CN105175341B - A kind of method for industrializing nitric acid synthesis butoconazole intermediate - Google Patents
A kind of method for industrializing nitric acid synthesis butoconazole intermediate Download PDFInfo
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- CN105175341B CN105175341B CN201510648978.3A CN201510648978A CN105175341B CN 105175341 B CN105175341 B CN 105175341B CN 201510648978 A CN201510648978 A CN 201510648978A CN 105175341 B CN105175341 B CN 105175341B
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- 238000000034 method Methods 0.000 title claims abstract description 29
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 230000015572 biosynthetic process Effects 0.000 title abstract description 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 title description 7
- 229960005074 butoconazole Drugs 0.000 title description 7
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 title description 7
- 229910017604 nitric acid Inorganic materials 0.000 title description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 239000000047 product Substances 0.000 claims abstract description 32
- 238000003756 stirring Methods 0.000 claims abstract description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 27
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- ZHPWRQIPPNZNML-UHFFFAOYSA-N butoconazole nitrate Chemical compound O[N+]([O-])=O.C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 ZHPWRQIPPNZNML-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960002120 butoconazole nitrate Drugs 0.000 claims abstract description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000012065 filter cake Substances 0.000 claims abstract description 15
- 238000001556 precipitation Methods 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 11
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 150000002460 imidazoles Chemical class 0.000 claims abstract description 8
- 239000012312 sodium hydride Substances 0.000 claims abstract description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 56
- BTANRVKWQNVYAZ-UHFFFAOYSA-N Sec-butyl alcohol Natural products CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims description 24
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 19
- 239000007787 solid Substances 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- JQZAEUFPPSRDOP-UHFFFAOYSA-N 1-chloro-4-(chloromethyl)benzene Chemical compound ClCC1=CC=C(Cl)C=C1 JQZAEUFPPSRDOP-UHFFFAOYSA-N 0.000 claims description 9
- 238000005119 centrifugation Methods 0.000 claims description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 7
- 230000000977 initiatory effect Effects 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- 239000011777 magnesium Substances 0.000 claims description 5
- 229910052749 magnesium Inorganic materials 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 4
- 238000013517 stratification Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 4
- XVFCQNOEUBBZES-UHFFFAOYSA-N ClC1=CC=C(C=C1)CCC(C)O.[Cl] Chemical compound ClC1=CC=C(C=C1)CCC(C)O.[Cl] XVFCQNOEUBBZES-UHFFFAOYSA-N 0.000 abstract 1
- 239000012535 impurity Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000013067 intermediate product Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- VNBFUGOVQMFIRN-UHFFFAOYSA-N 1-chlorobutan-2-ol Chemical compound CCC(O)CCl VNBFUGOVQMFIRN-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000001273 butane Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 3
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 3
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical class ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005457 optimization Methods 0.000 description 2
- RMVRSNDYEFQCLF-UHFFFAOYSA-N phenyl mercaptan Natural products SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RBACIKXCRWGCBB-UHFFFAOYSA-N 1,2-Epoxybutane Chemical compound CCC1CO1 RBACIKXCRWGCBB-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 208000031872 Body Remains Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 201000007096 Vulvovaginal Candidiasis Diseases 0.000 description 1
- KKWDHUMYGILVHS-UHFFFAOYSA-N [K].C(=O)=O Chemical compound [K].C(=O)=O KKWDHUMYGILVHS-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- -1 p-chlorobenzylchloride grignard Reagent Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a kind of method of industrialized production Butoconazole Nitrate intermediate.It the described method comprises the following steps：(1) using imidazoles and sodium hydride as raw material, cooled down after the heating stirring in DMF solution, fully reaction, 1 chlorine 4 (4 chlorphenyl) 2 butanol are slowly added dropwise, is cooled down after heating stirring, fully reaction, obtains reaction solution；(2) reaction solution obtained by taking step (1), sequentially adds n-hexane and frozen water, is sufficiently stirred, and to stopping filtering after separating out precipitation, washs filter cake, centrifugal drying, is recrystallized, produced with ethyl acetate and activated carbon.Method provided by the invention is comprehensively preferred to the condition during synthesis and parameter progress, improves the purity and yield of product, is more suitable for large-scale industrial production.
Description
Technical field
The present invention relates to the synthesis technique of Butoconazole Nitrate, and in particular to a kind of nitric acid synthesis butoconazole intermediate 1- (2-
Hydroxyl -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles method.
