CN106831496A - The preparation method of Guanfacine Hydrochloride - Google Patents
The preparation method of Guanfacine Hydrochloride Download PDFInfo
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- CN106831496A CN106831496A CN201611233811.1A CN201611233811A CN106831496A CN 106831496 A CN106831496 A CN 106831496A CN 201611233811 A CN201611233811 A CN 201611233811A CN 106831496 A CN106831496 A CN 106831496A
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- guanfacine
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- hydrochloride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07C273/00—Preparation of urea or its derivatives, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
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Abstract
The invention discloses a kind of preparation method of Guanfacine Hydrochloride.With 2,6 fenacs and methoxyl group isourea hydrochloride are initiation material, and Guanfacine Hydrochloride is obtained through catalyzing and condensing, ammonolysis, into salt, purifying.The preparation method reaction condition is gentle, simple to operate, compared with prior art, reduces operating procedure, reduces total reaction time, reduces energy consumption, pollutes smaller, is conducive to environmental protection.
Description
Technical field
The present invention relates to pharmaceutical field on pharmaceutical formulation techniques, more particularly to a kind of preparation side of Guanfacine Hydrochloride
Method.
Background technology
Guanfacine Hydrochloride belongs to drug for hypertension, for treating moderate to severe hypertension.Chemical name be N- amidino groups-
2-（2,6- dichlorophenyls）Acetamide mono-hydrochloric salts, its molecular formula is：C9H9Cl2N3OHCl, molecular weight is 282.55, structure
Formula is：
Guanfacine Hydrochloride is insoluble in water and ethanol for white to off-white color crystalline powder, there is of a relatively high dissolving in methyl alcohol
Degree（>30mg/mg）.
Guanfacine Hydrochloride is selective α2- adrenocepter synergist, is used to treat moderate to severe hypertension earliest,
With the tablet for administration being administered orally, in the trade name Tenex in the U.S., specification is 1mg or 2mg.
Due to Guanfacine Hydrochloride, the medicine has very strong central action, and the binding of drug to plasma proteins rate is high, commonly
Dosage form release rate is too fast so that peak plasma concentrations are higher, induces its side effect, such as drowsiness, dizziness, difficulty falling asleep, nausea,
Vomiting, forgetful etc..
At present, the synthesis report of Guanfacine Hydrochloride is few, and the method for document report mainly has following 5 kinds.
Method one：2,6- dichloro benzyl cyanides are dissolved in methyl alcohol, are slowly added to the concentrated sulfuric acid, and 80 DEG C of heating carry out alcoholysis, insulation
12h, reaction finishes to be slowly added into the methyl alcohol containing a small amount of water stirs 30min, after Distillation recovery major part methyl alcohol, adds
Suitable quantity of water, is extracted with ethyl acetate, and organic layer dries revolving and removes ethyl acetate, obtains 2,6- fenac methyl esters；By 2,6-
Fenac methyl esters is dissolved in isopropanol, and then solution is added in the aqueous isopropanol of guanidine, and 10h is stirred at room temperature, and vacuum is taken out
Filter to obtain guanfacine crude product.To being added in crude product after isopropanol is tuned into pulpous state, pH value about 1~2 is adjusted with acidic alcohol, vacuum filtration,
Insoluble matter is removed, filtrate is concentrated to give Guanfacine Hydrochloride；
The method prepares 2,6- fenac methyl esters with the concentrated sulfuric acid, and the concentrated sulfuric acid is easily remained.
Method two：2,6- fenacs are added in the toluene solution of guanidine after being dissolved in toluene, and 120 DEG C are heated to reflux 12h,
Vacuum distillation removes toluene, obtains guanfacine crude product, guanfacine crude product is added in isopropanol and is tuned into pulpous state, is adjusted with acidic alcohol
Section pH value about 1~2, vacuum filtration removes insoluble matter, and filtrate is concentrated to give Guanfacine Hydrochloride；
The method process is simple, but the larger toluene of toxicity has been used as reaction dissolvent.
