CN107759509A - A kind of synthetic method of tropicamide - Google Patents
A kind of synthetic method of tropicamide Download PDFInfo
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- CN107759509A CN107759509A CN201711037123.2A CN201711037123A CN107759509A CN 107759509 A CN107759509 A CN 107759509A CN 201711037123 A CN201711037123 A CN 201711037123A CN 107759509 A CN107759509 A CN 107759509A
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
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Abstract
The present invention relates to a kind of production method of chemicals, more particularly to a kind of synthetic method of tropicamide, using phenyl ethyl malonate as raw material; after hydrolysis and acylation; after being condensed with the picoline amine of N ethyls 4, reduction reaction occurs with boron hydride, tropicamide is made.The cost of material that synthetic method provided by the invention uses is low, and intermediate product property is stable, and impurity is few, reduces the operating procedures such as purifying, simplifies technique；Reaction condition is safe, gentle, does not introduce extremely toxic substance, is advantageous to industry's enlarging production；By the optimization to raw material proportioning, the total recovery of reaction has been brought up to 65%, substantially increase yield, reduce production cost.
Description
Technical field
The present invention relates to chemical medicine field, and in particular to a kind of synthetic method of compound, more particularly to a kind of tropine
The synthetic method of acid amides.
Background technology
Tropicamide is anticholinergic agent, is parasympathetic nerve depressant, is used in field of ophthalmology for funduscopy and diagnosis
Preferred mydriatic, also ciliary muscle anesthesia effect.Nineteen fifty-five is synthesized first by Roche companies, is concealed in U.S.'s medicine respectively
In allusion quotation, British Pharmacopoeia and Japanese Pharmacopoeia.Clinically in addition to being used alone, used more with compound formulation.The towering pharmacy strain of Japan
Formula commercial firm is using 0.5% tropicamide and the compound formulation of 0.5% PHENYLEPHRINE HYDROCHLORIDE.The knot of tropicamide and atropine
Structure is similar, thus checks that eyeground, rainbow membranous body are scorching applied to clinic, such as mydriasis with the similar pharmacology of atropine
Deng.According to external clinical report, 10min starts mydriasis after tropicamide eye droppings, and 15-20min pupils footpath reaches maximum, sustainable
1.5h, 5-8h are resilient.Tropicamide has many advantages, such as mydriasis is rapid, and convalescence is short compared to other mydriatics.Tropoyl
The physicochemical property of amine：White crystals are in powdered, bitter, are dissolved in ethanol, chloroform and acetone, are slightly soluble in water, insoluble in petroleum ether,
This product aqueous solution (1: 500) 6.5<pH<8.0,96-100 DEG C of fusing point.
The A of CN 103159672 disclose a kind of preparation method of tropicamide, which solve intermediate product stability difference
Problem, but yield rate is relatively low (maintaining essentially in less than 50%), the impurity of intermediate reaction is more, is significantly increased during for producing
Cost, it is not easy promotion and application.
The content of the invention
In order to solve the above technical problems, the invention provides a kind of synthetic method of tropicamide, the total recovery of reaction carries
Up to 65%, reaction condition is gentle, and production cost is greatly reduced.
For up to this purpose, present invention employs following technical scheme：
The present invention provides a kind of synthetic method of tropicamide, and methods described is using phenyl ethyl malonate as raw material, warp
After hydrolyzing and being acylated, after being condensed with N- ethyl -4- picolines amine, reduction reaction occurs with boron hydride, tropicamide is made；
Wherein, the mol ratio of the phenyl ethyl malonate, N- ethyls -4- picolines amine and boron hydride is 1:
(2-10):(4-30), for example, it may be 1:2:4、1:3:4、1:4:5、1:5:6、1:6:7、1:7:8、1:8:9、1:9:10、1:
10:11、1:3:5、1:4:6、1:7:5 or 1:5:4 and all point values for including of above range, it will not enumerate herein.
Inventor has found, if total recovery can be not only greatly reduced by adding excessive reaction raw materials, can also produce it is more in
Between product, it is necessary to increase purifying filtration step.Therefore, the present invention passes through lot of experiments, draws said ratio, makes total receipts of reaction
Rate reaches metastable higher level, maintains essentially in 55-62%, reaches as high as 65% or so.If limited beyond the present invention
Scope, total recovery substantially reduces, and causes the harmful effects such as the waste of reaction raw materials.
