CN103848756B - Preparation method of teriflunomide and intermediate thereof - Google Patents
Preparation method of teriflunomide and intermediate thereof Download PDFInfo
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- CN103848756B CN103848756B CN201410124053.4A CN201410124053A CN103848756B CN 103848756 B CN103848756 B CN 103848756B CN 201410124053 A CN201410124053 A CN 201410124053A CN 103848756 B CN103848756 B CN 103848756B
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Abstract
The invention belongs to the technical field of medicinal chemistry and discloses a preparation method of teriflunomide and an intermediate thereof. The preparation method of the teriflunomide provided by the invention comprises the following steps: getting a compound with a structure as shown in formula I and an azide in an organic solvent to generate nucleophilic substitution reaction to generate a compound with the structure as shown in formula II; getting and mixing the compound with the structure as shown in the formula II with the organic solvent, heating to obtain the compound with the structure as shown in formula III; under inert-gas protection and alkaline conditions, getting the compound with the structure as shown in the formula III and the compound with the structure as shown in the formula IV to generate electrophilic addition and isomerization reaction in the organic solvent to obtain the teriflunomide. According to the preparation method of the teriflunomide provided by the invention, the reaction intermediate is not needed to be purified, operation is simple, yield of the teriflunomide is improved, production cost of the teriflunomide is lowered, and therefore, the preparation method is more beneficial to industrial production of the teriflunomide.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, particularly the preparation method of Teriflunomide and intermediate thereof.
Background technology
Teriflunomide (Teriflunomide) is a kind of oral pyrimidine synthesis inhibitor and immunomodulator, is the active metabolite of leflunomide, by the de novo synthesis suppressing dihydroorate dehydrogenase to block pyrimidine.Teriflunomide is by U.S. Sanofi-aventis(Sanofi-Aventis) company's exploitation, ratify listing on September 12nd, 2012 by FDA, commodity are called Aubagio, are used for the treatment of relapsive sclerosis, are carrying out III phase clinical study at present.The molecular formula of Teriflunomide is: C
12h
9f
3n
20
2, molecular weight is 270.2, has such as formula the structure shown in V:
Teriflunomide is as a kind of oral medicine, and its 7mg dosage is used for the treatment of relapsing remitting multiple sclerosis disease by U.S.'s approval; Also get the Green Light in European, Australia, Argentina, Chile and Korea S equally.Teriflunomide 14mg dosage all demonstrates in two III phase clinical studyes has active effect to the recovery of deformity.As a kind of new oral medicine, the security that Teriflunomide is good and tolerance, be subject to the favor to the unsatisfied patient of conventional injection curative effect of medication possibly.Some scientific research institutions that China is domestic and pharmaceuticals also start to launch research to Teriflunomide, are mainly used in treating for skin disease, but also do not have granted listing at home.But in view of the medicinal properties that it is good, Teriflunomide will have good development prospect in future.
At present, the preparation method for Teriflunomide mainly contains following three major types:
First kind synthetic method: mainly with 5-methyl-isoxazole-4-formic acid starting raw material or the intermediate by synthesis 5-methyl-isoxazole-4-formic acid, then with 4-trifluoromethyl-aniline Reactive Synthesis Teriflunomide, concrete synthetic route is as follows:
This class methods General reactions step is on the high side, be not easy to intermediate purification, total recovery is on the low side, and uses a large amount of acyl chlorides in building-up process, very easily etching apparatus, produce a large amount of acid mists and sour water, and then contaminate environment.
Equations of The Second Kind method: with 2-cyanoacetic acid and derivative thereof and 4-5-trifluoromethylaniline for raw material.First 2-cyanoacetic acid is prepared into acyl chlorides by these class methods, is then obtained by reacting corresponding acid amides with 4-5-trifluoromethylaniline, then with Acetyl Chloride 98Min. effect, intermolecular condensation reaction occurs and obtains target product, synthetic route is as follows:
Use a large amount of chloride reagents in this class methods reaction process, to equipment and environmental injury larger.
3rd class methods: these class methods are similar to Equations of The Second Kind Measures compare, mainly with 2-cyanoacetic acid and derivative thereof and 4-5-trifluoromethylaniline for raw material; With Equations of The Second Kind method unlike, the in the end step structure that is material construction α, β unsaturated enol nitrile with 1-methyl-2-epichlorohydrin, namely obtain target product, synthetic route is as follows:
The method great majority of existing synthesis Teriflunomide need to experience acylation reaction, and produce a large amount of acid mists, severe corrosion equipment, contaminate environment, add production cost; On the other hand, the intermediate product of these methods synthesis needs purifying, complex steps, and total recovery is low, is unfavorable for the reduction of production cost.So urgent need one is simple to operate, yield is high, and the preparation method of the Teriflunomide that cost is low is beneficial to its suitability for industrialized production.
Summary of the invention
In view of this, goal of the invention of the present invention is the preparation method providing a kind of Teriflunomide and intermediate thereof.The preparation method of Teriflunomide provided by the invention, reaction intermediate does not need purifying, simple to operate, the yield that improves Teriflunomide, reduces the production cost of Teriflunomide, is more conducive to its suitability for industrialized production.
In order to realize goal of the invention of the present invention, the present invention adopts following technical scheme:
The invention provides a kind of preparation method of Teriflunomide, comprise the following steps:
Step 1: get the compound with structure shown in formula I and triazo-compound and nucleophilic substitution reaction occurs in organic solvent generate the compound with structure shown in formula II;
Step 2: get the compound that step 1 gained has a structure shown in formula II and mix with organic solvent, heating, must have the compound of structure shown in formula III;
Step 3: under protection of inert gas, alkaline condition, gets the compound that step 2 gained has a structure shown in formula III, with the compound with structure shown in formula IV, electrophilic addition, isomerization reaction occurs in organic solvent, to obtain final product;
The preparation method of Teriflunomide provided by the invention is with 4-trifluoromethylbenzoic acid, the compound namely with structure shown in formula I is that raw material has prepared triazo-compound, namely there is the compound of structure shown in formula II, carry out heating generation Curtius rearrangement (Ke Erdisi rearrangement) afterwards and obtain 4-(trifluoromethyl) phenyl isocyanate, namely there is the compound of structure shown in formula III.Because the by product of Curtius rearrangement is gas nitrogen, so namely products therefrom can be used for preparing Teriflunomide with the compound generation electrophilic addition with structure shown in formula IV, isomerization reaction without the need to being further purified.The active character that preparation method provided by the invention make use of isocyanic ester reacts with the compound with structure shown in formula IV and has synthesized Teriflunomide, this preparation method adopts simple to operate and free of contamination Curtius rearrangement reaction to prepare isocyanic ester, make the preparation method of Teriflunomide provided by the invention simple to operate, and improve the yield of Teriflunomide, be more conducive to the suitability for industrialized production of Teriflunomide.
