CN102617579A - Preparation method of ibudilast - Google Patents
Preparation method of ibudilast Download PDFInfo
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- CN102617579A CN102617579A CN2012100856696A CN201210085669A CN102617579A CN 102617579 A CN102617579 A CN 102617579A CN 2012100856696 A CN2012100856696 A CN 2012100856696A CN 201210085669 A CN201210085669 A CN 201210085669A CN 102617579 A CN102617579 A CN 102617579A
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Abstract
A preparation method of ibudilast relates to medicine compound compounding and aims at resolving the problem that the existing preparation method of the ibudilast is difficult to operate or low in yield and cannot achieve industrial production accordingly. The method includes 1 preparing 1-amino-2-picoline oxide and 2 adopting the 1-amino-2-picoline oxide to prepare the ibudilast. The method has the advantages that the preparation method is convenient in post-processing, the yield is 80% to 95%, and type and quantity of used solvent in industrialization are reduced; 2 medicine and agents used in the method are low in price, easy to obtain, high in yield and low in cost, thereby being suitable for industrialized production; and 3 a final product of the method is prepared by reduced pressure distillation and purification, and the purity can reach over 99%. The preparation method is mainly used in preparation of the ibudilast.
Description
Technical field
It is synthetic to the present invention relates to a kind of pharmaceutical compound, is specifically related to a kind of preparation method of KC-404.
Background technology
2-methyl isophthalic acid-[2-(1-methylethyl)-pyrazolo [1; 5-a] pyrimidin-3-yl]-1-acetone (KC-404, general medicine name: IBUDILAST) be the antiallergic property anti-asthmatic, can pick up anti-leukotriene and platelet activation factor; Promote the secretion of respiratory mucus, the function of respiratory tract cilium; Strengthen the effect of prostacyclin, the cerebral blood flow increasing amount is improved the brain metabolism.Be used to treat bronchial asthma, cerebral vessels embolism sequela, cerebral arteriosclerosis etc.
The preparation method of KC-404 mainly contains following two kinds:
Method one: (The Jourrtal of Organic Chemistry, 1968,33,3766～3770) synthetic route is following:
This route is that raw material obtains 1-amino-2-methyl pyridine iodide with the 2-picoline, obtains target compound with pyrimidine, isobutyryl chloride effect afterwards.The final product that obtains in this route needs column chromatography to purify, thereby has strengthened operation easier, and the used elutriant of column chromatography is a benzene in addition, and toxicity is bigger, is not suitable for suitability for industrialized production.
Method two: (Journal of the American Chemical Society, 2005,127,751-760) synthetic route is following:
This route is that raw material and thionamic acid potassium obtain 1-amino-2-methyl pyridine iodide under the effect of salt of wormwood with the 2-picoline, obtains target compound with the isobutyric anhydride effect afterwards.The first step reaction treatment in this route is locked, and yield is low, is not suitable for industrialized production.
Therefore the KC-404 method of existing preparation exists operational difficulty or yield low, causes realizing the problem of industrialized production.
Summary of the invention
The KC-404 method that the present invention will solve existing preparation exists operational difficulty or yield low, causes realizing the problem of industrialized production, and a kind of preparation method of KC-404 is provided.
