CN101134732A - New method for preparing 2-{4-[[(3,5-dimethylaniline)carbonyl ]methyl]phenoxy}-2-methyl sodium propionate and its crystal in water - Google Patents
New method for preparing 2-{4-[[(3,5-dimethylaniline)carbonyl ]methyl]phenoxy}-2-methyl sodium propionate and its crystal in water Download PDFInfo
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Abstract
The present invention proposes new process of preparing sodium 2-{4-[[(3, 5-dimethylanilino)carbonyl]methyl]phenoxy}-2-methyl propionate (Efaproxiral sodium). The process includes three steps, acylation reaction, O-alkylation reaction of phenol and purification; and the target product has purity up to 99.50 % and no acetone and ethanol impurities contained. The process has facile material, simple operation, short reaction period, high product purity and low cost, and is suitable for industrial production. Structural analysis shows that the obtained Efaproxiral sodium product is in one new crystalline state.
Description
Technical field
The present invention is preparation 2-{4-[[(3, the 5-xylidine) carbonyl] methyl] phenoxy group-of 2 Methylpropionic acid sodium (Efaproxiral sodium) salt new be suitable for industrialized method, and the new crystalline form and the monocrystalline that make by this method.This compound is the sensitizer of cancer radiation.
Technical background
The Efaproxiral sodium salt, its structure is as follows:
This compound popular name Efaproxiral sodium still has research and development code name RSR-13, GSJ61, JP4, KDD86, and RS4 in addition.
Efaproxiral is the radiocurable sensitizer of tumor of Allos Therapeutics company exploitation.Its pharmacological action is that it can make oxyphorase and the chemical equilibrium of oxygen bonded move towards the direction that discharges oxygen, thereby increased the concentration of oxygen in the tissue and help suppressing growth of tumor.It has carried out clinical trial to many kinds of tumors as radiotherapeutic sensitizer over past ten years, has obtained significant auxiliary usefulness.Efaproxiral is an ancillary drug that the radiotherapy of many tumours is all had remarkable usefulness.
The synthetic route of Efaproxiral sodium salt generally is to adopt with p-hydroxyphenylaceticacid and 3, and the 5-xylidene(s) is the at first synthetic amide intermediate of starting raw material, and then this amide intermediate is transformed into the Efaproxiral sodium salt.
The synthetic of Efaproxiral since nineteen ninety-one repeatedly improved, and its representational document is PCT/WO91/12235 (open day, on September 17th, 1991); PCT/WO92/20335, United States Patent (USP) PCT/US5705521 (open day, on January 6th, 1998); PCT/WO2005/102305 (open day, on November 3rd, 2005); PCT/WO2005/102308 (open day, on November 3rd, 2005).Chinese patent application CN200410093313.2, publication number CN1660782A.
The initial technology (WO91/12235) of preparation amide intermediate was during Efaproxiral was synthetic,
But this technology can not high yield obtains the para hydroxybenzene Acetyl Chloride 98Min., and esterification has taken place our 70% para hydroxybenzene Acetyl Chloride 98Min. of having an appointment that studies show that, reacts as follows:
Therefore, the yield of the thick product of formed amide intermediate 50-60% only.In addition, use refluxing xylene reaction (～143 ℃ of reactions), the color of product is a chocolate.Use SOCl2 to prepare acyl chlorides and can produce a large amount of HCl and SO
2Gas, this has caused the serious environmental governing problem.Using dimethylbenzene to make solvent carries out back flow reaction people's health and environment is also had serious harm.Document says and can obtain 86% yield that we only obtain 57% at experiment.
In order to avoid the harm of SOCl2, document (WO92/20335 US5705521) has proposed use PC15 and 1,3 again, and 5-trimethylbenzene one-step synthesis goes out this intermediate,
Use PCl
5With 1,3,, there has not been SOCl though 5-trimethylbenzene has shortened reactions steps 160 ℃ of back flow reaction
2Harm, but used PCl5, the quality of product, labor condition all exists with using SOCl the influence of environment
2With the dimethylbenzene similar problem, the industrialization that is unsuitable for preparing amide intermediate equally.
