol, subsequently by concentrating and refrigerated separation salt, perhaps with excess acid at the water immiscible solvent, for example react in ether, ethyl acetate or the methylene dichloride, wherein salt spontaneously separates.
Pharmaceutical composition of the present invention can use suitable manner and with any suitable form, for example with tablet, capsule, pulvis or syrupy form oral cavity or the sterile solution form administered parenterally commonly used to be used to inject.
Pharmaceutical preparation of the present invention can be by the ordinary method preparation of this area.For example tablet can pass through mixed active component and conventional auxiliary material and/or thinner, pressing mixt preparation in conventional tabletting machine subsequently.The example of auxiliary material or thinner comprises W-Gum, yam starch, talcum, Magnesium Stearate, gelatin, lactose, natural gum etc.Can use any other auxiliary material or color additives, fragrance, sanitas etc., as long as they are compatible with active ingredient.
The solution that is used to inject can be by the solvent that is used to inject in a part, and lytic activity component and possible additive in the preferred sterilized water, regulator solution are to required volume, and sterilized solution and the peace bottle of packing into suitable or bottle prepare.Can add the conventional appropriate addn that uses, for example osmotic pressure regulator, sanitas, antioxidant etc. in any this area.
EXAMPLE Example 15-tertbutyloxycarbonyl-2-benzo [c] furanone
(100g 0.56mole) is suspended in the pyridine (1200ml), and (211g, 1.12mole), mixture at room temperature stirred 30 minutes to add p-toluenesulfonyl chlorine with 5-carboxyl-2-benzo [c] furanone.(54g 0.73mole), at room temperature placed reaction mixture 3 days under effectively stirring to add tertiary butyl alcohol.In clear solution impouring frozen water, filter out sedimentary crystallization.Recrystallized product from 2-propyl alcohol (500ml).Yield 123g, 94%.DSC is initial: 151.5 ℃.Embodiment 25-(the 2-third oxygen carbonyl)-2-benzo [c] furanone
Method A): (36g 0.2mole) is suspended in the thionyl chloride (100ml), adds DMF (1.5ml), and mixture was refluxed 1 hour with 5-carboxyl-2-benzo [c] furanone.Add toluene (200ml), vacuum evaporating solvent adds 2-propyl alcohol (200ml), and mixture was refluxed 30 minutes.After being cooled to 0 ℃, filter out crystallization, wash with cold 2-propyl alcohol (50ml).Yield 38g, 87%.DSC is initial: 144 ℃.
Method B): (52g 0.25mole) is suspended in the 2-propyl alcohol (1000ml), adds Ti (iPrO) with 5-ethoxycarbonyl-2-benzo [c] furanone 4(38g 0.14mole), refluxes mixture 3 hours, and reaction mixture is cooled to 0 ℃, filters out crystallization, washs with cold 2-propyl alcohol (70ml).Yield: 47g, 85%.Initial 144 ℃ of DSC.Embodiment 35-tertiary butyl formamyl-2-benzo [c] furanone
(36g 0.2mole) is suspended in the thionyl chloride (100ml), adds DMF (1.5ml), and mixture was refluxed 1 hour with 5-carbonyl-2-benzo [c] furanone.Add toluene (200ml), vacuum evaporating solvent.Resistates is dissolved among the THF (200ml), and (31g is in THF 0.42mole) (200ml) solution to add tert-butylamine at 5 ℃.Mixture is warmed to room temperature, and stirring is spent the night.With reaction mixture impouring frozen water (400ml), filtering for crystallizing.Water (100ml) wash crystallization.Yield 41g, DSC is initial: 189.5 ℃.Embodiment 41-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-formic acid tertiary butyl ester oxalate
Will be by 4-bromofluorobenzene (31.5g, 0.18mole) and magnesium cut (5.1g, 0.21mole) anhydrous THF (150ml) drips of solution of 4-fluorophenyl magnesium bromide of preparation is added to 5-tertbutyloxycarbonyl-2-benzo [c] furanone (35.1g is in anhydrous THF (150ml) suspension 0.15mole).Temperature is remained below 5 ℃, and after adding, reaction mixture at room temperature stirred 3 hours.
Will by the 3-dimethylaminopropyl chlorine among the anhydrous THF (150ml) (21.9g, 0.18mole) and magnesium cut that (5.1g, 0.21mole) the Er Ge Liya solution of preparation adds in the reaction mixture.In adition process, temperature is remained below 10 ℃, under agitation make reaction at room temperature continue to spend the night.