A kind of preparation method of KC-404 specifically accomplishes: one, at first azanol oxygen sulfonic acid is dissolved in the solvent, under condition of ice bath, dropwise adds the 2-picoline then according to the following steps; After adding, the 2-picoline is warming up to 50 ℃～90 ℃; And under temperature is 50 ℃～90 ℃, react 0.5h～1h, add mineral alkali I then, and low whipping speed is to be stirred to no bubble under 100r/min～300r/min to produce; Be that 45r/min～90r/min, temperature are 40 ℃～60 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then; The solid that obtains adopts absolute ethanol washing 2～3 times, converges the filtrating that washing obtains, and is dropwise to add mineral acid under-15 ℃～-10 ℃ or organic acid carries out acidification in temperature; The acidification time is 0.5h～1h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants; The quality of the oxygen of azanol described in step 1 sulfonic acid and the volume ratio of solvent are 1g: (2mL～15mL); The mol ratio of 2-picoline that adds described in the step 1 and azanol oxygen sulfonic acid is (1～3): 1; The mol ratio of mineral alkali I that adds described in the step 1 and azanol oxygen sulfonic acid is 1: (1～1.5); The absolute ethyl alcohol that single wash described in the step 1 adopts with revolve that to steam the solid mass ratio that obtains be 1: (1～3); The mineral acid that adds described in the step 1 is 1 with collecting the volume ratio converge the filtrating that washing obtains: (7～10), and perhaps the organic acid of said adding is 1 with collecting the volume ratio of converging the filtrating that washing obtains: (7～10); Two, at first join 1-amino-2-methyl pyridine acidulants and mineral alkali II in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 110 ℃～170 ℃ in temperature then, the reaction times is 6h～12h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 10～12, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404; The mol ratio of isobutyric anhydride that adds described in the step 2 and 1-amino-2-methyl pyridine acidulants is (5～10): 1; The mol ratio of mineral alkali II that adds described in the step 2 and 1-amino-2-methyl pyridine acidulants is 1.5: 1; The deionized water that adds described in the step 2 is (2～4) with filtering the volume ratio that obtains filtrating: 1.
Advantage of the present invention: one, convenient post-treatment of the present invention, yield is higher, uses solvent types and usage quantity when having reduced industriallization; Two, among the present invention employed medicine and reagent cheap, be easy to get, yield is high, cost is low, therefore is fit to industrial amplification production; Three, finished product of the present invention makes through the underpressure distillation purifying, and product purity is high.
Description of drawings
Fig. 1 be the test one the preparation KC-404 proton nmr spectra (
1H NMR) figure; Fig. 2 is infrared (IR) figure of test one preparation KC-404.
Embodiment
Embodiment one: this embodiment is a kind of preparation method of KC-404, specifically accomplishes according to the following steps:
One, at first azanol oxygen sulfonic acid is dissolved in the solvent; Under condition of ice bath, dropwise add the 2-picoline then, be warming up to 50 ℃～90 ℃ after the 2-picoline adds, and under temperature is 50 ℃～90 ℃, react 0.5h～1h; Add mineral alkali I then; And low whipping speed is to be stirred to no bubble under 100r/min～300r/min to produce, and is that 45r/min～90r/min, temperature are 40 ℃～60 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then, and the solid that obtains adopts absolute ethanol washing 2～3 times; Converge the filtrating that washing obtains; And be dropwise to add mineral acid under-15 ℃～-10 ℃ or organic acid carries out acidification in temperature, the acidification time is 0.5h～1h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants;
Two, at first join 1-amino-2-methyl pyridine acidulants and mineral alkali II in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 110 ℃～170 ℃ in temperature then, the reaction times is 6h～12h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 10～12, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404.
The quality of the sulfonic acid of azanol oxygen described in this embodiment step 1 and the volume ratio of solvent are 1g: (2mL～15mL); The mol ratio of 2-picoline that adds described in the step 1 and azanol oxygen sulfonic acid is (1～3): 1; The mol ratio of mineral alkali I that adds described in this embodiment step 1 and azanol oxygen sulfonic acid is 1: (1～1.5); The absolute ethyl alcohol that single wash described in this embodiment step 1 adopts with revolve that to steam the solid mass ratio that obtains be 1: (1～3); The mineral acid that adds described in this embodiment step 1 is 1 with collecting the volume ratio converge the filtrating that washing obtains: (7～10), and perhaps the organic acid of said adding is 1 with collecting the volume ratio of converging the filtrating that washing obtains: (7～10);
The mol ratio of isobutyric anhydride that adds described in this embodiment step 2 and 1-amino-2-methyl pyridine acidulants is (5～10): 1; The mol ratio of mineral alkali II that adds described in this embodiment step 2 and 1-amino-2-methyl pyridine acidulants is 1.5: 1; The deionized water that adds described in this embodiment step 2 is (2～4) with filtering the volume ratio that obtains filtrating: 1.
This embodiment convenient post-treatment, yield is higher, uses solvent types and usage quantity when having reduced industriallization.
In this embodiment employed medicine and reagent cheap, be easy to get, yield is high, cost is low, therefore is fit to industrial amplification production.
