CN103833660A - Preparation method of lamotrigine and intermediate thereof - Google Patents
Preparation method of lamotrigine and intermediate thereof Download PDFInfo
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- CN103833660A CN103833660A CN201410115200.1A CN201410115200A CN103833660A CN 103833660 A CN103833660 A CN 103833660A CN 201410115200 A CN201410115200 A CN 201410115200A CN 103833660 A CN103833660 A CN 103833660A
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- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 50
- 229960001848 lamotrigine Drugs 0.000 title claims abstract description 48
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 34
- 229910001511 metal iodide Inorganic materials 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- XOGGUFAVLNCTRS-UHFFFAOYSA-N tetrapotassium;iron(2+);hexacyanide Chemical compound [K+].[K+].[K+].[K+].[Fe+2].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-].N#[C-] XOGGUFAVLNCTRS-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 7
- 238000006482 condensation reaction Methods 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 56
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 21
- 235000007715 potassium iodide Nutrition 0.000 claims description 12
- 229960004839 potassium iodide Drugs 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 11
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 8
- OTXHZHQQWQTQMW-UHFFFAOYSA-N (diaminomethylideneamino)azanium;hydrogen carbonate Chemical compound OC([O-])=O.N[NH2+]C(N)=N OTXHZHQQWQTQMW-UHFFFAOYSA-N 0.000 claims description 4
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 229910021612 Silver iodide Inorganic materials 0.000 claims description 4
- AJSHDAOMUKXVDC-UHFFFAOYSA-N butan-1-amine;sulfuric acid Chemical compound CCCC[NH3+].OS([O-])(=O)=O AJSHDAOMUKXVDC-UHFFFAOYSA-N 0.000 claims description 4
- 150000003242 quaternary ammonium salts Chemical group 0.000 claims description 4
- 229940045105 silver iodide Drugs 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000007333 cyanation reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000276 potassium ferrocyanide Substances 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- -1 compound 2,3 dichloro benzoyl chloride Chemical class 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000012216 screening Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 4
- 230000007613 environmental effect Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YBONBWJSFMTXLE-UHFFFAOYSA-N 2,3-dichlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC(Cl)=C1Cl YBONBWJSFMTXLE-UHFFFAOYSA-N 0.000 description 2
- FIBBFBXFASKAON-UHFFFAOYSA-N 2,3-dichlorobenzoyl cyanide Chemical compound ClC1=CC=CC(C(=O)C#N)=C1Cl FIBBFBXFASKAON-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229940072170 lamictal Drugs 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- QAOJBHRZQQDFHA-UHFFFAOYSA-N 2,3-dichlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1Cl QAOJBHRZQQDFHA-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000020925 Bipolar disease Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- FPLYNRPOIZEADP-UHFFFAOYSA-N octylsilane Chemical group CCCCCCCC[SiH3] FPLYNRPOIZEADP-UHFFFAOYSA-N 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
- C07D253/06—1,2,4-Triazines
- C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
- C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D253/075—Two hetero atoms, in positions 3 and 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
Abstract
The invention relates to the technical field of medicinal chemistry and particularly discloses a preparation method of lamotrigine and an intermediate thereof. The preparation method of lamotrigine comprises cyanation, condensation reaction and cyclization reaction. By adopting potassium ferrocyanide as a cyanating agent and adopting a specific catalyst combination of a phase transfer catalyst and a metal iodide, the preparation method disclosed by the invention is environment-friendly, efficient and safe in reaction and suitable for pharmaceutical industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, particularly the preparation method of lamotrigine and intermediate thereof.
Background technology
Lamotrigine (lamotrigine), chemical name LAMICTAL, molecular formula: C
9h
7n
5cL
2, structure is suc as formula shown in I:
Lamotrigine, is developed by GlaxoSmithKline PLC company of Britain, the LAMICTAL by name of the medicine commodity containing lamotrigine product selling on market.Lamotrigine is identified in treatment CNS disease, particularly epilepsy, pain, edema, multiple sclerosis and psychosis indication and comprises that bipolarity mental disorder (bipolar disorder) aspect is effective.The preparation method of lamotrigine, prior art has been reported, such as US6111101, US6639072 etc.The classical synthetic route of prior art is, formula II compound 2,3 dichloro benzoyl chloride prepares intermediate formula III compound through cyanogenation, and intermediate formula III compound and aminoguanidine bicarbonate obtain formula IV compound through condensation reaction, formula IV compound, through ring-closure reaction, makes lamotrigine.The structure of formula II compound, intermediate formula III compound, formula IV compound is as follows respectively:
Wherein, in the preparation process of intermediate formula III compound, all need to use hypertoxic metal cyanides, and temperature of reaction is high, long reaction time.As US4602417, be to react with cuprous cyanide with 2,3 dichloro benzoyl chloride to obtain formula III compound; US6111101 reacts reaction in 16 hours with 2,3 dichloro benzoyl chloride and cupric cyanide in acetonitrile and reflux in toluene to obtain formula III compound.
