SORRY.........WILL BE UPDATED ............IN DRAFT MODE
memantine hydrochloride is as illustrated below.
Formula: Ci2H22CIN Molecular weight: 215.81 U.S. Patent No. 3,391,142
NMR......http://file.selleckchem.com/downloads/nmr/S204301-Memantine-HCl-HNMR-Selleck.pdf
HPLC http://file.selleckchem.com/downloads/hplc/S204301-Memantine-hydrochloride-Namenda-HPLC-Selleck.pdf
.......................................................................
IF THERE IS ONE METHYL EXTRA
Example 7: l-Amino-3.5.7-trimethyladamantane hydrochloride (Me-MMN*HC1) synthesis
16.2 g (20 ml) of n-butanol, 2.3 g of l-acetamido-3,5,7-dimethyladamantane, and 3.6 g of 89.9% potassium hydroxide were added to a 50 ml reactor equipped with a condenser, a mechanical stirrer, and a thermometer at 20-250C under nitrogen. After addition, the internal temperature rises to 40-450C without external cooling. The resulting suspension is heated to 128-132°C over 20-30min and a solution is obtained. After 15hrs at 128-132°C (slight reflux), the reaction is considered to be complete (unreacted 1- acetamido-3,5,7-dirnethyladarnantane less than 5%).
After cooling to 45-500C, water (20ml) is added to form a biphasic system. After stirring (5min) and standing (15min) at 20-250C phases are separated. The aqueous phase is discarded and the organic phase is washed with water (2 x 20 ml). The obtained organic solution is acidified with HCl to pH 1 and the solution is concentrated under vacuum until a semisolid is obtained. At this point, after cooling to 45-500C, ethyl acetate (40ml) is added. The obtained suspension is cooled to 0±3°C and after 3hrs the suspension is filtered and the recovered solid is washed three times with ethyl acetate (6ml each). Wet white solid is dried under vacuum at 55-600C for 15hrs. Dry weight, 1.93g. 1H NMR is reported:
1H-NMR in CD3OD (298K)
http://www.google.com.ar/patents/EP1999100A1?cl=en
Memantine hydrochloride, l-amino-3,5-dimethyladamantane hydrochloride, is one of a small group of drugs known as Tricyclic Antivirals (TAVs), and provides good and persistent activation of central nervous system N-methyl-d-aspartate (NMDA) receptors, such that it can be used in the treatment of Parkinson's and Alzheimer's diseases. The chemical structure of memantine hydrochloride is as illustrated below.
Formula: Ci2H22CIN Molecular
weight: 215.81 U.S. Patent No. 3,391,142 ('"142 patent") discloses the
synthesis of memantine hydrochloride and its precursor,
l-acetamido-3,5-dimethyladamantane, according to following scheme.
In the first reaction, l-bromo-3,5-diτnethyladamantane
reacts with 17 moles of acetonitrile and 35 moles of sulphuric acid at
room temperature to give the crude intermediate product in 100 percent
yield. The intermediate product is subjected to alkaline hydrolysis with
sodium hydroxide in diethylene glycol by refluxing at a temperature
greater than 1900C for six hours. The hydrolyzed product is
diluted with water, followed by several benzene extractions, and the
memantine free base is recovered by solvent distillation. The free base
is then diluted with ether, and the addition of hydrogen chloride gas
provides crude memantine hydrochloride. The crude product is then
crystallized from a mixture of ethanol and ether. The '142 patent also
discloses the compounds: l-bromo-3,5,7-trimethyladamantane
(Br-TMAD) and l-bromo-3-methyladamantane (Br-MMAD)
U.S. Patent No. 5,061,703 also discloses the compounds:
l-Amino-3,5,7- trimethyladamantane hydrochloride (Me-MMN*HC1) and
l-Amino-3- methyladamantane hydrochloride (DesMe-MMN*HCl).
Like any synthetic compound, memantine hydrochloride salt can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in memantine hydrochloride salt or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the API, memantine hydrochloride, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."
The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time" ("RRT") to identify impurities. (Strobel p. 922). The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
Those skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L.R.; Kirkland, J.J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See also U.S. Patent No. 6,333,198, incorporated herein by reference.
The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).
The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the reference standard compound using the technique known as "standard addition." In the "standard addition technique", at least two samples are prepared by adding known and differing amounts of the internal standard. (Strobel pp. 391-393, Snyder pp. 571, 572). The proportion of the detector response due to the reference standard present in the mixture without the addition can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero concentration of the reference standard. (See, e.g., Strobel, Fig. 11.4 p. 392). The response of a detector in GC or HPLC (e.g. UV detectors or refractive index detectors) can be and typically is different for each compound eluting from the GC or HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Summary of the Invention In one embodiment the present invention provides a process for preparing memantine HCl having less than about 0.15% of one or both of of Ac-NH-TMAD and Ac- NH -MMAD comprising measuring an amount of at least one or both of N-acetyl-1- amino-3,5,7-trimethyladamantane (Ac-NH-TMAD) and N-acetyl-l-amino-3- methyladamantane (Ac-NH -MMAD) in a batch of l-acetamido-3,5-dimethyladamantane, selecting a batch of l-acetamido-3,5-dimethyladamantane having less than about 0.15% of one or both of of Ac-NH-TMAD or Ac-NH -MMAD and converting the selected batch of l-acetamido-3,5-dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl or MeMMN HCl.