This embodiment finished product makes through the underpressure distillation purifying, and product purity is high.
Embodiment two: this embodiment with the difference of embodiment one is: the solvent described in the step 1 is selected from deionized water, methylene dichloride, benzene, toluene and YLENE.Other is identical with embodiment one.
Embodiment three: this embodiment with one of embodiment one or two difference is: the mineral alkali I described in the step 1 is salt of wormwood, yellow soda ash, sodium hydroxide or Pottasium Hydroxide.Other is identical with embodiment one or two.
Embodiment four: this embodiment with one of embodiment one to three difference is: the mineral acid described in the step 1 is concentrated hydrochloric acid, Hydrogen bromide or hydroiodic acid HI, and described organic acid is oxalic acid, toxilic acid, succsinic acid, tartrate or oxysuccinic acid.Other is identical with embodiment one to three.
Embodiment five: this embodiment with one of embodiment one to four difference is: the mineral alkali II described in the step 2 is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash and salt of wormwood.Other is identical with embodiment one to four.
Embodiment six: this embodiment with one of embodiment one to five difference is: the extraction concrete operations described in the step 2 are following: the product that at room temperature adopts extraction agent extraction heating reflux reaction 6h～12h to obtain; Separate and obtain extraction phase; Adopt then till pH=7 ± 0.1 of deionized water wash extraction phase to extraction phase, and the volume ratio of single wash extraction phase and deionized water is 1: (2～4); The volume ratio of the product that described extraction agent and heating reflux reaction 6h～12h obtain is (2～4): 1, and described extraction agent is ETHYLE ACETATE, toluene, methylene dichloride or ether.Other is identical with embodiment one to five.
Embodiment seven: this embodiment with one of embodiment one to six difference is: the concentrated concrete operations described in the step 2 are following: at first adopt the extraction phase after SODIUM SULPHATE ANHYDROUS 99PCT will wash to carry out drying; Filter then; And the filtrating that will obtain rotating speed be 45r/min～90r/min, temperature be 40 ℃～60 ℃ adopt the rotary evaporation methods to revolve to steam produce to the thing phlegma till, promptly obtain concentrating after product.Other is identical with embodiment one to seven.
Embodiment eight: one of this embodiment and embodiment one to seven difference is: the underpressure distillation concrete operations described in the step 2 are following: the resistates after will concentrating carries out underpressure distillation, collects bp110～175 ℃/1kPa fraction.Other is identical with embodiment one to seven.
Embodiment nine: this embodiment with one of embodiment one to eight difference is: the recrystallization concrete operations described in the step 2 are following: at first the fraction of collecting is cooled to 10 ℃～25 ℃; Obtain faint yellow solid; In faint yellow solid, add normal hexane then; And be warming up to 50 ℃～68 ℃, and be 50 ℃～68 ℃ insulation 5min～10min in temperature, be cooled to 10 ℃～25 ℃ then; And under temperature is 10 ℃～25 ℃, being incubated 0.5h～1h, last warp filters and promptly obtains KC-404; The quality of described faint yellow solid and the volume ratio of normal hexane are 1g: (1mL～2mL), promptly obtain KC-404.Other is identical with embodiment one to eight.
Adopt following verification experimental verification effect of the present invention:
Test one: a kind of preparation method of KC-404, specifically accomplish according to the following steps:
One, at first the azanol oxygen sulfonic acid of 5.65kg is dissolved in the deionized water of 12L; Under condition of ice bath, dropwise add the 2-picoline of 13.95kg then, be warming up to 70 ℃ after the 2-picoline adds, and under temperature is 70 ℃, react 0.5h; Add salt of wormwood then; And low whipping speed is to be stirred to no bubble under the 200r/min to produce, and is that 70r/min, temperature are 50 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then, and the solid that obtains adopts absolute ethanol washing 2 times; Converge the filtrating that washing obtains; And carry out acidification for dropwise adding hydroiodic acid HI under-15 ℃ in temperature, the acidification time is 0.5h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants;
Two, at first join 1-amino-2-methyl pyridine acidulants and salt of wormwood in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 140 ℃ in temperature then, the reaction times is 8h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 11, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404.