Preferably, the preparation method of Teriflunomide provided by the invention, in step 1, triazo-compound is inorganic triazo-compound and/or organic azide.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, triazo-compound used in step 1 is inorganic triazo-compound.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, inorganic triazo-compound used in step 1 is NaN
3.
Preferably, the preparation method of Teriflunomide provided by the invention, when triazo-compound is inorganic triazo-compound in step 1, has the compound of structure shown in formula I with the amount of substance of inorganic triazo-compound than being 1:1 ~ 1.5;
Preferably, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the temperature of nucleophilic substitution reaction is 15 DEG C ~ 30 DEG C.
Preferably, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the time of nucleophilic substitution reaction is 4h ~ 6h.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the catalyzer of nucleophilic substitution reaction is Ph
3p.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the activating reagent of nucleophilic substitution reaction is NCS.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, organic solvent is specially one in THF, ether, acetonitrile or methyl tertiary butyl ether or both above mixtures.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, organic solvent is specially THF.
Preferably, the preparation method of Teriflunomide provided by the invention, triazo-compound used in step 1 is organic azide.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, organic azide used in step 1 is (PhO)
2pON
3.
Preferably, the preparation method of Teriflunomide provided by the invention, when triazo-compound described in step 1 is organic azide, nucleophilic substitution reaction alkali used is Et
3n, K
2cO
3or one in DIPEA or both above mixtures.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, nucleophilic substitution reaction alkali used is specially Et
3n.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, having the compound of structure shown in formula I with the ratio of the amount of substance of organic azide is 1:1.1 ~ 3;
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, when triazo-compound is organic azide in step 1, there is the amount of substance of the compound of structure shown in formula I, the organic azide alkali used with nucleophilic substitution reaction than being 1:1.1 ~ 3:1.1 ~ 3;
Preferably, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, the temperature of nucleophilic substitution reaction is 35 DEG C ~ 45 DEG C.
Preferably, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, the time of nucleophilic substitution reaction is 4h ~ 10h.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, organic solvent is one in DMF, THF or acetonitrile or both above mixtures.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, when in step 1, triazo-compound is organic azide, organic solvent is DMF.
Preferably, the preparation method of Teriflunomide provided by the invention, in step 2, organic solvent is one in acetonitrile, toluene or dimethylbenzene or both above mixtures.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, the organic solvent in step 2 is specially toluene.
Preferably, the preparation method of Teriflunomide provided by the invention, in g/mL, the mass volume ratio of the compound and organic solvent in step 2 with structure shown in formula II is 1:6 ~ 20.
Preferably, the preparation method of Teriflunomide provided by the invention, in step 2, the temperature of heating is 100 DEG C ~ 120 DEG C.
Preferably, the preparation method of Teriflunomide provided by the invention, in step 2, the time of heating is 14h ~ 20h.
Preferably, the preparation method of Teriflunomide provided by the invention, step 3 neutral and alkali condition is by EtONa, MeONa, NaH, t-BuOK, CaH
2or one in LDA or both above mixtures provide.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, step 3 neutral and alkali condition is provided by NaH.
Preferably, the preparation method of Teriflunomide provided by the invention, the compound in step 3 with structure shown in formula III is 1:1 ~ 2 with the amount of substance ratio of the compound with structure shown in formula IV;
Preferably, the preparation method of Teriflunomide provided by the invention, the compound have the compound of structure shown in formula III in step 3, having structure shown in formula IV is 1:1 ~ 2:1 ~ 2 with the amount of substance ratio of the alkali of the alkaline condition provided;
Preferably, the preparation method of Teriflunomide provided by the invention, the temperature of reaction of electrophilic addition, isomerization reaction in step 3 is 60 DEG C ~ 80 DEG C.
Preferably, the preparation method of Teriflunomide provided by the invention, the reaction times of electrophilic addition, isomerization reaction in step 3 is 24h ~ 48h.
Preferably, the preparation method of Teriflunomide provided by the invention, rare gas element used in step 3 is nitrogen.
Preferably, the preparation method of Teriflunomide provided by the invention, in step 3, organic solvent is polar aprotic solvent.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, step 3 Semi-polarity aprotic solvent is one in THF, dioxane or methyl alcohol or both above mixtures.
In other embodiment of the present invention, the preparation method of Teriflunomide provided by the invention, step 3 Semi-polarity aprotic solvent is THF.
Preferably, the preparation method of Teriflunomide provided by the invention, also comprises 2 times ~ 4 times re-crystallization step after electrophilic addition, isomerization reaction in step 3.
In some embodiments of the invention, the preparation method of Teriflunomide provided by the invention, in step 3, recrystallization solvent for use is MeOH, EtOAc, CH
2cl
2, CHCl
3, EtOH, Et
2o, THF, Acetone, CH
3one in CN or i-PrOH or both above mixtures.
In some embodiments of the invention, in the preparation method of Teriflunomide provided by the invention, recrystallization solvent for use is specially MeOH and/or EtOAc.
Preferably, in the preparation method of Teriflunomide provided by the invention, in recrystallization, the temperature of crystallization is 10 DEG C ~ 25 DEG C.
Because preparation method's step provided by the invention is few, by product is few, make electrophilic addition in step 3, isomerization reaction by product is few, only need 2 times ~ 4 recrystallizations can obtain the Teriflunomide of purity 99.5% ~ 99.9%, the suitability for industrialized production being more conducive to Teriflunomide simple to operate.
