CN105384600B - A kind of method of industrialized production Butoconazole Nitrate intermediate - Google Patents
A kind of method of industrialized production Butoconazole Nitrate intermediate Download PDFInfo
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- CN105384600B CN105384600B CN201510648562.1A CN201510648562A CN105384600B CN 105384600 B CN105384600 B CN 105384600B CN 201510648562 A CN201510648562 A CN 201510648562A CN 105384600 B CN105384600 B CN 105384600B
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- C07C29/64—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by simultaneous introduction of -OH groups and halogens
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- 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
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Abstract
The present invention relates to a kind of method of chlorine 4 (4 chlorphenyl) 2 butanol of industrialized production Butoconazole Nitrate intermediate 1.It the described method comprises the following steps：(1) iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount is taken, the p-chlorobenzylchloride diethyl ether solution that 35~45 parts of concentration are 0.2~0.4g/ml is slowly added dropwise, drips back flow reaction after finishing, obtains p-chlorobenzylchloride RMgBr；The epoxychloropropane diethyl ether solution that 15~25 parts of concentration are 0.25~0.45g/ml is slowly added dropwise again, drips back flow reaction after finishing, obtains reaction solution；(2) reaction solution obtained by taking step (1), dilute sulfuric acid is added under condition of ice bath, stratification, retains organic phase, concentration, rectifying, produces.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 production technology of Butoconazole Nitrate, and in particular to Butoconazole Nitrate intermediate 1- chloro- 4- (4- chlorobenzenes
Base) -2- butanol production 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, research of the prior art to the medicine focuses mostly in laboratory level, the large-scale production for medicine and
Speech, Butoconazole Nitrate complex manufacturing, the cost of prior art offer are higher, and product yield and purity can not meet industry
The needs of 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 conjunction of Butoconazole Nitrate intermediate 1- chloro- 4- (4- chlorphenyls) -2- butanol
Into method.
The chemical constitution of the chloro- 4- of 1- (4- the chlorphenyls) -2- butanol is as follows.
The method of the invention comprises the following steps：
(1) iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount is taken, 35~45 parts of concentration are slowly added dropwise as 0.2
~0.4g/ml p-chlorobenzylchloride diethyl ether solution, back flow reaction after finishing is dripped, obtains p-chlorobenzylchloride RMgBr；It is slowly added dropwise 15 again~
The epoxychloropropane diethyl ether solution that 25 parts of concentration are 0.25~0.45g/ml, back flow reaction after finishing is dripped, obtains reaction solution；
(2) reaction solution obtained by taking step (1), dilute sulfuric acid is added under condition of ice bath, stratification, retains organic phase, it is dense
Contracting, rectifying, are produced.
Step (1) the of the present invention magnesium powder and the mass volume ratio of initiation ether are 1.5~2.5kg/50ml.
The concentration of step (1) the p-chlorobenzylchloride diethyl ether solution is 0.25~0.3g/ml.
P-chlorobenzylchloride diethyl ether solution, which is slowly added dropwise, described in step (1) is specially：With 2~4ml/s speed at 30~40 DEG C
Degree is added dropwise；The condition of back flow reaction is after the complete p-chlorobenzylchloride diethyl ether solution of drop：Reacted 0.5~1.5 hour at 35~40 DEG C.It is preferred that
Ground, in the step (1), chlorobenzyl chloride diethyl ether solution is added dropwise with 3ml/s speed at 35 DEG C, drop flows back anti-at 37 DEG C after finishing
Answer 1h.
The concentration of step (1) the epoxychloropropane diethyl ether solution is 0.33~0.37g/ml.Drop finishes epoxychloropropane second
The condition of back flow reaction is after ethereal solution：Reacted 1~2 hour at 35~40 DEG C, preferably react 1.5h at 37 DEG C.
The present invention is carried out preferably, acquisition prepares nitre on the basis of being carried out preferably to step (1) to the scheme of step (2)
The preferred scheme of sour butoconazole intermediate 1- chloro- 4- (4- chlorphenyls) -2- butanol.
