CN109251219A - A new class of Memantine analog and its synthetic method - Google Patents
A new class of Memantine analog and its synthetic method Download PDFInfo
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- CN109251219A CN109251219A CN201811494378.6A CN201811494378A CN109251219A CN 109251219 A CN109251219 A CN 109251219A CN 201811494378 A CN201811494378 A CN 201811494378A CN 109251219 A CN109251219 A CN 109251219A
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- formula
- memantine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
Abstract
The present invention provides a new class of Memantine analog and its salt, and the structure of Memantine analog is as shown in formula I:
Description
Technical field
The present invention is field of medicinal chemistry, is related to a series of new Memantine analogs, and in particular to type I compound and its
Salt.
Background technique
Memantine is the treatment dementia disease drug developed by German Merz company, is novel, the low moderate affinity of one kind, electricity
Pressure rely on, uncompetitive N-methyl-D-Asp (NMDA) receptor antagonist, can Noncompetitive Block nmda receptor, drop
Nmda receptor caused by hypoglutamatergic is overexcited, and Apoptosis is prevented, and is improved memory, is the medicine of novel improvement cognitive function
Object.2 months 2002, the European patent drug committee (CPMP) ratify its be used in, the treatment of severe Alzheimer's disease patient,
The same year August is listed in Germany, and on October 17th, 2003 is ratified by U.S. Food and Drug Administration (FDA) for treating
In, severe Alzheimer's disease patient.Further investigations have shown that memantine is to light, moderate Alzheimer's disease patient
Also effectively.Alzheimer disease (Alzheimer disease, AD), also known as senile dementia, be common complaint among the elderly it
One, it is mainly shown as failure of memory and recognition capability obstacle etc., is a kind of gradual nervous function retrograde degeneration's disease.
Memantine is approved for treatment Alzheimer disease.
The hot spot that structural modification is still drug development is carried out to the adamantane amine drug such as Memantine, needs activity at present
Better compound can apply to clinical treatment or facilitate further developmental research.
Summary of the invention
It is an object of the invention to disclose a new class of Memantine analog and its synthetic method, activity is more preferable, more has
Conducive to the clinical use and further developmental research of drug.
To achieve the above object, the present invention provides a new class of Memantine analog and its salt, Memantine analog
Structure is as shown in formula I:
In formula I:
R is selected from H, CH3 or CH2CH3；
R1 and R2 simultaneously or be respectively selected from substitution and unsubstituted C1-6 alkyl, C1-6 miscellaneous alkyl, C3-6 member naphthenic base
Or C3-6 membered heterocycloalkyl.
In some embodiments, R, R1 are identical substituent group or different substituents with R2.
In some embodiments, salt is hydrochloride, oxalates or tartrate, the salt be Memantine analog with
Acid effect obtains.
The present invention also provides a kind of synthetic methods of compound shown in formula I, anti-through 3 steps using adamantane as starting material
Target compound shown in formula I should be obtained, reaction equation involved in the synthetic route is as follows:
In some embodiments, the reaction of 3 steps is respectively bromination reaction, hydrolysis and amidation process.
In some embodiments, the specific steps of bromination reaction are as follows: in reaction flask, sequentially add adamantane, NBS and
Methylene chloride, for 24 hours, filtering, filter cake is washed to neutrality for room temperature reaction, and dry, ethyl alcohol recrystallization obtains Light yellow crystals, i.e., intermediate
Body 1.
In some embodiments, the specific steps of hydrolysis are as follows: deionized water and intermediate are added in reaction flask
1, sodium hydrate aqueous solution, antipyretic back flow reaction 4h, dilute hydrochloric acid tune PH to 7 is added dropwise, ethyl acetate extraction merges organic layer, ice
After water washing, anhydrous sodium sulfate is dry, filters, and filtrate concentration obtains intermediate 2.
In some embodiments, the specific steps of amidation process are as follows: intermediate 2, anhydrous four are added in reaction flask
Hydrogen furans and methylisopropylamino formyl chloride, are stirred overnight at room temperature, and after addition ice water extraction is gone out, are concentrated under reduced pressure, remove tetrahydro furan
It mutters, ethyl acetate extraction merges organic layer, and ice water is washed to neutrality, and anhydrous sodium sulfate is dry, filters, filtrate concentration, residue second
Alcohol recrystallization, obtains white crystal, i.e. target compound shown in formula I.
Compared with prior art, the beneficial effects of the present invention are: disclosed a new class of Memantine analog,
Its activity is more preferable, is more advantageous to the clinical use and further developmental research of drug.
Specific embodiment
Below with reference to each embodiment, the present invention is described in detail, but it should be stated that, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according to these embodiments in made function, method or structure
Equivalent transformation or substitution, all belong to the scope of protection of the present invention within.
Unless otherwise specified, the term " room temperature " in each embodiment of this specification is specially 23 DEG C；When term " h " is specially
Between measurement unit: hour；Term " min " is specially time measurement unit: minute；Term " ml " is specially volume unit: milliliter；
Gram term " g " is unit of weight, i.e.,.
