CN101775009B - Composite method of itraconazole and refining method - Google Patents
Composite method of itraconazole and refining method Download PDFInfo
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- CN101775009B CN101775009B CN200910076939A CN200910076939A CN101775009B CN 101775009 B CN101775009 B CN 101775009B CN 200910076939 A CN200910076939 A CN 200910076939A CN 200910076939 A CN200910076939 A CN 200910076939A CN 101775009 B CN101775009 B CN 101775009B
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- 238000000034 method Methods 0.000 title claims abstract description 23
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 20
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title abstract description 17
- 238000007670 refining Methods 0.000 title abstract description 10
- 239000002131 composite material Substances 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 25
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 9
- 150000001875 compounds Chemical class 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 7
- 239000011707 mineral Substances 0.000 claims description 7
- 239000012044 organic layer Substances 0.000 claims description 7
- 230000003647 oxidation Effects 0.000 claims description 7
- 238000007254 oxidation reaction Methods 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- -1 itraconazole compound Chemical class 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 3
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 claims description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 125000004799 bromophenyl group Chemical group 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 5
- 239000012046 mixed solvent Substances 0.000 abstract description 5
- 239000000047 product Substances 0.000 abstract description 5
- 238000007086 side reaction Methods 0.000 abstract description 5
- 239000012043 crude product Substances 0.000 abstract description 2
- 150000007529 inorganic bases Chemical class 0.000 abstract description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract 2
- 230000036632 reaction speed Effects 0.000 abstract 1
- MBGGBVCUIVRRBF-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(=O)C1CCS(=O)C1=CC=CC=C1 MBGGBVCUIVRRBF-UHFFFAOYSA-N 0.000 abstract 1
- 229960003329 sulfinpyrazone Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- VCLRPNVTIUOTBM-UHFFFAOYSA-N O1C(NC=C1)=O.N1CCNCC1 Chemical compound O1C(NC=C1)=O.N1CCNCC1 VCLRPNVTIUOTBM-UHFFFAOYSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 7
- 238000000746 purification Methods 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 235000017550 sodium carbonate Nutrition 0.000 description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 235000010755 mineral Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- BIVUUOPIAYRCAP-UHFFFAOYSA-N aminoazanium;chloride Chemical compound Cl.NN BIVUUOPIAYRCAP-UHFFFAOYSA-N 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000003444 phase transfer catalyst Substances 0.000 description 2
- 150000003459 sulfonic acid esters Chemical class 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- JUSXLWAFYVKNLT-UHFFFAOYSA-N 2-bromobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1Br JUSXLWAFYVKNLT-UHFFFAOYSA-N 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- UVCJGUGAGLDPAA-UHFFFAOYSA-N ensulizole Chemical compound N1C2=CC(S(=O)(=O)O)=CC=C2N=C1C1=CC=CC=C1 UVCJGUGAGLDPAA-UHFFFAOYSA-N 0.000 description 1
- 229960000655 ensulizole Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- LUMVCLJFHCTMCV-UHFFFAOYSA-M potassium;hydroxide;hydrate Chemical compound O.[OH-].[K+] LUMVCLJFHCTMCV-UHFFFAOYSA-M 0.000 description 1
- 238000013094 purity test Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a composite method of itraconazole, which comprises the steps: taking piperazine sulfinpyrazone, antioxygen and inorganic base to react at the temperature of 30 DEG C to 60 DEG C for 20 minutes to 40 minutes and adding sulfonic ester at the temperature of 50 DEG C to 110 DEG C and reacting for 0.5 hour to 3 hours. The method has fast reaction speed and low reaction temperature and can effectively reduce the generation of side reaction. The invention also provides a refining method of itraconazole, which comprising the steps: recrystallizing crude products by the mixed solvent of two organic solvents and obtaining the qualified product by one-time refining; and the refining method has simple and convenient operation and high yield.
Description
Technical field:
The present invention relates to the compound method of itraconazole, the invention still further relates to the process for purification of itraconazole.
Background technology:
Itraconazole is an antifungal drug in triazole class, and its English name is Itraconazole.
The synthetic itraconazole of traditional method is that sulphonate, piperazine oxazolone and mineral alkali are joined the condensation that heats up in the solvent.The transformation efficiency of reaction is lower like this, and impurity is more, causes low, the unstable product quality of reaction yield.