In prior art about the preparation method of lamotrigine, because needs use hypertoxic metal cyanides, and temperature of reaction high (generally need to reach 160 DEG C), long reaction time (generally answering minimum reaction 7 hours), cause not environmental protection of preparation method, and preparation process is tediously long, thereby be unfavorable for suitability for industrialized production.
Summary of the invention
Main purpose of the present invention is for above-mentioned the above-mentioned problems in the prior art, and a kind of environmental protection, efficient lamotrigine preparation method are provided, and meanwhile, the invention provides a kind of preparation method of lamotrigine intermediate formula III compound.
In order to realize foregoing invention object, the technical solution used in the present invention is as follows:
The preparation method of lamotrigine, comprises step:
Step (1) cyanogenation: formula II compound reacts under catalyst action with yellow prussiate of potash,
Obtain intermediate formula III compound:
Step (2) condensation reaction: intermediate formula III compound reacts with aminoguanidine bicarbonate, obtains formula IV compound:
Step (3) ring-closure reaction: formula IV compound, through cyclization, obtains lamotrigine;
The described catalyzer of step (1) is the composition of phase-transfer catalyst and metal iodide, and described phase-transfer catalyst is quaternary ammonium salt.
The preparation method of lamotrigine of the present invention, in step (1), abandon the hypertoxic prussiate using in prior art, the yellow prussiate of potash of what Select to use was nontoxic can be used as food additive, and coordinate the selection of catalyst composition, not only environmental friendliness of the preparation method who obtains, and speed of response increases, temperature of reaction is less demanding, is more applicable to suitability for industrialized production.
As preferably, the preparation method of aforesaid lamotrigine, described phase-transfer catalyst is selected from any mixture of any or they of benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate.
As further preferably, the preparation method of aforesaid lamotrigine, described metal iodide is selected from any mixture of any or they of potassiumiodide or Silver iodide.
As further preferred again, the preparation method of aforesaid lamotrigine, described phase-transfer catalyst is Tetrabutyl amonium bromide, described metal iodide is potassiumiodide.
As further preferred, the preparation method of aforesaid lamotrigine, the quality of described phase-transfer catalyst is 1～5% of formula II compound quality, the quality of described metal iodide is 1～5% of formula II compound quality.In the present invention, by the ratio of screening phase-transfer catalyst and metal iodide, can further improve speed of response and temperature of reaction is effectively reduced.
As further preferred, the preparation method of aforesaid lamotrigine, the quality of described phase-transfer catalyst is 1.5～2% of formula II compound quality, the quality of described metal iodide is 3～5% of formula II compound quality.
As most preferably, the preparation method of aforesaid lamotrigine, the mass ratio of described phase-transfer catalyst and metal iodide is 1:2～3.
As preferably, the preparation method of aforesaid lamotrigine, the temperature of reaction of described step (1) is 90～100 DEG C, the reaction times of described step (1) is 3～3.5 hours.The preparation method of lamotrigine of the present invention, by screening catalyst composition of the present invention, the temperature of reaction of step (1) is controlled at 90～100 DEG C, 3～3.5 hours reaction times, can react completely, and the lamotrigine product yield and the purity that obtain are significantly improved compared with prior art.
As second object of the present invention, the invention provides the preparation method of intermediate formula III compound, under catalyst action, react and obtain with yellow prussiate of potash by formula II compound,
Described catalyzer is the composition of phase-transfer catalyst and metal iodide, described phase-transfer catalyst is quaternary ammonium salt, described metal iodide is selected from any mixture of any or they of potassiumiodide or Silver iodide, and described temperature of reaction is 90～100 DEG C, and the described reaction times is 3～3.5 hours.
As preferably, the preparation method of aforesaid intermediate formula III compound, described phase-transfer catalyst is selected from any mixture of any or they of benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate, and described metal iodide is potassiumiodide.As further preferred, the preparation method of aforesaid intermediate formula III compound, described phase-transfer catalyst is Tetrabutyl amonium bromide.