In reaction mixture impouring frozen water (300ml) and ammonium chloride saturated solution (100ml), vacuum-evaporation THF.Add ethyl acetate (300ml), separate organic phase, water (2 * 100ml) and salt solution (50ml) wash.(2 * 100ml) extract organic phases, add 4M sodium hydroxide (100ml) at aqueous phase and obtain 9 or higher pH with 2M hydrochloric acid.Water layer extracts with ethyl acetate (400ml), and organic phase water (100ml), salt solution (50ml) washing are with sal epsom (20g) drying.
(45.5g 0.45mole), is cooled to 5 ℃ with solution, and (19.5g, the 0.17mole) solution in ethyl acetate (100ml) after adding, are under agitation placed reaction mixture 1 hour to drip methylsulfonyl chlorine to add triethylamine to organic phase.With 0.1M sodium hydroxide (2 * 100ml) washing reaction mixtures, dry (sal epsom, 10g) organic phase, vacuum evaporating solvent.The material (the 15g title compound is free alkali) that obtains thus is dissolved in the acetone (120ml), and (13.5g 0.15mole) handles with the anhydrous oxalic acid that is dissolved in acetone (120ml).Mixture at room temperature placed spend the night the oxalate of filtering-depositing.Yield: 34g, 43%.Initial 172 ℃ of DSC.
1H NMR (DMSO-d 6, 500MHz): 1.43 (1H, m), 1.47-1.57 (10H, s+m), 2.21 (2H, t, J=10Hz), 2.63 (6H, s), 2.97 (2H, t, J=10Hz), 5.14 (1H, d, J=12.5Hz), 5.22 (1H, d, J=12.5Hz), 7.16 (2H, t, J=8.5Hz), 7.56 (2H, dt, J=1.2Hz J=8.5Hz), 7.60 (1H, d, J=8.5Hz), 7.82 (1H, s), 8.86 (1H, d, J=8.5Hz). ultimate analysis, calculated value: C 26H 32N 1F 1O 7C, 63.78:H, 6.60:N, 2.86. measured value: C, 63.95:H, 6.51:N, 3.14.
Be prepared as follows compound with similar method by difference 5-(the 2-third oxygen carbonyl)-2-benzo [c] furanone and 5-(ethoxycarbonyl)-2-benzo [c] furanone: 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, the different benzo of 3-dihydro [c] furans-5-formic acid 2-propyl diester oxalate yield 20g, crystallization in (42%) acetone.DSC begins: 79 ℃.
1H NMR (DMSO-D 6, 250MHz): 1.40 (6H, d, J=6.5Hz), 1.40-1.60 (2H, m), 2.20 (2H, t, J=10Hz), 2.63 (6H, s), 2.98 (2H, t, J=10Hz), 5.12 (1H, septet, J=6.5Hz), 5.15 (1H, d, J=12.5Hz), 5.24 (1H, d, J=12.5Hz), 7.18 (2H, t, J=8.5Hz), (7.57 2H, dt, J=1.2Hz J=8.5Hz), 7.63 (1H, d, J=8.5Hz), 7.88 (1H, s), 8.90 (1H, d, J=8.5Hz). ultimate analysis, calculated value: C 23H 28N 1F 1O 3, 1.1 (COOH) 2C, 62.41:H, 6.27:N, 2.90. measured value: C, 62.41:H, 6.34:N, (3.21.1-3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, the different benzo of 3-dihydro [c] furans-5-formic acid ethyl ester oxalate yield 14.1g, crystallization in (30%) acetone.DSC begins: 148 ℃. 1H?NMR(DMSO-d 6，500MHz)：1.31(3H，t，J＝7.5Hz)，1.44(1H，m)，1.55(1H，m)，2.22(2H，t，J＝10Hz)，2.64(6H，s)，3.00(2H，t，J＝10Hz)，4.39(2H，q，J＝7.5Hz)，5.15(1H，d，J＝12.5Hz)，5.23(1H，d，J＝12.5Hz)，7.15(2H，t，J＝8.5Hz)，7.58(2H，dt，J＝1.2Hz?J＝8.5Hz)，7.65(1H，d，J＝8.5Hz)，7.89(1H，s)，8.92(1H，d，J＝8.5Hz)。Ultimate analysis, calculated value: C 26H 32NF 1O 7, 1.5H 2O; C, 59.00:H, 6.40:N, 2.86. measured value: C, 58.99:H, 5.93:N, 2.92. embodiment 55-(tertiary butyl formamyl)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, the different benzo of 3-dihydro [c] furans oxalate
Will be by 4-bromofluorobenzene (42g; 0.24mole) and magnesium chips (7g; 0.29mole) anhydrous THF (120ml) drips of solution of 4-fluorophenyl magnesium bromide of preparation is added to 5-tertiary butyl formamyl-2-benzo [c] furanone (23.3g is in anhydrous THF (120ml) suspension 0.1mole).Temperature is remained below 5 ℃, and after adding, reaction mixture at room temperature stirred 3 hours.