In 200710056778.4 one Chinese patent application, in two phase solvents, realize condensation reaction with phase-transfer catalyst, earlier sulphonate is dissolved in the solvent such as toluene; Add inorganic base aqueous solution, inhibitor and quaternary ammonium salt-type phase transfer catalyst again; Add piperazine oxazolone temperature rising reflux reaction 5～20 hours then, be cooled to 40 ℃ then, divide the phase of anhydrating; Continue to be cooled to 20～30 ℃, cross and filter the itraconazole bullion.The shortcoming of this method is that the solvent amount of two-phase system is big, speed of response is slow, long reaction time, temperature required height.In addition, though the bullion yield that this method obtains is 90%, color is relatively poor.For reaching the purity more than 98% of pharmacopeia regulation, need be refining through repeatedly, cause productive rate lower.
Therefore, need set up a kind of new synthetic itraconazole method, transformation efficiency when improving sulphonate and the condensation reaction of piperazine oxazolone, and reduce side reaction, improve itraconazole bullion yield.
In addition, need to improve the process for purification of itraconazole bullion, to improve the total recovery of end product.
Summary of the invention:
One of the object of the invention is to set up a kind of new itraconazole compound method, solves that side reaction is many in the existing technology, yield is low, problems such as final product quality difference and refining difficulty.Another object of the present invention is to find a kind of easy to operate, itraconazole process for purification that yield is high.
Itraconazole compound method provided by the invention is: earlier piperazine oxazolone, oxidation inhibitor, mineral alkali were reacted 20～40 minutes at 30～60 ℃, add sulphonate then, 50～110 ℃ of reactions 0.5～3 hour, obtain the itraconazole bullion.
Said piperazine oxazolone is 2,4-dihydro-4-[4-[4-(4-hydroxy phenyl)-1-piperazinyl] phenyl]-2-(1-methyl-propyl)-]-3H-1,2, the 4-triazole-]-3-ketone.Formula as follows.
Said sulphonate be suitable-[2-(2; The 4-dichlorophenyl)-2-(1H-1,2,4-triazole-1-yl)-1; 3-dioxolane-4]-the substituted sulfonic acid ester, wherein the substituted sulfonic acid ester be selected from methanesulfonate ester, phenylbenzimidazole sulfonic acid ester, to bromophenyl sulphonate, p-methylphenyl sulphonate etc.Formula as follows, wherein R represent methylidene, phenyl, to bromophenyl or p-methylphenyl etc.The mol ratio of piperazine oxazolone and sulphonate is 1: 1.1～1.5;
Sulphonate piperazine oxazolone
Itraconazole
Said oxidation inhibitor is selected from Hydrazine Hydrate 80 and salt, mercaptoethanol or BHT, and the mol ratio of piperazine oxazolone and oxidation inhibitor is 1: 0.05～0.1;
Said mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, sodium hydride, potassium hydride KH etc., and the mol ratio of piperazine oxazolone and mineral alkali is 1: 1.3～1.8;
Can use solvents such as DMF, DMA, DMSO, HMPT in the first step reaction.After reaction finishes, can reaction solution impouring alkali aqueous solution be added organic solvent, tell organic layer after, filter, concentrate bullion.Buck is the aqueous solution of sodium hydroxide, Pottasium Hydroxide, yellow soda ash, sodium hydrogencarbonate, and concentration is 5～10%;
The present invention also provides a kind of process for purification of itraconazole bullion, with the mixed solvent recrystallization of bullion with two kinds of organic solvents, only needs can obtain qualified finished product through once refining, and easy and simple to handle, yield is high.
Employed mixed solvent such as following table:
Crude product refining is with mixed solvent title and ratio
| Solvent 1: solvent 2 | Available solvent volume ratio | The preferred solvent volume ratio |
| Toluene: ETHYLE ACETATE | 1～3∶1 | 2∶1 |
| Methylene dichloride: ETHYLE ACETATE | 1∶1～5 | 1∶3 |
| THF: ETHYLE ACETATE | 3～7∶1 | 5∶1 |
| Methylene dichloride: ethanol | 1∶3～8 | 1∶5 |
Problems such as the present invention has solved mainly that side reaction is many in the existing technology, yield is low, final product quality difference and refining difficulty.Compared following characteristics with prior art:
1. adopt homogeneous system, thereby speed of response is accelerated greatly, temperature of reaction also reduces greatly;
2. in reaction medium, add oxidation inhibitor, effectively reduced the generation of side reaction, become easy thereby make to make with extra care;
3. set up mixed solvent to the finished product process for purification, made finished product once refining qualified, efficiently solved quality and yield two large problems.