As preferably, the preparation method of aforesaid intermediate formula III compound, the quality of described phase-transfer catalyst is 1～5% of formula II compound quality, and the quality of described metal iodide is 1～5% of formula II compound quality, and the mass ratio of described phase-transfer catalyst and metal iodide is 1:2～3.As most preferably, the preparation method of aforesaid intermediate formula III compound, the quality of described phase-transfer catalyst is 1.5～2% of formula II compound quality, the quality of described metal iodide is 3～5% of formula II compound quality.
As preferably, the preparation method of aforesaid intermediate formula III compound, temperature of reaction is 90～100 DEG C, the reaction times is 3～3.5 hours.
Compared with prior art, the invention has the beneficial effects as follows:
One, in prior art, the preparation method of lamotrigine and intermediate thereof need use hypertoxic prussiate, such as cuprous cyanide etc.In the present invention, contriver obtains yellow prussiate of potash by screening, replaces hypertoxic prussiate of the prior art, preparation method's environmental friendliness of the lamotrigine that the present invention obtains and intermediate thereof.
Two, in prior art, the preparation method's of lamotrigine and intermediate thereof temperature of reaction is 90～100 DEG C, and the reaction times is 3～3.5 hours.In the present invention, contriver obtains the catalyst composition of phase-transfer catalyst and metal iodide by screening, especially further screen the consumption of phase-transfer catalyst and metal iodide, invention temperature of the present invention is obviously reduced compared with prior art, and the reaction times effectively shortens, make the preparation method of lamotrigine of the present invention and intermediate thereof safer, efficient.
Three, in prior art, still not about yellow prussiate of potash as cyanidization agent, and with the specific catalyst composition of phase-transfer catalyst and metal iodide, the report being used in conjunction with.The present invention is used in conjunction with by aforementioned cyanidization agent and catalyst composition, and screen its usage ratio, the lamotrigine preparation method who obtains, under the nontoxic prerequisite of reactant, can safely, efficiently obtain end product, and end product yield and purity all effectively improve.
Embodiment
Below in conjunction with embodiment, foregoing invention content of the present invention is described in further detail.
But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following embodiment.Without departing from the idea case in the present invention described above, according to ordinary skill knowledge and customary means, make various replacements and change, all should comprise within the scope of the invention.
In following examples and test example, the chromatographic condition of HPLC is as follows:
(1) intermediate formula III compound 2,3-dichloro benzoyl cyanide and formula IV compound 2-cyano group-(2,3-dichlorophenyl)-2-guanidine imido grpup acetonitrile
Chromatographic column: octyl silane group silica gel is packed column
Moving phase: acetonitrile-0.05mol/L ammonium acetate solution (35:65), acetic acid is adjusted pH to 6.0
Detect wavelength: 306nm
(2) lamotrigine
Chromatographic column: octadecyl silane is packed column
Moving phase: methyl alcohol-0.5% triethylamine solution (36:64), phosphorus acid for adjusting pH value to 4.0
Detect wavelength: 265nm
Embodiment 1 the present embodiment is the preparation method of lamotrigine and intermediate formula III compound
Step (1) cyanogenation, prepares intermediate formula III compound 2,3-dichloro benzoyl cyanide
Being with in churned mechanically reactor throw-in type II compound 2 successively, 3-dichlorobenzoyl chloride 50kg(238.7mol), Tetrabutyl amonium bromide 0.77kg(2.4mol), potassiumiodide 2kg(12.0mol), yellow prussiate of potash 17.6kg(47.8mol), be warming up to 90～100 DEG C of stirring reactions 3～3.5 hours.React complete, add toluene 200L to dissolve, filtering insolubles.Reclaim toluene by concentrating under reduced pressure, then add ethanol dispersible solid, centrifugal, obtain intermediate formula III compound 2,3-dichloro benzoyl cyanide light yellow solid 46.2kg, yield 96.7%.
HPLC analyzes:
2,3-dichloro benzoyl cyanide 99.2%
2 3,dichloro benzoic acid 99 0.6%
Step (2) condensation reaction: preparation formula IV compound 2-cyano group-(2,3-dichlorophenyl)-2-guanidine imido grpup acetonitrile
Drop into purified water 200kg being with in churned mechanically reactor, slowly add sulfuric acid 360kg.Then control 20～25 DEG C of temperature, add aminoguanidine bicarbonate 80kg (587.8mol) in batches, finish, stir 0.5～1 hour.Add that step (1) makes 2,3-dichloro benzoyl cyanide 40kg(200.0mol), control 60～65 DEG C of stirring reactions of temperature 6～8 hours.React complete, be down to room temperature, filter, filter cake is adjusted to alkalescence with 50% aqueous sodium hydroxide solution.By centrifugal and washing, and at 60 DEG C of drying under reduced pressure, obtain IV compound 42kg, yield 82.0%.