Will by the 3-dimethylaminopropyl chlorine among the anhydrous THF (100ml) (14.6g, 0.12mole) and magnesium cut that (3.4g, 0.14mole) the Er Ge Liya solution of preparation adds in the reaction mixture.In adition process, temperature is remained below 10 ℃, under agitation make reaction at room temperature continue to spend the night.
In reaction mixture impouring frozen water (250ml) and ammonium chloride saturated solution (100ml), vacuum-evaporation THF.Add ethyl acetate (300ml), separate organic phase, water (2 * 100ml) and salt solution (50ml) wash.(2 * 100ml) extract organic phases, add 4M sodium hydroxide (100ml) at aqueous phase and obtain 9 or higher pH with 2M hydrochloric acid.Water layer extracts with ethyl acetate (400ml), and organic phase water (100ml), salt solution (50ml) washing are with sal epsom (20g) drying.
(45.5g 0.45mole), is cooled to 5 ℃ with solution, and (19.5g, the 0.17mole) solution in ethyl acetate (100ml) after adding, are under agitation placed reaction mixture 1 hour to drip methylsulfonyl chlorine to add triethylamine to organic phase.With 0.1M sodium hydroxide (2 * 100ml) washing reaction mixtures, dry (sal epsom, 10g) organic phase, vacuum evaporating solvent.The material (the 15g title compound is free alkali) that obtains thus is dissolved in the acetone (100ml), and (10g 0.11mole) handles with the anhydrous oxalic acid that is dissolved in acetone (100ml).Stir down and mixture was at room temperature placed 3 days the oxalate of filtering-depositing.Yield: 7g, 14%.Initial 167 ℃ of DSC. 1H NMR (DMSO-d 6, 500MHz): 1.35 (9H, s), 1.37-1.58 (2H, m+m), 2.21 (2H, t, J=10Hz), 2.61 (6H, s), 2.96 (2H, t, J=10Hz), 5.12 (1H, d, J=12.5Hz), 5.20 (1H, d, J=12.5Hz), 7.15 (2H, t, J=8.5Hz), 7.52 (1H, d, J=8.5Hz), 7.57 (2H, dt, J=1.3Hz J=8.5Hz), and 7.67-7.75 (3H, s+br s+d, J=8.5Hz). ultimate analysis, calculated value: C 26H 32N 1F 1O 7C, 63.91:H, 6.82:N, 5.73. measured value: C, 63.53:H, 6.82:N, 5.81. embodiment 61-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, the different benzo of 3-dihydro [c] furans-5-formonitrile HCN oxalate
Method A): with 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, (20g 0.048mole) is dissolved in the acetate (100ml) the different benzo of 3-dihydro [c] furans-5-formic acid tertiary butyl ester oxalate, adds HBr (20ml, in 33% acetate), stir down and placed 10 minutes.Solvent removed in vacuo, resistates and toluene (100ml) coevaporation.Resistates is dissolved in toluene (80ml) and thionyl chloride (80ml).Add DMF (1ml), mixture was refluxed 1 hour.Vacuum evaporating solvent is dissolved in resistates in the ethyl acetate (100ml), and ammonium hydroxide (100ml, 25% aqueous solution) and ice (100g) are mixed and adds, and places 30 minutes under good the stirring.Organic phase water (50ml) and salt solution (20ml) washing are with sal epsom (10g) drying.Solvent removed in vacuo is dissolved in resistates in the thionyl chloride (40ml), refluxes 2 hours.Add toluene (100ml), solvent removed in vacuo.Add toluene (100ml), organic phase is washed with 2N sodium hydroxide (100ml) and water (50ml).Solvent removed in vacuo, the product purified by flash chromatography that obtains obtains title compound, is free alkali oily matter.