The salt of wormwood that adds described in this testing sequence one and the mol ratio of azanol oxygen sulfonic acid are 1: 1.2; The absolute ethyl alcohol that single wash described in this testing sequence one adopts with revolve that to steam the solid mass ratio that obtains be 1: 2; It is 1: 9 that the hydroiodic acid HI that adds described in this testing sequence one converges the volume ratio of washing the filtrating that obtains with collection.
The isobutyric anhydride that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 7.5: 1; The salt of wormwood that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 1.5: 1; The deionized water that adds described in this testing sequence two is 2: 1 with filtering the volume ratio that obtains filtrating.
Extraction concrete operations described in this testing sequence two are following: the product that at room temperature adopts extraction agent extraction heating reflux reaction 9h to obtain; Separate and obtain extraction phase; Adopt then till pH=7 ± 0.1 of deionized water wash extraction phase to extraction phase, and the volume ratio of single wash extraction phase and deionized water is 1: 3; The volume ratio of the product that described extraction agent and heating reflux reaction 9h obtain is 3: 1, and described extraction agent is ETHYLE ACETATE, toluene, methylene dichloride or ether.
Concentrated concrete operations described in this testing sequence two are following: at first adopt the extraction phase after SODIUM SULPHATE ANHYDROUS 99PCT will wash to carry out drying; Filter then; And the filtrating that will obtain rotating speed be 70r/min, temperature be 50 ℃ adopt the rotary evaporation methods to revolve to steam produce to the thing phlegma till, promptly obtain concentrating after product.
Underpressure distillation concrete operations described in this testing sequence two are following: the resistates after will concentrating carries out underpressure distillation, collects bp110～175 ℃/1kPa fraction.
Recrystallization concrete operations described in this testing sequence two are following: at first the fraction of collecting is cooled to 20 ℃; Obtain faint yellow solid, in faint yellow solid, add normal hexane then, and be warming up to 63 ℃; In temperature is 63 ℃ of insulation 7min; Be cooled to 20 ℃ then, and under temperature is 20 ℃, be incubated 50min, last warp filters and promptly obtains KC-404; The quality of described faint yellow solid and the volume ratio of normal hexane are 1g: 2mL.
Can know that through weighing the KC-404 that obtains at last is 7.0kg; Can know that through calculating yield is 82.60%; Detect through fusing point and can know that obtaining the KC-404 fusing point is 53.5 ℃～54 ℃, the purity of the KC-404 for preparing through this test of high-efficient liquid phase chromatogram technique analysis is 99.5%.
Detect the KC-404 that this test prepares through nuclear magnetic resonance technique, it is following to detect data:
1H?NMR(400MHz，CDCl
3)δ8.49(d，J＝6.9Hz，1H)，8.04(d，J＝9.0Hz，1H)，7.39(ddd，J＝8.9，6.9，1.1Hz，1H)，6.90(td，J＝6.9，1.2Hz，1H)，3.79(hept，J＝6.8Hz，1H)，3.35(hept，J＝6.8Hz，1H)，1.41(d，J＝6.9Hz，6H)，1.26(d，J＝6.8Hz，6H).
Detect the KC-404 that this test prepares through infrared technique, it is following to detect data
TR：2924.5，1646.7，1505.3，1258.0，1189.9，1080.9，970.8，746.9cm
-1
But the structural formula through above-mentioned detection data knowledge capital test preparation KC-404 is:
Test two: a kind of preparation method of KC-404, specifically accomplish according to the following steps:
One, at first the azanol oxygen sulfonic acid of 8.48kg is dissolved in the deionized water of 20L; Under condition of ice bath, dropwise add the 2-picoline of 20.93kg then, be warming up to 80 ℃ after the 2-picoline adds, and under temperature is 80 ℃, react 45min; Add salt of wormwood then; And low whipping speed is to be stirred to no bubble under the 200r/min to produce, and is that 70r/min, temperature are 50 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then, and the solid that obtains adopts absolute ethanol washing 2 times; Converge the filtrating that washing obtains; And in temperature for dropwise adding mineral acid under-15 ℃ or organic acid carries out acidification, the acidification time is 0.5h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants;
Two, at first join 1-amino-2-methyl pyridine acidulants and salt of wormwood in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 140 ℃ in temperature then, the reaction times is 8h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 11, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404.