HPLC analyzes: 99.6%.
Step (3) ring-closure reaction: preparationⅠcompound lamotrigine
In churned mechanically reactor, drop into successively purified water 600kg, potassium hydroxide 6kg, 2-cyano group-(2,3-dichlorophenyl)-2-guanidine imido grpup acetonitrile 40kg, back flow reaction 2～3 hours being with.React complete, be down to room temperature, centrifugal, washing, and at 60 DEG C of drying under reduced pressure, obtain lamotrigine crude product 37.4kg, yield 93.5%, HPLC:99.9%.By Virahol/purified water mixing solutions recrystallization, obtain lamotrigine 34kg.
HPLC analyzes: 100.0%
NMR
1H(DMSO，500MHz）,δ(ppm)：6.47（S,2H,-NH
2）,6.6-6.8（S，2H，-NH
2），7.2-7.5（m，2H,ArH）,7.68(d,1H,ArH).
IR（KB
r）：3450.2，3316.7，1645.5，1618.2，1555.6，1490.1，793.1cm
-1
Embodiment 2 the present embodiment are the preparation method of lamotrigine and intermediate formula III compound
Step (1) cyanogenation, makes intermediate formula III compound 2,3-dichloro benzoyl cyanide
Being with in churned mechanically reactor throw-in type II compound 2 successively, 3-dichlorobenzoyl chloride 100g(477.4mmol), Tetrabutyl amonium bromide 1g(3.1mmol), potassiumiodide 1g(6.0mmol), yellow prussiate of potash 35.2g(95.56mmol), be warming up to 90～100 DEG C of stirring reactions 3～3.5 hours.React complete, add toluene 400ml to dissolve, filtering insolubles.Reclaim toluene by concentrating under reduced pressure, then add ethanol dispersible solid, filter, obtain intermediate formula III compound 2,3-dichloro benzoyl cyanide light yellow solid 67.2g, yield 70.4%.
Step (2)～step (3) is with embodiment 1.
Embodiment 3 the present embodiment are the preparation method of lamotrigine and intermediate formula III compound
Step (1) cyanogenation, makes intermediate formula III compound 2,3-dichloro benzoyl cyanide
Being with in churned mechanically reactor throw-in type II compound 2 successively, 3-dichlorobenzoyl chloride 100g, (477.4mmol), Tetrabutyl amonium bromide 5g(15.5mmol), potassiumiodide 5g(30.1mmol), yellow prussiate of potash 35.2g(95.56mmol), be warming up to 90～100 DEG C of stirring reactions 3～3.5 hours.React complete, add toluene 400ml to dissolve, filtering insolubles.Reclaim toluene by concentrating under reduced pressure, then add ethanol dispersible solid, filter, obtain intermediate formula III compound 2,3-dichloro benzoyl cyanide light yellow solid 91.7g, yield 96.0%.
Embodiment 4 the present embodiment are the preparation method of lamotrigine and intermediate formula III compound
Step (1) cyanogenation, makes intermediate formula III compound 2,3-dichloro benzoyl cyanide
Being with in churned mechanically reactor throw-in type II compound 2,3 dichloro benzoyl chloride 100g, Tetrabutyl amonium bromide 2g, potassiumiodide 3g, yellow prussiate of potash 35.2g successively, be warming up to 90～100 DEG C of stirring reactions 3～3.5 hours.React complete, add toluene 400ml to dissolve, filtering insolubles.Reclaim toluene by concentrating under reduced pressure, then add ethanol dispersible solid, filter, obtain intermediate formula III compound 2,3-dichloro benzoyl cyanide light yellow solid, yield 90.2%.
Test example is about screening of catalyst test example below 1
Test is divided into six groups, and reactions steps and temperature of reaction, reaction times, the charging capacity of formula II compound was 100g with embodiment 1, and catalyzer composition and intermediate III yield, purity are in table 1.