Go out oxalate by the acetone crystallization.Yield: 9.0g (43%).Initial 156 ℃ of DSC. 1HNMR (DMSO-d 6, 500MHz): 1.40 (1H, m), 1.50 (1H, m), 2.21 (2H, t, J=10Hz), 2.61 (6H, s), 2.95 (2H, t, J=10Hz), 5.15 (1H, d, J=12.5Hz), 5.22 (1H, d, J=12.5Hz), 7.17 (2H, t, J=8.5Hz), 7.58 (2H, dt, J=1.2Hz J=8.5Hz), 7.63 (1H, d, J=8.5Hz), 7.80 (1H, d, J=8.5Hz), 8.82 (1H, s). ultimate analysis, calculated value: C 22H 23N 2F 1O 5C, 63.75:H, 5.60:N, 6.76.Measured value C, 63.12:H, 6.59:N, 6.66.
Method B): with 5-(tertiary butyl formamyl)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1, (1g 0.002mole) is dissolved in the thionyl chloride (10ml) the different benzo of 3-dihydro [c] furans oxalate, and mixture was refluxed 2 hours.Add toluene (10ml), solvent removed in vacuo.Resistates is dissolved in the ethyl acetate (15ml), with ammonium hydroxide (5ml, 25% aqueous solution) and ice (5g) mixing and adding, phase-splitting.Dried over mgso is used in organic phase water (10ml) washing.Behind vacuum evaporating solvent, crystallization title compound from acetone.Yield 0.66g, 78%.DSC is initial: 156 ℃.

Claims (21)

1.一种制备氰酞氟苯胺的方法，其包括如下步骤：将如下式IV化合物：式  IV其中R1是C1-6烷基，和X是O或NH，依次与4-卤素-氟苯基的格利雅试剂反应，得到式IVa化合物：式  IVa其中R1和X是如上定义的，与3-卤素-N，N-二甲基-丙基胺的格利雅试剂反应，进行如下式V化合物的环闭合：
Figure A9880694500023
式 V其中R1和X是如上定义的，和将得到的如下式VI化合物转化为相应的5-氰基衍生物，即氰酞氟苯胺，式  VI其中R1和X是如上定义的，它作为碱或可药用的盐分离。1. A method for preparing cyanophthalofluoroaniline, comprising the steps of: the following formula IV compound: Formula IV wherein R is C 1-6 alkyl, and X is O or NH, reacts sequentially with the Grignard reagent of 4-halogen-fluorophenyl to give the compound of formula IVa: Formula IVa wherein R and X are as defined above, reacts with the Grignard reagent of 3-halo-N,N-dimethyl-propylamine to effect ring closure of compounds of formula V as follows:
Figure A9880694500023
Formula V wherein R and X are as defined above, and converting the resulting compound of formula VI into the corresponding 5-cyano derivative, i.e. cyanophthalofluoroaniline, Formula VI wherein R and X are as defined above, which is isolated as a base or a pharmaceutically acceptable salt. 2.权利要求1的方法，其中X是O。2. The method of claim 1, wherein X is O. 3.权利要求1的方法，其中X是NH。3. The method of claim 1, wherein X is NH. 4.权利要求2或3的方法，其中R1是乙基、丙基或丁基，优选乙基、2-丙基或叔丁基，最优选叔丁基。4. The method of claim 2 or 3, wherein R 1 is ethyl, propyl or butyl, preferably ethyl, 2-propyl or tert-butyl, most preferably tert-butyl. 5.权利要求1-4的方法，其中使用的格利雅试剂是卤化镁，优选氯化镁、溴化镁或碘化镁。5. Process according to claims 1-4, wherein the Grignard reagent used is a magnesium halide, preferably magnesium chloride, magnesium bromide or magnesium iodide. 6.权利要求5的方法，其中在第一步骤中使用的格利雅试剂是溴化镁盐。6. The method of claim 5, wherein the Grignard reagent used in the first step is a magnesium bromide salt. 7.权利要求5的方法，其中在第二步骤中使用的格利雅试剂是氯化镁。7. The method of claim 5, wherein the Grignard reagent used in the second step is magnesium chloride. 8.权利要求1-6任何一项的方法，其中式V化合物的环闭合通过用无机酸，例如硫酸或磷酸或有机酸，例如甲磺酸、对甲苯磺酸或三氟乙酸进行的酸性环闭合进行。8. The method of any one of claims 1-6, wherein the ring closure of the compound of formula V is carried out by an acidic ring closure with an inorganic acid, such as sulfuric acid or phosphoric acid, or an organic acid, such as methanesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. Closure proceeds. 