Preferably, the mol ratio of phenyl ethyl malonate, N- ethyls -4- picolines amine and boron hydride is：1:(2-
6):(4-20), preferably 1:(2-3):(5-10), for example, it may be 1:2:4、1:3:4、1:4:5、1:5:6、1:6:7、1:2:
8、1:3:9、1:4:10、1:2:11、1:3:5、1:4:6、1:4:5 or 1:5:4 and all point values for including of above range, herein not
Enumerate again.
Preferably, the described method comprises the following steps：
1) using phenyl ethyl malonate as raw material, hydrolysis occurs in basic solvent, obtains intermediate product A；
2) with thionyl chloride and/or thionyl chloride acylation reaction occurs for intermediate product A, obtains intermediate product B；
3) with N- ethyl -4- picolines amine condensation reaction occurs for intermediate product B, obtains intermediate product C；
4) with boron hydride reduction reaction occurs for intermediate product C, and tropicamide is made.
The synthetic line of the present invention is by raw material of phenyl ethyl malonate by hydrolysis, and acylated, condensation, reduction is made
Tropicamide, it is specific as follows shown：
Preferably, the step 1) basic solvent is inorganic base solvent, and the inorganic base is preferably NaOH, Na2CO3、KOH
Or K2CO3In any one or at least two mixture, such as can be NaOH and Na2CO3Mixture, Na2CO3、KOH
And K2CO3Mixture and all possible combination of above-mentioned four kinds of materials, will not enumerate herein.
Preferably, the pH of the step 1) hydrolysis is 8-12, preferably 8.5-10, for example, can be 8.1,8.2,
8.3rd, 8.4,8.5,8.6,8.7,8.7,8.9,9,9.5,10,10.5,11,11.5,12 and its comprising all point values, herein not
Enumerate again.
Preferably, the temperature of the step 1) hydrolysis is 0-35 DEG C, for example, can be 1 DEG C, 2 DEG C, 3 DEG C, 4 DEG C, 5
DEG C, 6 DEG C, 7 DEG C, 8 DEG C, 9 DEG C, 11 DEG C, 15 DEG C, 21 DEG C, 25 DEG C, 30 DEG C, 35 and its comprising all point values, herein no longer one by one
Enumerate, preferably 10-20 DEG C.
Preferably, the time of the step 1) hydrolysis is 0.5-8h, for example, can be 0.6h, 1h, 1.5h, 2h,
2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h and its comprising all point values, no longer arrange one by one herein
Lift, preferably 2-6h.
After the completion of reaction, after adding ethyl acetate extraction, layering, collection organic phase, concentration is dried, obtains the centre of solid-state
Product A.
Preferably, the mol ratio of phenyl ethyl malonate and inorganic base is 1 in step 1):(2-8), for example, it may be
1:2.5、1:3.5、1:4、1:4.5、1:5、1:5.5、1:6.5、1:7、1:7.5 and its comprising all point values, it is not another herein
One enumerates, and preferably 1:(3-6).
Preferably, the step 2) acylation reaction is carried out in a solvent, and the solvent is dichloromethane, tetrahydrofuran, chlorine
In imitative or inorganic solvent any one or at least two mixed solvent, such as can be dichloromethane and chloroform mixing it is molten
Agent, the mixed solvent of tetrahydrofuran, chloroform and inorganic solvent, or dichloromethane, tetrahydrofuran, chloroform and inorganic solvent it is mixed
The all possible combination of bonding solvent and above-mentioned solvent, will not enumerate herein as space is limited,.
Preferably, the inorganic solvent is NaOH, K2CO3、Na2CO3In any one or at least two mixing it is molten
Agent, such as can be NaOH and K2CO3Mixed solvent, or NaOH, K2CO3And Na2CO3Mixed solvent and above-mentioned solvent
All possible combination, will not enumerate herein as space is limited,.
Preferably, step 2) the intermediate product A and the mol ratio of thionyl chloride and/or thionyl chloride are 1:(2-20),
Preferably 1:(3-9), such as can be 1:4、1:5、1:6、1:7、1:8、1:10、1:11、1:12、1:13、1:14、1:15 or 1:
19 and above range within all point value, will not enumerate herein.
Preferably, the temperature of the step 2) acylation reaction is 0-60 DEG C, preferably 5-40 DEG C, for example, can be 1 DEG C, 2
DEG C, 3 DEG C, 4 DEG C, 5 DEG C, 6 DEG C, 7 DEG C, 8 DEG C, 9 DEG C, 10 DEG C, 15 DEG C, 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 45 DEG C, 50 DEG C or 55 DEG C
And all point value within above range, it will not enumerate herein.