The salt of wormwood that adds described in this testing sequence one and the mol ratio of azanol oxygen sulfonic acid are 1: 1.2; The absolute ethyl alcohol that single wash described in this testing sequence one adopts with revolve that to steam the solid mass ratio that obtains be 1: 2; It is 1: 9 that the mineral acid that adds described in this testing sequence one converges the volume ratio of washing the filtrating that obtains with collection.
The isobutyric anhydride that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 7.5: 1; The salt of wormwood that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 1.5: 1; The deionized water that adds described in this testing sequence two is 2: 1 with filtering the volume ratio that obtains filtrating.
Extraction concrete operations described in this testing sequence two are following: the product that at room temperature adopts extraction agent extraction heating reflux reaction 9h to obtain; Separate and obtain extraction phase; Adopt then till pH=7 ± 0.1 of deionized water wash extraction phase to extraction phase, and the volume ratio of single wash extraction phase and deionized water is 1: 3; The volume ratio of the product that described extraction agent and heating reflux reaction 9h obtain is 3: 1, and described extraction agent is ETHYLE ACETATE, toluene, methylene dichloride or ether.
Concentrated concrete operations described in this testing sequence two are following: at first adopt the extraction phase after SODIUM SULPHATE ANHYDROUS 99PCT will wash to carry out drying; Filter then; And the filtrating that will obtain rotating speed be 70r/min, temperature be 50 ℃ adopt the rotary evaporation methods to revolve to steam produce to the thing phlegma till, promptly obtain concentrating after product.
Underpressure distillation concrete operations described in this testing sequence two are following: the resistates after will concentrating carries out underpressure distillation, collects bp110～175 ℃/1kPa fraction.
Recrystallization concrete operations described in this testing sequence two are following: at first the fraction of collecting is cooled to 20 ℃; Obtain faint yellow solid, in faint yellow solid, add normal hexane then, and be warming up to 63 ℃; In temperature is 63 ℃ of insulation 7min; Be cooled to 20 ℃ then, and under temperature is 20 ℃, be incubated 50min, last warp filters and promptly obtains KC-404; The quality of described faint yellow solid and the volume ratio of normal hexane are 1g: 2mL.
Can know that through weighing the KC-404 that obtains at last is 7.2kg; Can know that through calculating yield is 91.14%; Detect through fusing point and can know that obtaining the KC-404 fusing point is 53.5 ℃～54 ℃, the purity of the KC-404 for preparing through this test of high-efficient liquid phase chromatogram technique analysis is 99.0%.
Test three: a kind of preparation method of KC-404, specifically accomplish according to the following steps:
One, at first the azanol oxygen sulfonic acid of 11.30kg is dissolved in the deionized water of 25L; Under condition of ice bath, dropwise add the 2-picoline of 27.90kg then, be warming up to 90 ℃ after the 2-picoline adds, and under temperature is 90 ℃, react 45min; Add salt of wormwood then; And low whipping speed is to be stirred to no bubble under the 200r/min to produce, and is that 70r/min, temperature are 50 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then, and the solid that obtains adopts absolute ethanol washing 2 times; Converge the filtrating that washing obtains; And in temperature for dropwise adding mineral acid under-15 ℃ or organic acid carries out acidification, the acidification time is 0.5h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants;
Two, at first join 1-amino-2-methyl pyridine acidulants and salt of wormwood in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 140 ℃ in temperature then, the reaction times is 8h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 11, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404.
The salt of wormwood that adds described in this testing sequence one and the mol ratio of azanol oxygen sulfonic acid are 1: 1.2; The absolute ethyl alcohol that single wash described in this testing sequence one adopts with revolve that to steam the solid mass ratio that obtains be 1: 2; It is 1: 9 that the mineral acid that adds described in this testing sequence one converges the volume ratio of washing the filtrating that obtains with collection.
The isobutyric anhydride that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 7.5: 1; The salt of wormwood that adds described in this testing sequence two and the mol ratio of 1-amino-2-methyl pyridine acidulants are 1.5: 1; The deionized water that adds described in this testing sequence two is 2: 1 with filtering the volume ratio that obtains filtrating.