Method three：2,6- dichloro phenyllacetyl chlorides are dissolved in acetone, are added dropwise in the acetone soln of S- methyl isothioureas.Room temperature
Stirring 2h, boils off acetone and obtains S- methyl-N-（2,6- dichloro phenylacetyl groups）Isothiourea, isopropanol is dissolved in by product, is passed through ammonia
4h is stirred at room temperature, partial solvent, cooling crystallization is boiled off.Vacuum filtration obtains guanfacine crude product.It is tuned into isopropanol is added in crude product
After pulpous state, pH value about 1~2 is adjusted with acidic alcohol, vacuum filtration removes insoluble matter, and filtrate is concentrated to give Guanfacine Hydrochloride；
Acetone is the method use, the ammonia for transporting, storing is difficult.
Method four：2,6- dichloro benzyl cyanides are dissolved in ethanol, caustic alcohol is added, 30min is stirred at room temperature, be subsequently adding formic acid
Ethyl ester, is stirred at room temperature 4h, obtains α-aldehyde radical -2, and 6- dichloro benzyl cyanides are dissolved in ethanol, after adding caustic alcohol stirring 30min, adds salt
Sour guanidine, is stirred at room temperature 4h, and vacuum filtration removes inorganic salts, obtains α-guanidine methylene -2, and 6- dichloro benzyl cyanide solution adds in solution
Enter concentrated hydrochloric acid, 80 DEG C of heating stirring 4h, concentration naturally cools to room temperature crystallization, and vacuum filtration obtains Guanfacine Hydrochloride；
2, the 6- dichloro benzyl cyanide prices used in the method are higher, are unfavorable for industrialized production.
Method five：By guanidine hydrochloride, sodium isopropylate and isopropanol 200ml, after 24h is stirred at room temperature, vacuum filtration removes dechlorination
Change sodium, to the aqueous isopropanol that 2,6- fenac methyl esters is added in filtrate, after 15min is stirred at room temperature, recycling design is cold
But, solid is separated out.After adding isopropanol to be tuned into pulpous state in solid, it is 1~2 to be adjusted to pH value with the ethanol solution of hydrogen chloride, very
Empty suction filtration, removes insoluble matter, after filtrate concentration, adds appropriate ether, separates out white, needle-shaped crystals, and vacuum filtration obtains guanidine hydrochloride
The pungent crude product of method；
The ethanol solution of the hydrogen chloride that the method is used is difficult to buy and stores, and uses controlled ether.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of preparation method of Guanfacine Hydrochloride.By the technology of the present invention side
Case prepares Guanfacine Hydrochloride, simple to operate, compared with prior art, reduces operating procedure, reduces total reaction time, reduces
Energy consumption.Whole preparation process pollutant emission seldom, pollutes very little, is conducive to environmental protection.
In order to solve the above problems, the technical solution adopted by the present invention is：
The present invention provides a kind of preparation method of Guanfacine Hydrochloride, and the preparation method is comprised the following steps.
The preparation of a, methoxyl group isourea methanol solution：With methoxyl group isourea hydrochloride（Ⅰ）It is raw material with highly basic, methyl alcohol is molten
Agent；First, to methyl alcohol and highly basic is added in reaction bulb, heating for dissolving adds methoxyl group isourea hydrochloride, and 50 ~ 60 DEG C of stirrings are anti-
1 ~ 3h is answered, room temperature is cooled to, filtered, take filtrate, obtain methoxyl group isourea（Ⅱ）Methanol solution；
Described highly basic is any in sodium methoxide, caustic alcohol and sodium isopropylate；Described methoxyl group isourea hydrochloride with
The mol ratio of highly basic is 1:1~1.5；Described methoxyl group isourea hydrochloride and methyl alcohol therebetween addition ratio be 1g：2
~5mL.
