CN111233670A - Memantine hydrochloride impurity compound and preparation method thereof - Google Patents
Memantine hydrochloride impurity compound and preparation method thereof Download PDFInfo
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- CN111233670A CN111233670A CN202010156639.4A CN202010156639A CN111233670A CN 111233670 A CN111233670 A CN 111233670A CN 202010156639 A CN202010156639 A CN 202010156639A CN 111233670 A CN111233670 A CN 111233670A
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- memantine hydrochloride
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- dimethyladamantane
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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 45
- 229960000967 memantine hydrochloride Drugs 0.000 title claims abstract description 41
- 239000012535 impurity Substances 0.000 title claims abstract description 40
- 150000001875 compounds Chemical class 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title abstract description 13
- ZKRLSFWMHYKXNW-UHFFFAOYSA-N 3,5-dimethyl-7-nitroadamantan-1-ol Chemical compound C1C(C2)(C)CC3(O)CC1(C)CC2([N+]([O-])=O)C3 ZKRLSFWMHYKXNW-UHFFFAOYSA-N 0.000 claims abstract description 28
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims abstract description 18
- QUCXLVDIVQWYJR-UHFFFAOYSA-N 1-bromo-3,5-dimethyladamantane Chemical compound C1C(C2)CC3(C)CC1(C)CC2(Br)C3 QUCXLVDIVQWYJR-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 19
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 8
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 8
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 229960004640 memantine Drugs 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 239000007800 oxidant agent Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 5
- 238000006467 substitution reaction Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000013558 reference substance Substances 0.000 abstract description 4
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 230000033444 hydroxylation Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 19
- 238000001514 detection method Methods 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000010791 quenching Methods 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 3
- 238000003929 heteronuclear multiple quantum coherence Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LBWCITVBZLTEKW-UHFFFAOYSA-N 3,5-dimethyladamantan-1-ol Chemical compound C1C(C2)CC3(C)CC1(C)CC2(O)C3 LBWCITVBZLTEKW-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease 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
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000002072 distortionless enhancement with polarization transfer spectrum Methods 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000036967 uncompetitive effect Effects 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/13—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups
- C07C205/18—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by hydroxy groups having nitro groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
The invention discloses a memantine hydrochloride impurity compound 1-nitro-7-hydroxy-3, 5-dimethyl adamantane and a preparation method thereof, wherein the compound takes 1-bromo-3, 5-dimethyl adamantane as a raw material, performs substitution reaction with acetamide in a molten state, then hydrolyzes and salifies in an alkaline environment, and is obtained after hydroxylation and oxidation, and the impurity compound is used as a reference substance for controlling the quality of memantine hydrochloride and controlling the quality of memantine hydrochloride.
Description
Technical Field
The invention belongs to the field of medical chemistry, and particularly relates to a memantine hydrochloride impurity compound 1-nitro-7-hydroxy-3, 5-dimethyl adamantane and a preparation method thereof.
Background
Memantine hydrochloride is a voltage-dependent, intermediate affinity, uncompetitive NMDA receptor antagonist. It can block the neuron damage caused by the pathological increase of the glutamic acid concentration, and is clinically used for treating the moderate-severe to severe Alzheimer-type dementia.
The preparation method of memantine hydrochloride mainly uses 1-bromo-3, 5-dimethyl adamantane as raw material, and prepares memantine hydrochloride through substitution, hydrolysis and salification reaction. However, 1-hydroxy-3, 5-dimethyladamantane as an impurity is highly likely to be generated in the substitution process, and 1-nitro-7-hydroxy-3, 5-dimethyladamantane as an impurity is highly likely to be generated in the oxidation reaction in the subsequent synthesis or storage process, so that the quality and safety of memantine hydrochloride products are affected. Due to the similar structure of the compound, great difficulty is brought to the subsequent quality control of memantine hydrochloride.
