CN109824518A - A kind of preparation method of memantine hydrochloride - Google Patents
A kind of preparation method of memantine hydrochloride Download PDFInfo
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- CN109824518A CN109824518A CN201711183920.1A CN201711183920A CN109824518A CN 109824518 A CN109824518 A CN 109824518A CN 201711183920 A CN201711183920 A CN 201711183920A CN 109824518 A CN109824518 A CN 109824518A
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- CN
- China
- Prior art keywords
- formamide
- acid
- chloro
- hydrochloric acid
- dimethyladamantane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- LDDHMLJTFXJGPI-UHFFFAOYSA-N memantine hydrochloride Chemical compound Cl.C1C(C2)CC3(C)CC1(C)CC2(N)C3 LDDHMLJTFXJGPI-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 229960000967 memantine hydrochloride Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 43
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000002994 raw material Substances 0.000 claims abstract description 9
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 21
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 150000007522 mineralic acids Chemical class 0.000 claims description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
- 229960004640 memantine Drugs 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- -1 formyl amine Chemical class 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001914 filtration Methods 0.000 claims description 2
- 238000006170 formylation reaction Methods 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 238000005516 engineering process Methods 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract description 2
- HTHVSMTZYMMWKO-UHFFFAOYSA-N formamide Chemical compound NC=O.NC=O HTHVSMTZYMMWKO-UHFFFAOYSA-N 0.000 abstract description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 208000024827 Alzheimer disease Diseases 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 238000009434 installation Methods 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 206010039966 Senile dementia Diseases 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- PXDRFQZLDWZHPX-UHFFFAOYSA-N 1-chloro-3,5-dimethyladamantane Chemical compound C1C(C2)CC3(C)CC1(C)CC2(Cl)C3 PXDRFQZLDWZHPX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 230000003796 beauty Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 2
- 229960003805 amantadine Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- CWNOIUTVJRWADX-UHFFFAOYSA-N 1,3-dimethyladamantane Chemical compound C1C(C2)CC3CC1(C)CC2(C)C3 CWNOIUTVJRWADX-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 201000004810 Vascular dementia Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 208000004296 neuralgia Diseases 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 208000021722 neuropathic pain Diseases 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of preparation method of memantine hydrochloride.This method is with chloro- 3, the 5- dimethyladamantane of 1- for raw material, and through formamide formamide, hydrochloric acid hydrolysis, one-step method directly obtains target product, and yield can achieve 80%, and product purity is more than 99.0%.Compared with traditional synthesis technology, new process synthesis step is simple, significantly reduces production cost, and small pollution of the environment alleviates environmental problem caused by the production of memantine hydrochloride significantly.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of system for treating senile dementia memantine hydrochloride
Preparation Method.
Background technique
Memantine hydrochloride is first drug for being used for advanced stage Alzheimer disease (AD), is developed by German Merz company
Exploitation lists in the country such as moral, beauty, for treating neuropathic pain and vascular dementia.The prevention and treatment of senile dementia is one
The international problem of item, with the arrival of world's aging society, the senile note such as senile failure of memory, senile dementia
The prevention and treatment for recalling dysfunction, which seems, to become more and more important.Numerous studies data both domestic and external shows that every ten the elderlys just have one to show
Different degrees of dementia symptom, drastically influences people's health and quality of life.The U.S. is used for the relevant research of senile dementia
Expense is only second to AIDS and ranks second.
Memantine (Memantine hydrochloride), the entitled 3,5- dimethyl tricyclic [3.3.1.1] of chemistry
Decyl- 1- amine hydrochlorate.Clinic is mainly used for treating Parkinson's disease.This product is a kind of the non-of the moderate affinity of voltage-dependent
Competitive N- methyl-D-aspartate receptor antagonist, neuron damage caused by being increased with blocked glutamic acid concentration pathologic
Wound.
There are mainly three types of the traditional synthetic methods of memantine:
(1) replaced for raw material through urea with bromo- 3, the 5- dimethyladamantane of 1-, after ethylene glycol hydrolysis and hydrogen chloride is at salt
It obtains, total recovery 31%；
(2) with bromo- 3, the 5- dimethyladamantane of 1- for raw material, acetamido under the conditions of the acetonitrile concentrated sulfuric acid, sodium hydroxide
Under the conditions of hydrolyze after obtained again with hydrogen chloride at salt, total recovery 67.8%；
(3) with 1,3- dimethyladamantane for raw material, through nitric acid nitrating, after palladium carbon catalytic hydrogenating reduction again with hydrogen chloride at
Salt obtains, total recovery 78%.
Above method be not reaction acutely, when reaction, has strong rufous smog to release, and critical days is higher, or has big
The spent acid of amount generates, or nitrification, and the high requirements on the equipment such as catalytic hydrogenation are inconvenient, and reaction is not easy to control, it is difficult to realize work
Industry metaplasia produces.