Extraction concrete operations described in this testing sequence two are following: the product that at room temperature adopts extraction agent extraction heating reflux reaction 9h to obtain; Separate and obtain extraction phase; Adopt then till pH=7 ± 0.1 of deionized water wash extraction phase to extraction phase, and the volume ratio of single wash extraction phase and deionized water is 1: 3; The volume ratio of the product that described extraction agent and heating reflux reaction 9h obtain is 3: 1, and described extraction agent is ETHYLE ACETATE, toluene, methylene dichloride or ether.
Concentrated concrete operations described in this testing sequence two are following: at first adopt the extraction phase after SODIUM SULPHATE ANHYDROUS 99PCT will wash to carry out drying; Filter then; And the filtrating that will obtain rotating speed be 70r/min, temperature be 50 ℃ adopt the rotary evaporation methods to revolve to steam produce to the thing phlegma till, promptly obtain concentrating after product.
Underpressure distillation concrete operations described in this testing sequence two are following: the resistates after will concentrating carries out underpressure distillation, collects bp110～175 ℃/1kPa fraction.
Recrystallization concrete operations described in this testing sequence two are following: at first the fraction of collecting is cooled to 20 ℃; Obtain faint yellow solid, in faint yellow solid, add normal hexane then, and be warming up to 63 ℃; In temperature is 63 ℃ of insulation 7min; Be cooled to 20 ℃ then, and under temperature is 20 ℃, be incubated 50min, last warp filters and promptly obtains KC-404; The quality of described faint yellow solid and the volume ratio of normal hexane are 1g: 2mL.
Can know that through weighing the KC-404 that obtains at last is 7.15kg; Can know that through calculating yield is 90.50%; Detect through fusing point and can know that obtaining the KC-404 fusing point is 53.5 ℃～54 ℃, the purity of the KC-404 for preparing through this test of high-efficient liquid phase chromatogram technique analysis is 99.5%.
Claims (9)
1. the preparation method of a KC-404 is characterized in that the preparation method of KC-404 accomplishes according to the following steps:
One, at first azanol oxygen sulfonic acid is dissolved in the solvent; Under condition of ice bath, dropwise add the 2-picoline then, be warming up to 50 ℃～90 ℃ after the 2-picoline adds, and under temperature is 50 ℃～90 ℃, react 0.5h～1h; Add mineral alkali I then; And low whipping speed is to be stirred to no bubble under 100r/min～300r/min to produce, and is that 45r/min～90r/min, temperature are 40 ℃～60 ℃ and adopt the rotary evaporation methods to revolve to steam to constant weight at rotating speed then, and the solid that obtains adopts absolute ethanol washing 2～3 times; Converge the filtrating that washing obtains; And be dropwise to add mineral acid under-15 ℃～-10 ℃ or organic acid carries out acidification in temperature, the acidification time is 0.5h～1h, filters at last and promptly obtains 1-amino-2-methyl pyridine acidulants; The quality of the oxygen of azanol described in step 1 sulfonic acid and the volume ratio of solvent are 1g: (2mL～15mL); The mol ratio of 2-picoline that adds described in the step 1 and azanol oxygen sulfonic acid is (1～3): 1; The mol ratio of mineral alkali I that adds described in the step 1 and azanol oxygen sulfonic acid is 1: (1～1.5); The absolute ethyl alcohol that single wash described in the step 1 adopts with revolve that to steam the solid mass ratio that obtains be 1: (1～3); The mineral acid that adds described in the step 1 is 1 with collecting the volume ratio converge the filtrating that washing obtains: (7～10), and perhaps the organic acid of said adding is 1 with collecting the volume ratio of converging the filtrating that washing obtains: (7～10);
Two, at first join 1-amino-2-methyl pyridine acidulants and mineral alkali II in the isobutyric anhydride respectively; Be to carry out heating reflux reaction under 110 ℃～170 ℃ in temperature then, the reaction times is 6h～12h, is cooled to the room temperature after-filtration and obtains filtrating; Add deionized water then; And adopt salt of wormwood with pH regulator to 10～12, then successively through extraction, concentrate, underpressure distillation and recrystallization, promptly obtain KC-404; The mol ratio of isobutyric anhydride that adds described in the step 2 and 1-amino-2-methyl pyridine acidulants is (5～10): 1; The mol ratio of mineral alkali II that adds described in the step 2 and 1-amino-2-methyl pyridine acidulants is 1.5: 1; The deionized water that adds described in the step 2 is (2～4) with filtering the volume ratio that obtains filtrating: 1.