Currently, the united states pharmacopeia standard (USP40) specifies that a single unknown impurity of memantine hydrochloride bulk drug needs to be controlled below 0.10%, that tablets need to be controlled below 0.20% for a single unknown impurity, and that all total impurities need to be controlled below 0.50%. Therefore, the control of impurities is very important for the product quality of memantine hydrochloride bulk drugs or memantine hydrochloride preparations.
However, the memantine hydrochloride impurity compound 1-nitro-7-hydroxy-3, 5-dimethyl adamantane and the synthesis method thereof are not reported in any literature publication. The high-purity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane impurity can be used as an impurity reference substance in the detection standard of the finished memantine hydrochloride product, the positioning analysis and qualitative detection of the finished memantine hydrochloride product on the impurity can be improved, the quality of the finished memantine hydrochloride product is effectively controlled, and the safety of the medicine is ensured. The invention provides a synthesis method of high-purity memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane, which has important practical significance for effectively controlling the quality of memantine hydrochloride products.
Disclosure of Invention
The invention provides a memantine hydrochloride impurity compound 1-nitro-7-hydroxy-3, 5-dimethyl adamantane and a preparation method thereof, and the method has the advantages of easily obtained raw materials, simple operation and high purity of the obtained sample, and can be used as an impurity reference substance in the detection standard of a memantine hydrochloride finished product.
To carry out the invention, the following embodiments are provided.
In one aspect, the invention provides a memantine hydrochloride impurity compound which is 1-nitro-7-hydroxy-3, 5-dimethyladamantane.
In another aspect, the invention provides a process for preparing 1-nitro-7-hydroxy-3, 5-dimethyladamantane, which comprises oxidizing an intermediate III compound in an organic solvent,
wherein in the oxidation, an oxidant is m-chloroperoxybenzoic acid, or the organic solvent is 1, 2-dichloroethane, and the molar weight ratio of the intermediate III to the m-chloroperoxybenzoic acid is 1: 3-1: 6, preferably 1: 4.
The above process of the present invention further comprises the preparation of an intermediate III compound, which comprises the steps of:
a) reacting 1-bromo-3, 5-dimethyladamantane with acetamide to obtain an intermediate I;
b) carrying out hydrolysis reaction on the intermediate I in the presence of alkali, and adding hydrochloric acid for salifying after aftertreatment to obtain an intermediate II;
c) and (3) reacting the intermediate II in the presence of concentrated nitric acid and concentrated sulfuric acid, and then adding alkali to adjust the pH value to be more than 12 to obtain an intermediate III.
In the method of the present invention, in step a), the molar weight ratio of 1-bromo-3, 5-dimethyladamantane to acetamide is 1: 5-1: 10, preferably 1: 5; in the step b), the molar weight ratio of the intermediate I to the alkali is 1: 5-1: 9, preferably 1: 7.
In the above method of the present invention, the alkali used in step b) is sodium hydroxide or potassium hydroxide, preferably potassium hydroxide, and the alkali used in step c) for adjusting the pH is sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
In the method, the reaction temperature in the step a) is 120-150 ℃, and preferably 130-135 ℃; or the hydrolysis reaction temperature in the step b) is 120-140 ℃, and preferably 130-135 ℃.
In yet another aspect, the invention also provides the use of memantine impurity compound 1-nitro-7-hydroxy-3, 5-dimethyladamantane as an impurity control to control the quality of a product containing memantine.
The application is to detect the content of the 1-nitro-7-hydroxy-3, 5-dimethyl adamantane in memantine or hydrochloride thereof and a preparation containing memantine hydrochloride, such as a tablet, by GC or other detection methods, so as to ensure that the quality of memantine hydrochloride and a preparation product thereof meet the medically-allowable quality standard, and the detection method can adopt the detection conditions conventional in the field, such as GC test conditions.