b、1-（2-（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothioureas（Ⅳ）The preparation of methanol solution：With 2,6- bis-
Chlorobenzene acetic acid（Ⅲ）With methoxyl group isourea（Ⅱ）It is base stock, with 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethyl
Base urea hexafluorophosphoric acid ester（Abbreviation HATU）And DIPEA（Abbreviation DIPEA）It is catalyst, methyl alcohol is solvent；First
By raw material 2,6- fenacs, catalysts and solvents methyl alcohol are added in reaction vessel, by methoxyl group isourea first obtained in step a
Alcoholic solution is added in reaction bulb, at ambient temperature 1~3h of stirring reaction, obtains 1-（2-（2,6- dichlorophenyls）Acetyl group）-
2- methyl isothioureas（Ⅳ）Methanol solution；
The 2,6- fenacs and methoxyl group isourea mol ratio 1 therebetween:1.0~1.5；The 2,6- dichloro-benzenes second
Acid and the mol ratio between HATU, DIPEA are 1:0.05~0.1:0.15~0.3；The 2,6- fenacs and both methyl alcohol
Between addition ratio be 1g：2~3mL.
C, guanfacine（Ⅴ）Preparation：The 1- that step b is obtained（2-（2,6- dichlorophenyls）Acetyl group）The different sulphur of -2- methyl
Urea（Ⅳ）Methanol solution is added in reaction bulb, adds 25% ammoniacal liquor, 35 ~ 60 DEG C of 2 ~ 4h of stirring reaction to react after terminating, vacuum
Degree be not less than 0.085Mpa, at 40 DEG C decompression boil off methyl alcohol, residue is cooled to room temperature, and filtering, filter cake water slurry is washed twice, mistake
Filter, is rinsed twice with water, and 90 ~ 110 DEG C of 2 ~ 5h of drying of filter cake obtain guanfacine（Ⅴ）Crude product；
Described 2,6- fenacs and the mol ratio of 25% ammoniacal liquor are 1:1~2；Wash and starch water total amount be filter cake quality 3 ~
5 times, rinse water consumption total amount is 1 ~ 3 times of filter cake quality.
D, Guanfacine Hydrochloride（Ⅵ）The preparation of crude product：By guanfacine obtained in step c（Ⅴ）Crude product is dissolved completely in quality
In the ethanol of concentration 95%, filtered after being completely dissolved, the hydrochloric acid that mass concentration is 35~37%, regulation are added in gained filtrate
To 1~2, be stirred at room temperature carries out 20~40min of reaction to its pH value, and reaction terminates after under 50 DEG C, vacuum 0.085Mpa
Concentration removes 60% ethanol, is subsequently cooled to room temperature 2~3h of crystallization, and suction filtration obtains Guanfacine Hydrochloride（Ⅵ）Crude product, after recrystallization
To Guanfacine Hydrochloride highly finished product, finished product is obtained after dried process；
The guanfacine crude product and ethanol therebetween addition ratio be 1g：10~20mL.
According to the preparation method of above-mentioned Guanfacine Hydrochloride, gained recrystallization operation described in step d is as follows：By step d
During the Guanfacine Hydrochloride crude product that obtains adds mass concentration to be 95% ethanol, backflow is heated to, heat filtering, filtrate is cooled to room
2~3h of crystallization after temperature, suction filtration.
According to the preparation method of above-mentioned Guanfacine Hydrochloride, the dried process described in step d, its drying temperature is 105
DEG C, drying time is 5h, moisture content≤0.5% of products obtained therefrom after drying.
Positive beneficial effect of the invention.
1st, the present invention prepares Guanfacine Hydrochloride with 2,6- fenacs and methoxyl group isourea for raw material.The technology of the present invention
Scheme prepares Guanfacine Hydrochloride, and reaction condition is gentle, simple to operate, compared with prior art, reduces operating procedure, reduces
Total reaction time, reduces energy consumption.Whole preparation process pollutant emission seldom, pollutes very little, is conducive to environmental protection.
2nd, solvent is done using methyl alcohol in preparation process of the present invention, is almost reclaimed completely, reduce environmental pollution, saved into
This.
3rd, by washing in preparation process of the present invention, catalyst, solvent and inorganic salts are removed, is reduced residual in finished product
Stay.
4th, recrystallized in preparation process of the present invention and solvent is done using 95% ethanol, it is recyclable, it is pollution-free, and
Cost is relatively low, can reduce the residual of solvent, improves the Guanfacine Hydrochloride quality of pharmaceutical grade.
5th, in whole preparation process of the present invention, seldom, almost there be not organic residue in medicine for pollutant emission；Using this hair
The drug quality of bright technical scheme synthesis is good, and environmental pollution very little meets environmental protection.