Present invention also offers a kind of preparation method of Teriflunomide intermediate, comprise the following steps:
Step 1: get the compound with structure shown in formula I and triazo-compound and nucleophilic substitution reaction occurs in organic solvent generate the compound with structure shown in formula II;
Step 2: get the compound that step 1 gained has a structure shown in formula II and mix with organic solvent, heating, to obtain final product;
This Teriflunomide intermediate is for having the compound of structure shown in formula III;
The preparation method with the compound of structure shown in formula III of research report mainly contains two classes, and the first kind is phosgenation synthesis method, and this preparation method needs the phosgene using severe toxicity, there is serious potential safety hazard, is not suitable for suitability for industrialized production.Equations of The Second Kind is for raw material with 4-5-trifluoromethylaniline (namely having the compound of structure shown in formula VI), with 1,1'-carbonyl dimidazoles (namely having the compound of structure shown in formula VII) reacts and prepares under the effect of strong dehydrating agent, lower and unnecessary in the last handling process dehydrating agent of the reactive behavior of this reaction not easily eliminates, such that product purity is low, yield is low.So the production cost at present with the compound of structure shown in formula III is higher, expensive, be not suitable for industrialized production.Preparation method provided by the invention is after preparing triazo-compound, carry out heating and Curtius rearrangement (Ke Erdisi rearrangement) occurs, obtain product, make use of Curtius rearrangement reaction dexterously, simple to operate pollution-free, and because the by product of Curtius rearrangement reaction is gas nitrogen, so products therefrom purity is high, can for the preparation of Teriflunomide without the need to being further purified
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in step 1, triazo-compound is inorganic triazo-compound and/or organic azide.
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, triazo-compound used in step 1 is inorganic triazo-compound.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, inorganic triazo-compound used in step 1 is NaN
3.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, when triazo-compound used in step 1 is inorganic triazo-compound, has the compound of structure shown in formula I with the amount of substance of inorganic triazo-compound than being 1:1 ~ 1.5;
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, when triazo-compound used in step 1 is inorganic triazo-compound, the temperature of nucleophilic substitution reaction is 15 DEG C ~ 30 DEG C.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, when triazo-compound used in step 1 is inorganic triazo-compound, the time of nucleophilic substitution reaction is 4h ~ 6h.
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the catalyzer of nucleophilic substitution reaction is Ph
3p.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, the activating reagent of nucleophilic substitution reaction is NCS.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, organic solvent is specially one in THF, ether, acetonitrile or methyl tertiary butyl ether or both above mixtures.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is inorganic triazo-compound, organic solvent is specially THF.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in step 1, triazo-compound is organic azide.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, organic azide used in step 1 is (PhO)
2pON
3.
Preferably, the invention provides the preparation method of Teriflunomide intermediate, when in step 1, triazo-compound is organic azide, the alkali of nucleophilic substitution reaction is Et
3n, K
2cO
3or one in DIPEA or both above mixtures.
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, the alkali that in step 1, nucleophilic substitution reaction is used is specially Et
3n.
Preferably, the invention provides the preparation method of Teriflunomide intermediate, when triazo-compound is organic azide in step 1, there is the compound of structure shown in formula I with the amount of substance of organic azide than being 1:1.1 ~ 3;
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, when triazo-compound is organic azide in step 1, there is the compound of structure shown in formula I, organic azide and provide the amount of substance of the alkali of alkaline condition than being 1:1.1 ~ 3:1.1 ~ 3;
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is organic azide, the temperature of nucleophilic substitution reaction is 35 DEG C ~ 45 DEG C.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is organic azide, the time of nucleophilic substitution reaction is 4h ~ 10h.
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is organic azide, organic solvent is one in DMF, THF or acetonitrile or both above mixtures.
In other embodiment of the present invention, the preparation method of Teriflunomide intermediate provided by the invention, when in step 1, triazo-compound is organic azide, organic solvent is DMF.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in step 2, organic solvent is one in acetonitrile, toluene or dimethylbenzene or both above mixtures.
During the generation of aromatics isocyanic ester, generally need the longer reaction times, preparation method provided by the invention adopts acetonitrile, toluene or dimethylbenzene to be conducive to having the generation of the compound of structure shown in formula III.
In some embodiments of the invention, the preparation method of Teriflunomide intermediate provided by the invention, the organic solvent in step 2 is specially toluene.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in g/mL, the mass volume ratio of the compound and organic solvent in step 2 with structure shown in formula II is 1:6 ~ 20.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in step 2, the temperature of heating is 100 DEG C ~ 120 DEG C.
Preferably, the preparation method of Teriflunomide intermediate provided by the invention, in step 2, the time of heating is 14h ~ 20h.
The invention provides the preparation method of a kind of Teriflunomide and intermediate thereof.The preparation method of Teriflunomide provided by the invention comprises the following steps: get the compound with structure shown in formula I and triazo-compound and nucleophilic substitution reaction occurs in organic solvent generate the compound with structure shown in formula II; Get the compound that gained has a structure shown in formula II to mix with organic solvent, heating, must have the compound of structure shown in formula III; Under protection of inert gas, alkaline condition, get the compound that gained has a structure shown in formula III, with the compound with structure shown in formula IV, electrophilic addition, isomerization reaction occur in organic solvent, to obtain final product.The active character that the preparation method of Teriflunomide provided by the invention make use of isocyanic ester reacts with the compound with structure shown in formula IV and has synthesized Teriflunomide, this preparation method adopts simple to operate and utilizes free of contamination Curtius rearrangement reaction to prepare isocyanic ester, preparation method's intermediate product of Teriflunomide provided by the invention is made not need purifying, simple to operate, the yield that improves Teriflunomide, reduce the production cost of Teriflunomide, more be conducive to the suitability for industrialized production of Teriflunomide
Accompanying drawing explanation
Fig. 1 shows the mass spectrogram of the compound as white solid that embodiment 3 prepares;
Fig. 2 shows the proton nmr spectra spectrogram of the compound as white solid that embodiment 3 prepares;
Fig. 3 shows the carbon-13 nmr spectra spectrogram of the compound as white solid that embodiment 3 prepares;
Fig. 4 shows the Teriflunomide HPLC detection figure that embodiment 3 prepares, and wherein appearance time 39.431min is the peak that Teriflunomide is corresponding, and appearance time 28.865min is impurity peaks; Appearance time is that the peak area that 39.431min is corresponding accounts for 99.95% of total peak area; Appearance time is that the peak area that 28.865min is corresponding accounts for 0.05% of total peak area.