Background technology
Butoconazole Nitrate (Butoconazole nitrate) is a kind of medicine for being clinically used to treat outer vaginal candida
Thing, have the characteristics that evident in efficacy, recurrence rate is low, better tolerance, adverse reaction rate are low.
Butoconazole Nitrate chemical constitution is as follows：
Keith A.M.Walker, Allen C.Braemer are equal to the article " 1- [4- (4- delivered for 1978
Chlorophenyl)-2-(2,6-dichlorophenylthio)-n-butyl]-1H-imidaz ole nitrate,a new
In potent antifungal agent ", the synthetic method of Butoconazole Nitrate is disclosed；In recent years, the scholar such as Zhang Haibo for
The synthetic method of the medicine has also been reported.
The main body synthetic route of Butoconazole Nitrate is as follows：
However, the research of the multipair medicine of prior art focuses mostly in laboratory level, the large-scale production for medicine
For, Butoconazole Nitrate complex manufacturing, the cost of prior art offer are higher, and product yield and purity can not meet work
The needs of industry metaplasia production.
The content of the invention
The purpose of the present invention is the defects of overcoming prior art, by being carried out comprehensively to the condition during synthesis and parameter
Adjustment, there is provided a kind of Butoconazole Nitrate synthetic method for meeting pharmaceutical factory large-scale industrial production needs.
Specifically, the invention provides a kind of Butoconazole Nitrate intermediate 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -
The synthetic method of 1 hydrogen-imidazoles.
The chemical constitution of 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is as follows.
Method provided by the invention comprises the following steps：
(1) using imidazoles and sodium hydride as raw material, cooled down after the heating stirring in DMF solution, fully reaction, 1- is slowly added dropwise
Chloro- 4- (4- chlorphenyls) -2- butanol, heating stirring, cooled down after fully reacting, obtain reaction solution；
(2) reaction solution obtained by taking step (1), sequentially adds n-hexane and frozen water, is sufficiently stirred, to after stopping precipitation precipitation
Filtering, filter cake is washed, centrifugal drying, is recrystallized, produced with ethyl acetate and activated carbon.
The addition of step (2) described n-hexane is the 20~25% of reaction solution weight.
In the step (2), after adding n-hexane, 10~20min is stirred with 1~5 revolutions per second of speed, adds frozen water.
The addition of step (2) described frozen water is the 300~400% of reaction solution weight.
Step (2) is described to be sufficiently stirred specially：Stirred to precipitation with 1~5 revolutions per second of speed and fully separated out.
Step (2) it is described washing filter cake be specially：With the water washing 1~2 time for accounting for 1/3~1/2 times of filter cake weight.It is described from
The heart is dried：With 2500~3000r/min of rotating speed 50~70min of pelleted by centrifugation.
The addition of the ethyl acetate and activated carbon be respectively 2~3 times of centrifugal drying products therefrom weight and 0.04~
0.06 times.The condition of the recrystallization is specially：- 7~-3 DEG C, stand 10~16 hours.
Methods described also includes：At 45~55 DEG C, recrystallization products therefrom is dried.
The present invention is carried out preferably, acquisition prepares nitre on the basis of being carried out preferably to step (2) to the scheme of step (1)
The preferred scheme of sour butoconazole intermediate 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles.
The step (1) is preferably：The sodium hydride DMF solution that 5~9 parts of concentration are 10~30% is taken, under condition of ice bath,
The imidazoles DMF solution that 5~9 parts of concentration are 10~30%, heating stirring reaction is slowly added dropwise；After cooling, 3~7 parts are slowly added to
The chloro- 4- of 1- (4- chlorphenyls) -2- butanol, heating stirring reaction, after cooling, obtains reaction solution.