4th, illustrate：
Fig. 1 invented technology reaction equations
The liquid-phase chromatographic analysis figure of the products obtained therefrom of Fig. 2 embodiment of the present invention 1.
5th, specific embodiment
The present invention is expanded on further with reference to embodiments, but is not intended to limit present disclosure.
Embodiment 1：
The preparation of a, methoxyl group isourea methanol solution
Three mouthfuls of reaction bulbs are taken, 100ml methyl alcohol, 15.7g sodium methoxides, heating for dissolving is added.Add 32.3g methoxyl group isourea hydrochlorides
I.e. chemical compounds I, 60 DEG C of stirring reaction 2h, are cooled to room temperature, filtering, take filtrate, obtain the methoxyl group isourea i.e. methyl alcohol of compound ii
Solution；
b、1-（2-（2,6- dichlorophenyls）Acetyl group）The preparation of -2- methyl isothiourea methanol solutions
Tri- mouthfuls of reaction bulbs of 250ml are taken, 50g2 is added, 6- fenacs are compound III, add 100ml methyl alcohol, 4.6gHATU
And 4.7gDIPEA, add methoxyl group isourea methanol solution obtained in step a, 30 DEG C of stirring reaction 2h to stop reaction, obtain 1-（2-
（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothioureas are the methanol solution of compounds Ⅳ；
The preparation of c, guanfacine crude product
To 1- obtained in step b（2-（2,6- dichlorophenyls）Acetyl group）The ammonia of 51.2g 25% is added in -2- methyl isothiourea solution
Water, 45 DEG C of stirring reaction 3h, vacuum 0.085Mpa, 40 DEG C of decompressions steam methyl alcohol, and residue is cooled to room temperature.Filtering, filter cake
Washed twice with 200ml water slurrys, filtering, and rinsed 2 times with 100ml water, 100 DEG C of filter cake dries 3h, obtains guanfacine crude product and chemical combination
The 47g of thing V；
The preparation of d, Guanfacine Hydrochloride
Obtained guanfacine crude product is dissolved in the ethanol of 700ml 95%, insoluble matter is filtered off.To addition concentrated hydrochloric acid in filtrate to pH=
1, stir 30 min.With Rotary Evaporators, in 50 DEG C, under vacuum 0.085Mpa, concentration removes 60% solvent, residue cooling
To 30 DEG C, crystallization 3 hours filters to obtain the Guanfacine Hydrochloride crude product i.e. 53g of compound VI；
Guanfacine Hydrochloride crude product is dissolved in the ethanol of 550ml 95%, is heated to backflow, and heat filtering, filtrate is cooled to 30 DEG C, crystallization 2
Hour, filtering, 105 DEG C of drying obtain the g of finished product 32.6 in 5 hours.
Embodiment 2：
The preparation of a, methoxyl group isourea methanol solution
Three mouthfuls of reaction bulbs are taken, 150ml methyl alcohol, 23.8g caustic alcohols, heating for dissolving is added.Add 32.3g methoxyl group isourea hydrochlorides
I.e. chemical compounds I, 50 DEG C of stirring reaction 3h, are cooled to room temperature, filtering, take filtrate, obtain the methoxyl group isourea i.e. methyl alcohol of compound ii
Solution；
b、1-（2-（2,6- dichlorophenyls）Acetyl group）The preparation of -2- methyl isothiourea methanol solutions
Tri- mouthfuls of reaction bulbs of 500ml are taken, it is compound III 50g to add 2,6- fenacs, adds 150ml methyl alcohol, 9.2gHATU
Methoxyl group isourea methanol solution obtained in step a, 25 DEG C of stirring reaction 3h is added to stop reaction, obtain 1- with 9.4gDIPEA（2-
（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothioureas are the methanol solution of compounds Ⅳ；
The preparation of c, guanfacine crude product
To 1- obtained in step b（2-（2,6- dichlorophenyls）Acetyl group）The ammonia of 68.4g 25% is added in -2- methyl isothiourea solution
Water, 35 DEG C of stirring reaction 4h, vacuum 0.085Mpa, 40 DEG C of decompressions steam methyl alcohol, and residue is cooled to room temperature.Filtering, filter cake
Washed twice with 200ml water slurrys, filtering, and rinsed 2 times with 100ml water, 110 DEG C of filter cake dries 2h, obtains guanfacine crude product i.e. chemical combination
The 45g of thing V；
The preparation of d, Guanfacine Hydrochloride
Obtained guanfacine is dissolved in the ethanol of 900ml 95%, insoluble matter is filtered off.To adding concentrated hydrochloric acid to pH=1 in filtrate, stir
Mix 30 min.With Rotary Evaporators in 50 DEG C, under vacuum 0.085Mpa, concentration removes 60% solvent, and residue is cooled to 30
DEG C, crystallization 2h.Filter to obtain the Guanfacine Hydrochloride i.e. crude product 48g of compound VI；
Guanfacine Hydrochloride crude product is dissolved in the ethanol of 500ml 95%, is heated to backflow, and heat filtering, filtrate is cooled to 30 DEG C, crystallization 2
Hour, filtering, 105 DEG C of drying obtain the g of finished product 30.4 in 5 hours.