2. the preparation method of a kind of KC-404 according to claim 1 is characterized in that the solvent described in the step 1 is selected from deionized water, methylene dichloride, benzene, toluene and YLENE.
3. the preparation method of a kind of KC-404 according to claim 2 is characterized in that the mineral alkali I described in the step 1 is salt of wormwood, yellow soda ash, sodium hydroxide or Pottasium Hydroxide.
4. according to the preparation method of claim 1,2 or 3 described a kind of KC-404s, it is characterized in that the mineral acid described in the step 1 is concentrated hydrochloric acid, Hydrogen bromide or hydroiodic acid HI, described organic acid is oxalic acid, toxilic acid, succsinic acid, tartrate or oxysuccinic acid.
5. the preparation method of a kind of KC-404 according to claim 4 is characterized in that the mineral alkali II described in the step 2 is selected from sodium hydroxide, Pottasium Hydroxide, yellow soda ash and salt of wormwood.
6. the preparation method of a kind of KC-404 according to claim 5; It is characterized in that the extraction concrete operations described in the step 2 are following: the product that at room temperature adopts extraction agent extraction heating reflux reaction 6h～12h to obtain; Separate and obtain extraction phase; Adopt then till pH=7 ± 0.1 of deionized water wash extraction phase to extraction phase, and the volume ratio of single wash extraction phase and deionized water is 1: (2～4); The volume ratio of the product that described extraction agent and heating reflux reaction 6h～12h obtain is (2～4): 1, and described extraction agent is ETHYLE ACETATE, toluene, methylene dichloride or ether.
7. the preparation method of a kind of KC-404 according to claim 6; It is characterized in that the concentrated concrete operations described in the step 2 are following: at first adopt the extraction phase after SODIUM SULPHATE ANHYDROUS 99PCT will wash to carry out drying; Filter then; And the filtrating that will obtain rotating speed be 45r/min～90r/min, temperature be 40 ℃～60 ℃ adopt the rotary evaporation methods to revolve to steam produce to the thing phlegma till, promptly obtain concentrating after product.
8. the preparation method of a kind of KC-404 according to claim 7, it is characterized in that the underpressure distillation concrete operations described in the step 2 are following: the resistates after will concentrating carries out underpressure distillation, collects bp110～175 ℃/1kPa fraction.
9. according to the preparation method of claim 6,7 or 8 described a kind of KC-404s; It is characterized in that the recrystallization concrete operations described in the step 2 are following: at first the fraction of collecting is cooled to 10 ℃～25 ℃; Obtain faint yellow solid, in faint yellow solid, add normal hexane then, and be warming up to 50 ℃～68 ℃; In temperature is 50 ℃～68 ℃ insulation 5min～10min; Be cooled to 10 ℃～25 ℃ then, and under temperature is 10 ℃～25 ℃, be incubated 0.5h～1h, last warp filters and promptly obtains KC-404; The quality of described faint yellow solid and the volume ratio of normal hexane are 1g: (1mL～2mL).
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| US3850941A (en) * | 1972-03-30 | 1974-11-26 | Kyorin Seiyaku Kk | 2-alkyl-3-acylpyrazolo(1,5-a)pyridines |
| WO2007146087A2 (en) * | 2006-06-06 | 2007-12-21 | Avigen, Inc. | SUBSTITUTED PYRAZOLO [1,5-α] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3850941A (en) * | 1972-03-30 | 1974-11-26 | Kyorin Seiyaku Kk | 2-alkyl-3-acylpyrazolo(1,5-a)pyridines |
| WO2007146087A2 (en) * | 2006-06-06 | 2007-12-21 | Avigen, Inc. | SUBSTITUTED PYRAZOLO [1,5-α] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE |
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| WENYING CHAI ET AL.: "Non-imidazole Heterocyclic Histamine H3 Receptor Antagonists", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
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