Recent years, the preparation of amide intermediate has obtained remarkable progress, does not promptly use SOCl
2Or PCl
5, make p-hydroxyphenylaceticacid with 3, the 5-xylidine is direct back flow reaction in diformazan is stupid, removes the water of generation simultaneously, can finish this reaction.Realized at present suitability for industrialized production (WO2005/102305, WO2005/102308).Patent does not provide yield, according to document (J.Med.Chem.2000,43,4726-4737), in dimethylbenzene, reflux three days three nights, the laboratory productive rate can reach 87%.But our repeated experiments shows this yield and is difficult to reach, and product is a chocolate.Refluxing xylene also existed serious labor condition and environmental problem for up to three days three nights.
Bioengineering Inst. Co., Ltd., Hangzhou Huadong Medicine Group applied for Efaproxiral sodium salt preparation method's patent (CN1660782A) on December 21st, 2004.This invents most important innovation is to have adopted distinctive reaction medium-carbonylic imidazole as condensing agent in acylation reaction, productive rate 86.7%. but need to use the carbonylic imidazole of molar weight, and this has increased raw materials cost.
Preparing the oldest patent technology of Efaproxiral sodium salt (PCT patent WO91/12235, open day, on September 17th, 1991) by above-mentioned amide intermediate is to carry out following O-alkylated reaction and separation and Extraction,
This is a common method that is prepared alcoxyl or benzene oxycarboxylic acid by alcohol or phenol.But the target product here is the sodium salt of this carboxylic acid of preparation, and therefore, above technology is not reasonably used this alkylation.There is two large problems:
1. the original product of this reaction is exactly the Efaproxiral sodium salt, but this technology does not go to obtain it immediately, but it is transformed into acid, obtains re-using NaOH or NaHCO3 or sodium methoxide solution after the acid and is transformed into sodium salt.Because the aqueous solution behind the reaction solution removal acetone is residual acetone and other impurity still, obtaining Efaproxiral acid after the acidifying is a kind of semisolid, can not filter, can only adopt the method for extracted with diethyl ether to obtain mixture, remove behind the ether again that crystallization purifying just obtains purer acid in organic solvent.Such processing makes yield very low, even also feel difficulty more to be difficult to realize industrialization in the laboratory.Therefore, be sodium salt though this reaction produces, but around a great circle just obtain sodium salt, the separation-extraction technology of product is irrational.
2. document technology (PCT/WO92/20335, PCT/US5705521 etc.) also used an irrational composition of raw materials: if the amide intermediate of 1 mole (255g) is carried out alkylation, these patents have dropped into 13.75 moles of (550g) NaOH, the CHCl3 of 3.08 moles (250ml).But according to the reaction formula of following this alkylation, the amide intermediate of 1 mole (255g) only needs 1.0 moles in acetone (74ml), CHCl
31.0 mole (81ml), NaOH4.0 mole (160g).The NaOH and the CHCl of 3 times of volumes have promptly been used
3Having only acetone is again solvent, and its a large amount of inputs need.
NaOH, CHCl
3Charging capacity many more than 2 times, this makes side reaction increase.Drop into too many raw material, be not only unnecessary here and be deleterious.Therefore the optimum proportion that uses this method charging capacity is a problem that must solve.
Owing to above reason, the yield of the Efaproxiral acid of this old technology very low (68%), being transformed into sodium salt again will be lower.O-alkylated reaction is the maturation method of a preparation alcoxyl commonly used or benzene oxycarboxylic acid.Method is well, but because technology is unreasonable, makes step many, operate numerous, poor working environment, yield is low, the cost height.Therefore, the technology of this old preparation Efaproxiral sodium salt in recent years people it has been lost interest.But we find that through transforming, this technology is that starting material are cheap and easy to get, easy and simple to handle, the yield height, and cost is low, very is suitable for industrialized method.
This O-alkylation process of document prepares Efaproxiral sodium salt aftertreatment difficulty, and loaded down with trivial details, yield is low, patent WO2005/102305 in 2005, CN1660782A has adopted amide intermediate with the isobutyl ethyl bromide condensation, obtains ester, and basic hydrolysis obtains the Efaproxiral sodium salt then.