Embodiment 3：
The preparation of a, methoxyl group isourea methanol solution
Three mouthfuls of reaction bulbs are taken, 65ml methyl alcohol, 20g sodium isopropylates, heating for dissolving is added.Add 32.3g methoxyl group isourea hydrochlorides
I.e. chemical compounds I, 55 DEG C of stirring reaction 1h, are cooled to room temperature, filtering, take filtrate, obtain the methoxyl group isourea i.e. methyl alcohol of compound ii
Solution；
b、1-（2-（2,6- dichlorophenyls）Acetyl group）The preparation of -2- methyl isothiourea methanol solutions
Tri- mouthfuls of reaction bulbs of 500ml are taken, 50g 2 is added, 6- fenacs are compound III, add 100ml methyl alcohol, 6.9gHATU
Methoxyl group isourea methanol solution obtained in step a, 30 DEG C of stirring reaction 1h is added to stop reaction, obtain 1- with 7.0g DIPEA（2-
（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothioureas are the methanol solution of compounds Ⅳ；
The preparation of c, guanfacine crude product
To 1- obtained in step b（2-（2,6- dichlorophenyls）Acetyl group）The ammonia of 34.2g 25% is added in -2- methyl isothiourea solution
Water, 60 DEG C of stirring reaction 2h, vacuum 0.085Mpa, 40 DEG C of decompressions steam methyl alcohol, and residue is cooled to room temperature.Filtering, filter cake
Washed twice with 200ml water slurrys, filtering, and rinsed 2 times with 100ml water, 100 DEG C of filter cake dries 3h, obtains guanfacine i.e. compound V
Crude product 43g；
The preparation of d, Guanfacine Hydrochloride
Obtained guanfacine is dissolved in the ethanol of 650ml 95%, insoluble matter is filtered off.To adding concentrated hydrochloric acid to pH=1 in filtrate, stir
Mix 30 min.With Rotary Evaporators, in 50 DEG C, under vacuum 0.085Mpa, concentration removes 60% solvent, and residue is cooled to room
Temperature, crystallization 5 hours filters to obtain the Guanfacine Hydrochloride i.e. crude product 55g of compound VI；
Guanfacine Hydrochloride crude product is dissolved in the ethanol of 800ml 95%, is heated to backflow, and heat filtering, filtrate is cooled to 30 DEG C, crystallization 2
Hour, filtering, 105 DEG C of drying obtain the g of finished product 30.5 in 5 hours.