Table 1. catalyst screening
Can find out by above test example: (1) is not used catalyzer, and the catalyst composition that does not use the present invention to limit, in same reaction temperature with in the reaction times, the yield of intermediate formula III compound is very low, and purity is also poor; (2) select the catalytic materials composition of phase-transfer catalyst of the present invention and metal iodide, but beyond the mass ratio that the two ratio limits in the present invention time, because reaction not exclusively, cause yield low, find simultaneously, in the time that catalyst levels is increased to a certain degree, yield and purity is corresponding increasing not, increased on the contrary production cost.
Test example is the shaker test example about catalyst levels below 2
Test is divided into five groups, and reactions steps and temperature of reaction, reaction times, the charging capacity of formula II compound was 100g with embodiment 1, and yellow prussiate of potash charging capacity is 35.2g, and catalyzer composition and intermediate III yield, purity are in table 2.
The screening of table 2. catalyst levels ratio
Can find out by above test example: (1) is in the time that the amount ranges of phase-transfer catalyst and metal iodide is outside 1:2～1:3, lower than low, the purity difference of yield of this scope; Higher than this scope, yield can not obtain corresponding increase.(2), while selecting the usage ratio of phase-transfer catalyst of the present invention and metal iodide, yield is high, purity good.
Claims (10)
1. the preparation method of lamotrigine, is characterized in that, comprises step:
Step (1) cyanogenation: formula II compound reacts under catalyst action with yellow prussiate of potash, obtains intermediate formula III compound:
Step (2) condensation reaction: intermediate formula III compound reacts with aminoguanidine bicarbonate, obtains formula IV compound:
Step (3) ring-closure reaction: formula IV compound, through cyclization, obtains lamotrigine;
The described catalyzer of step (1) is the composition of phase-transfer catalyst and metal iodide, and described phase-transfer catalyst is quaternary ammonium salt.
2. the preparation method of lamotrigine according to claim 1, is characterized in that, described phase-transfer catalyst is selected from any mixture of any or they of benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate.
3. the preparation method of lamotrigine according to claim 2, is characterized in that, described metal iodide is selected from any mixture of any or they of potassiumiodide or Silver iodide.
4. the preparation method of lamotrigine according to claim 3, is characterized in that, described phase-transfer catalyst is Tetrabutyl amonium bromide, and described metal iodide is potassiumiodide.
5. according to the preparation method of the lamotrigine described in claim 1～4 any one, it is characterized in that, the quality of described phase-transfer catalyst is 1～5% of formula II compound quality, and the quality of described metal iodide is 1～5% of formula II compound quality.
6. the preparation method of lamotrigine according to claim 5, is characterized in that, the quality of described phase-transfer catalyst is 1.5～2% of formula II compound quality, and the quality of described metal iodide is 3～5% of formula II compound quality.
7. the preparation method of lamotrigine according to claim 1, is characterized in that, the mass ratio of described phase-transfer catalyst and metal iodide is 1:2～3.
8. the preparation method of intermediate formula III compound, is characterized in that, under catalyst action, react and obtain with yellow prussiate of potash by formula II compound,
Described catalyzer is the composition of phase-transfer catalyst and metal iodide, described phase-transfer catalyst is quaternary ammonium salt, described metal iodide is selected from any mixture of any or they of potassiumiodide or Silver iodide, and described temperature of reaction is 90～100 DEG C, and the described reaction times is 3～3.5 hours.
9. the preparation method of intermediate formula III compound according to claim 8, it is characterized in that, described phase-transfer catalyst is selected from any mixture of any or they of benzyltriethylammoinium chloride, tetrabutylammonium chloride, Tetrabutyl amonium bromide or 4-butyl ammonium hydrogen sulfate, and described metal iodide is potassiumiodide.
10. the preparation method of the intermediate formula III compound described according to Claim 8 or 9 any one, it is characterized in that, the quality of described phase-transfer catalyst is 1～5% of formula II compound quality, the quality of described metal iodide is 1～5% of formula II compound quality, and the mass ratio of described phase-transfer catalyst and metal iodide is 1:2～3.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN109467518A (en) * | 2018-11-14 | 2019-03-15 | 响水中山生物科技有限公司 | A kind of preparation method of benzoyl cyanide |
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Denomination of invention: Preparation method of lamotrigine and its intermediates Granted publication date: 20160713 Pledgee: Chengdu SME financing Company Limited by Guarantee Pledgor: CHENGDU YILUKANG MEDICAL TECHNOLOGY & SERVICE Co.,Ltd. Registration number: Y2024980010851 |