In one embodiment the present invention provides a process for preparing memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl or MeMMN HCl comprising measuring an amount of one or both of l-bromo-3,5,7- trimetyladamantane (Br-TMAD) or l-bromo-3-methyladamantane (Br-MMAD) in a batch of l-bromo-3,5-dimethyladamantane, selecting a batch having one or both of less than about 0.15% of Br-TMAD or less than about 0.20% area Br-MMAD and converting the batch of l-bromo-3,5-dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl and MeMMN HCl.
In one embodiment the present invention provides a process for reducing amount of impurities present in memantine HCl comprising measuring an amount of at least one or both of l-bromo-3,5,7-trimetyladamantane (Br-TMAD) and l-bromo-3- methyladamantane (Br-MMAD) in a batch of l-bromo-355-dimethyladamantane, selecting a batch having at least one of less than about 0.15% Br-TMAD or less than about 0.20% area Br-MMAD as measured by gas chromatography, and converting the batch of 1- bromo-3,5-dimethyladamantane to l-acetamido-3,5-dimethyladamantane; measuring an amount of at least one of N-acetyl-l-amino-3,5,7-trimethyladamantane (Ac-NH-TMAD) and N-acetyl-l-amino-3-methyladamantane (Ac-NH -MMAD) in a batch of 1-acetamido- 3,5-dimethyladamantane, selecting a batch of l-acetamido-3,5-dimethyladamantane having less than about 0.15% area by gas chromatography of at least one of Ac-NH- TMAD and Ac-NH -MMAD and converting the selected batch of l-acetamido-3,5- dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl and MeMMN HCl.
pronunciation (help·info)), also known as Alleppey, is the administrative headquarters of Alappuzha District of Kerala state of southern India. Alappuzha is the ...
.
memantine hydrochloride is as illustrated below.
NMR......http://file.selleckchem.com/downloads/nmr/S204301-Memantine-HCl-HNMR-Selleck.pdf
HPLC http://file.selleckchem.com/downloads/hplc/S204301-Memantine-hydrochloride-Namenda-HPLC-Selleck.pdf
| Molecular Weight (MW) | 215.76 |
|---|---|
| Formula | C12H21N.HCl |
| CAS No. | 41100-52-1 |
IF THERE IS ONE METHYL EXTRA
Example 7: l-Amino-3.5.7-trimethyladamantane hydrochloride (Me-MMN*HC1) synthesis
16.2 g (20 ml) of n-butanol, 2.3 g of l-acetamido-3,5,7-dimethyladamantane, and 3.6 g of 89.9% potassium hydroxide were added to a 50 ml reactor equipped with a condenser, a mechanical stirrer, and a thermometer at 20-250C under nitrogen. After addition, the internal temperature rises to 40-450C without external cooling. The resulting suspension is heated to 128-132°C over 20-30min and a solution is obtained. After 15hrs at 128-132°C (slight reflux), the reaction is considered to be complete (unreacted 1- acetamido-3,5,7-dirnethyladarnantane less than 5%).
After cooling to 45-500C, water (20ml) is added to form a biphasic system. After stirring (5min) and standing (15min) at 20-250C phases are separated. The aqueous phase is discarded and the organic phase is washed with water (2 x 20 ml). The obtained organic solution is acidified with HCl to pH 1 and the solution is concentrated under vacuum until a semisolid is obtained. At this point, after cooling to 45-500C, ethyl acetate (40ml) is added. The obtained suspension is cooled to 0±3°C and after 3hrs the suspension is filtered and the recovered solid is washed three times with ethyl acetate (6ml each). Wet white solid is dried under vacuum at 55-600C for 15hrs. Dry weight, 1.93g. 1H NMR is reported:
1H-NMR in CD3OD (298K)
http://www.google.com.ar/patents/EP1999100A1?cl=enMemantine hydrochloride, l-amino-3,5-dimethyladamantane hydrochloride, is one of a small group of drugs known as Tricyclic Antivirals (TAVs), and provides good and persistent activation of central nervous system N-methyl-d-aspartate (NMDA) receptors, such that it can be used in the treatment of Parkinson's and Alzheimer's diseases. The chemical structure of memantine hydrochloride is as illustrated below.