Preferably, the time of the step 2) acylation reaction is 2-22h, for example, can be 3h, 4h, 6h, 7h, 8h, 9h,
All point values, will not enumerate, preferably 5-15h herein in 12h, 14h, 16h, 18h or 20h and above range.Instead
After the completion of answering, unnecessary thionyl chloride and/or thionyl chloride is removed under reduced pressure, residue is used for the reaction of step 3).
Preferably, the step 3) condensation reaction is carried out in a solvent, and the solvent is pyridine, dichloromethane, tetrahydrochysene furan
Mutter, in chloroform or inorganic solvent any one or at least two mixed solvent, such as can be pyridine, dichloromethane and four
The inorganic solvent such as the mixed solvent of hydrogen furans, tetrahydrofuran, the mixed solvent of chloroform and inorganic solvent or simple water, and
The all possible combination of above-mentioned solvent, will not enumerate herein as space is limited,.
Preferably, the mol ratio of intermediate product B and N- ethyl -4- picoline amine is 1:(1.5-6), preferably 1:(3-
5), such as can be 1:1,6、1:1.7、1:1.8、1:1.9、1:2、1:2.5、1:3.5、1:4、1:4.5 or 1:5.5 and above-mentioned
In the range of all point value, will not enumerate herein；N- ethyl -4- picoline amine is first is dissolved in institute by concrete operation method
State in solvent, form mixture 1, then mixture 1 is added drop-wise in intermediate product B, because mixture 1 easily decomposes, therefore drip
Acceleration be not easy it is too fast, and temperature be not easy it is too high.After the completion of reaction, it is extracted with ethyl acetate, collects organic phase, dries, concentration,
Obtain intermediate product C.
Preferably, the temperature of the step 3) condensation reaction is 5-20 DEG C, preferably 10-15 DEG C, for example, can be 6 DEG C, 7
DEG C, 8 DEG C, 9 DEG C, 11 DEG C, 12 DEG C, 13 DEG C, 15 DEG C, 16 DEG C, 17 DEG C, point value all in 18 DEG C or 19 DEG C and above range,
It will not enumerate herein.
Preferably, the time of the step 3) condensation reaction is 1-20h, preferably 5-15h, for example, can be 2h, 3h,
All point values, will not enumerate herein in 4h, 6h, 7h, 8h, 9h, 12h, 14h, 16h, 18h or 19h and above range.
Preferably, the mol ratio of the intermediate product C in step 4) and boron hydride is 1:(1.5-5.5), preferably 1:(2-
4), such as can be 1:3、1:3.5、1:4.5 or 1:5 and above range in all point value, will not enumerate herein.
Preferably, the boron hydride is any one in hydroboration manganese, calcium borohydride, sodium borohydride or potassium borohydride
Or at least two mixture, such as can be mixture, calcium borohydride, sodium borohydride and the boron of hydroboration manganese and calcium borohydride
The mixture of hydrofining, or hydroboration manganese, calcium borohydride, the mixture of sodium borohydride and potassium borohydride, and above-mentioned boron hydrogen
The all possible combination of compound, will not enumerate herein as space is limited,.
Preferably, the pH of the step 4) reduction reaction is 7.5-10.5, preferably 9-10, for example, can be 7.6,7.7,
7.8th, 7.9,8,8.5 or 9.5 and above range in all point value, will not enumerate herein.
Preferably, the temperature of the reduction reaction is -8-70 DEG C, for example, can be -7 DEG C, -6 DEG C, -3 DEG C, -1 DEG C, 0 DEG C,
Own in 5 DEG C, 10 DEG C, 15 DEG C, 20 DEG C, 25 DEG C, 30 DEG C, 35 DEG C, 40 DEG C, 45 DEG C, 55 DEG C, 60 DEG C or 65 DEG C and above range
Point value, will not enumerate herein, be preferably -5-50 DEG C.
Preferably, the time of the reduction reaction is 2-22h, for example, can be 3h, 4h, 6h, 7h, 8h, 9h, 12h, 14h,
All point values, will not enumerate, preferably 5-15h herein in 16h, 18h or 20h and above range.
Preferably, the step 4) reduction reaction is carried out in organic solvent.