This method yield height, easy and simple to handle.According to patent CN1660782A yield is 85.1%.But two shortcomings are arranged, the one, isobutyl ethyl bromide costs an arm and a leg, and this has increased production cost greatly; The 2nd, used bromo-derivative in this reaction, cause free radical reaction easily, therefore can produce a large amount of polymers in the reaction, this has brought difficulty and new requirement for the purifying of product.CN1660782A has adopted amide intermediate with the isobutyl ethyl bromide condensation, obtains ester, but they directly do not obtain it when having formed sodium salt after basic hydrolysis, but with 2M hydrochloric acid it is become acid, again at saturated NaHCO
3In become sodium salt.This is obviously also around a circle, has kept that technology of circling in the phenolic hydroxyl group O-alkylated reaction in the past.
As a pharmaceutical prod, the purifying of target product Efaproxiral sodium salt is the problem that need pay close attention to.PCT WO2005/102305 provide purification process, promptly uses ethanol and acetone that Efaproxiral sodium salt crude product is carried out recrystallization, but the index of the residual quantity of ethanol and acetone is less than 1000ppm and 500ppm in the final product.This shows in the end and to allow residual a considerable amount of ethanol and acetone in the product.This residual index especially for acetone, may be too high for the medicine of injection.Therefore, we have adopted new purification process for the finished product.
The Efaproxiral sodium salt all can have different crystalline state to occur in different solvents or under different crystallization conditions.PCT/US2005/013709 or WO2005/102308A2 (CRYSTALLINE AND AMORPHOUS FORMS OFEFAPROXIRAL SODIUM) themes as crystal form and the amorphous state of Efaproxiral Sodium, this patent application discloses nine kinds of crystal forms, and a kind of amorphous state.Provided the method for obtaining this compound crystal attitude and amorphous state.The powder X-ray that they provide-ray diffraction spectrogram has comprised many diffraction peaks, and these crystalline state are the mixtures that comprise many kinds of crystal formations of imperfect crystal formation.They have obtained a kind of monocrystalline, belong to triclinic(crystalline)system.
Summary of the invention
The technical problem to be solved in the present invention is that the reactions steps that exists in the preparation of Efaproxiral sodium salt is many, and the time is long, and by product is many, and yield is low, and environmental pollution is big, and the production cost height is unsuitable for problems such as industrialization.The present invention takes pains provides a step simple and direct, easy handling, and raw material is cheap and easy to get, product yield and purity height, cost is low, is suitable for the method for preparing the Efaproxiral sodium salt of suitability for industrialized production.In addition, our Efaproxiral sodium salt recrystallization in pure water that studies show that can improve the quality of product, the diverse product of crystalline state that obtains and document greatly.We have also obtained the monocrystalline of Efaproxiral sodium salt in water, and through X-ray diffraction determination, it belongs to oblique system.Contain 4 Efaproxiral sodium and 28 water moleculess in each structure cell.
The method that the present invention prepares the Efaproxiral sodium salt only comprises acidylate, three steps of O-alkylation and purifying:
1. acylation reaction
The present invention has adopted a kind of brand-new mode in acylation reaction, promptly do not use any solvent and allow p-hydroxyphenylaceticacid with 3,5-xylidine heating direct reaction.Reaction yield reaches 90-93%, is the white powder solid, can be directly used in next step reaction without recrystallization purifying.
This acylation reaction will be carried out 150-180 ℃ of scope, and the reaction times is 2-5 hour, and Best Times is 3-4 hour.
This reaction needed is used nitrogen (N
2) or argon gas (Ar), their effect one is that protective reaction is normally carried out, the 2nd, help the water that produces is taken out of fully.Aniline is the compound of easy oxidation, though because there is the protection of nitrogen or argon gas just to make 170-180 ℃ of reaction, still can access white high-quality product.Nitrogen (N
2) or the usage quantity of argon gas (Ar) need not be big, if excessive, can make too much 3, the 5-xylidine is taken out of.Because reaction solution is 150-180 ℃ of reaction, the water of generation had been hot gaseous, can disengage voluntarily, an amount of nitrogen (N
2) or argon gas (Ar) can help steam to disengage fully.