Embodiment
The invention discloses the preparation method of a kind of Teriflunomide and intermediate thereof.Those skilled in the art with reference to present disclosure, can prepare Teriflunomide and intermediate thereof, special needs to be pointed out is, all similar replacements and change apparent to those skilled in the art, and they are all deemed to be included in the present invention.Preparation method of the present invention and application are described by preferred embodiment, related personnel obviously can not depart from content of the present invention, spirit and scope this paper preparation method and application are changed or suitably change with combination, realize and apply the technology of the present invention.
Reagent used in the preparation method of a kind of Teriflunomide provided by the invention and intermediate thereof and raw material all can be buied by market.
Bilingual corresponding to the abbreviation of the reagent that the present invention uses or compound is in table 1.
Bilingual table corresponding to the abbreviation of the reagent that table 1 the present invention uses or compound
| DIPEA | DIPEA |
| Et 3N | Triethylamine |
| EtONa | Sodium ethylate |
| MeONa | Sodium methylate |
| t-BuOK | Potassium tert.-butoxide |
| CaH 2 | Hydrolith |
| LDA | Lithium diisopropylamine |
| THF | Tetrahydrofuran (THF) |
| DMF | DMF |
| NaH | Sodium hydride |
| MeOH | Methyl alcohol |
| EtOAc | Ethyl acetate |
| EtOH | Ethanol |
| Ph 3P | Triphenylphosphine |
| Acetone | Acetone |
| i-PrOH | Virahol |
| Et 2O | Ether |
| HCl | Hydrochloric acid |
| NCS | N-chlorosuccinimide |
| (PhO) 2PON 3 | Diphenyl phosphate azide/bis-phenoxy group phosphorous acid nitrine ester |
In order to enable those skilled in the art understand technical scheme of the present invention better, below in conjunction with embodiment, set forth the present invention further:
Embodiment 1 has the preparation of the compound of structure shown in formula II
In the round-bottomed flask of 3L, add sodiumazide 205g (3.15mol) successively, there is the compound 400g(2.1mol of structure shown in formula I, buy in Aladdin), triphenylphosphine 52.4g(0.2mol, buy in Aladdin), N-chlorosuccinimide 28g(0.2mol, buy in Aladdin), tetrahydrofuran (THF) 2.4L, 15 DEG C of stirring reactions 5 hours, follow the tracks of reaction complete to raw material reaction.The solvent of decompression removing 1.8L after completion of the reaction, then reaction solution is poured in 2L distilled water, stir 30min, filter, filter cake 200mL distilled water and 200mL washing with alcohol obtain 388g off-white color solid chemical compound, reaction weight yield 86%.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained off-white color solid chemical compound, its mass-spectrometric data is [M+H
+]=216.3.Its proton nmr spectra is:
1h-NMR (CDCl
3-d6) δ: 7.33 (d, J=8.0Hz, 2H), 7.46 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra is:
13c-NMR (CDCl
3-d6) δ: 121.2,121.7,122.2,122.8,126.4,127.8,134.3,136.7,188.0.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 2 has the preparation of the compound of structure shown in formula III
The 388g(1.8mol obtained by embodiment 1) off-white color solid chemical compound is transferred in the round-bottomed flask of 3L, add 2.4L toluene, 110 DEG C of heating reflux reactions 16 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 300mL anhydrous diethyl ether washing obtained, drying, obtains 354g faint yellow solid compound.
By mass spectrum, proton nmr spectra and proton nmr spectra qualification gained faint yellow solid compound.The mass-spectrometric data of this compound is [M+H
+]=188.3, its proton nmr spectra is:
1h-NMR (DMSO-d6) δ: 7.41 (d, J=8.0Hz, 2H), 7.48 (d, J=8.0Hz, 2H), carbon-13 nmr spectra is:
13c-NMR (DMSO-d6) δ: 121.2,121.9,122.6,123.3,125.0,126.8,127.6,133.3,135.2ppm, so the compound that the preparation method that the present embodiment provides obtains is for having the compound of structure shown in formula III, gained faint yellow solid compound directly can carry out the next step.
The preparation of embodiment 3 Teriflunomide
Faint yellow solid compound 354g(1.8mol by obtained for embodiment 2), be directly used in the synthesis of Teriflunomide.The compound 150g(1.8mol with structure shown in formula IV is added in the round-bottomed flask of 3L; buy in Beijing company limited of Hua Weirui section); dry THF(1.5L); sodium hydride 80g(2mol; in g/mL; be stored in kerosene with mass volume ratio 60%); 15 DEG C are stirred 1 hour; then slowly drip the obtained faint yellow compound 354g(1.8mol of embodiment 2) THF solution 800mL; within 1 hour, dropwise; after dropwising, reaction solution is heated to backflow, reacts 40 hours under 65 DEG C of conditions, in reaction process, use nitrogen protection.Add 500mL frozen water cancellation reaction after completion of the reaction, with the HCl of 2mol/L, the pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, by thick for gained product through ethyl acetate twice recrystallization, the volume of each recrystallization ethyl acetate used is 2.4L, and the temperature of crystallization is 20 DEG C, obtains 316g compound as white solid, yield 65%, total recovery 52%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.The mass spectrum of this compound as white solid is shown in Fig. 1, as seen from the figure its [M-H
+]=269.1.The proton nmr spectra spectrogram of this compound as white solid is shown in Fig. 2, and data are:
1h-NMR (DMSO-d6) δ: 10.84 (s, 1H), 10.08 (br, s, 1H), 7.78 (d, 2H), 7.65 (d, 2H), 2.25 (s, 3H).The carbon-13 nmr spectra spectrogram of this compound as white solid is shown in Fig. 3, and data are:
13c-NMR (DMSO-d6) δ: 23.3,80.1,119.0,119.8,120.2,122.3,122.9,123.4,125.2,126.1,141.7,166.1,186.9.Qualification result illustrates that the compound as white solid that the present embodiment obtains is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, Fig. 4 is shown in by HPLC collection of illustrative plates, and wherein appearance time 39.431min is the peak that Teriflunomide is corresponding, and appearance time 28.865min is impurity peaks; Appearance time is that the peak area that 39.431min is corresponding accounts for 99.95% of total peak area; Appearance time is that the peak area that 28.865min is corresponding accounts for 0.05% of total peak area, can be calculated according to areas of peak normalization method, and the purity of the Teriflunomide that the present embodiment obtains is 99.95%.