In one embodiment, the method for preparing 1-nitro-7-hydroxy-3, 5-dimethyladamantane as an impurity of the present invention comprises the following steps:
the preparation method comprises the following steps:
a) and adding the starting materials 1-bromo-3, 5-dimethyladamantane and acetamide into a reaction bottle for substitution reaction, and heating for reaction. After the reaction is finished, adding water for quenching, cooling and crystallizing, filtering and drying to obtain a white-like intermediate I;
b) adding the intermediate I, alkali and n-butanol into a reaction bottle for hydrolysis and salification reaction, heating for reaction, adding water for quenching after the reaction is finished, separating liquid, adding concentrated hydrochloric acid into an organic phase to adjust the pH value to 8-9, decompressing and concentrating to remove the organic phase, filtering and drying to obtain an intermediate II;
c) adding concentrated nitric acid and concentrated sulfuric acid into a reaction bottle under the ice-bath condition of hydroxylation reaction, stirring and activating for about 4 hours, then adding the intermediate II in batches, continuing to react for about 3 hours, and removing the ice bath. Reacting at room temperature for about 36h, adding ice water into the reaction solution, continuing stirring for about 30min, adding potassium hydroxide in portions to adjust the pH value of the reaction solution to be greater than 12, stirring for about 2h again, filtering, washing a filter cake with dichloromethane, separating the filtrate, concentrating the organic phase under reduced pressure, and separating by column chromatography to obtain an intermediate III;
d) adding m-chloroperoxybenzoic acid and 1, 2-dichloroethane into a reaction bottle for oxidation reaction, and heating for reflux activation. Slowly dripping 1, 2-dichloroethane solution of the intermediate III, after dripping, carrying out reflux reaction for about 3 hours, after the reaction is finished, washing the reaction solution by using 10% sodium hydroxide solution, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and carrying out column chromatography separation to obtain memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane.
In the above embodiment, in the method for preparing memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane, the molar weight ratio of the 1-bromo-3, 5-dimethyladamantane and the acetamide in the substitution reaction of step a) is 1: 5-1: 10, preferably 1: 5; the reaction temperature is 120-150 ℃, and preferably 130-135 ℃; step b), hydrolyzing and salifying to obtain an intermediate I, wherein the molar weight ratio of alkali to the intermediate I is 1: 5-1: 9, preferably 1: 7; the reaction temperature is 120-140 ℃, and preferably 130-135 ℃; the alkali reagent is one of sodium hydroxide and potassium hydroxide, and potassium hydroxide is preferred. The molar weight ratio of the oxidation reaction intermediate III to the m-chloroperoxybenzoic acid in the step d) is 1: 3-1: 6, preferably 1: 4.
The method of the invention has the following advantages:
the self-designed novel synthesis method has the advantages of easily obtained raw materials and simple operation, the purity GC detection of the obtained impurity sample is more than or equal to 98 percent, and the obtained impurity sample is subjected to1H-NMR、13The structure is confirmed by C-NMR, DEPT, HMQC and HMBC spectra, the detection kit can be used as an impurity reference substance in a memantine hydrochloride finished product detection standard, positioning analysis and qualitative detection of impurities by memantine hydrochloride finished product detection analysis can be improved, the quality of a memantine hydrochloride finished product is effectively controlled, and the safety of a medicine is ensured.
Drawings
FIG. 1 is a GC spectrum of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane;
FIGS. 2 to 3 show the content of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane1An H-NMR spectrum;
FIG. 4 shows the synthesis of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane13A C-NMR spectrum;
FIG. 5 is a DEPT spectrum of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane;
FIG. 6 is a HMQC spectrum of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane;
FIG. 7 is an HMBC spectrum of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyladamantane.
Detailed Description
The following examples are intended to further illustrate the nature of the invention, but not to limit the scope thereof.
The reaction formula of the preparation method of memantine hydrochloride impurities is as follows:
EXAMPLE 11 preparation of nitro-7-hydroxy-3, 5-dimethyladamantane
12.0g of 1-bromo-3, 5-dimethyladamantane and 14.6g of acetamide are added into a reaction flask, and the temperature is raised to 130 ℃ for reaction for about 8 hours. Water was added to quench, the mixture was filtered and the filter cake was dried to give a white solid, about 8.5g of intermediate I.