In this reaction 3, the 5-xylidine is excessive, and p-hydroxyphenylaceticacid is with 3, and the optimum mole ratio of 5-xylidine is 1.0: 1.0-1.3.More 3, the 5-xylidine there is no need, and is deleterious to environment especially.
After reaction finished, reaction solution just began to condense into hard solids at about 150 ℃.This will be behind cool to room temperature go dissolving with the NaOH of 2M, and then separates out and obtain the white powder solid with concentrated hydrochloric acid.Do the quality that helps to guarantee product like this.Because residual a spot of also responseless acid of meeting and amine in product, in last acidic solution, they all are easy to dissolving, thereby reaction raw materials can not remain in the product.
The present invention is owing to having adopted this solvent-free reactive mode, and is big for environment pollution, and big sulfur oxychloride, the dimethylbenzene of operator ' s health harm has all been avoided.Reaction times short (2-5 hour), easy handling, product quality is good, the yield height, therefore the plant factor height very is suitable for large-scale industrial production.
2.O-alkylated reaction
The present invention is that the O-alkylated reaction by amide intermediate directly obtains sodium salt, and its method is after O-alkylated reaction is removed acetone, to add an amount of water, under appropriate condition sodium salt is separated out.
This technology mainly is to have adopted rational ingredient proportion to the transformation of the O-alkylation process of document, reaction conditions and sodium salt crystal condition, and the transformation main points that we carry out are as follows:
1. the charge ratio of raw material is optimized NaOH, CHCl
3Significantly reduce with the charging capacity of acetone.The amide intermediate of 1 mole (255g) is carried out alkylation and is only used 5.25 moles of (210g) NaOH, the CHCl of 1.2 moles (100ml)
3Like this, NaOH has reduced 62%, CHCl
3Reduced 60%.The charging capacity of acetone also reduces to some extent,
4 liters by document become 3.2 liters, have reduced 20%.Charging capacity has significantly reduced, and side reaction has also reduced,
Efaproxiral sodium salt yield has improved, and reaches 90%.If consider the amide intermediate of recovery, yield reaches 93-95%.
2. drip CHCl
3Reaction solution meeting heat release is noted beginning to drip 15 ℃ of liquid temperature, and the liquid temperature is not above 20 ℃ during the dropping.Drip intact back, back in 15-20 ℃ of restir 1 hour, spend the night 20-25 ℃ of reaction then (8～15 hours, preferred 10-12 hour).
3. after reaction is finished, as far as possible thoroughly remove acetone.The amount that adds entry is that every mole amide intermediate is used the 1.0-2.5 premium on currency, and its optimum quantity is the 1.5-2.0 liter.
4. this reaction can produce sodium-chlor.Additional proper amount of sodium chloride can make sodium salt separate out more fully, and can increase the granularity of Efaproxiral sodium salt crystal.The amount that adds sodium-chlor is to drop into 1 mole amide intermediate and use 50-100 gram sodium-chlor.
5. separating out at 5-15 ℃ of sodium salt carried out, and optimum temps is 10-15 ℃.The time of separating out needs to be preferably under this temperature and to spend the night more than 6 hours.
6. sodium salt filters and will use saturated sodium hydrogen carbonate solution flushing, and this has guaranteed to access the Efaproxiral sodium salt of white crystals.
7. filtrate is added an amount of sodium bicarbonate and transfer pH7-8, unreacted amide intermediate can be separated out fully, the suction filtration amide intermediate that can obtain reclaiming immediately,
1HNMR shows that this is the good intermediate of quality, promptly can be used for alkylated reaction after the oven dry.
8. above filtrate can be used as waste water and discharges, and also can spend the night 10-15 ℃ of placement, can also separate out the Efaproxiral sodium salt of 2-4%.
3. purifying
The ultimate aim that to obtain high-quality Efaproxiral sodium salt be this research.