Specifically, the method for the invention preferably includes following steps：
(1) the sodium hydride DMF solution that 5~9 parts of concentration are 10~30% is taken, under condition of ice bath, with 1~3ml/s speed
The imidazoles DMF solution that 5~9 parts of concentration are 10~30% is added dropwise in degree while stirring, at 58~62 DEG C stirring reaction 55~
65min；After being cooled down with ice salt bath method, 3~7 parts of chloro- 4- of 1- (4- chlorphenyls) -2- butanol are slowly added to, are stirred at 58~62 DEG C
115~125min of reaction is mixed, after being cooled down with ice salt bath method, obtains reaction solution；
(2) take reaction solution obtained by step (1), add the n-hexane for accounting for the reaction solution weight 20~25%, with 1~5 turn/
After the speed of second stirs 10~20min, the frozen water for accounting for the reaction solution weight 300~400% is added, with 1~5 revolutions per second
Speed is stirred to stopping filtering after separating out precipitation, with the water washing filter cake 1~2 time for accounting for 1/3~1/2 times of filter cake weight, with rotating speed
2500~3000r/min pelleted by centrifugation dries 50~70min, with accounting for 2~3 times of the centrifugal drying products therefrom weight respectively
With 0.04~0.06 times of ethyl acetate and activated carbon, stand 10~16 hours at -7~-3 DEG C and recrystallized, 45~55
Recrystallization products therefrom is dried at DEG C, produced.
Due to being easily introduced a large amount of impurity in course of reaction of the present invention, including 1- (the chloro- 4- of 1- (4- chlorphenyls) butane-
2- yls) -1 hydrogen-imidazoles, 4- (4- (1 hydrogen-imidazoles -1- bases) phenyl) chloro- 2- butanol of -1- etc., after influenceing nitric acid synthesis butoconazole
Continuous process.The structure of the impurity is as shown in table 1.The present invention, can be notable by the optimization to course of reaction and relevant parameter
Reduce the generation of the impurity, so as to improve the intermediate 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and
The purity and yield of Butoconazole Nitrate finished product.
Table 1：Major impurity in 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles synthesis
It is of the present invention to be used to produce 1- (2- hydroxyls -4- (4- chlorobenzenes in order to meet the needs of large-scale industrial production
Base) butyl) the chloro- 4- of raw material 1- (4- chlorphenyls) -2- butanol of -1 hydrogen-imidazoles preferably uses chemical synthesis process to produce to obtain, and
The synthesis of follow-up Butoconazole Nitrate is directly used in using the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol for synthesizing gained as intermediate product.
However, in industrialization mass produces, it is easily introduced in the building-up process of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol
A large amount of impurity, including parachlorotoluene, chloromethylbenzene, 1,2- (4- chlorphenyls) ethane, the chloro- 4- of 1- (4- (chlorine) benzyl) benzene, 3- are chloro-
2- (4- chlorobenzyls) -1- propyl alcohol, 1,2- (4- chlorphenyls) epoxy butane etc. are, it is necessary to pass through the extraction of complexity, purification process ability
It is enough efficiently to remove, influence the subsequent process of nitric acid synthesis butoconazole.The structure of the impurity is as shown in table 2.
Table 2：Major impurity in the synthesis of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol
The present invention is in order to improve the yield of finished product Butoconazole Nitrate and purity, 4- (4- chlorobenzenes chloro- to intermediate product 1-
Base) preparation process of -2- butanol is optimized.By the optimization to above-mentioned course of reaction and relevant parameter, can significantly subtract
The generation of few impurity, simplifies purge process, to improve the pure of the chloro- 4- of intermediate 1- (4- the chlorphenyls) -2- butanol
Degree and yield, so as to improve the quality of Butoconazole Nitrate finished product.
Specifically, the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol can be prepared by the method comprised the following steps：
Take the iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount, be slowly added dropwise 35~45 parts of concentration for 0.2~
0.4g/ml p-chlorobenzylchloride diethyl ether solution, back flow reaction after finishing is dripped, obtains p-chlorobenzylchloride RMgBr；15~25 are slowly added dropwise again
The epoxychloropropane diethyl ether solution that part concentration is 0.25~0.45g/ml, drips back flow reaction after finishing, obtains reaction solution；In condition of ice bath
It is lower be slowly added dropwise into the reaction solution concentration be 20~30% sulfuric acid, to without solid residue when stop be added dropwise；Stratification,
Aqueous phase is abandoned, organic phase is concentrated, rectifying, obtains the chloro- 4- of intermediate product 1- (4- chlorphenyls) -2- butanol.