Preferably, the described method comprises the following steps：
1) using phenyl ethyl malonate as raw material, hydrolysis occurs in inorganic base solvent, obtains intermediate product A,
Wherein, the pH of hydrolysis is 8-12, and temperature is 0-35 DEG C, time 0.5-8h, phenyl ethyl malonate and inorganic base
Mol ratio is 1:(2-8)；
2) intermediate product A carries out acylation reaction in a solvent with thionyl chloride and/or thionyl chloride, obtains intermediate product B,
Wherein, the solvent is molten for any one in dichloromethane, tetrahydrofuran, chloroform or inorganic solvent or at least two mixing
Agent, intermediate product A are 1 with the mol ratio of thionyl chloride and/or thionyl chloride:(2-20), the temperature of the acylation reaction is 0-
60 DEG C, time 2-22h；
3) with N- ethyl -4- picoline amine condensation reaction occurs in a solvent for intermediate product B, obtains intermediate product C, its
In, the solvent be in pyridine, dichloromethane, tetrahydrofuran, chloroform or inorganic solvent any one or at least two it is mixed
The mol ratio of bonding solvent, the intermediate product B and N- ethyl -4- picoline amine is 1:(1.5-6), the temperature of the condensation reaction
Spend for 5-20 DEG C, time 1-20h；
4) with boron hydride reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, wherein, it is described
Boron hydride is the mixture of any one or at least two in hydroboration manganese, calcium borohydride, sodium borohydride or potassium borohydride,
The pH of the reduction reaction is 7.5-10.5, and temperature is -8-70 DEG C, time 2-22h.
Preferably, after the step 4) reduction reaction, in addition to the step of separation and Extraction tropicamide.
Preferably, the step of separation and Extraction tropicamide specifically includes：
A) gained feed liquid after reduction reaction is gone in separation and Extraction tank, after adding watery hydrochloric acid and/or ethyl acetate, point
Go out organic solvent layer, water layer chloroform recovery, merge chloroform and organic solvent, use anhydrous Na2SO4It is dried overnight, obtains solution D；
B) solution D sealing decompression is steamed into chloroform, steams sticky to feed liquid, obtain feed liquid E；
C) feed liquid E is ground, until separating out crystallization F；
D) filtering for crystallizing F, it is washed out, dries, obtain tropicamide.
Preferably, the temperature that decompression steams chloroform in step b) is 20-60 DEG C, for example, can be 25 DEG C, 30 DEG C, 35 DEG C,
All possible point value in 45 DEG C or 55 DEG C and above range, will not enumerate, preferably 40-50 DEG C, to prevent temperature herein
Height is spent, tropicamide easily decomposes, and influences yield rate.
Preferably, step c) is described is ground to：Feed liquid E and ethyl acetate are added into mortar to be ground, prevent nature knot
Crystalline substance forms lump, is not easy to filter, therefore is preferably ground to crystal precipitation.
Preferably, the step d) washings are to be washed with ethyl acetate.
Preferably, the temperature dried in step d) is less than 35 DEG C, preferably 20-30 DEG C, for example, can be 25 DEG C, 15
DEG C, 12 DEG C, 11 DEG C, all optional point values such as 10 DEG C or 5 DEG C, will not enumerate herein.
Compared with prior art, synthetic method provided by the invention at least has the advantages that：
(1) cost of material that synthetic method provided by the invention uses is low, cheap and easy to get, and intermediate product property is stable, secondary
Product and impurity are few, and are easy to remove, and reduce the operating procedures such as purifying, simplify technique；Eliminate toxicity caused by residue
With the influence to end-product tropicamide；
(2) reaction condition is safe, gentle, does not introduce extremely toxic substance, is advantageous to industry's enlarging production；
(3) by the optimization to raw material proportioning, the total recovery of reaction has been brought up to 65%, substantially increase yield, drop
Low production cost.
Embodiment
For ease of understanding the present invention, it is as follows that the present invention enumerates embodiment.Those skilled in the art are it will be clearly understood that the implementation
Example is only to aid in understanding the present invention, is not construed as the concrete restriction to the present invention.
Embodiment 1
1) using 10mol phenyl ethyl malonates as raw material, hydrolysis occurs in inorganic base solvent, obtains middle production
Thing A, wherein, the pH of hydrolysis is 8, and temperature is 0 DEG C, time 0.5h, mole of phenyl ethyl malonate and inorganic base
Than for 1:2；
2) intermediate product A carries out acylation reaction with thionyl chloride in dichloromethane solvent, obtains intermediate product B, middle
The mol ratio of product A and thionyl chloride is 1:2, the temperature of the acylation reaction is 0 DEG C, time 2h；
3) with 20molN- ethyl -4- picoline amine condensation reaction occurs in tetrahydrofuran solvent for intermediate product B, obtains
Mol ratio to intermediate product C, the intermediate product B and N- ethyl -4- picoline amine is 1:1.5, the condensation reaction
Temperature is 5 DEG C, time 1h；
4) with 40mol calcium borohydrides reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, wherein,
The pH of the reduction reaction is 7.5, and temperature is -7 DEG C, time 2h.