Embodiment 4 has the preparation of the compound of structure shown in formula II
In the round-bottomed flask of 5L, add sodiumazide 195g (3.0mol) successively, there is the compound 570g(3.0mol of structure shown in formula I, buy in Aladdin), triphenylphosphine 79g(0.3mol, buy in Aladdin), N-chlorosuccinimide 41g(0.3mol, buy in Aladdin), acetonitrile 4.2L, 30 DEG C of stirring reactions 4 hours, follow the tracks of reaction complete to raw material reaction.The solvent of decompression removing 2.0L after completion of the reaction, then reaction solution is poured in 2L distilled water, stir 30min, filter, filter cake 500mL distilled water and 500mL washing with alcohol obtain 497g off-white color solid chemical compound, reaction weight yield 77%.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained off-white color solid chemical compound, its mass-spectrometric data is [M+H
+]=216.3.Its proton nmr spectra is:
1h-NMR (CDCl
3-d6) δ: 7.29 (d, J=8.0Hz, 2H), 7.42 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra is:
13c-NMR (CDCl
3-d6) δ: 121.3,121.9,122.6,122.7,126.2,127.5,134.5,136.9,188.1.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 5 has the preparation of the compound of structure shown in formula III
The 166g(0.77mol that Example 4 is obtained) off-white color solid chemical compound is transferred in the round-bottomed flask of 5L, add 3.4L dimethylbenzene, 120 DEG C of heating reflux reactions 14 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 200mL anhydrous diethyl ether washing obtained, drying, obtains 100g faint yellow solid compound.
By mass spectrum, proton nmr spectra and proton nmr spectra qualification gained faint yellow solid compound.Mass-spectrometric data is [M+H
+]=188.3, its proton nmr spectra is:
1h-NMR (DMSO-d6) δ: 7.41 (d, J=8.0Hz, 2H), 7.48 (d, J=8.0Hz, 2H), carbon-13 nmr spectra is:
13c-NMR (DMSO-d6) δ: 121.2,121.9,122.6,123.3,125.0,126.8,127.6,133.3,135.2ppm, the faint yellow solid compound that the preparation method obtaining the present embodiment and provide through structure elucidation obtains is for having the compound of structure shown in formula III, and gained faint yellow solid compound directly can carry out the next step.
The preparation of embodiment 6 Teriflunomide
Faint yellow solid compound 100g(0.53mol by obtained for embodiment 5), be directly used in the synthesis of Teriflunomide.The compound 88g(1.06mol with structure shown in formula IV is added in the round-bottomed flask of 3L; buy in Beijing company limited of Hua Weirui section); dry methyl alcohol (1L); 73g EtONag(1.06mol), 25 DEG C are stirred 1 hour, then slowly drip the obtained faint yellow solid compound 100g(0.53mol of embodiment 5) methanol solution 200mL; within 1 hour, dropwise; after dropwising, reaction solution is heated to backflow, reacts 48 hours under 60 DEG C of conditions, in reaction process, use nitrogen protection.Add 500mL frozen water cancellation reaction after completion of the reaction, with the HCl of 2mol/L, the pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, by thick for gained product through methyl alcohol four recrystallizations, the volume of each recrystallization methyl alcohol used is 0.6L, and the temperature of crystallization is 25 DEG C, obtains 72g compound as white solid, yield 51%, total recovery 27%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.Mass-spectrometric data [the M-H of this compound as white solid
+]=269.1, hydrogen nuclear magnetic resonance modal data is:
1h-NMR (DMSO-d6) δ: 10.85 (s, 1H), 10.08 (br, s, 1H), 7.75 (d, 2H), 7.63 (d, 2H), 2.23 (s, 3H), carbon-13 nmr spectra data are:
13c-NMR (DMSO-d6) δ: 23.4,80.3,119.5,119.2,120.5,122.5,122.7,123.1,125.0,126.0,141.9,166.3,186.0.The compound as white solid obtaining the present embodiment obtained through structure elucidation is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, the purity that can be calculated the Teriflunomide that the present embodiment obtains according to areas of peak normalization method is 99.95%.