Specifically, the method for the invention preferably includes following steps：
(1) iodine of 1.5~2.5 parts of magnesium powders, initiation ether and catalytic amount is taken, with 2~4ml/s speed at 30~40 DEG C
The p-chlorobenzylchloride diethyl ether solution that 35~45 parts of concentration are 0.25~0.3g/ml is added dropwise in degree, and drop reacts 0.5 after finishing at 35~40 DEG C
~1.5 hours, obtain p-chlorobenzylchloride RMgBr；The epoxy chloropropionate that 15~25 parts of concentration are 0.33~0.37g/ml is slowly added dropwise again
Alkane diethyl ether solution, drop are reacted 1~2 hour after finishing at 35~40 DEG C, obtain reaction solution；
(2) reaction solution obtained by step (1) is taken, it is dense with 1~3ml/s speed dropwise addition under 0~10 DEG C, at the uniform velocity stirring condition
Spend the sulfuric acid for 24~26%, to without solid residue when stop be added dropwise；8~12min of standing makes liquid after at the uniform velocity stirring 5~15min
Body is layered；Aqueous phase is abandoned, takes organic phase to be concentrated under the conditions of -0.05~0MPa, 50~60 DEG C untill no ether steams, rectifying is received
Collect 160~180 DEG C/10mmHg cut, produce.
Due to being easily introduced a large amount of impurity, including parachlorotoluene, chloromethylbenzene, 1,2- (4- in course of reaction of the present invention
Chlorphenyl) ethane, the chloro- 4- of 1- (4- (chlorine) benzyl) benzene, the chloro- 2- of 3- (4- chlorobenzyls) -1- propyl alcohol, 1,2- (4- chlorphenyls) epoxy
Butane etc., it is necessary to by complexity extraction, purification process can efficiently remove, influence the follow-up mistake of nitric acid synthesis butoconazole
Journey.The structure of the impurity is as shown in table 1.The present invention can be substantially reduced by the optimization to course of reaction and relevant parameter
The generation of the impurity, simplifies purge process, so as to improve the chloro- 4- of intermediate 1- (4- the chlorphenyls) -2- butanol and
The purity and yield of Butoconazole Nitrate finished product.
Table 1：Major impurity in the synthesis of 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
Butoconazole Nitrate intermediate 1- chloro- 4- (4- chlorphenyls) -2- butanol is prepared according to the following steps：
(1) take the iodine of 2kg magnesium powders, 50ml ether and catalytic amount, at 35 DEG C using 3ml/s speed be added dropwise 40kg concentration as
0.27g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 1 hour after finishing at 37 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 37 DEG C after finishing, must reacted
Liquid；
(2) take reaction solution obtained by step (1), under 4 DEG C, at the uniform velocity stirring condition using 2ml/s speed be added dropwise concentration as
25% sulfuric acid, to without solid residue when stop be added dropwise；Standing 10min makes liquid layered after at the uniform velocity stirring 10min；Abandon aqueous phase,
Organic phase is taken to be concentrated under the conditions of -0.01MPa, 55 DEG C untill no ether steams, rectifying collects 160~180 DEG C/10mmHg's
Cut, after drying, produce.
After testing, the yield of the present embodiment product is 84.5%.Target product and impurity are contained using HPLC and standard items
Amount is detected.After testing, the content of the chloro- 4- of target product 1- (4- chlorphenyls) -2- butanol is 95.51%, parachlorotoluene
Content is 2.43%, and the content of chloromethylbenzene is 0.22%, and the content of 1,2- (4- chlorphenyls) ethane is the chloro- 4- of 0.84%, 1-
The content of (4- (chlorine) benzyl) benzene is that the content of the chloro- 2- of 0.18%, 3- (4- chlorobenzyls) -1- propyl alcohol is 0.21%, 1,2- (4- chlorine
Phenyl) epoxy butane content be 0.02%.