Preferably, the chloro- 4- of the 1- (4- chlorphenyls) -2- butanol can be prepared by the method comprised the following steps：
Take 1.5~2.5 parts of magnesium powders, the ether of initiating amount and the iodine of catalytic amount, the magnesium powder and the quality of initiation ether
Volume ratio is 1.5~2.5kg/50ml；At 30~40 DEG C using 2~4ml/s speed be added dropwise 35~45 parts of concentration as 0.25~
0.3g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 0.5~1.5 hour after finishing at 35~40 DEG C, obtain the examination of p-chlorobenzylchloride grignard
Agent；The epoxychloropropane diethyl ether solution that 15~25 parts of concentration are 0.33~0.37g/ml is slowly added dropwise again, 35~40 after drop is complete
Reacted 1~2 hour at DEG C, obtain reaction solution；With 1~3ml/s speed to the reaction under 0~10 DEG C, at the uniform velocity stirring condition
In liquid be added dropwise concentration be 24~26% sulfuric acid, to without solid residue when stop be added dropwise；At the uniform velocity stir 5~15min after stand 8~
12min makes liquid layered；Abandon aqueous phase, take organic phase be concentrated under the conditions of -0.05~0MPa, 50~60 DEG C no ether steam for
Only, 160~180 DEG C/10mmHg cut is collected in rectifying, obtains the chloro- 4- of 1- (4- chlorphenyls) -2- butanol.
The method of the invention may be directly applied to industrialized production Butoconazole Nitrate.Specifically, Butoconazole Nitrate
Can be by including being synthesized the step of being carried out continuously described in following S1~S4：
S1：Take 1.5~2.5 parts of magnesium powders, the ether of initiating amount and the iodine of catalytic amount, the magnesium powder and the matter of initiation ether
Amount volume ratio is 1.5~2.5kg/50ml；35~45 parts of concentration are added dropwise as 0.25 using 2~4ml/s speed at 30~40 DEG C
~0.3g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 0.5~1.5 hour after finishing at 35~40 DEG C, obtain p-chlorobenzylchloride grignard
Reagent；Be slowly added dropwise the epoxychloropropane diethyl ether solution that 15~25 parts of concentration are 0.33~0.37g/ml again, drop finish after 35~
Reacted 1~2 hour at 40 DEG C, obtain reaction solution；With 1~3ml/s speed to described anti-under 0~10 DEG C, at the uniform velocity stirring condition
Answer in liquid be added dropwise concentration be 24~26% sulfuric acid, to without solid residue when stop be added dropwise；8 are stood after at the uniform velocity stirring 5~15min
~12min makes liquid layered；Aqueous phase is abandoned, takes organic phase to be concentrated into no ether under the conditions of -0.05~0MPa, 50~60 DEG C and steams
Untill, 160~180 DEG C/10mmHg cut is collected in rectifying, obtains the chloro- 4- of intermediate product 1- (4- chlorphenyls) -2- butanol；
S2：The sodium hydride DMF solution of concentration 10~30% is taken, under condition of ice bath, is stirred with 1~3ml/s speed side
The imidazoles DMF solution of concentration 10~30% is added dropwise in side, 55~65min of stirring reaction at 58~62 DEG C, is cooled down with ice salt bath method
Afterwards, be slowly added to 1- chloro- 4- (4- chlorphenyls) -2- butanol obtained by step S1, the sodium hydride DMF solution, imidazoles DMF solution with
The weight ratio of the chloro- 4- of 1- (4- chlorphenyls) -2- butanol is 5~9：5~9：3~7；At 58~62 DEG C stirring reaction 115~
125min, after being cooled down with ice salt bath method, obtain reaction solution；Added in the reaction solution and account for the reaction solution weight 20~25%
N-hexane, after stirring 10~20min with 1~5 revolutions per second of speed, add the ice for accounting for the reaction solution weight 300~400%
Water, stirred to stopping filtering after separating out precipitation with 1~5 revolutions per second of speed, filtered with the water washing for accounting for 1/3~1/2 times of filter cake weight
Cake 1~2 time, 50~70min is dried with 2500~3000r/min of rotating speed pelleted by centrifugation, with accounting for respectively obtained by the centrifugal drying
The ethyl acetate and activated carbon that 2~3 times and 0.04~0.06 times of products weight, stand 10~16 hours at -7~-3 DEG C and carry out weight
Crystallization, recrystallization products therefrom is dried at 45~55 DEG C, obtains intermediate product 1- (2- hydroxyls -4- (4- chlorphenyls) fourths
Base) -1 hydrogen-imidazoles；
S3：By the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles with weight than 2~5：25~35 dissolvings