Above technology can access the crystallization first time product of the good Efaproxiral sodium salt of quality.This product is used ethanol, and acetone is that solvent recrystallization has obtained the product of crystallization for the second time.
Have acetone for fear of final product, ethanol impurity, we are adopting ethanol, after acetone is solvent recrystallization, carried out water again and done the solvent heating for dissolving, heat filtering behind the activated carbon decolorizing carries out crystallization for the third time, this has guaranteed to dissolve in the final product impurity of organic solvent, and water-soluble and water-fast impurity has all been removed.
With water is solvent recrystallization, and the ratio of sodium salt and water is an important factor that influences quality product and yield.Suitable ratio is weight ratio Efaproxiral sodium salt: water=1: 3.5-4.0.
According to this ratio, just dissolved fully at about 55 ℃ of sodium salts, be heated to 70 ℃ and can add proper amount of active carbon and decolour.
The separating out of sodium salt slowly is cooled to 15-20 ℃ and spends the night and finish.Can adopt and leave standstill crystallization and stirring and crystallizing, they can obtain the product of different crystalline state.Yield reaches 85-89%.
After crystalline mixture filtered, the sodium salt of the 10-15% that has an appointment still was dissolved in the water and does not separate out, and must reclaim, and a simple and effective method is to adopt the method for saltouing that sodium salt is separated out.The salt that we use is sodium bicarbonate and sodium-chlor.Sodium bicarbonate and amount of sodium chloride are that every liter of filtrate adds 20g sodium bicarbonate and 125g sodium-chlor, and undecomposed Efaproxiral sodium salt just can be separated out substantially.Filter, oven dry obtains quality and well reclaims sodium salt, and can be directly used in next time is the recrystallization of solvent with water.Considering the sodium salt of recovery, is that the recrystallization yield of solvent can reach 93-95% with water.
Recrystallization can access new crystalline products in water, and powder x-ray diffraction (XPDP) spectrogram shows its crystalline state and document (WO2005/102308A2, PCT/US2005/013709) complete difference.
4. single crystal preparation and single crystal structure
But what obtain according to above crystallization condition in water is powder crystal, and it is impossible obtaining relatively large monocrystalline.Our monocrystalline is to use the Efaproxiral sodium of 5 grams, adds 60ml water, and dissolving adds powder crystal that a small amount of above method obtains again as crystal seed, obtains in the long-time placement of room temperature.Another method is to add 50ml ethanol after Efaproxiral sodium is dissolved in water again, adds crystal seed behind the mixing again.Experiment shows, can obtain monocrystalline faster like this.Ethanol does not participate in crystallization but can promote the growth of monocrystalline.
X-ray diffraction spectrogram such as Fig. 1 of Efaproxiral sodium monocrystalline, a, b is shown in the c.This monocrystalline belongs to oblique system, and each structure cell contains 4 Efaproxiral sodium molecules.What is interesting is and contain large quantity of moisture in the crystal, each structure cell has comprised 28 water moleculess, and wherein 20 water moleculess directly are coordinated to 4 Na
+Per 10 water moleculess are with 2 Na
+Coordination forms an independently inorganic ligand.2 water moleculess whiles and two Na are wherein arranged
+Coordination, so each Na
+Ligancy be 6.This has formed 4 irregular octahedrons in each structure cell.Stratiform of these inorganic ligands formation (Fig. 1, b, c).Na
+----OH
2Between distance be that (Fig. 1 a), illustrates H to the 2.4-2.5 dust
2O is to Na
+Coordination be very weak.Therefore, in room temperature, these water moleculess just can break away from crystal and evaporate.The organic moiety of Efaproxiral sodium formed another lamina (Fig. 1, b, c).Obviously, this two-layer mainly be to rely on Na
+Positive charge and the carboxyl (electrostatic attraction of negative charge COO-) and become one.Also have 4 water moleculess also near this inorganic coordination sphere (Fig. 1, c), in addition 4 water moleculess be dispersed between the organism of 4 Efaproxiral sodium (Fig. 1, c).And combining between organic layer and the organic layer mainly is the adsorption that relies on Van der Waals force.The X of this spectrogram-ray detection data see Table 1.