Embodiment 2
1) using 10mol phenyl ethyl malonates as raw material, hydrolysis occurs in inorganic base solvent, obtains middle production
Thing A, wherein, the pH of hydrolysis is 12, and temperature is 34 DEG C, time 8h, mole of phenyl ethyl malonate and inorganic base
Than for 1:8；
2) intermediate product A carries out acylation reaction with thionyl chloride in dichloromethane solvent, obtains intermediate product B, middle
The mol ratio of product A and thionyl chloride is 1:20, the temperature of the acylation reaction is 60 DEG C, time 22h；
3) with 100molN- ethyl -4- picoline amine condensation reaction occurs in tetrahydrofuran solvent for intermediate product B, obtains
Mol ratio to intermediate product C, the intermediate product B and N- ethyl -4- picoline amine is 1:6, the temperature of the condensation reaction
Spend for 20 DEG C, time 20h；
4) with 300mol calcium borohydrides reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, its
In, the pH of the reduction reaction is 10.5, and temperature is 70 DEG C, time 22h.
Embodiment 3
1) using 10mol phenyl ethyl malonates as raw material, hydrolysis occurs in inorganic base solvent, obtains middle production
Thing A, wherein, the pH of hydrolysis is 10, and temperature is 18 DEG C, time 4h, mole of phenyl ethyl malonate and inorganic base
Than for 1:5；
2) intermediate product A carries out acylation reaction with thionyl chloride in dichloromethane solvent, obtains intermediate product B, middle
The mol ratio of product A and thionyl chloride is 1:11, the temperature of the acylation reaction is 30 DEG C, time 12h；
3) with 60molN- ethyl -4- picoline amine condensation reaction occurs in tetrahydrofuran solvent for intermediate product B, obtains
Mol ratio to intermediate product C, the intermediate product B and N- ethyl -4- picoline amine is 1:3.5, the condensation reaction
Temperature is 12 DEG C, time 10h；
4) with 170mol potassium borohydrides reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, its
In, the pH of the reduction reaction is 9, and temperature is 30 DEG C, time 12h.
Embodiment 4
1) using 10mol phenyl ethyl malonates as raw material, hydrolysis occurs in inorganic base solvent, obtains middle production
Thing A, wherein, the pH of hydrolysis is 9, and temperature is 17 DEG C, time 3.5h, mole of phenyl ethyl malonate and inorganic base
Than for 1:5；
2) intermediate product A carries out acylation reaction with thionyl chloride in dichloromethane solvent, obtains intermediate product B, middle
The mol ratio of product A and thionyl chloride is 1:11, the temperature of the acylation reaction is 10 DEG C, time 12h；
3) with 60molN- ethyl -4- picoline amine condensation reaction occurs in tetrahydrofuran solvent for intermediate product B, obtains
Mol ratio to intermediate product C, the intermediate product B and N- ethyl -4- picoline amine is 1:3, the temperature of the condensation reaction
Spend for 10 DEG C, time 10h；
4) with 170mol potassium borohydrides reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, its
In, the pH of the reduction reaction is 8, and temperature is 30 DEG C, time 12h.
Embodiment 5
1) using 10mol phenyl ethyl malonates as raw material, hydrolysis occurs in inorganic base solvent, obtains middle production
Thing A, wherein, the pH of hydrolysis is 9, and temperature is 15 DEG C, time 6h, the mol ratio of phenyl ethyl malonate and inorganic base
For 1:7；
2) intermediate product A carries out acylation reaction with thionyl chloride in dichloromethane solvent, obtains intermediate product B, middle
The mol ratio of product A and thionyl chloride is 1:18, the temperature of the acylation reaction is 40 DEG C, time 18h；
3) with 60molN- ethyl -4- picoline amine condensation reaction occurs in tetrahydrofuran solvent for intermediate product B, obtains
Mol ratio to intermediate product C, the intermediate product B and N- ethyl -4- picoline amine is 1:5, the temperature of the condensation reaction
Spend for 14 DEG C, time 17h；
4) with 190mol potassium borohydrides reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, its
In, the pH of the reduction reaction is 9, and temperature is 50 DEG C, time 18h.