Embodiment 7 has the preparation of the compound of structure shown in formula II
In the round-bottomed flask of 3L, add sodiumazide 78g (1.2mol) successively, there is the compound 190g(1.0mol of structure shown in formula I, buy in Aladdin), triphenylphosphine 27g(0.1mol, buy in Aladdin), N-chlorosuccinimide 13g(0.1mol, buy in Aladdin), THF2.0L, 25 DEG C of stirring reactions 6 hours, follow the tracks of reaction complete to raw material reaction.The solvent of decompression removing 1L after completion of the reaction, then reaction solution is poured in 2L distilled water, stir 30min, filter, filter cake 300mL distilled water and 300mL washing with alcohol obtain 198g off-white color solid chemical compound, reaction weight yield 92%.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained off-white color solid chemical compound, its mass-spectrometric data is [M+H
+]=216.3.Its proton nmr spectra is:
1h-NMR (CDCl
3-d6) δ: 7.34 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra is:
13c-NMR (CDCl
3-d6) δ: 121.0,121.9,122.0,122.6,126.41,127.1,134.7,136.3,188.1.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 8 has the preparation of the compound of structure shown in formula III
The 198g(0.92mol obtained by embodiment 7) off-white color solid chemical compound is transferred in the round-bottomed flask of 3L, add 0.6L toluene 0.6L dimethylbenzene, 120 DEG C of heating reflux reactions 20 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 300mL anhydrous diethyl ether washing obtained, drying, obtains 120g faint yellow solid compound.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained faint yellow solid compound, its mass-spectrometric data is [M+H
+]=188.3, its proton nmr spectra is:
1h-NMR (DMSO-d6) δ: 7.40 (d, J=8.0Hz, 2H), 7.45 (d, J=8.0Hz, 2H), carbon-13 nmr spectra is:
13c-NMR (DMSO-d6) δ: 121.0,121.7,122.3,123.1,125.1,126.5,127.3,133.0,135.0ppm, the compound that the preparation method that the present embodiment provides obtains is for having the compound of structure shown in formula III, and gained faint yellow solid compound directly can carry out the next step
The preparation of embodiment 9 Teriflunomide
Faint yellow solid compound 120g(0.65mol by obtained for embodiment 8), be directly used in the synthesis of Teriflunomide.The compound 54g(0.65mol with structure shown in formula IV is added in the round-bottomed flask of 3L; buy in Beijing company limited of Hua Weirui section); dry THF (1.2L); slowly drip LDA285mL(0.71mol; 2.5mol/L); 25 DEG C are stirred 1 hour; then slowly drip the obtained faint yellow solid compound 120g(0.65mol of embodiment 8) THF solution 200mL; within 1 hour, dropwise; after dropwising, reaction solution is heated to backflow; react 35 hours under 80 DEG C of conditions, in reaction process, use nitrogen protection.Add 500mL frozen water cancellation reaction after completion of the reaction, with the HCl of 2mol/L, the pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, by thick for gained product mixing solutions four recrystallizations through methyl alcohol and ethyl acetate, each recrystallization solution used is the mixing solutions 1L of methyl alcohol and ethyl acetate, both volume ratios are 1:1, the temperature of crystallization is 10 DEG C, obtain 105g compound as white solid, yield 62%, total recovery 39%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.Mass-spectrometric data [the M-H of this compound as white solid
+]=269.1, hydrogen nuclear magnetic resonance modal data is:
1h-NMR (DMSO-d6) δ: 10.80 (s, 1H), 10.01 (br, s, 1H), 7.79 (d, 2H), 7.67 (d, 2H), 2.24 (s, 3H), carbon-13 nmr spectra data are:
13c-NMR (DMSO-d6) δ: 23.6,80.2,119.8,119.5,120.4,122.5,122.5,123.7,125.0,126.0,141.7,166.9,186.1.The compound as white solid obtaining the present embodiment obtained through structure elucidation is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, can be calculated according to areas of peak normalization method, the purity of the Teriflunomide that the present embodiment obtains is 99.95%.
Embodiment 10 has the preparation of the compound of structure shown in formula II
605g bis-phenoxy group phosphorous acid nitrine ester (2.2mol is added in the round-bottomed flask of 3L, buy in lark prestige), triethylamine 222g(2.2mol), DMF2L, 15 DEG C stir 30min become slowly to drip after clarification until solution there is the compound 380g(2.0mol of structure shown in formula I) DMF solution 300mL, stir 5 hours under 35 DEG C of conditions, follow the tracks of reaction complete to raw material reaction.Poured into by reaction solution after completion of the reaction in 20L distilled water, stir 30min, filter, filter cake 800mL distilled water and 800mL washing with alcohol obtain 395g off-white color solid chemical compound, reaction weight yield 92%.
Mass spectrum, proton nmr spectra, carbon-13 nmr spectra is adopted to identify gained off-white color solid chemical compound, mass spectrum [M+H
+]=216.3.Its proton nmr spectra
1h-NMR (CDCl
3-d6) δ: 7.30 (d, J=8.0Hz, 2H), 7.40 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra
13c-NMR (CDCl
3-d6) δ: 121.1,121.9,122.1,122.5,126.5,127.0,134.1,136.1,188.7.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 11 has the preparation of the compound of structure shown in formula III
The 395g(1.84mol obtained by embodiment 10) off-white color solid chemical compound is transferred in the round-bottomed flask of 5L, add 3L toluene, 110 DEG C of heating reflux reactions 18 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 350mL anhydrous diethyl ether washing obtained, after drying, obtain 224g faint yellow solid compound.
By mass spectrum, proton nmr spectra and proton nmr spectra qualification gained faint yellow solid compound.Mass spectrum [the M+H of this faint yellow solid compound
+]=188.3.The hydrogen nuclear magnetic resonance modal data of this faint yellow solid compound is:
1h-NMR (DMSO-d6) δ: 7.49 (d, J=8.0Hz, 2H), 7.47 (d, J=8.0Hz, 2H).The carbon-13 nmr spectra data of this faint yellow solid compound are:
13c-NMR (DMSO-d6) δ: 121.6,121.5,122.7,123.6,125.3,126.0,127.8,133.6,135.3ppm.So the faint yellow solid compound that the preparation method that the present embodiment provides obtains is for having the compound of structure shown in formula III, gained faint yellow solid compound directly can carry out the next step.
The preparation of embodiment 12 Teriflunomide
Faint yellow solid crude compound obtained for embodiment 11 is directly used in the synthesis of Teriflunomide.The compound 153g(1.84mol with structure shown in formula IV is added) in the round-bottomed flask of 3L; dry THF(1.5L); sodium hydride (81g; 2mol; in g/mL; be stored in kerosene with mass volume ratio 60%); 25 DEG C are stirred 1 hour; then slowly drip the obtained faint yellow solid compound 224g(1.2mol of embodiment 11) THF solution 800mL; within about 1 hour, dropwise; after dropwising, reaction solution is heated to backflow, reacts 40 hours under 65 DEG C of conditions, in reaction process, use nitrogen protection.Add 500mL frozen water cancellation reaction after completion of the reaction, the HCl(aq. with 2mol/L) pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, through ethyl acetate twice recrystallization, the volume of each recrystallization ethyl acetate used is 2.4L, and the temperature of crystallization is 20 DEG C, obtains 333g compound as white solid, yield 67%, total recovery 40%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.The mass-spectrometric data of this compound as white solid is [M-H
+]=269.1, basically identical with Teriflunomide target molecular weight MW=270.Mass-spectrometric data [the M-H of this compound as white solid
+]=269.1, hydrogen nuclear magnetic resonance modal data is:
1h-NMR (DMSO-d6) δ: 10.87 (s, 1H), 10.04 (br, s, 1H), 7.78 (d, 2H), 7.68 (d, 2H), 2.25 (s, 3H), carbon-13 nmr spectra data are:
13c-NMR (DMSO-d6) δ: 23.5,80.3,119.1,119.0,120.8,122.2,122.4,123.9,125.1,126.2,141.1,166.0,186.0.The compound as white solid obtaining the present embodiment obtained through structure elucidation is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, can be calculated according to areas of peak normalization method, the purity of the Teriflunomide that the present embodiment obtains is 99.5%.