The present invention provides a new class of Memantine analog and its salt, and the structure of Memantine analog is as shown in formula I:
In formula I:
R is selected from H, CH3 or CH2CH3；
R1 and R2 simultaneously or be respectively selected from substitution and unsubstituted C1-6 alkyl, C1-6 miscellaneous alkyl, C3-6 member naphthenic base
Or C3-6 membered heterocycloalkyl.
In some embodiments, R, R1 are identical substituent group or different substituents with R2.
In some embodiments, salt is hydrochloride, oxalates or tartrate, the salt be Memantine analog with
Acid effect obtains.
The present invention also provides a kind of synthetic methods of compound shown in formula I, anti-through 3 steps using adamantane as starting material
Target compound shown in formula I should be obtained, reaction equation involved in the synthetic route is as follows:
The reaction of 3 steps is respectively bromination reaction, hydrolysis and amidation process.
Compound shown in formula I mainly includes with flowering structure:
Embodiment 1
The preparation of compound B-26
1, the synthesis of intermediate 1
In 5L reaction flask, 136g adamantane, 200gNBS and methylene chloride 2L are sequentially added, room temperature reaction for 24 hours, is filtered,
Filter cake is washed to neutrality, dry, and ethyl alcohol recrystallization obtains Light yellow crystals 106g.
2, the synthesis of intermediate 2
Deionized water 1L and 106g intermediate 1 is added in 3L three-necked flask, and 1M sodium hydrate aqueous solution 600ml is added dropwise, antipyretic
Back flow reaction 4h, dilute hydrochloric acid tune PH to 7, ethyl acetate extract (200ml ╳ 3), merge organic layer, after ice water washing, anhydrous sulphur
Sour sodium is dry, filters, filtrate concentration, and gained intermediate 2 is directly used in react in next step.
3, the synthesis of compound B-26
Step reaction gained intermediate 2, anhydrous tetrahydro furan 1.2L and dimethylaminoethyl chloride is added in 3L three-necked flask
60g is stirred overnight at room temperature, and after addition 200ml ice water extraction is gone out, is concentrated under reduced pressure, removes tetrahydrofuran, ethyl acetate extracts (200ml
╳ 3), merge organic layer, ice water is washed to neutrality, and anhydrous sodium sulfate is dry, is filtered, and filtrate concentration, residue ethyl alcohol recrystallization obtains
White crystal 95g.
Embodiment 2
The preparation of 7 hydrochloride of compound B-11
1, the synthesis of intermediate 1
In 5L reaction flask, 164g dimethyladamantane, 200gNBS and methylene chloride 2L are sequentially added, is reacted at room temperature
For 24 hours, it filters, filter cake is washed to neutrality, and dry, ethyl alcohol recrystallization obtains Light yellow crystals 120g.
2, the synthesis of intermediate 2
Deionized water 1L and 120g intermediate 1 is added in 3L three-necked flask, and 1M sodium hydrate aqueous solution 600ml is added dropwise, antipyretic
Back flow reaction 4h, dilute hydrochloric acid tune PH to 7, ethyl acetate extract (200ml ╳ 3), merge organic layer, after ice water washing, anhydrous sulphur
Sour sodium is dry, filters, filtrate concentration, and gained intermediate 2 is directly used in react in next step.
3, the preparation of compound B-11 7
Step reaction gained intermediate 2, anhydrous tetrahydro furan 1.2L and the first and second base carbamyl chlorides are added in 3L three-necked flask
60g is stirred overnight at room temperature, and after addition 200ml ice water extraction is gone out, is concentrated under reduced pressure, removes tetrahydrofuran, ethyl acetate extracts (200ml
╳ 3), merge organic layer, ice water is washed to neutrality, and anhydrous sodium sulfate is dry, is filtered, and filtrate concentration, residue ethyl alcohol recrystallization obtains
White crystal 102g.
Embodiment 3
The preparation of compound B29
1, the synthesis of intermediate 1
In 5L reaction flask, 192g adamantane, 200gNBS and methylene chloride 2L are sequentially added, room temperature reaction for 24 hours, is filtered,
Filter cake is washed to neutrality, dry, and ethyl alcohol recrystallization obtains Light yellow crystals 132g.
2, the synthesis of intermediate 2
Deionized water 1L and 106g intermediate 1 is added in 3L three-necked flask, and 1M sodium hydrate aqueous solution 600ml is added dropwise, antipyretic
Back flow reaction 4h, dilute hydrochloric acid tune PH to 7, ethyl acetate extract (200ml ╳ 3), merge organic layer, after ice water washing, anhydrous sulphur
Sour sodium is dry, filters, filtrate concentration, and gained intermediate 2 is directly used in react in next step.
3, the preparation of compound B29
Step reaction gained intermediate 2, anhydrous tetrahydro furan 1.2L and methylisopropylamino first is added in 3L three-necked flask
Acyl chlorides 60g, is stirred overnight at room temperature, and after addition 200ml ice water extraction is gone out, is concentrated under reduced pressure, and removes tetrahydrofuran, ethyl acetate extraction
(200ml ╳ 3) merges organic layer, and ice water is washed to neutrality, and anhydrous sodium sulfate is dry, filters, filtrate concentration, residue ethyl alcohol weight
Crystallization, obtains white crystal 99g.