Comparative example 1
Step is same as Example 1, and phenyl ethyl malonate is 1mol only in step 1), remaining step all same.
Comparative example 2
Step is same as Example 1, and phenyl ethyl malonate is 25mol only in step 1), remaining step all same.
Comparative example 3
Step is same as Example 1, and N- ethyls -4- picolines amine is 10mol only in step 3), and remaining step is homogeneous
Together.
Comparative example 4
Step is same as Example 1, and N- ethyls -4- picolines amine is 130mol only in step 3), and remaining step is homogeneous
Together.
Comparative example 5
Step is same as Example 1, and boron hydride is 20mol only in step 4), remaining step all same.
Comparative example 6
Step is same as Example 1, and boron hydride is 400mol only in step 4), remaining step all same.
Comparative example 7
Step is same as Example 1, and the mol ratio of phenyl ethyl malonate and inorganic base is 1 only in step 1):1, its
Remaining step all same.
Comparative example 8
Step is same as Example 1, and the mol ratio of phenyl ethyl malonate and inorganic base is 1 only in step 1):10, its
Remaining step all same.
Comparative example 9
Step is same as Example 1, and the mol ratio of intermediate product A and thionyl chloride is 1 only in step 2):1, remaining step
All same.
Comparative example 10
Step is same as Example 1, and the mol ratio of intermediate product A and thionyl chloride is 1 only in step 2):30, remaining step
Rapid all same.
Comparative example 11
Step is same as Example 1, and the mol ratio of intermediate product B and N- ethyls -4- picoline amine is only in step 3)
1:1, remaining step all same.
Comparative example 12
Step is same as Example 1, and the mol ratio of intermediate product B and N- ethyls -4- picoline amine is only in step 3)
1:10, remaining step all same.
Comparative example 13
Step is same as Example 1, and the mol ratio of intermediate product B and N- ethyls -4- picoline amine is only in step 3)
1:20, remaining step all same.
Comparative example 14
Step is same as Example 1, and the temperature of acylation reaction is -10 DEG C only in step 2), remaining step all same.
Comparative example 15
Step is same as Example 1, and the temperature of acylation reaction is 80 DEG C only in step 2), remaining step all same.
Comparative example 16
Step is same as Example 1, and the temperature of condensation reaction is 0 DEG C only in step 3), remaining step all same.Comparative example
17
Step is same as Example 1, and the temperature of condensation reaction is 40 DEG C only in step 3), remaining step all same.
Overall yield of reaction refers to the number of the product of output by chemically reacting, and theoretical yield refers to perfectly balanced
In reaction can output maximum product volume, but actual production is often less than theoretical yield., can be with to embody reaction efficiency
Total recovery is calculated using following formula：Total recovery %=(actual production/theoretical yield) × 100%.According to above formula,
Embodiment 1-5 and comparative example 1-17 total recovery is calculated, as a result as shown in table 1.
The yield statistical form of table 1
| Test object | Total recovery % | Test object | Total recovery % |
| Embodiment 1 | 65.275 | Comparative example 7 | 45.882 |
| Embodiment 2 | 64.184 | Comparative example 8 | 43.541 |
| Embodiment 3 | 63.923 | Comparative example 9 | 44.717 |
| Embodiment 4 | 66.284 | Comparative example 10 | 38.638 |
| Embodiment 5 | 63.169 | Comparative example 11 | 37.615 |
| Comparative example 1 | 43.912 | Comparative example 12 | 43.712 |
| Comparative example 2 | 49.279 | Comparative example 13 | 40.826 |
| Comparative example 3 | 45.135 | Comparative example 14 | 38.958 |
| Comparative example 4 | 39.767 | Comparative example 15 | 39.735 |
| Comparative example 5 | 42.014 | Comparative example 16 | 40.218 |
| Comparative example 6 | 43.718 | Comparative example 17 | 42.186 |
As it can be seen from table 1 as shown in embodiment 1-5 result, the present invention makes reaction by the optimization to raw material proportioning
Total recovery brought up to 65%, and stability is good, substantially increases yield, reduces production cost.In addition, the present invention provides
The cost of material that uses of synthetic method it is low, cheap and easy to get, intermediate product property is stable, and accessory substance and impurity are few, and are easy to remove
Go, reduce the operating procedures such as purifying, simplify technique；Eliminate toxicity caused by residue and the shadow to end-product tropicamide
Ring；Reaction condition is safe, gentle, does not introduce extremely toxic substance, is advantageous to industry's enlarging production.And comparative example 1-17 total recovery
Generally below 40%, illustrate that the proportioning of each component raw material and acylation reaction and the temperature of condensation reaction are for total in the present invention
Yield has large effect, and total recovery is significantly reduced if not in the framework of the present definition, therefore the side of the present invention
Method has very significant effect for the total recovery for improving reaction.