Adding 8.5g of intermediate I, 15.1g of potassium hydroxide and 30mL of n-butanol into a reaction bottle, and heating to 130 ℃ for overnight reaction. And after the reaction is finished, adding 30mL of water for quenching, separating liquid, extracting the water phase twice by using n-butyl alcohol, combining organic phases, adding concentrated hydrochloric acid to adjust the pH value to be 8-9, decompressing and concentrating to remove the organic phase, filtering and drying to obtain about 6.1g of an intermediate II.
Under ice-bath conditions, 6.1mL of concentrated nitric acid and 61.0mL of concentrated sulfuric acid were added to the reaction flask, and the mixture was stirred and activated for about 4 hours. Then, 6.1g of intermediate II was added in portions, and after continuing the reaction for 3 hours, the ice bath was removed. Reacting at room temperature for about 36h, adding ice water into the reaction solution, continuing stirring for about 30min, adding potassium hydroxide in portions to adjust the pH value to be more than 12, and stirring again for about 2 h. Filtering, washing a filter cake by dichloromethane, separating liquid from the filtrate, concentrating an organic phase, and carrying out column chromatography separation to obtain about 4.4g of an intermediate III.
15.5g of m-chloroperoxybenzoic acid and 155mL of 1, 2-dichloroethane are added into a reaction bottle and heated for reflux activation. 4.4g of intermediate III in 44mL of 1, 2-dichloroethane was slowly added dropwise, and the reaction was refluxed for about 3 hours after completion of the addition. After the reaction, the reaction solution was washed with 10% sodium hydroxide solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering, decompressing and concentrating the filtrate, and separating by column chromatography to obtain 3.8g of memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane (total yield 34.18%).
The obtained memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane is treated by1H-NMR、13C-NMR, DEPT, HMQC and HMBC spectrums confirm that the structure is correct, and the purity is 100 percent through GC detection.1H-NMR(400MHz，CDCl3+D2O)：δ2.088(s，2H，CH2-10),1.838(t，4H，CH2-2，CH2-6),1.714(s，1H，OH-7),1.439(q，4H，CH2-8，CH2-9),1.185(s，2H，CH2-4),1.017(s，6H，CH3-11，CH3-12)；13C-NMR (400MHz, CDCl 3): delta 86.970(C-1), 70.706(C-7), 49.846(C-8, C-9), 48.816(C-4), 46.731(C-10), 45.706(C-2, C-6), 34.894(C-3, C-5), 28.798(C-11, C-12). Specifically, the retention time of 1-nitro-7-hydroxy-3, 5-dimethyladamantane is 53.270 in figure 1, figure 2, figure 3, figure 4, figure 5, figure 6 and figure 7.
Example 21-Nitro-7-hydroxy-3, 5-dimethyladamantane
12g of 1-bromo-3, 5-dimethyladamantane and 18.2g of acetamide are added into a reaction bottle, and the temperature is raised to 135 ℃ for reaction for about 8 hours. Water was added to quench, the mixture was filtered and the filter cake was dried to give a white solid, about 8.6g of intermediate I.
Adding 8.6g of intermediate I, 10.9g of sodium hydroxide and 40mL of n-butanol into a reaction bottle, and heating to 130 ℃ for overnight reaction. And after the reaction is finished, adding 40mL of water for quenching, separating liquid, extracting the water phase twice by using n-butanol, combining organic phases, adding concentrated hydrochloric acid to adjust the pH value to 8-9, decompressing and concentrating to remove the organic phase, filtering and drying to obtain about 5.7g of an intermediate II.
5.7mL of concentrated nitric acid and 57.0mL of concentrated sulfuric acid were added to the reaction flask under ice-bath conditions, and the mixture was activated with stirring for about 4 hours. Then, 5.7g of intermediate II was added in portions, and after continuing the reaction for 3 hours, the ice bath was removed. Reacting at room temperature for about 36h, adding ice water into the reaction solution, continuing stirring for about 30min, adding potassium hydroxide in portions to adjust the pH value to be more than 12, and stirring again for about 2 h. Filtering, washing a filter cake by dichloromethane, separating liquid from the filtrate, concentrating an organic phase, and carrying out column chromatography separation to obtain about 4.0g of an intermediate III.