Embodiment 13 has the preparation of the compound of structure shown in formula II
99g bis-phenoxy group phosphorous acid nitrine ester (0.36mol buys in lark prestige), K is added in the round-bottomed flask of 3L
2cO
325g(0.18mol), triethylamine 18g(0.18mol), DMF100mL, THF1000mL, 25 DEG C stir 30min become slowly to drip after clarification until solution there is the compound 23g(0.12mol of structure shown in formula I) DMF solution 50mL, stir 4 hours under 45 DEG C of conditions, follow the tracks of reaction complete to raw material reaction.Poured into by reaction solution after completion of the reaction in 20L distilled water, stir 30min, filter, filter cake 100mL distilled water and 100mL washing with alcohol obtain 22g off-white color solid chemical compound, reaction weight yield 86%.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained off-white color solid chemical compound, its its mass-spectrometric data is [M+H
+]=216.3.Its proton nmr spectra is:
1h-NMR (CDCl
3-d6) δ: 7.30 (d, J=8.0Hz, 2H), 7.43 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra is:
13c-NMR (CDCl
3-d6) δ: 121.4,121.9,122.4,122.5,126.8,127.9,134.6,136.3,188.1.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 14 has the preparation of the compound of structure shown in formula III
The 22g(0.1mol obtained by embodiment 13) off-white color solid chemical compound is transferred in the round-bottomed flask of 1L, add 440mL acetonitrile, 120 DEG C of heating reflux reactions 14 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 350mL anhydrous diethyl ether washing obtained, after drying, obtain 16.8g faint yellow solid compound.
By mass spectrum, proton nmr spectra and proton nmr spectra qualification gained faint yellow solid compound.The mass-spectrometric data of this faint yellow solid compound is [M+H
+]=188.3, its proton nmr spectra is:
1h-NMR (DMSO-d6) δ: 7.48 (d, J=8.0Hz, 2H), 7.49 (d, J=8.0Hz, 2H), carbon-13 nmr spectra is:
13c-NMR (DMSO-d6) δ: 121.1,121.0,122.5,123.8,125.3,126.0,127.4,133.1,135.0ppm, known through structure elucidation, the faint yellow solid compound that the preparation method that the present embodiment provides obtains is for having the compound of structure shown in formula III, and gained faint yellow solid compound directly can carry out the next step.
The preparation of embodiment 15 Teriflunomide
The 16.8g(0.09mol obtained by embodiment 14) faint yellow solid crude compound is directly used in the synthesis of Teriflunomide.The compound 15g(0.18mol with structure shown in formula IV is added) in the round-bottomed flask of 1L; dry dioxane (250mL); t-BuOK10g (0.09mol); MeONa4.9g (0.09mol); 30 DEG C are stirred 1 hour; then slowly drip the obtained faint yellow solid compound 16.8g(0.09mol of embodiment 14) dioxane solution 200mL; within about 1 hour, dropwise; after dropwising, reaction solution is heated to backflow; react 48 hours under 60 DEG C of conditions, in reaction process, use nitrogen protection.Add 500mL frozen water cancellation reaction after completion of the reaction, the HCl(aq. with 2mol/L) pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, mixing solutions twice recrystallization through methyl alcohol, ethanol and acetone, wherein the volume ratio of methyl alcohol, ethanol and acetone is 1:1:1, the volume of the mixed solution of each recrystallization methyl alcohol used, ethanol and acetone is 210mL, the temperature of crystallization is 25 DEG C, obtain 15.2g compound as white solid, yield 62%, total recovery 48%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.Mass-spectrometric data [the M-H of this compound as white solid
+]=269.1, hydrogen nuclear magnetic resonance modal data is:
1h-NMR (DMSO-d6) δ: 10.84 (s, 1H), 10.08 (br, s, 1H), 7.71 (d, 2H), 7.64 (d, 2H), 2.24 (s, 3H), carbon-13 nmr spectra data are:
13c-NMR (DMSO-d6) δ: 23.0,80.0,119.1,119.7,120.0,122.1,122.5,123.8,125.0,126.0,141.9,166.0,186.7.The compound as white solid obtaining the present embodiment obtained through structure elucidation is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, can be calculated according to areas of peak normalization method, the purity of the Teriflunomide that the present embodiment obtains is 99.95%.
Embodiment 16 has the preparation of the compound of structure shown in formula II
222.7g bis-phenoxy group phosphorous acid nitrine ester (0.8mol is added in the round-bottomed flask of 2L, buy in lark prestige), DIPEA103g(0.8mol), triethylamine 81g(0.8mol), acetonitrile 670mL, 30 DEG C stir 30min become slowly to drip after clarification until solution there is the compound 76g(0.4mol of structure shown in formula I) acetonitrile solution 220mL, stir 10 hours under 40 DEG C of conditions, follow the tracks of reaction complete to raw material reaction.Poured into by reaction solution after completion of the reaction in 20L distilled water, stir 30min, filter, filter cake 300mL distilled water and 300mL washing with alcohol obtain 76.5g off-white color solid chemical compound, reaction weight yield 89%.
Adopt mass spectrum, proton nmr spectra, carbon-13 nmr spectra to identify gained off-white color solid chemical compound, its mass-spectrometric data is [M+H
+]=216.3.Its proton nmr spectra is:
1h-NMR (CDCl
3-d6) δ: 7.39 (d, J=8.0Hz, 2H), 7.49 (d, J=8.0Hz, 2H); Carbon-13 nmr spectra is:
13c-NMR (CDCl
3-d6) δ: 121.0,121.9,122.1,122.2,126.5,127.6,134.3,136.4,188.1.Through structure elucidation for having the compound of structure shown in formula II, gained off-white color solid chemical compound can be directly used in next step reaction without the need to being further purified,
Embodiment 17 has the preparation of the compound of structure shown in formula III
The 76.5g(0.356mol obtained by embodiment 16) off-white color solid chemical compound is transferred in the round-bottomed flask of 1L, add 155mL dimethylbenzene, 155mL toluene, 155mL acetonitrile, 100 DEG C of heating reflux reactions 20 hours, follow the tracks of reaction distillation after raw material reaction is complete and remove desolventizing, the crude product 350mL anhydrous diethyl ether washing obtained, after drying, obtain 61.2g faint yellow solid compound.