Embodiment 2
Compared with Example 1, differ only in, the step (1) is specially：
(1) iodine of 1.5kg magnesium powders, 50ml ether and catalytic amount is taken, 35kg concentration is added dropwise with 2ml/s speed at 30 DEG C
For 0.25g/ml p-chlorobenzylchloride diethyl ether solution, drop is reacted 0.5 hour after finishing at 35 DEG C, obtains p-chlorobenzylchloride RMgBr；Again
The epoxychloropropane diethyl ether solution that 15kg concentration is 0.33g/ml is slowly added dropwise, drop is reacted 1 hour at 35 DEG C after finishing, must reacted
Liquid.
The yield of the present embodiment product is 78.1%.
After testing, the content of the chloro- 4- of target product 1- (4- chlorphenyls) -2- butanol is 90.11%, the content of parachlorotoluene
For 7.51%, the content of chloromethylbenzene is 0.20%, and the content of 1,2- (4- chlorphenyls) ethane is the chloro- 4- (4- of 1.63%, 1-
(chlorine) benzyl) content of benzene is that the content of the chloro- 2- of 0.19%, 3- (4- chlorobenzyls) -1- propyl alcohol is 0.67%, 1,2- (4- chlorobenzenes
Base) epoxy butane content be 0.06%.
Embodiment 3
Compared with Example 1, differ only in, the step (1) is specially：
(1) iodine of 2.5kg magnesium powders, 50ml ether and catalytic amount is taken, 45kg concentration is added dropwise with 4ml/s speed at 40 DEG C
For 0.3g/ml p-chlorobenzylchloride diethyl ether solution, drop is reacted 1.5 hours after finishing at 40 DEG C, obtains p-chlorobenzylchloride RMgBr；Delay again
Slow that the epoxychloropropane diethyl ether solution that 25kg concentration is 0.37g/ml is added dropwise, drop is reacted 2 hours at 40 DEG C after finishing, must reacted
Liquid.
The yield of the present embodiment product is 75.8%.
After testing, the content of the chloro- 4- of target product 1- (4- chlorphenyls) -2- butanol is 83.12%, the content of parachlorotoluene
For 12.33%, the content of chloromethylbenzene is 0.55%, and the content of 1,2- (4- chlorphenyls) ethane is the chloro- 4- (4- of 2.31%, 1-
(chlorine) benzyl) content of benzene is that the content of the chloro- 2- of 0.41%, 3- (4- chlorobenzyls) -1- propyl alcohol is 0.53%, 1,2- (4- chlorobenzenes
Base) epoxy butane content be 0.03%.
Embodiment 4
Compared with Example 1, differ only in：In the step (1), the addition speed of p-chlorobenzylchloride diethyl ether solution is
10ml/s；
After testing, the content of the chloro- 4- of target product 1- (4- chlorphenyls) -2- butanol is 80.25% in products therefrom.
Comparative example 1
Compared with Example 1, differ only in：In the step (1), the concentration of p-chlorobenzylchloride diethyl ether solution is 0.5g/
Ml, the concentration of the epoxychloropropane diethyl ether solution is 0.5g/ml；
After testing, the content of the chloro- 4- of target product 1- (4- chlorphenyls) -2- butanol is 75.33% in products therefrom.
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 (2)
- A kind of 1. method of industrialized production Butoconazole Nitrate intermediate, it is characterised in that the intermediate is the chloro- 4- (4- of 1- Chlorphenyl) -2- butanol, it the described method comprises the following steps：(1) take the iodine of 2kg magnesium powders, 50ml ether and catalytic amount, at 35 DEG C using 3ml/s speed be added dropwise 40kg concentration as 0.27g/ml p-chlorobenzylchloride diethyl ether solution, drop are reacted 1 hour after finishing at 37 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 37 DEG C after finishing, must reacted Liquid；(2) reaction solution obtained by step (1) is taken, concentration is added dropwise as 25% using 2ml/s speed under 4 DEG C, at the uniform velocity stirring condition Sulfuric acid, to without solid residue when stop be added dropwise；Standing 10min makes liquid layered after at the uniform velocity stirring 10min；Aqueous phase is abandoned, is taken organic Mutually it is concentrated under the conditions of -0.01MPa, 55 DEG C untill no ether steams, 160~180 DEG C/10mmHg cut is collected in rectifying, After drying, produce.
- 2. application of claim 1 methods described in industrialized production Butoconazole Nitrate.
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