CN109516920B - Synthesis method of amantadine - Google Patents
Synthesis method of amantadine Download PDFInfo
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- CN109516920B CN109516920B CN201811385510.XA CN201811385510A CN109516920B CN 109516920 B CN109516920 B CN 109516920B CN 201811385510 A CN201811385510 A CN 201811385510A CN 109516920 B CN109516920 B CN 109516920B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- 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
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Abstract
The invention discloses a method for synthesizing amantadine, which comprises the following steps: adding 1-bromoadamantane and ammonium bicarbonate into a high-pressure kettle, uniformly mixing, heating to the reaction temperature for amination reaction, cooling to room temperature after the reaction is finished, adding water for stirring, separating out solid, filtering, washing a filter cake with water to obtain a yellow amantadine crude product, dissolving the crude product in a recrystallization solvent for recrystallization to obtain a white solid, namely an amantadine product; the reaction formula is as follows:
Description
Technical Field
The invention relates to a synthetic method of amantadine.
Background
Adamantane is a highly symmetrical cage-like hydrocarbon, the whole ring system has the structural characteristics of perfect symmetry and high stability, and adamantane molecules can also undergo the reactions of skeleton rearrangement, oxidation, alkylation and the like under certain conditions, so that the adamantane molecules have strong designability, and have wide application in the aspects of medicines, functional polymers, lubricants, surfactants, catalysts, photographic materials and the like, and are called a new generation of fine chemical raw materials (Yang Hu Po, Li Bin. the current situation and the progress of synthesis technology of cage-like hydrocarbon adamantane. the proceedings of the Hunan engineering institute, 2005, 15(4): 92.). Amantadine is an amino derivative of adamantane, and the amantadine and derivatives thereof generally have good fat solubility and low toxicity and show unique pharmacological action, so far, a plurality of amantadine derivatives and salts thereof (such as amantadine, rimantadine, trodamide, xodamide, dopamine, hydrochloride thereof, carboxylate thereof and the like) have been found to have special drug properties clinically, and can be used for resisting virus, resisting tumor and reducing blood fat or used as cerebral vasodilators, artificial blood and treating Parkinson's syndrome and the like (Wanglinfeng, Zhaxian, Huhongyu, adamantane derivatives and bioactive drugs thereof.Biochemical engineering2017, 3(1): 70); in addition, the method has potential application in the fields of synthesizing novel functional polymer materials, molecular sieves and the like. In view of this, the research on the synthesis method of amantadine has been receiving much attention.
Regarding the synthesis method of amantadine, there are three main routes reported in the literature:
1. adamantane is used as a starting material, and reacts with halogen to generate halogenated adamantane, and then reacts with an amination reagent to perform amination reaction to obtain amantadine (chemical system of Lanzhou university. amantadine hydrochloride).Pharmaceutical industry1973, 4(6): 14.), as shown in formula (I-1);
2. adamantane is used as a starting material, and is subjected to nitration reaction to generate 1-nitro adamantane, and then is reduced to obtain amantadine (Park, KK; OH, CH; Sim, WJ. Chemoselective reduction of nitroarenes and nitroalkanes by sodium dithionite using octalviogen an electron transfer catalyst.J.Org. Chem,1995, 606202) is shown as formula (I-2);
3. the research on the derivatives of adamantanamine is advanced by using adamantane as a starting material, synthesizing adamantanol nitrate through an oxidation reaction of a nitric acid-sulfuric acid system, and performing amination to obtain the adamantanamine (niu hui, li hui, lang shui, etc.).Medical science Exercise machine2016, 40, 59.) as shown in formula (I-3).
At present, the formula (I-1) route is mainly adopted in the industry, namely, the process for synthesizing amantadine by bromo-amantadine is adopted, and urea is commonly used as an amination reagent (Shao Gui, Bayberry, Wu Chun Li).Chemical intermediate2009, (7): 55.), the process has the advantages of short reaction period, high yield, low cost, etc. In the method, although the cost of the urea is low, the dosage of the urea needs to be greatly excessive, the urea is difficult to recover due to the decomposition of the urea into organic wastes such as isocyanic acid, cyanuric acid, ammelide and the like in a high-temperature reaction, and the treatment cost of waste water and waste residue is high. Patent US5599998(Kraus, GA. Method for)the synthesis of adamantane amines, U.S. Pat. No. 5,5599998, 1997-02-04) reported a method in which bromoadamantane (halide) was reacted with lithium metal followed by reaction with amination reagents such as hydroxylamine-O-sulfonate, monochloramine, etc. under ultrasonic conditions to give amantadine. The reaction needs to use metallic lithium, the price is high, the reaction needs ultrasonic conditions, the process is complex, and the final yield is not high. Also, in the related patent, amantadine is obtained by using liquid ammonia as an aminating agent and reacting the mixture at about 170 ℃ for 15 hours under a closed condition (Mills, J; Krumkalns, E. Adamantanyl secondary amines. U.S. 3391142, 1966-07-02.). However, the reaction time of the method is too long and the reaction yield is less than 15%.
Disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a method for synthesizing amantadine, which has the advantages of stable process, low price, less three wastes and higher yield.
A synthetic method of amantadine is characterized in that 1-bromoadamantane and ammonium bicarbonate are added into a high-pressure kettle, are uniformly mixed, are heated to the reaction temperature for amination reaction, are cooled to the room temperature after the reaction is finished, are added with water and stirred to separate out solid, are filtered, are washed by filter cake water to obtain crude amantadine, and are dissolved in a solvent for recrystallization to obtain white solid, namely an amantadine product; the reaction formula is as follows:
the method for synthesizing amantadine is characterized in that the feeding molar ratio of 1-bromoadamantane to ammonium bicarbonate is 1: 2.0-30, and preferably 1: 5.0-10.
The synthesis method of amantadine is characterized in that the temperature for amination is 110-160 ℃, and preferably 120-140 ℃; the time for amination reaction is 2-10 h, preferably 3-6 h.
The method for synthesizing amantadine is characterized in that a solvent used for recrystallization is a mixed solution of water and a water-soluble organic solvent, and the volume ratio of the water to the water-soluble organic solvent is 1: 1.0-9.0, preferably 1: 1.0-4.0.
The method for synthesizing amantadine is characterized in that the water-soluble organic solvent is one or a mixture of more than two of methanol, ethanol, propanol, isopropanol, acetone, tetrahydrofuran and acetonitrile.
The method for synthesizing amantadine is characterized in that the water-soluble organic solvent is one or a mixture of more than two of ethanol, acetone, tetrahydrofuran and acetonitrile.
The invention takes 1-bromo-adamantane as a raw material, ammonium bicarbonate as an amination reagent to prepare amantadine, the reaction is carried out in a heating and melting state, the ammonium bicarbonate is heated and decomposed to generate ammonia gas, carbon dioxide and water, wherein the ammonia gas and the 1-bromo-adamantane are subjected to amination reaction, byproducts such as the carbon dioxide, excessive ammonia gas and the like generated by decomposition of the ammonium bicarbonate can be directly queued, the undecomposed ammonium bicarbonate can be easily removed by washing, and the washed ammonium bicarbonate can be recycled. Therefore, compared with the prior urea which is commonly used in industrialization as the amination reagent, the amination reagent has the advantages of low reaction cost, less three wastes, convenient post-treatment, higher yield and the like.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 39.5g (0.5 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 125 ℃ for reaction, and continuously reacting for 4 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake with water to obtain a yellow amantadine crude product, and recrystallizing the crude product by using a mixed solution of 20mL of water and 20mL of ethanol to obtain 12.6g of white solid (the white solid is the amantadine product), wherein the yield is 83.6%.
Melting point: 205-207 ℃;1H NMR (500 MHz, CDCl3) δ 8.19 (s, 2H), 2.08 (m, 4H), 1.82(m, 3H), 1.70 (m, 4H), 1.57 (m, 4H)。
example 2
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 55.3g (0.7 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 130 ℃ for reaction, and continuously reacting for 5 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 10mL of water and 30mL of mixed solution acetone to obtain 13.1g of white solid (the white solid is the amantadine product), wherein the yield is 86.8%.
Example 3
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 79.0g (1 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 135 ℃ for reaction, and continuously reacting for 6 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product with 8mL of water and 32mL of tetrahydrofuran to obtain 14.3g of white solid (the white solid is the amantadine product), wherein the yield is 94.7%.
Example 4
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 47.4g (0.6 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 120 ℃ for reaction, and continuously reacting for 5 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 10mL of water and 30mL of acetonitrile to obtain 12.7g of white solid (the white solid is the amantadine product), wherein the yield is 84.1%.
Example 5
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 63.2g (0.8 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 140 ℃ for reaction, and continuously reacting for 4 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 15mL of water and 25mL of ethanol to obtain 13.4g of white solid (the white solid is the amantadine product), wherein the yield is 88.7%.
Example 6
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 39.5g (0.5 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 125 ℃ for reaction, and continuously reacting for 4 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 20mL of water and 20mL of acetonitrile to obtain 12.7g of white solid (the white solid is the amantadine product), wherein the yield is 84.2%.
Example 7
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 71.1g (0.9 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 130 ℃ for reaction, and continuously reacting for 6 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 10mL of water and 30mL of tetrahydrofuran to obtain 14.0g of white solid (the white solid is the amantadine product), wherein the yield is 92.7%.