9.权利要求1-6任何一项的方法，其中式V化合物经不稳定酯，优选同时酯化和碱加入的碱性环闭合进行。9. The process according to any one of claims 1-6, wherein the compound of formula V is carried out by basic ring closure of an unstable ester, preferably simultaneous esterification and base addition. 10.权利要求8的方法，其中不稳定酯是甲磺酰基、对甲苯磺酰基、10-樟脑磺酰基、三氟乙酰基或三氟甲磺酰基的酯并且碱是三乙胺、二甲基苯胺或吡啶。10. The method of claim 8, wherein the labile ester is an ester of methanesulfonyl, p-toluenesulfonyl, 10-camphorsulfonyl, trifluoroacetyl or trifluoromethanesulfonyl and the base is triethylamine, dimethyl aniline or pyridine. 11.权利要求2的方法，其中X是O，基团R1-X-CO-向氰基的转化优选经相应的酰胺基团进行。11. The method of claim 2, wherein X is O, the conversion of the group R1 -X-CO- to the cyano group preferably takes place via the corresponding amide group. 12.权利要求10的方法，其中R1-X-CO-至酰胺的反应通过用酸或碱水解，随后转化为酰氯和通过与氨或烷基胺，优选叔丁基胺反应胺化进行。12. The process of claim 10, wherein the reaction of R1 - X-CO- to the amide is carried out by hydrolysis with acid or base followed by conversion to acid chloride and amination by reaction with ammonia or alkylamine, preferably tert-butylamine. 13.权利要求11的方法，其中通过使用合适的酸，例如氢溴酸、盐酸、氢溴酸/乙酸进行水解。13. The method of claim 11, wherein the hydrolysis is carried out by using a suitable acid, such as hydrobromic acid, hydrochloric acid, hydrobromic acid/acetic acid. 14.权利要求11的方法，其中通过使用合适的碱，优选碳酸钾、氢氧化钠或氢氧化钾进行水解。14. The method of claim 11, wherein the hydrolysis is carried out by using a suitable base, preferably potassium carbonate, sodium hydroxide or potassium hydroxide. 15.权利要求8的方法，其中R1-X-CO-至酰胺的反应通过酯与氨或烷基胺在压力和加热下反应进行。15. The method of claim 8, wherein the reaction of R1 - X-CO- to the amide is carried out by reacting the ester with ammonia or an alkylamine under pressure and heat. 16.权利要求9-14的任何一项的方法，其中通过与脱水剂，优选亚硫酰氯或五氯化磷反应将酰胺转化为氰基。16. A process according to any one of claims 9-14, wherein the amide is converted to the cyano group by reaction with a dehydrating agent, preferably thionyl chloride or phosphorus pentachloride. 17.权利要求1-15的任何一项的方法，其特征在于在用于环闭合反应之前，式V化合物分离成旋光对映体，从而得到(S)-对映体。17. Process according to any one of claims 1-15, characterized in that the compound of formula V is separated into the optical antipodes before being used in the ring closure reaction, thereby obtaining the (S)-enantiomer. 18.具有式IVa的用于制备氰酞氟苯胺的中间体：
Figure A9880694500041
式  IVa其中R1是C1-6烷基和X是O或NH。18. An intermediate for the preparation of cyanophthalofluoroaniline having the formula IVa:
Figure A9880694500041
Formula IVa wherein R 1 is C 1-6 alkyl and X is O or NH. 19.具有式V的用于制备氰酞氟苯胺的中间体：式  V其中R1是C1-6烷基和X是O或NH。19. An intermediate for the preparation of cyanophthalofluoroaniline having the formula V: Formula V wherein R 1 is C 1-6 alkyl and X is O or NH. 20.具有式VI的用于制备氰酞氟苯胺的中间体：
Figure A9880694500051
式 VI其中R1是C1-6烷基和X是O或NH。20. An intermediate for the preparation of cyanophthalofluoroaniline having the formula VI:
Figure A9880694500051
Formula VI wherein R 1 is C 1-6 alkyl and X is O or NH. 21.含有权利要求1-16任何一项的方法制备的氰酞氟苯胺的抗抑郁药物组合物。21. The antidepressant pharmaceutical composition containing the cyanophthalide prepared by the method of any one of claims 1-16.
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