The crystal data and the structure elucidation of table 1.Efaproxiral sodium salt.
Identification?code 1
Empirical?formula C20?H35?N?Na?O11
Formula?weight 488.48
Temperature 293(2)K
Wavelength 0.71073A
Crystal?system，space?group Monoclinic，P2(1)/c
Unit?cell?dimensions a＝28.261(6)A alpha＝90deg.
b＝6.1580(12)A beta＝96.32(3)deg.
c＝14.819(3)A gamma＝90deg.
Volume 2563.3(9)A^3
Z，Calculated?density 4，1.266Mg/m^3
Absorption?coefficient 0.116mm^-1
F(000) 1044
Crystal?size 0.80x0.80x0.40mm
Theta?range?for?data?collection?3.33to27.48deg.
Limiting?indices -36<＝h<＝36，-7<＝k<＝7，-19<＝1<＝19
Reflections?collected/unique 22894/5833[R(int)＝0.0534]
Completeness?to?theta＝27.48 99.6％
Absorption?correction None
Max.and?min.transmission 0.9550and0.9127
Refinement?method Full-matrix?least-squares?on?F^2
Data/restraints/parameters 5833/0/354
Goodness-of-fit?on?F^21.022
Final?R?indices[I>2sigma(I)] R1＝0.0454，wR2＝0.1332
R?indices(all?data) R1＝0.0621，wR2＝0.1504
Largest?diff.peak?and?hole 0.255and-0.267e.A^-3
5.Efaproxiral sodium salt leaves standstill the powder x-ray diffraction spectrogram of crystallization gained target product in water
According to embodiment 3, the Efaproxiral sodium salt is being the solvent activated carbon decolorizing with water, and behind the heat filtering, if adopt different crystallization conditions and different drying conditionss, the crystallization meeting of Efaproxiral sodium salt in water obtains the product of different crystalline state.They have different powder x-ray diffraction spectrograms, and these crystal forms are not a kind of crystal formations, but the mixture of many kinds of crystal formations (comprising unformed).
But the powder x-ray diffraction spectrogram that leaves standstill the crystallization products obtained therefrom in water has outstanding feature.Its spectrogram only have 2 a θ=3.5-3.9 ° strong peak (Fig. 2, Fig. 3).This has shown the diffraction peak of the very high crystalline state of repeatability.Obviously, it is that above single crystal structure has lost water, but its basic structure still exists and causes.If not leaving standstill crystallization, but stirred crystallization or stirred crystallization in various degree will obtain comprising the unformed diffraction spectrogram that contains many peaks (Fig. 4).
Description of drawings
The crystalline structure of Fig. 1 Efaproxiral sodium salt monocrystalline that crystallization obtains in water.
Fig. 2 is in envrionment temperature 10-15 ℃ standing over night, filters 50 ℃ of baking ovens 12 hours, the powder x-ray diffraction spectrogram of products therefrom.It is the unimodal of that 2 θ=3.9 °, only poke amount assorted peak seldom basically.Experiment shows that this product also dries easily in room temperature, illustrates that these water moleculess just break away from crystal easily in room temperature.
Fig. 3 is that the sample of Fig. 2 crystalline state is again at the powder x-ray diffraction spectrogram of 4 hours products of 50 ℃ of vacuum rotary dehydrations.3.9 ° unimodally still exist, but those little assorted peaks have disappeared, and have become unformed.This crystalline state that those assorted peak representatives are described is destroyed easily under 50 ℃ of rotation vacuum, but the crystal of the unimodal representative of 2 θ=3.9 ° remains stable.
Fig. 4 is that the sample of Fig. 3 revolves the powder x-ray diffraction spectrogram that steams 6 hours products therefroms in 70 ℃ of vacuum again.Most of crystal has become unformed.Illustrate that these 3.9 ° of unimodal crystalline state are destroyed easily more than 70 ℃.