Applicant states that the present invention illustrates the detailed process equipment of the present invention and technological process by above-described embodiment,
But the invention is not limited in above-mentioned detailed process equipment and technological process, that is, it is above-mentioned detailed not mean that the present invention has to rely on
Process equipment and technological process could be implemented.Person of ordinary skill in the field it will be clearly understood that any improvement in the present invention,
The addition of equivalence replacement and auxiliary element to each raw material of product of the present invention, selection of concrete mode etc., all fall within the present invention's
Within the scope of protection domain and disclosure.
Claims (10)
1. a kind of synthetic method of tropicamide, it is characterised in that methods described is using phenyl ethyl malonate as raw material, through water
After solving and being acylated, after being condensed with N- ethyl -4- picolines amine, reduction reaction occurs with boron hydride, tropicamide is made；
Wherein, the mol ratio of the phenyl ethyl malonate, N- ethyls -4- picolines amine and boron hydride is 1:(2-
10):(4-30)。
2. synthetic method as claimed in claim 1, it is characterised in that the phenyl ethyl malonate, N- ethyl -4- methyl
The mol ratio of pyridine amine and boron hydride is 1:(2-6):(4-20), preferably 1:(2-3):(5-10).
3. synthetic method as claimed in claim 1 or 2, it is characterised in that the described method comprises the following steps：
1) using phenyl ethyl malonate as raw material, hydrolysis occurs in basic solvent, obtains intermediate product A；
2) with thionyl chloride and/or thionyl chloride acylation reaction occurs for intermediate product A, obtains intermediate product B；
3) with N- ethyl -4- picolines amine condensation reaction occurs for intermediate product B, obtains intermediate product C；
4) with boron hydride reduction reaction occurs for intermediate product C, and tropicamide is made.
4. synthetic method as claimed in claim 3, it is characterised in that the step 1) basic solvent is inorganic base solvent, institute
It is preferably NaOH, Na to state inorganic base2CO3, KOH or K2CO3In any one or at least two mixture；
Preferably, the pH of the step 1) hydrolysis is 8-12, preferably 8.5-10；
Preferably, the temperature of the step 1) hydrolysis is 0-35 DEG C, preferably 10-20 DEG C；
Preferably, the time of the step 1) hydrolysis is 0.5-8h, preferably 2-6h；
Preferably, the mol ratio of phenyl ethyl malonate and inorganic base is 1 in step 1):(2-8), preferably 1:(3-6).
5. the synthetic method as described in claim 3 or 4, it is characterised in that the step 2) acylation reaction is carried out in a solvent,
The solvent is the mixed solvent of any one or at least two in dichloromethane, tetrahydrofuran, chloroform or inorganic solvent；
Preferably, the inorganic solvent is NaOH, K2CO3、Na2CO3In any one or at least two mixed solvent；
Preferably, step 2) the intermediate product A and the mol ratio of thionyl chloride and/or thionyl chloride are 1:(2-20), preferably
For 1:(3-9)；
Preferably, the temperature of the step 2) acylation reaction is 0-60 DEG C, preferably 5-40 DEG C；
Preferably, the time of the step 2) acylation reaction is 2-22h, preferably 5-15h.
6. such as the synthetic method any one of claim 3-5, it is characterised in that the step 3) condensation reaction is in solvent
Middle progress, the solvent are any one or at least two in pyridine, dichloromethane, tetrahydrofuran, chloroform or inorganic solvent
Mixed solvent；
Preferably, the mol ratio of intermediate product B and N- ethyl -4- picoline amine is 1:(1.5-6), preferably 1:(3-5)；
Preferably, the temperature of the step 3) condensation reaction is 5-20 DEG C, preferably 10-15 DEG C；
Preferably, the time of the step 3) condensation reaction is 1-20h, preferably 5-15h.
7. such as the synthetic method any one of claim 3-6, it is characterised in that intermediate product C and boron in step 4)
The mol ratio of hydride is 1:(1.5-5.5), preferably 1:(2-4)；
Preferably, the boron hydride be hydroboration manganese, calcium borohydride, sodium borohydride or potassium borohydride in any one or extremely
Few two kinds mixture；
Preferably, the pH of the step 4) reduction reaction is 7.5-10.5, preferably 9-10；
Preferably, the temperature of the reduction reaction is -8-70 DEG C, is preferably -5-50 DEG C；
Preferably, the time of the reduction reaction is 2-22h, preferably 5-15h；
Preferably, the step 4) reduction reaction is carried out in organic solvent.