Summary of the invention
The present invention provides a kind of methods of completely new synthetic hydrochloric acid Memantine, are with chloro- 3, the 5- dimethyladamantane of 1-
Raw material, through formamide formamide, hydrochloric acid hydrolysis, one-step method directly obtains target product, and total recovery can achieve 80%, product
Purity is more than 99.0%.Compared with traditional synthesis technology, new process synthesis step is simple, significantly reduces production cost, right
The pollution of environment is small, alleviates environmental problem caused by the production of memantine hydrochloride significantly.
The specific preparation method of the present invention includes the following steps:
By the chloro- 3,5- dimethyladamantane of 1- and formamide, 1:0.5~10 react at 60~150 DEG C in molar ratio
It 1~12 hour, without isolation, continuously adds inorganic acid and acidolysis occurs, adjust pH value with inorganic base, then extract through organic solvent,
It is acidified hydrochloric acid salt, final filtration dries to obtain memantine hydrochloride, and yield is 80% or more, and product purity is more than 99.0%.
Starting material in the present invention is the chloro- 3,5- dimethyladamantane of 1-.
Using formamide as aminating reaction reagent in the present invention, formamide includes the formyl amine aqueous solution of various concentration, formyl
Amine also serves as reaction dissolvent.
The chloro- 3,5- dimethyladamantane of 1-, formamide match excellent 1:1~5 in molar ratio in the present invention.
The preferred hydrochloric acid of inorganic acid, hydrobromic acid, sulfuric acid or phosphoric acid, more preferable hydrochloric acid, hydrobromic acid in the present invention.
The preferred sodium hydroxide of inorganic base of the invention, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or bicarbonate
One of potassium or mixture, more preferable sodium hydroxide, potassium hydroxide.
Preferably 80~100 DEG C of formylation reaction temperature of the invention.Reaction time preferably 4~8 hours.
The advantages of preparation method of the present invention, is；
(1) raw material used is cheap and easy to get.It is raw material that pervious technique, which mostly uses greatly bromo- 3, the 5- dimethyladamantane of 1-,
It is raw material that chloro- 3, the 5- dimethyladamantane of 1- more cheap and easy to get is then used in the present invention, reduces cost of material, raising
The competitiveness of product in market；
(2) reaction also effectively reduces pyroreaction bring by-product and impurity, greatly improves in homogeneous middle progress
The content of product memantine hydrochloride, the purity is high (99% or more GC purity) of the memantine hydrochloride of acquisition；
(3) reactive mode of one kettle way is taken in reaction, and acylation reaction occurs for chloro- 3, the 5- dimethyladamantane of 1- and formamide
Afterwards, without isolation, it is directly added into inorganic acid and acidolysis occurs, reduce the loss during reaction transfer, yield significantly improves, always
Yield reaches 80% or more.
Specific embodiment
Case study on implementation 1
At room temperature, into the reactor of installation mechanical agitator and the cold energy device that flows back, chloro- 3, the 5- diformazan of 1- is sequentially added
Base adamantane 88g formamide 170g, finishes, to exothermic process after rise to 80 DEG C of insulated and stirreds 4 hours.Room is down in reaction
Concentrated hydrochloric acid heating is added hydrolysis 5 hours in temperature, cooling, and it is 12~14 that reaction solution, which is adjusted to pH value with sodium hydroxide solution, is added
The extraction of 100ml methylene chloride is added concentrated hydrochloric acid into salt, filters, and drying obtains white crystalline solid memantine hydrochloride 62.9g,
Yield 80.7%, GC purity 99.1%.
Case study on implementation 2
At room temperature, into the reactor of installation mechanical agitator and the cold energy device that flows back, chloro- 3, the 5- diformazan of 1- is sequentially added
Base adamantane 88g formamide 170g, finishes, to exothermic process after rise to 60 DEG C of insulated and stirreds 8 hours.Room is down in reaction
Concentrated hydrochloric acid heating is added hydrolysis 5 hours in temperature, cooling, and it is 12~14 that reaction solution, which is adjusted to pH value with sodium hydroxide solution, is added
The extraction of 100ml methylene chloride is added concentrated hydrochloric acid into salt, filters, and drying obtains white crystalline solid memantine hydrochloride 59.7g,
Yield 76.6%, GC purity 98.9%.