Embodiment
Provide following preparation example and embodiment, make those skilled in the art can more be expressly understood and implement the present invention.They should not be interpreted as limiting the scope of the invention, and only are its illustration and representative.
Acylation reaction
In the four-necked bottle of a 2000ml, drop into 4-hydroxyl phenylacetic acid 304 grams (2mol), 3,5-xylidine 300ml (2.4mol), the feeding argon gas (the 0.1-0.2 liter/minute).Heat temperature raising to about 80 ℃, starts and stirs.Be warming up to 150 ℃ of water that begin to disengage generation, these water vapour are separated out by a prolong.Rise to 175 ℃ with about 60 minutes temperature.Continue reaction 3 hours at 175 ℃ then.Be cooled to room temperature, form hard solids.Use the NaOH solution stirring dissolved solids thing of the 2M of 2 * 1000ml.And then dilute this alkaline solution with the water of 2 times of amounts, and under effectively stirring,, be 1-2 with 36% hydrochloric acid accent pH more earlier with the hydrochloric acid of 1M, separate out a large amount of white precipitates.Vacuum filtration, the water flushing, 100 ℃ of oven dry are spent the night, and get white powder solid 467 grams, theoretical yield 510 grams, yield 91.8%.
The O-alkylated reaction prepares the Efaproxiral sodium salt
In the three-necked bottle of a 5000ml, drop into amide intermediate 255 grams (1mol), chippy powder NaOH210 gram (5.25mol), acetone 3200ml, stirred 30 minutes at 25-30 ℃, be cooled to 15 ℃, drip chloroform 100ml (1.23mol), dripped about 1 hour at 15-20 ℃.Continue reaction 1 hour in this temperature, spend the night 20-25 ℃ of reaction then.Vacuum is removed superfluous acetone, adds the NaCl75 gram, 40 ℃ water 1900ml.Dissolution residual substance and NaCl.Be cooled to 10-15 ℃ under stirring, in this temperature standing over night.Suction filtration is with the saturated NaHCO of 500ml
3The solution flush cake.Dried 24 hours for 50 ℃, obtain 317.5 gram white crystalline powder.Filtrate is used NaHCO
3Transfer pH8-9 to separate out unreacted amide intermediate, suction filtration is dried immediately, gets 11.0 gram faint yellow solids.Filtrate is spent the night at 10-15 ℃, separates out sodium salt crystal again, suction filtration, and oven dry gets 10.3g.Obtain Efaproxiral sodium salt primary crystallization product (crude product) 327.8 grams altogether.Theoretical yield 363.4 grams, sodium salt yield 90.2%.Consider the amide intermediate of recovery, the yield of sodium salt is 94.5%.
The purifying of Efaproxiral sodium salt
With 530 gram crude product Efaproxiral sodium salts (primary crystallization product), 800ml ethanol drops into the three-necked bottle of 5000ml, in stirring at room, up to separating out mass crystallization, is warming up to 50 ℃, adds 1600ml acetone, the crystallization dissolving., stirred 1 hour until separating out a large amount of white powder crystallizations 45-50 ℃ of stirring, add 1600ml acetone again, stir and be cooled to 10-15 ℃, stirred 2 hours in this temperature in this temperature.Filter, use the 150ml acetone rinsing, spend the night, obtain crystallization second time product 440.5 grams of Efaproxiral sodium salt, yield 83.1% 50 ℃ of vacuum-dryings.Solvent is removed in the filtrate decompression distillation, adds 400ml water, heating for dissolving, and activated carbon decolorizing filters.Filtrate adds 10g sodium bicarbonate and 80g sodium-chlor, stirring and dissolving, and a large amount of white precipitates are separated out in cooling.Filter, 50 ℃ of oven dry obtain reclaiming Efaproxiral sodium salt 55.0g.Consider the sodium salt of recovery, the yield of Efaproxiral sodium salt crystallization for the second time product is 92.7%.