8. such as the synthetic method any one of claim 3-7, it is characterised in that the described method comprises the following steps：
1) using phenyl ethyl malonate as raw material, hydrolysis occurs in inorganic base solvent, obtains intermediate product A, wherein,
The pH of hydrolysis is 8-12, and temperature is 0-35 DEG C, time 0.5-8h, the mol ratio of phenyl ethyl malonate and inorganic base
For 1:(2-8)；
2) intermediate product A carries out acylation reaction in a solvent with thionyl chloride and/or thionyl chloride, obtains intermediate product B, its
In, the solvent is that the mixing of any one or at least two in dichloromethane, tetrahydrofuran, chloroform or inorganic solvent is molten
Agent, intermediate product A are 1 with the mol ratio of thionyl chloride and/or thionyl chloride:(2-20), the temperature of the acylation reaction is 0-
60 DEG C, time 2-22h；
3) with N- ethyl -4- picoline amine condensation reaction occurs in a solvent for intermediate product B, obtains intermediate product C, wherein,
The solvent is that the mixing of any one or at least two in pyridine, dichloromethane, tetrahydrofuran, chloroform or inorganic solvent is molten
The mol ratio of agent, the intermediate product B and N- ethyl -4- picoline amine is 1:(1.5-6), the temperature of the condensation reaction are
5-20 DEG C, time 1-20h；
4) with boron hydride reduction reaction occurs in organic solvent for intermediate product C, and tropicamide is made, wherein, the boron hydrogen
Compound is the mixture of any one or at least two in hydroboration manganese, calcium borohydride, sodium borohydride or potassium borohydride, described
The pH of reduction reaction is 7.5-10.5, and temperature is -8-70 DEG C, time 2-22h.
9. such as the synthetic method any one of claim 3-8, it is characterised in that the step 4) reduction reaction it
Afterwards, in addition to the step of separation and Extraction tropicamide；
Preferably, the step of separation and Extraction tropicamide specifically includes：
A) gained feed liquid after reduction reaction is gone in separation and Extraction tank, after adding watery hydrochloric acid and/or ethyl acetate, separated
Solvent layer, water layer chloroform recovery, merge chloroform and organic solvent, use anhydrous Na2SO4It is dried overnight, obtains solution D；
B) solution D sealing decompression is steamed into chloroform, steams sticky to feed liquid, obtain feed liquid E；
C) feed liquid E is ground, until separating out crystallization F；
D) filtering for crystallizing F, it is washed out, dries, obtain tropicamide.
10. synthetic method as claimed in claim 9, it is characterised in that the temperature that decompression steams chloroform in step b) is 20-60
DEG C, preferably 40-50 DEG C；
Preferably, step c) is described is ground to：Feed liquid E and ethyl acetate are added into mortar to be ground；
Preferably, the step d) washings are to be washed with ethyl acetate；
Preferably, the temperature dried in step d) is less than 35 DEG C, preferably 20-30 DEG C.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022134316A1 (en) * | 2020-12-23 | 2022-06-30 | 无锡济煜山禾药业股份有限公司 | Preparation method for tropicamide |
| KR102662895B1 (en) | 2022-01-04 | 2024-05-03 | 주식회사 한서켐 | Method for preparing high purity tropicamide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159672A (en) * | 2012-07-16 | 2013-06-19 | 湖南尔文生物科技有限公司 | Preparation method of tropine amide |
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2017
- 2017-10-30 CN CN201711037123.2A patent/CN107759509A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103159672A (en) * | 2012-07-16 | 2013-06-19 | 湖南尔文生物科技有限公司 | Preparation method of tropine amide |
Non-Patent Citations (1)
| Title |
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| SILVIA DEIL ET AL.: "SYNTHESIS, CHARACTERIZATION AND PHARMACOLOGICAL PROFILE OF TROPICAMIDE ENANTIOMERS", 《LIFE SCIENCES》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022134316A1 (en) * | 2020-12-23 | 2022-06-30 | 无锡济煜山禾药业股份有限公司 | Preparation method for tropicamide |
| KR102662895B1 (en) | 2022-01-04 | 2024-05-03 | 주식회사 한서켐 | Method for preparing high purity tropicamide |
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