Embodiment
The sample purity test condition
Use THEREMO BDS (4.6 * 100mm, 5 μ m) chromatographic column, (2: 8～5: 5, V: V) gradient elution, flow velocity 1.0ml/min detected wavelength 225nm, 25 ℃ of column temperatures, sample size 10 μ l with acetonitrile+27g/L tetrabutyl metabisulfite solution.
Embodiment 1
In the four-hole bottle that has stirring, inlet pipe, TM, prolong, at N
2Protection add down 10g piperazine oxazolone, 1.3g sodium hydrate solid, 0.15ml 80% Hydrazine Hydrate 80 and 80mlDMF.Stirring is warming up to 40 ℃ of reactions 40 minutes, adds the 11.6g methanesulfonates then, and heat temperature raising to 60 ℃, react 1.5 hours, and TLC monitors no piperazine oxazolone and is reaction end.
Reaction is cooled to 20 ℃, in reaction solution impouring 100ml 10% sodium hydroxide solution after finishing; Add 150ml methylene dichloride and layering in separating funnel, organic layer is washed with 100ml 10% sodium hydroxide solution, and water is washed till neutrality again; Anhydrous magnesium sulfate drying filters, and drains; Filter cake is used the 10ml eluent methylene chloride, filtrating is concentrated into dried, bullion.
Add 100ml toluene then, the intensification stirring and dissolving adds 50ml ETHYLE ACETATE, and slowly solid is separated out in cooling, yield 90%, and purity 99.2%, quality meet the European Pharmacopoeia standard.
Embodiment 2
In the four-hole bottle that has stirring, inlet pipe, TM, prolong, at N
2Protection add down 10g piperazine oxazolone, 2.5g Pottasium Hydroxide, 0.18ml mercaptoethanol and 80mlDMF.Stir, oil bath is heated to 60 ℃, and reaction is 20 minutes under this temperature, adds the 18.4g p-toluenesulfonic esters then, and heat temperature raising to 100 ℃, react 1 hour, and TLC monitors no piperazine oxazolone and is reaction end.
Reaction is cooled to 20 ℃, in reaction solution impouring 100ml 5% potassium hydroxide solution after finishing; Add 150ml methylene dichloride and layering in separating funnel, organic layer is washed with 100ml 5% potassium hydroxide solution, and water is washed till neutrality again; Anhydrous magnesium sulfate drying filters, and drains; Filter cake is used the 10ml eluent methylene chloride, filtrating is concentrated into dried, bullion.
Add the 100ml THF then, the intensification stirring and dissolving adds 20ml ETHYLE ACETATE, and slowly solid is separated out in cooling, yield 87%, and purity 99.5%, quality meet the European Pharmacopoeia standard.
Embodiment 3
In the four-hole bottle that has stirring, inlet pipe, TM, prolong, at N
2Protection add down 10g piperazine oxazolone, 1.2g 65% sodium hydride, 0.17 gram hydrazine hydrogen chloride and 80ml DMSO.Stir, oil bath is heated to 40 ℃, and reaction is 40 minutes under this temperature, adds the 13.5g p-toluenesulfonic esters then, and heat temperature raising to 60 ℃, react 1.5 hours, and TLC monitors no piperazine oxazolone and is reaction end.
Reaction is cooled to 20 ℃, in reaction solution impouring 100ml 10% sodium carbonate solution after finishing; Add 150ml methylene dichloride and layering in separating funnel, organic layer is washed with 100ml 10% sodium carbonate solution, and water is washed till neutrality again; Anhydrous magnesium sulfate drying filters, and drains; Filter cake is used the 10ml eluent methylene chloride, filtrating is concentrated into dried, bullion.