Case study on implementation 3
At room temperature, into the reactor of installation mechanical agitator and the cold energy device that flows back, chloro- 3, the 5- diformazan of 1- is sequentially added
Base adamantane 88g formamide 240g, finishes, to exothermic process after rise to 60 DEG C of insulated and stirreds 8 hours.Room is down in reaction
Concentrated hydrochloric acid heating is added hydrolysis 5 hours in temperature, cooling, and it is 12~14 that reaction solution, which is adjusted to pH value with sodium hydroxide solution, is added
The extraction of 100ml methylene chloride is added concentrated hydrochloric acid into salt, filters, and drying obtains white crystalline solid memantine hydrochloride 59.0g,
Yield 75.7%, GC purity 98.8%.
Case study on implementation 4
At room temperature, into the reactor of installation mechanical agitator and the cold energy device that flows back, chloro- 3, the 5- diformazan of 1- is sequentially added
Base adamantane 88g formamide 140g, finishes, to exothermic process after rise to 80 DEG C of insulated and stirreds 6 hours.Room is down in reaction
Concentrated hydrochloric acid heating is added hydrolysis 5 hours in temperature, cooling, and it is 12~14 that reaction solution, which is adjusted to pH value with sodium hydroxide solution, is added
200ml ethyl alcohol is extracted twice, and merges ethyl alcohol phase, and concentrated hydrochloric acid is added into salt, filters, drying, obtains white crystalline solid hydrochloric acid beauty
Amantadine 63.0g, yield 80.9%, GC purity 99.2%.
Case study on implementation 5
At room temperature, into the reactor of installation mechanical agitator and the cold energy device that flows back, chloro- 3, the 5- diformazan of 1- is sequentially added
Base adamantane 88g formamide 140g, finishes, to exothermic process after rise to 100 DEG C of insulated and stirreds 4 hours.Room is down in reaction
Concentrated hydrochloric acid heating is added hydrolysis 5 hours in temperature, cooling, and it is 12~14 that reaction solution, which is adjusted to pH value with sodium hydroxide solution, is added
200ml ethyl alcohol is extracted twice, and merges ethyl alcohol phase, and concentrated hydrochloric acid is added into salt, filters, drying, obtains white crystalline solid hydrochloric acid beauty
Amantadine 63.1g, yield 81.0%, GC purity 99.5%.
Claims (6)
1. a kind of preparation method of memantine hydrochloride, which is characterized in that with chloro- 3, the 5- dimethyladamantane of 1- for raw material, one
Footwork prepares memantine, by chloro- 3, the 5- dimethyladamantane of 1- and formamide in molar ratio 1:0.5 ~ 10 at 60 ~ 150 DEG C
Under react 1 ~ 12 hour, without isolation, continuously add inorganic acid and acidolysis occur, pH value is adjusted with inorganic base, then through organic
Solvent extraction is acidified hydrochloric acid salt, and final filtration drying obtains memantine hydrochloride, and yield is 80% or more, and product purity is super
Cross 99.0%.
2. the method according to claim 1, wherein formamide includes each using formamide as aminating reaction reagent
The formyl amine aqueous solution of kind concentration, formamide also serve as reaction dissolvent.
3. being pressed the method according to claim 1, wherein chloro- 3, the 5- dimethyladamantane of 1-, formamide proportion are excellent
Molar ratio 1:1 ~ 5.
4. the method according to claim 1, wherein the preferred hydrochloric acid of inorganic acid, hydrobromic acid, sulfuric acid or phosphoric acid, more
It is preferred that hydrochloric acid, hydrobromic acid.
5. the method according to claim 1, wherein the preferred sodium hydroxide of inorganic base, potassium hydroxide, sodium carbonate,
One of potassium carbonate, sodium bicarbonate or saleratus or mixture, more preferable sodium hydroxide, potassium hydroxide.
6. the method according to claim 1, wherein preferably 80 ~ 100 DEG C of formylation reaction temperature, when reaction
Between preferably 4 ~ 8 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711183920.1A CN109824518A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of memantine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711183920.1A CN109824518A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of memantine hydrochloride |
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| Publication Number | Publication Date |
|---|---|
| CN109824518A true CN109824518A (en) | 2019-05-31 |
Family
ID=66858993
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| CN201711183920.1A Pending CN109824518A (en) | 2017-11-23 | 2017-11-23 | A kind of preparation method of memantine hydrochloride |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN116947644A (en) * | 2023-07-26 | 2023-10-27 | 山东轩鸿生物医药有限公司 | A kind of preparation method of memantine hydrochloride |
-
2017
- 2017-11-23 CN CN201711183920.1A patent/CN109824518A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111072491A (en) * | 2019-12-14 | 2020-04-28 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN111072491B (en) * | 2019-12-14 | 2022-11-04 | 老河口瑞祥化工有限公司 | Preparation method of memantine hydrochloride |
| CN116947644A (en) * | 2023-07-26 | 2023-10-27 | 山东轩鸿生物医药有限公司 | A kind of preparation method of memantine hydrochloride |
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