Claims (3)
1. in a kind of preparation method of Guanfacine Hydrochloride, it is characterised in that the preparation method is comprised the following steps：
The preparation of a, methoxyl group isourea methanol solution：With methoxyl group isourea hydrochloride and highly basic as raw material, methyl alcohol is solvent；It is first
First, to adding methyl alcohol and highly basic in reaction bulb, heating for dissolving adds methoxyl group isourea hydrochloride, and 50 ~ 60 DEG C of stirring reactions 1 ~
3h, is cooled to room temperature, filtering, takes filtrate, obtains methoxyl group isourea methanol solution；
Described highly basic is any in sodium methoxide, caustic alcohol and sodium isopropylate；Described methoxyl group isourea hydrochloride with
The mol ratio of highly basic is 1:1~1.5；Described methoxyl group isourea hydrochloride and methyl alcohol therebetween addition ratio be 1g：2
~5mL；
b、1-（2-（2,6- dichlorophenyls）Acetyl group）The preparation of -2- methyl isothiourea methanol solutions：With 2,6- fenacs
It is base stock with methoxyl group isourea, with 2- (7- aoxidizes BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester（Letter
Claim HATU）And DIPEA（Abbreviation DIPEA）It is catalyst, methyl alcohol is solvent；First by raw material 2,6- dichloro-benzenes
Acetic acid, catalyst and methyl alcohol are added in reaction vessel, and methoxyl group isourea methanol solution obtained in step a is added into reaction bulb
In, 1~3h of stirring reaction, obtains 1- at ambient temperature（2-（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothiourea methyl alcohol is molten
Liquid；
The 2,6- fenacs and methoxyl group isourea mol ratio 1 therebetween:1.0~1.5；The 2,6- dichloro-benzenes second
Acid and the mol ratio between HATU, DIPEA are 1:0.05~0.1:0.15~0.3；The 2,6- fenacs and both methyl alcohol
Between addition ratio be 1g：2~3mL；
The preparation of c, guanfacine：The 1- that step b is obtained（2-（2,6- dichlorophenyls）Acetyl group）- 2- methyl isothiourea methyl alcohol is molten
Liquid is added in reaction bulb, adds 25% ammoniacal liquor, 35 ~ 60 DEG C of 2 ~ 4h of stirring reaction to react after terminating, vacuum 0.085Mpa, 40
Decompression boils off methyl alcohol at DEG C, and residue is cooled to room temperature, and filtering, filter cake water slurry is washed twice, filtering, is rinsed twice with water, filter
90 ~ 110 DEG C of 2 ~ 5h of drying of cake, obtain guanfacine crude product；
Described 2,6- fenacs and the mol ratio of 25% ammoniacal liquor are 1:1~2；Wash and starch water total amount be filter cake quality 3 ~
5 times, rinse water consumption total amount is 1 ~ 3 times of filter cake quality；
The preparation of d, Guanfacine Hydrochloride crude product：Guanfacine crude product obtained in step c is dissolved completely in the ethanol of mass concentration 95%
In, filtered after being completely dissolved, the hydrochloric acid that mass concentration is 35~37% is added in gained filtrate, its pH value is adjusted to 1~2,
Being stirred at room temperature carries out 20~40min of reaction, and reaction terminates to remove 60% second after concentration under 50 DEG C, vacuum 0.085Mpa
Alcohol, is subsequently cooled to room temperature 2~3h of crystallization, and suction filtration obtains Guanfacine Hydrochloride crude product, Guanfacine Hydrochloride is obtained after recrystallization and is refined
Product, obtain finished product after dried process；
The guanfacine crude product and ethanol therebetween addition ratio be 1g：10~20mL.
2. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterised in that：Gained is tied again described in step d
Crystalline substance operation is as follows：During Guanfacine Hydrochloride crude product that step d is obtained adds mass concentration to be 95% ethanol, backflow, heat are heated to
Filtering, filtrate is cooled to 2~3h of crystallization after room temperature, suction filtration is carried out after crystallization.
3. the preparation method of Guanfacine Hydrochloride according to claim 1, it is characterised in that：At drying described in step d
Reason, its drying temperature is 105 DEG C, and drying time is 5h, moisture content≤0.5% of products obtained therefrom after drying.
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| CN115028554A (en) * | 2022-08-10 | 2022-09-09 | 广东科泰鼎润药业科技有限公司 | Guanfacine hydrochloride and preparation method thereof |
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| CN115028554A (en) * | 2022-08-10 | 2022-09-09 | 广东科泰鼎润药业科技有限公司 | Guanfacine hydrochloride and preparation method thereof |
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Application publication date: 20170613 |
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