(Br-TMAD) and l-bromo-3-methyladamantane (Br-MMAD)
Like any synthetic compound, memantine hydrochloride salt can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in memantine hydrochloride salt or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API. It is also known in the art that impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage, and the manufacturing process, including the chemical synthesis. Process impurities include unreacted starting materials, chemical derivatives of impurities contained in starting materials, synthetic by-products, and degradation products.
In addition to stability, which is a factor in the shelf life of the API, the purity of the API produced in the commercial manufacturing process is clearly a necessary condition for commercialization. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially absent. For example, the International Conference on Harmonization of Technical Requirements for Registration for Human Use ("ICH") Q7A guidance for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. At certain stages during processing of the API, memantine hydrochloride, it must be analyzed for purity, typically, by HPLC, TLC or GC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. As discussed above, in the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.
Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram, or a spot on a TLC plate. (Strobel p. 953, Strobel, H. A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd dd. (Wiley & Sons: New York 1989)). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."
The retention time can vary about a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time" ("RRT") to identify impurities. (Strobel p. 922). The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.
Those skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L.R.; Kirkland, J.J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response. See also U.S. Patent No. 6,333,198, incorporated herein by reference.
The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).
The reference standard can serve as an internal standard when, without the deliberate addition of the reference standard, an unknown mixture contains a detectable amount of the reference standard compound using the technique known as "standard addition." In the "standard addition technique", at least two samples are prepared by adding known and differing amounts of the internal standard. (Strobel pp. 391-393, Snyder pp. 571, 572). The proportion of the detector response due to the reference standard present in the mixture without the addition can be determined by plotting the detector response against the amount of the reference standard added to each of the samples, and extrapolating the plot to zero concentration of the reference standard. (See, e.g., Strobel, Fig. 11.4 p. 392). The response of a detector in GC or HPLC (e.g. UV detectors or refractive index detectors) can be and typically is different for each compound eluting from the GC or HPLC column. Response factors, as known, account for this difference in the response signal of the detector to different compounds eluting from the column.
As is known by those skilled in the art, the management of process impurities is greatly enhanced by understanding their chemical structures and synthetic pathways, and by identifying the parameters that influence the amount of impurities in the final product.
Summary of the Invention In one embodiment the present invention provides a process for preparing memantine HCl having less than about 0.15% of one or both of of Ac-NH-TMAD and Ac- NH -MMAD comprising measuring an amount of at least one or both of N-acetyl-1- amino-3,5,7-trimethyladamantane (Ac-NH-TMAD) and N-acetyl-l-amino-3- methyladamantane (Ac-NH -MMAD) in a batch of l-acetamido-3,5-dimethyladamantane, selecting a batch of l-acetamido-3,5-dimethyladamantane having less than about 0.15% of one or both of of Ac-NH-TMAD or Ac-NH -MMAD and converting the selected batch of l-acetamido-3,5-dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl or MeMMN HCl.
In one embodiment the present invention provides a process for preparing memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl or MeMMN HCl comprising measuring an amount of one or both of l-bromo-3,5,7- trimetyladamantane (Br-TMAD) or l-bromo-3-methyladamantane (Br-MMAD) in a batch of l-bromo-3,5-dimethyladamantane, selecting a batch having one or both of less than about 0.15% of Br-TMAD or less than about 0.20% area Br-MMAD and converting the batch of l-bromo-3,5-dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl and MeMMN HCl.
In one embodiment the present invention provides a process for reducing amount of impurities present in memantine HCl comprising measuring an amount of at least one or both of l-bromo-3,5,7-trimetyladamantane (Br-TMAD) and l-bromo-3- methyladamantane (Br-MMAD) in a batch of l-bromo-355-dimethyladamantane, selecting a batch having at least one of less than about 0.15% Br-TMAD or less than about 0.20% area Br-MMAD as measured by gas chromatography, and converting the batch of 1- bromo-3,5-dimethyladamantane to l-acetamido-3,5-dimethyladamantane; measuring an amount of at least one of N-acetyl-l-amino-3,5,7-trimethyladamantane (Ac-NH-TMAD) and N-acetyl-l-amino-3-methyladamantane (Ac-NH -MMAD) in a batch of 1-acetamido- 3,5-dimethyladamantane, selecting a batch of l-acetamido-3,5-dimethyladamantane having less than about 0.15% area by gas chromatography of at least one of Ac-NH- TMAD and Ac-NH -MMAD and converting the selected batch of l-acetamido-3,5- dimethyladamantane to memantine HCl containing less than about 0.15% of at least one of DesMe-MMN HCl and MeMMN HCl.
Alleppey kerala INDIA.....Alappuzha
Alappuzha - Wikipedia, the free encyclopedia
en.wikipedia.org/wiki/Alappuzha
Table in restaurant after eating fish, Alleppey, Kerala, India, South Asia,
PAGODA RESORTS ALLEPPEY KERALA INDIA
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