Example 8
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 47.4g (0.6 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 125 ℃ for reaction, and continuously reacting for 4 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake to obtain a yellow crude product of amantadine, and recrystallizing the crude product by using 15mL of water and 25mL of acetone to obtain 12.5g of white solid (the white solid is the amantadine product), wherein the yield is 82.8%.
Example 9
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 63.2g (0.8 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 120 ℃ for reaction, and continuously reacting for 3 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake with water to obtain a yellow crude product of amantadine, and recrystallizing the crude product with a mixed solution of 10mL of water, 10mL of ethanol and 20mL of acetone to obtain 12.7g of white solid (the white solid is the amantadine product), wherein the yield is 84.1%.
Example 10
Adding 21.5g (0.1 mol) of 1-bromoadamantane and 55.3g (0.7 mol) of ammonium bicarbonate into a 250 mL autoclave, uniformly mixing, directly heating to 135 ℃ for reaction, and continuously reacting for 5 hours; after the reaction is finished, cooling the reaction liquid to room temperature, adding water, and stirring to separate out a solid; filtering, washing a filter cake with water to obtain a yellow crude product of amantadine, and recrystallizing the crude product with a mixed solution of 10mL of water, 10mL of ethanol, 10mL of acetone and 10mL of acetonitrile to obtain 14.1g of white solid (the white solid is the amantadine product), wherein the yield is 93.0%.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (6)
1. A synthetic method of amantadine is characterized in that 1-bromoadamantane and ammonium bicarbonate are added into a high-pressure kettle, are uniformly mixed, are heated to the reaction temperature for amination reaction, are cooled to the room temperature after the reaction is finished, are added with water and stirred to separate out solid, are filtered, are washed by filter cake water to obtain crude amantadine, and are dissolved in a solvent for recrystallization to obtain white solid, namely an amantadine product; the reaction formula is as follows:
the feeding molar ratio of the 1-bromoadamantane to the ammonium bicarbonate is 1: 2.0-30;
the temperature for carrying out the amination reaction is 110-160 ℃, and the time for carrying out the amination reaction is 2-10 h;
the solvent used for recrystallization is a mixed solution of water and a water-soluble organic solvent, and the volume ratio of the water to the water-soluble organic solvent is 1: 1.0-9.0.
2. The method for synthesizing amantadine according to claim 1, characterized in that the feeding molar ratio of 1-bromoadamantane to ammonium bicarbonate is 1: 5.0-10.
3. The method for synthesizing amantadine according to claim 1, characterized in that the temperature for amination is 120-140 ℃; the time for amination reaction is 3-6 h.
4. The method for synthesizing amantadine according to claim 1, characterized in that the volume ratio of water to the water-soluble organic solvent is 1: 1.0-4.0.
5. The method according to claim 4, wherein the water-soluble organic solvent is one or a mixture of two or more of methanol, ethanol, propanol, acetone, tetrahydrofuran, and acetonitrile.
6. The method according to claim 5, wherein the water-soluble organic solvent is one or a mixture of two or more of ethanol, acetone, tetrahydrofuran, and acetonitrile.
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| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
| CN114409547A (en) * | 2022-01-27 | 2022-04-29 | 浙江普洛康裕制药有限公司 | Continuous production method and device of amantadine |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599998A (en) * | 1994-10-24 | 1997-02-04 | Iowa State University Research Foundation, Inc. | Method for the synthesis of adamantane amines |
| CN1424304A (en) * | 2002-12-12 | 2003-06-18 | 厦门市先端科技有限公司 | Preparation for aniline, phenol and derivative thereof |
| CN108084033A (en) * | 2017-12-29 | 2018-05-29 | 山东诚汇双达药业有限公司 | A kind of preparation method of N, N- diethyl ethylenediamine |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5599998A (en) * | 1994-10-24 | 1997-02-04 | Iowa State University Research Foundation, Inc. | Method for the synthesis of adamantane amines |
| CN1424304A (en) * | 2002-12-12 | 2003-06-18 | 厦门市先端科技有限公司 | Preparation for aniline, phenol and derivative thereof |
| CN108084033A (en) * | 2017-12-29 | 2018-05-29 | 山东诚汇双达药业有限公司 | A kind of preparation method of N, N- diethyl ethylenediamine |
Non-Patent Citations (3)
| Title |
|---|
| 2-氨基-4,6-二甲氧基-1,3,5-三嗪的合成;胡建洲等;《化工中间体》;20031231(第22期);第24-25页 * |
| 甘氨酸的合成工艺研究;《今日农药》;20111231(第11期);第28-29页 * |
| 金刚烷胺盐酸盐的合成;兰州大学化学系;《中国医药工业杂志》;19731231(第6期);第14-15页 * |
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