In dichloromethane, at 15~25 DEG C with 1~2ml/s speed be added dropwise with the 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -
1 hydrogen-imidazoles weight ratio is 2~5：2~5 thionyl chloride, is to slowly warm up to 30~35 DEG C, insulation reaction 0.5~1.5 hour,
Again in 55~65 DEG C of back flow reactions 0.5~1.5 hour, less than 20 DEG C are slowly cooled to, obtains reaction solution；The side in the reaction solution
Stir side and water of the temperature not higher than 20 DEG C is added with 0.1~1ml/s speed, the volume ratio of the reaction solution and water is 0.004
~0.006：1, then natrium carbonicum calcinatum is added with 1.0~1.5kg/L, filter, abandon solid, filtrate is concentrated at 50~60 DEG C
Untill being steamed without dichloromethane, dry, obtain intermediate product 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles；
S4：By the 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles and 2,6- thiophenol dichlorobenzenes, Carbon Dioxide
Potassium and acetone are with weight ratio 4~6：4~6：1~4：30~50 mixing, back flow reaction 4.5~5.5 hours at 55~65 DEG C, are mended
It is 0.5~1 to add with the 1- (the chloro- 4- of 2- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles weight ratio：4~6 Anhydrous potassium carbonate,
Back flow reaction 6.5~7.5 hours at 55~65 DEG C, with 0~4 DEG C of recirculated water Slow cooling, in 2800~2900r/min conditions
10~30min of lower centrifugation, solid is abandoned, retain liquid, as filtrate；No acetone is concentrated the filtrate at 55~65 DEG C to steam,
Obtain concentrate；The extract for accounting for 6~10 times of its weight is added in the concentrate, it is 2 that weight ratio is included in the extract
~3：1~3：1~2 ether, acetone and water；After stirring 5~15min under conditions of not higher than 20 DEG C, stand, abandon aqueous phase,
Retain organic phase；It is dense with 1~3ml/s speed dropwise addition in the organic phase under ice bath, 1~2 revolutions per second of stirring condition
Spend the nitric acid for 65~70%, to stop generation precipitation after under conditions of 2800~2900r/min of rotating speed centrifugation 20~
40min, filtrate is abandoned, retain solid；Be sufficiently stirred after the filter cake is mixed with the ether of 3~4 times of weight, rotating speed 2800~
20~40min is centrifuged under conditions of 2900r/min, abandons liquid, retains solid；The solid retained after ether is washed and 6~8 times
It is sufficiently stirred after the acetone mixing of weight, 20~40min is centrifuged under conditions of 2800~2900r/min of rotating speed, abandons liquid, is protected
Solid is stayed, is dried 3~7 hours under the conditions of 45~55 DEG C, -0.5~0.5Mpa, produces Butoconazole Nitrate.
Method provided by the invention is easy to operate, and raw material and dosage are reasonable, reduce potential safety hazard；Gained Butoconazole Nitrate
The yield and purity of intermediate are higher, can avoid the generation of plurality of impurities, it is ensured that nitric acid synthesis butoconazole subsequent step is suitable
Profit carries out and the quality of end-product Butoconazole Nitrate, suitable for large-scale industrial production.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1
1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is prepared according to following steps：
(1) the sodium hydride DMF solution that 7kg concentration is 20% is taken, under condition of ice bath, with 2ml/s speed while stirring
The imidazoles DMF solution that 7kg concentration is 20%, the stirring reaction 60min at 60 DEG C is added dropwise；After being cooled down with ice salt bath method, slowly add
Enter the chloro- 4- of 5kg1- (4- chlorphenyls) -2- butanol, the stirring reaction 120min at 60 DEG C, after being cooled down with ice salt bath method, must react
Liquid；
(2) reaction solution obtained by step (1) is taken, the n-hexane for accounting for the reaction solution weight 25% is added, with 3 revolutions per seconds of speed
After degree stirring 15min, the frozen water for accounting for the reaction solution weight 350% is added, is stirred to stopping and separated out with 3 revolutions per seconds of speed
Filter after precipitation, with the water washing filter cake 1 time for accounting for 1/3 times of filter cake weight, dried with rotating speed 2825r/min pelleted by centrifugation
60min, with the ethyl acetate and activated carbon for accounting for 2.5 times and 0.05 times of the centrifugal drying products therefrom weight respectively, at -5 DEG C
Stand 13 hours to be recrystallized, recrystallization products therefrom is dried at 50 DEG C, produced.