Add the 100ml THF then, the intensification stirring and dissolving adds 20ml ETHYLE ACETATE, and slowly solid is separated out in cooling, yield 89%, and purity 99.0%, quality meet the European Pharmacopoeia standard.
Embodiment 4
In the four-hole bottle that has stirring, inlet pipe, TM, prolong, at N
2Protection add down 10g piperazine oxazolone, 1.7g sodium hydride solid, 0.08 gram hydrazine hydrogen chloride and 80ml DMSO.Stir, oil bath is heated to 60 ℃, and reaction is 20 minutes under this temperature, adds the 18.4g p-toluenesulfonic esters then, and heat temperature raising to 80 ℃, react 0.5 hour, and TLC monitors no piperazine oxazolone and is reaction end.
Reaction is cooled to 20 ℃, in reaction solution impouring 100ml 5% sodium hydroxide solution after finishing; Add 150ml methylene dichloride and layering in separating funnel, organic layer is washed with 100ml 5% sodium hydroxide solution, and water is washed till neutrality again; Anhydrous magnesium sulfate drying filters, and drains; Filter cake is used the 10ml eluent methylene chloride, filtrating is concentrated into dried, bullion.
Add the 40ml methylene dichloride then, the intensification stirring and dissolving adds 120ml ETHYLE ACETATE, and slowly solid is separated out in cooling, yield 91%, and purity 99.2%, quality meet the European Pharmacopoeia standard.
Embodiment 5
In the four-hole bottle that has stirring, inlet pipe, TM, prolong, at N
2Protection add down 10g piperazine oxazolone, 1.3g sodium hydrate solid, 0.56 gram BHT and 80ml DMSO.Stir, oil bath is heated to 60 ℃, and reaction is 20 minutes under this temperature, adds the 18.4g p-toluenesulfonic esters then, and heat temperature raising to 80 ℃, react 0.5 hour, and TLC monitors no piperazine oxazolone and is reaction end.
Reaction is cooled to 20 ℃, in reaction solution impouring 100ml 10% sodium carbonate solution after finishing; Add 150ml methylene dichloride and layering in separating funnel, organic layer is washed with 100ml 10% sodium carbonate solution, and water is washed till neutrality again; Anhydrous magnesium sulfate drying filters, and drains; Filter cake is used the 10ml eluent methylene chloride, filtrating is concentrated into dried, bullion.
Add the 30ml methylene dichloride then, the intensification stirring and dissolving adds 150ml ethanol, and slowly solid is separated out in cooling, yield 88%, and purity 99.1%, quality meet the European Pharmacopoeia standard.
Claims (3)
1. the itraconazole compound method after 20 minutes～40 minutes, adds formula I compound 50 ℃～110 ℃ reactions 0.5 hour～3 hours 30 ℃～60 ℃ reactions with formula II compound, oxidation inhibitor, mineral alkali; The mol ratio of formula II compound and formula I compound is 1: 1.1～1.5; Reaction solvent is selected from DMF, DMA, DMSO or HMPT; Said oxidation inhibitor is selected from Hydrazine Hydrate 80 and salt, mercaptoethanol or BHT; After reaction finishes,, add organic solvent with reaction solution impouring alkali aqueous solution, tell organic layer after, filter, concentrate bullion;
Formula I formula II
Among the formula I, R is selected from methyl, phenyl, to bromophenyl or p-methylphenyl.
2. the described compound method of claim 1, reaction solvent is selected from DMF or DMSO; The mol ratio of formula II compound and oxidation inhibitor is 1: 0.05～0.1.
3. claim 1 or 2 described compound methods, said mineral alkali is selected from sodium hydroxide, Pottasium Hydroxide, sodium hydride, potassium hydride KH, and the mol ratio of formula II compound and mineral alkali is 1: 1.3～1.8.
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| CN101012222A (en) * | 2007-02-13 | 2007-08-08 | 天津力生制药股份有限公司 | Method of synthesizing Itraconazole |
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|---|---|---|---|---|
| CN101012222A (en) * | 2007-02-13 | 2007-08-08 | 天津力生制药股份有限公司 | Method of synthesizing Itraconazole |
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| Title |
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| 贺宝元等.伊曲康唑区域和几何异构体的合成及结构阐明.《中国医药工业杂志》.2003,第34卷(第10期),481-483. * |
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