With the secondary crystal product of 530 gram Efaproxiral sodium salts, 2000ml distilled water, the three-necked bottle of input 5000ml is heated to dissolving (～50 ℃) fully under stirring, be heated to 70 ℃, adds the 100g gac, at 70-75 ℃ of decolouring 30 minutes, heat filtering.Filtrate is～15 ℃ thermostat container standing over night.Efaproxiral sodium can be separated out (figure) with needle-like crystal, amplify observation can find it actual be a very thin rectangle crystal.Smash formed crystalline solid to pieces, suction filtration, filter cake washes with a small amount of 0 ℃ water.50 ℃ of oven dry 12 hours,, obtain Efaproxiral sodium salt elaboration (medicinal, moisture＜0.3%) 456.9 grams, yield 86.2% then 50 ℃ of vacuum-dryings 6 hours.HPLC detects, content 99.50%.
50 gram sodium bicarbonates and 250 gram sodium-chlor are added stirring and dissolving in the filtrate, and residual Efaproxiral sodium salt can be separated out in crystallization, suction filtration, and oven dry obtains reclaiming sodium salt 50.6 grams.Consider that this reclaims, the yield of Efaproxiral sodium salt elaboration is 95.3%.
Claims (10)
1. method for preparing the Efaproxiral sodium salt, the structure of this compound is as follows:
Its reactions steps is as follows:
(1) acylation reaction
(2) phenol O-alkylated reaction
(3) purifying
With water is that solvent leaves standstill recrystallization acquisition Efaproxiral crystals of sodium salt.
2. according to the preparation method of claim 1, it is characterized in that the described acylation reaction of step (1) is to feed nitrogen (N
2) or the situation of argon gas (Ar) under, with p-hydroxyphenylaceticacid with 3,5-xylidine heating direct reaction and do not use solvent, p-hydroxyphenylaceticacid is with 3, the optimum mole ratio of 5-xylidine is 1.0: 1.0-1.3.
3. according to the preparation method of claim 2, it is characterized in that the described acylation reaction of step (1) carries out at 150 ℃-180 ℃, the reaction times is 2-5 hour, Best Times is 3-4 hour.
4. according to the preparation method of claim 1, it is characterized in that the CHCl of step (2)
3Add-on only need drop into 1.0-1.3 theory demands amount doubly, CHCl
3Add the back that finishes and continue reaction, the reaction times is 8～15 hours, preferred 10～12 hours.
5. according to the preparation method of claim 4, it is characterized in that reaction finish remove acetone after, add entry, the Efaproxiral sodium salt is separated out, the amount that adds entry is that every mole amide intermediate is used the 1.0-2.5 premium on currency, its optimum quantity is the 1.5-2.0 liter.
6. according to the preparation method of claim 5, it is characterized in that leaving standstill of Efaproxiral sodium salt separated out at 5-20 ℃ carries out, and optimum temps is 10-15 ℃.
7. according to the preparation method of claim 5, it is characterized in that adding sodium-chlor to increase the Efaproxiral sodium salt amount of separating out, add-on is that every mole amide intermediate is used 50-100 gram sodium-chlor.
8. according to the preparation method of claim 1, the Efaproxiral crystals of sodium salt that it is characterized in that step (3) is to separate out in 10-20 ℃ pure water, weight ratio Efaproxiral sodium salt: water=1.0: 3.5-4.0.
9. the Efaproxiral crystals of sodium salt of preparation method's gained of a claim 8, it is characterized in that this crystalline powder x-ray diffraction spectrogram be only have one 2 θ be 3.5-3.9 ° unimodal.
10. the monocrystalline that forms in water of the Efaproxiral sodium salt of a claim 1 is characterized in that this monocrystalline belongs to oblique system, comprises 4 Efaproxiral sodium salt molecules and 28 water moleculess in each structure cell.
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| CN 200710132097 CN101134732B (en) | 2007-09-21 | 2007-09-21 | New method for preparing 2-{4-[[(3,5-dimethylaniline)carbonyl ]methyl]phenoxy}-2-methyl sodium propionate and its crystal in water |
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| US20070299136A1 (en) * | 2004-04-22 | 2007-12-27 | Allos Therapeutics, Inc. | Crystalline and Amorphous Forms of Efaproxiral Sodium |
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