After testing, the yield of the present embodiment product is 71.4%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, the content of target product 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is
The content of 99.31%, 1- (the chloro- 4- of 1- (4- chlorphenyls) butane -2- bases) -1 hydrogen-imidazoles be 0.57%, 4- (4- (1 hydrogen-imidazoles -
1- yls) phenyl) the chloro- 2- butanol of -1- content be 0.08%.
Embodiment 2
Compared with Example 1, differ only in, the step (2) is specially：
(2) reaction solution obtained by step (1) is taken, the n-hexane for accounting for the reaction solution weight 20% is added, with 1 revolutions per second of speed
After degree stirring 10min, the frozen water for accounting for the reaction solution weight 300% is added, is stirred to stopping and separated out with 1 revolutions per second of speed
Filter after precipitation, with the water washing filter cake 1 time for accounting for 1/3 times of filter cake weight, dried with rotating speed 2825r/min pelleted by centrifugation
50min, it is quiet at -7 DEG C with the ethyl acetate and activated carbon for accounting for 2 times and 0.04 times of the centrifugal drying products therefrom weight respectively
Put 10 hours and recrystallized, recrystallization products therefrom is dried at 45 DEG C, produced.
After testing, the yield of the present embodiment product is 69.31%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, the content of target product 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is
The content of 98.55%, 1- (the chloro- 4- of 1- (4- chlorphenyls) butane -2- bases) -1 hydrogen-imidazoles be 0.93%, 4- (4- (1 hydrogen-imidazoles -
1- yls) phenyl) the chloro- 2- butanol of -1- content be 0.12%.
Embodiment 3
Compared with Example 1, differ only in, the step (2) is specially：
(2) reaction solution obtained by step (1) is taken, the n-hexane for accounting for the reaction solution weight 25% is added, with 5 revolutions per seconds of speed
After degree stirring 20min, the frozen water for accounting for the reaction solution weight 400% is added, is stirred to stopping and separated out with 5 revolutions per seconds of speed
Filter after precipitation, with the water washing filter cake 2 times for accounting for 1/2 times of filter cake weight, dried with rotating speed 2825r/min pelleted by centrifugation
70min, it is quiet at -3 DEG C with the ethyl acetate and activated carbon for accounting for 3 times and 0.06 times of the centrifugal drying products therefrom weight respectively
Put 16 hours and recrystallized, recrystallization products therefrom is dried at 55 DEG C, produced.
After testing, the yield of the present embodiment product is 68.18%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, the content of target product 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is
The content of 99.13%, 1- (the chloro- 4- of 1- (4- chlorphenyls) butane -2- bases) -1 hydrogen-imidazoles be 0.61%, 4- (4- (1 hydrogen-imidazoles -
1- yls) phenyl) the chloro- 2- butanol of -1- content be 0.07%.
Embodiment 4
Compared with Example 1, differ only in：In the step (2), addition accounts for reaction solution weight obtained by step (1)
50% n-hexane, after 10 revolutions per seconds of speed stirring 15min, the frozen water for accounting for the reaction solution weight 200% is added, with
10 revolutions per seconds of speed stirs to stopping and separates out precipitation.
After testing, the yield of products therefrom is 58.67%, target product 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1
The content of hydrogen-imidazoles is 99.08%.
Embodiment 5
Compared with Example 1, differ only in：In the step (2), centrifugal drying is to be centrifuged with rotating speed 2000r/min
90min。
After testing, the content of target product 1- (2- hydroxyls -4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles is in products therefrom
82.69%.