14.1g of m-chloroperoxybenzoic acid and 141mL of 1, 2-dichloroethane are added into a reaction flask, and the temperature is increased for reflux activation. 4.0g of intermediate III in 40mL of 1, 2-dichloroethane solution was slowly added dropwise, and the reaction was refluxed for about 3 hours after the addition. After the reaction, the reaction solution was washed with 10% sodium hydroxide solution, and the organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating the filtrate under reduced pressure, and separating by column chromatography to obtain memantine hydrochloride impurity 1-nitro-7-hydroxy-3, 5-dimethyl adamantane 3.3g (GC purity 99.2%, total yield 29.68%).
Claims (10)
1. An impurity compound of memantine hydrochloride is 1-nitro-7-hydroxy-3, 5-dimethyl adamantane,
2. a method for preparing 1-nitro-7-hydroxy-3, 5-dimethyl adamantane comprises oxidizing intermediate III compound in organic solvent,
3. the process of claim 2, wherein the oxidizing agent is m-chloroperoxybenzoic acid, or the organic solvent is 1, 2-dichloroethane.
4. The process of claim 2, wherein said intermediate III compound is prepared by a process comprising the steps of:
a) reacting 1-bromo-3, 5-dimethyladamantane with acetamide to obtain an intermediate I;
b) carrying out hydrolysis reaction on the intermediate I in the presence of alkali, and adding hydrochloric acid for salifying after aftertreatment to obtain an intermediate II;
c) and (3) reacting the intermediate II in the presence of concentrated nitric acid and concentrated sulfuric acid, and then adding alkali to adjust the pH value to be more than 12 to obtain an intermediate III.
5. The method according to claim 4, wherein in the step a), the molar weight ratio of the 1-bromo-3, 5-dimethyladamantane to the acetamide is 1: 5-1: 10, preferably 1: 5.
6. The process of claim 4, wherein in step b), the molar weight ratio of the intermediate I to the base is 1: 5-1: 9, preferably 1: 7.
7. The method of claim 4, wherein the base in step b) or step c) is sodium hydroxide or potassium hydroxide.
8. The process according to claim 4, wherein the reaction temperature of step a) is 120 to 150 ℃, preferably 130 to 135 ℃; or the reaction temperature in the step b) is 120-140 ℃, preferably 130-135 ℃.
9. The method of claim 3, wherein the molar weight ratio of the intermediate III to the m-chloroperoxybenzoic acid is 1: 3-1: 6, preferably 1: 4.
10. Use of the impurity compound 1-nitro-7-hydroxy-3, 5-dimethyladamantane as a control to control the quality of a product containing memantine.
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| CN202010156639.4A Pending CN111233670A (en) | 2020-03-09 | 2020-03-09 | Memantine hydrochloride impurity compound and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101412678A (en) * | 2008-10-29 | 2009-04-22 | 苏州大学 | Method for synthesizing memantine hydrochloride |
| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| CN103483205A (en) * | 2013-10-12 | 2014-01-01 | 合肥久诺医药科技有限公司 | Preparation method of high-purity memantine hydrochloride |
| CN107365255A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of industrialized memantine production method |
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2020
- 2020-03-09 CN CN202010156639.4A patent/CN111233670A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009153806A2 (en) * | 2008-05-09 | 2009-12-23 | Sairam Organics Pvt. Ltd. | Process for preparing memantine hydrochloride substantially free of !mpurities |
| CN101412678A (en) * | 2008-10-29 | 2009-04-22 | 苏州大学 | Method for synthesizing memantine hydrochloride |
| CN103483205A (en) * | 2013-10-12 | 2014-01-01 | 合肥久诺医药科技有限公司 | Preparation method of high-purity memantine hydrochloride |
| CN107365255A (en) * | 2016-05-11 | 2017-11-21 | 常州制药厂有限公司 | A kind of industrialized memantine production method |
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