By mass spectrum, proton nmr spectra and proton nmr spectra qualification gained faint yellow solid compound.The mass-spectrometric data of this faint yellow solid compound is [M+H
+]=188.3, its proton nmr spectra is:
1h-NMR (DMSO-d6) δ: 7.44 (d, J=8.0Hz, 2H), 7.47 (d, J=8.0Hz, 2H), carbon-13 nmr spectra is:
13c-NMR (DMSO-d6) δ: 121.8,121.0,122.1,123.3,125.4,126.6,127.8,133.7,135.9ppm, through structure elucidation, the preparation method that the present embodiment provides obtains faint yellow solid compound for having the compound of structure shown in formula III, and gained faint yellow solid compound directly can carry out the next step.
The preparation of embodiment 18 Teriflunomide
61.2g faint yellow solid crude compound obtained for embodiment 17 is directly used in the synthesis of Teriflunomide.The compound 27.2g(0.32mol with structure shown in formula IV is added) in the round-bottomed flask of 2L, dry dioxane (620mL), sodium hydride 4g (0.16mol, in g/mL, be stored in kerosene with mass volume ratio 60%), hydrolith 6.7g (0.16mol), 15 DEG C are stirred 1 hour, then slowly drip the obtained faint yellow solid compound 61.2g(0.32mol of embodiment 17) dioxane solution 200mL, within about 1 hour, dropwise, after dropwising, reaction solution is heated to backflow, react 24 hours under 80 DEG C of conditions, nitrogen protection is used in reaction process.Add 500mL frozen water cancellation reaction after completion of the reaction, the HCl(aq. with 2mol/L) pH of reaction solution is adjusted to neutrality, extracting 3 times each consumptions with EtOAc is 500mL, merges organic phase saturated NaCl aqueous solution 800mL washing, anhydrous Na
2sO
4drying, concentrating under reduced pressure, mixing solutions twice recrystallization through i-PrOH and methyl alcohol, the volume ratio of i-PrOH and methyl alcohol is 2:1, the volume of the mixing solutions of each recrystallization i-PrOH used and methyl alcohol is 600mL, the temperature of crystallization is 10 DEG C, obtain 58.8g compound as white solid, yield 66%, total recovery 54%.
Mass spectrum, proton nmr spectra and carbon-13 nmr spectra is adopted to carry out Structural Identification to gained compound as white solid.Mass-spectrometric data [the M-H of this compound as white solid
+]=269.1, hydrogen nuclear magnetic resonance modal data is:
1h-NMR (DMSO-d6) δ: 10.88 (s, 1H), 10.07 (br, s, 1H), 7.79 (d, 2H), 7.66 (d, 2H), 2.26 (s, 3H), carbon-13 nmr spectra data are:
13c-NMR (DMSO-d6) δ: 23.5,80.2,119.1,119.9,120.3,122.4,122.0,123.5,125.3,126.2,141.8,166.2,186.0.The compound as white solid obtaining the present embodiment obtained through structure elucidation is Teriflunomide.Detect the purity of the Teriflunomide that the present embodiment obtains with HPLC, can be calculated according to areas of peak normalization method, the purity of the Teriflunomide that the present embodiment obtains is 99.9%.
Below be only the preferred embodiment of the present invention, it should be pointed out that above-mentioned preferred implementation should not be considered as limitation of the present invention, protection scope of the present invention should be as the criterion with claim limited range.For those skilled in the art, without departing from the spirit and scope of the present invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (10)
1. a preparation method for Teriflunomide, is characterized in that, comprises the following steps:
Step 1: get the compound with structure shown in formula I and triazo-compound and nucleophilic substitution reaction occurs in organic solvent generate the compound with structure shown in formula II;
Step 2: the compound described in getting with structure shown in formula II mixes with organic solvent, heating, must have the compound of structure shown in formula III;
Step 3: under protection of inert gas, alkaline condition, there is electrophilic addition, isomerization reaction in the compound described in getting with structure shown in formula III and the compound with structure shown in formula IV, to obtain final product in organic solvent;
2. preparation method according to claim 1, is characterized in that, triazo-compound described in step 1 is inorganic triazo-compound and/or organic azide.
3. the preparation method according to claim 1 or 2 any one, is characterized in that, when triazo-compound described in step 1 is organic azide, described nucleophilic substitution reaction alkali used is Et
3n, K
2cO
3or one in DIPEA or both above mixtures.
4. preparation method according to claim 1, is characterized in that, organic solvent described in step 2 is one in acetonitrile, toluene or dimethylbenzene or both above mixtures.
5. preparation method according to claim 1, is characterized in that, described in step 3, alkaline condition is by EtONa, MeONa, NaH, t-BuOK, CaH
2or one in LDA or both above mixtures provide.
6. preparation method according to claim 1, is characterized in that, also comprises 2 times ~ 4 times re-crystallization step after electrophilic addition, isomerization reaction described in step 3.
7. preparation method according to claim 6, is characterized in that, described recrystallization solvent for use is MeOH, EtOAc, CH
2cl
2, CHCl
3, EtOH, Et
2o, THF, acetone, CH
3one in CN or i-PrOH or both above mixtures.
8. a preparation method for Teriflunomide intermediate, is characterized in that, comprises the following steps:
Step 1: get the compound with structure shown in formula I and triazo-compound and nucleophilic substitution reaction occurs in organic solvent generate the compound with structure shown in formula II;
Step 2: the compound described in getting with structure shown in formula II mixes with organic solvent, heating, to obtain final product;
Described Teriflunomide intermediate is for having the compound of structure shown in formula III;
9. preparation method according to claim 8, is characterized in that, triazo-compound described in step 1 is inorganic triazo-compound and/or organic azide.
10. preparation method according to claim 9, is characterized in that, when triazo-compound described in step 1 is organic azide, the alkali of described nucleophilic substitution reaction is Et
3n, K
2cO
3or one in DIPEA or both above mixtures.
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