Embodiment 6
1- chloro- 4- (4- chlorphenyls) -2- butanol is prepared using following methods：
Take the iodine of 2.5kg magnesium powders, 50ml ether and catalytic amount, at 35 DEG C using 3ml/s speed be added dropwise 40kg concentration as
0.28g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 1 hour after finishing at 38 DEG C, obtain p-chlorobenzylchloride RMgBr；It is slow again
The epoxychloropropane diethyl ether solution that 20kg concentration is 0.35g/ml is added dropwise, drop is reacted 1.5 hours at 38 DEG C after finishing, must reacted
Liquid；Concentration is added dropwise as 25% sulfuric acid into the reaction solution using 2ml/s speed under 4 DEG C, at the uniform velocity stirring condition, to without solid
Stop being added dropwise when body remains；Standing 10min makes liquid layered after at the uniform velocity stirring 10min；Abandon aqueous phase, take organic phase-
0.01MPa, it is concentrated under the conditions of 55 DEG C untill no ether steams, 160~180 DEG C/10mmHg cut is collected in rectifying, is dried
Afterwards, the chloro- 4- of 1- (4- chlorphenyls) -2- butanol is obtained, purity 95.51%,
It is used for embodiment 1~5 using the chloro- 4- of the 1- (4- chlorphenyls) -2- butanol as raw material.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (3)
- A kind of 1. method of industrialized production Butoconazole Nitrate intermediate, it is characterised in that the intermediate be 1- (2- hydroxyls- 4- (4- chlorphenyls) butyl) -1 hydrogen-imidazoles, it the described method comprises the following steps：(1) the sodium hydride DMF solution for taking 5~9 parts of concentration to be 10~30%, under condition of ice bath, is slowly added dropwise 5~9 parts of concentration For 10~30% imidazoles DMF solution, heating stirring reaction；After cooling, be slowly added to 3~7 parts of chloro- 4- of 1- (4- chlorphenyls)- 2- butanol, heating stirring reaction, after cooling, obtains reaction solution；(2) reaction solution obtained by taking step (1), sequentially adds n-hexane and frozen water, the addition of the n-hexane is reaction solution weight The 20~25% of amount, after adding n-hexane, 10~20min is stirred with 1~5 revolutions per second of speed, adds and accounts for reaction solution weight 300~400% frozen water, stirred to precipitation with 1~5 revolutions per second of speed and fully separated out, to stopping filtering after separating out precipitation, washed Filter cake is washed, with 2500~3000r/min of rotating speed 50~70min of pelleted by centrifugation, is added equivalent to centrifugal drying products therefrom weight The ethyl acetate and activated carbon of 0.04~0.06 times equivalent to centrifugal drying products therefrom weight of 2~3 times of amount, at -7~-3 DEG C Stand 10~16 hours and recrystallize, produce.
- 2. according to the method for claim 1, it is characterised in that the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol by including with The method of lower step is prepared：The iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount is taken, it is 0.2~0.4g/ that 35~45 parts of concentration, which are slowly added dropwise, Ml p-chlorobenzylchloride diethyl ether solution, back flow reaction after finishing is dripped, obtains p-chlorobenzylchloride RMgBr；15~25 parts of concentration are slowly added dropwise again For 0.25~0.45g/ml epoxychloropropane diethyl ether solution, back flow reaction after finishing is dripped, obtains reaction solution；To institute under condition of ice bath State be slowly added dropwise in reaction solution concentration be 20~30% sulfuric acid, to without solid residue when stop be added dropwise；Stratification, abandon water Phase, organic phase is concentrated, rectifying, obtain the chloro- 4- of 1- (4- chlorphenyls) -2- butanol.
- 3. application of the methods described of claim 1 or 2 in industrialized production Butoconazole Nitrate.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005070897A1 (en) * | 2004-01-27 | 2005-08-04 | Richter Gedeon Vegyészeti Gyár Rt. | High purity butoconazole nitrate with specified particle size and a process for preparation thereof |
| CN101328110A (en) * | 2007-06-20 | 2008-12-24 | 北京德众万全药物技术开发有限公司 | Preparation of butoconazole nitrate intermediate |
| US20090176831A1 (en) * | 2007-06-14 | 2009-07-09 | Osta Biotechnologies | Compounds and Methods for Treating Cancer and Diseases of the Central Nervous System |
| CN103880596A (en) * | 2012-12-21 | 2014-06-25 | 凌沛学 | Preparation method of butoconazole nitrate intermediate suitable for industrial production |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005070897A1 (en) * | 2004-01-27 | 2005-08-04 | Richter Gedeon Vegyészeti Gyár Rt. | High purity butoconazole nitrate with specified particle size and a process for preparation thereof |
| US20090176831A1 (en) * | 2007-06-14 | 2009-07-09 | Osta Biotechnologies | Compounds and Methods for Treating Cancer and Diseases of the Central Nervous System |
| CN101328110A (en) * | 2007-06-20 | 2008-12-24 | 北京德众万全药物技术开发有限公司 | Preparation of butoconazole nitrate intermediate |
| CN103880596A (en) * | 2012-12-21 | 2014-06-25 | 凌沛学 | Preparation method of butoconazole nitrate intermediate suitable for industrial production |
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