Disclosed a new class of Memantine analog, activity is more preferable, is more advantageous to the clinical use of drug
With further developmental research.
The series of detailed descriptions listed above only for feasible embodiment of the invention specifically
Protection scope bright, that they are not intended to limit the invention, it is all without departing from equivalent implementations made by technical spirit of the present invention
Or change should all be included in the protection scope of the present invention.
It is obvious to a person skilled in the art that invention is not limited to the details of the above exemplary embodiments, Er Qie
In the case where without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, the present embodiments are to be considered as illustrative and not restrictive, and the scope of the present invention is by appended power
Benefit requires rather than above description limits, it is intended that all by what is fallen within the meaning and scope of the equivalent elements of the claims
Variation is included within the present invention.
In addition, it should be understood that although this specification is described in terms of embodiments, but not each embodiment is only wrapped
Containing an independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should
It considers the specification as a whole, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
The other embodiments being understood that.
Claims (8)
1. a new class of Memantine analog and its salt, which is characterized in that the structure of the Memantine analog is as shown in formula I:
In formula I:
R is selected from H, CH3 or CH2CH3；
R1 and R2 simultaneously or be respectively selected from substitution and unsubstituted C1-6 alkyl, C1-6 miscellaneous alkyl, C3-6 member naphthenic base or
C3-6 membered heterocycloalkyl.
2. a new class of Memantine analog according to claim 1 and its salt, which is characterized in that R, R1 are identical with R2
Substituent group or different substituents.
3. a new class of Memantine analog according to claim 1 and its salt, which is characterized in that the salt is hydrochloric acid
Salt, oxalates or tartrate, the salt are that Memantine analog is obtained with acid effect.
4. a kind of synthetic method of compound shown in formula I, which is characterized in that it reacts to obtain using adamantane as starting material through 3 steps
Target compound shown in formula I, reaction equation involved in the synthetic route are as follows:
5. the synthetic method of compound shown in a kind of formula I according to claim 4, which is characterized in that the 3 step reaction point
It Wei not bromination reaction, hydrolysis and amidation process.
6. the synthetic method of compound shown in a kind of formula I according to claim 5, which is characterized in that the bromination reaction
Specific steps are as follows: in reaction flask, sequentially add adamantane, NBS and methylene chloride, room temperature reaction for 24 hours, filtering, filter cake water
It is washed till neutrality, dry, ethyl alcohol recrystallization obtains Light yellow crystals, i.e. intermediate 1.
7. the synthetic method of compound shown in a kind of formula I according to claim 6, which is characterized in that the hydrolysis
Specific steps are as follows: deionized water and intermediate 1 are added in reaction flask, sodium hydrate aqueous solution, antipyretic back flow reaction is added dropwise
4h, dilute hydrochloric acid tune PH to 7, ethyl acetate extraction merge organic layer, and after ice water washing, anhydrous sodium sulfate is dry, filters, filtrate
Concentration, obtains intermediate 2.
8. the synthetic method of compound shown in a kind of formula I according to claim 7, which is characterized in that the amidation is anti-
The specific steps answered are as follows: intermediate 2, anhydrous tetrahydro furan and methylisopropylamino formyl chloride, room temperature are added in reaction flask
It is stirred overnight, after addition ice water extraction is gone out, is concentrated under reduced pressure, removes tetrahydrofuran, ethyl acetate extracts, and merging organic layer, ice water is washed
It washs to neutrality, anhydrous sodium sulfate is dry, filters, and filtrate concentration, residue ethyl alcohol recrystallization obtains white crystal, i.e. target shown in formula I
Compound.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110039874A1 (en) * | 2007-10-16 | 2011-02-17 | Northeastern University | Monoacylglycerol lipase inhibitors for modulation of cannabinoid activity |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
-
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- 2018-12-07 CN CN201811494378.6A patent/CN109251219A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110039874A1 (en) * | 2007-10-16 | 2011-02-17 | Northeastern University | Monoacylglycerol lipase inhibitors for modulation of cannabinoid activity |
| CN106946713A (en) * | 2017-03-13 | 2017-07-14 | 张家港九力新材料科技有限公司 | A kind of preparation method of memantine |
Non-Patent Citations (4)
| Title |
|---|
| A.BENALIL等: "A Convenient and General Synthesis of Alkylcarbamates from Tertiary Isocyanates and Alcohols", 《SYNTHESIS》 * |
| ACS: "STN检索报告", 《REG数据库》 * |
| CHIH-WEI TSAI等: "Synthesis of adamantane-containing methacrylate polymers: Characterization of thermal, mechanical,dielectric and optical properties", 《MATER. EXPRESS》 * |
| ZHENG L等: "Probe to Bifunctional Memantine Derivatives for Treatment of Alzheimer"s Disease", 《J PHARM BIOMED SCI》 * |
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