CN111170849A - Synthesis method of 3-amino-1-adamantanol - Google Patents
Synthesis method of 3-amino-1-adamantanol Download PDFInfo
- Publication number
- CN111170849A CN111170849A CN202010028740.1A CN202010028740A CN111170849A CN 111170849 A CN111170849 A CN 111170849A CN 202010028740 A CN202010028740 A CN 202010028740A CN 111170849 A CN111170849 A CN 111170849A
- Authority
- CN
- China
- Prior art keywords
- adamantanol
- amino
- adamantane
- bromo
- tert
- Prior art date
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- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 title claims abstract description 24
- 238000001308 synthesis method Methods 0.000 title abstract description 5
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims abstract description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 12
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 10
- JBEPFZCYCKRHTN-UHFFFAOYSA-N C(=O)O.C12CC3CC(CC(C1)C3)C2 Chemical compound C(=O)O.C12CC3CC(CC(C1)C3)C2 JBEPFZCYCKRHTN-UHFFFAOYSA-N 0.000 claims abstract description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 8
- SXDBWCPKPHAZSM-UHFFFAOYSA-M bromate Inorganic materials [O-]Br(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-M 0.000 claims abstract description 7
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- DJUDQBVINJIMFO-JZVMUCMXSA-N (5r,7s)-3-bromoadamantane-1-carboxylic acid Chemical compound C([C@@H](C1)C2)[C@@H]3CC1(Br)CC2(C(=O)O)C3 DJUDQBVINJIMFO-JZVMUCMXSA-N 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 4
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 claims abstract description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims abstract description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 235000019253 formic acid Nutrition 0.000 claims abstract description 4
- 238000010438 heat treatment Methods 0.000 claims abstract description 4
- 239000003960 organic solvent Substances 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 239000000758 substrate Substances 0.000 claims abstract description 4
- 238000000967 suction filtration Methods 0.000 claims abstract description 4
- 238000001291 vacuum drying Methods 0.000 claims abstract description 4
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 3
- 238000002360 preparation method Methods 0.000 claims description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 241000486679 Antitype Species 0.000 description 1
- VLLNJDMHDJRNFK-UHFFFAOYSA-N adamantan-1-ol Chemical compound C1C(C2)CC3CC2CC1(O)C3 VLLNJDMHDJRNFK-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 230000009615 deamination Effects 0.000 description 1
- 238000006481 deamination reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 229940052761 dopaminergic adamantane derivative Drugs 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 229920001002 functional polymer Polymers 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000010687 lubricating oil Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- 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
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 3-amino-1-adamantanol, which takes adamantane formic acid as a substrate and comprises the following steps: (1) slowly adding adamantane formic acid into the liquid bromine, and synthesizing the 3-bromine-1-adamantane formic acid under the action of an anhydrous aluminum trichloride catalyst; (2) reacting the synthesized 3-bromo-1-adamantanecarboxylic acid with triethylamine, diphenyl phosphorazide and tert-butyl alcohol at 80-110 ℃ for 12-16 hours in an organic solvent to synthesize 3-bromo-1-tert-butoxycarbonylamamidated adamantane; (3) carrying out reflux reaction on 3-bromo-1-tert-butoxycarbonylamantadine in a hydrobromic acid solution with the excessive molar concentration of 10% for 24-48 hours, (4) adding the synthesized bromate type 3-amino-1-adamantanol in a sodium hydroxide solution with the same molar concentration, heating to 30 ℃ while stirring, cooling to separate out a solid, carrying out suction filtration, and carrying out vacuum drying to obtain the 3-amino-1-adamantanol. The method has the characteristics of simple steps, easy operation, environmental friendliness, low cost, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to the field of adamantanol preparation, and in particular relates to a synthesis method of 3-amino-1-adamantanol.
Background
Adamantane is a cyclic tetrahedral hydrocarbon with highly symmetrical molecular structure, similar to a lattice unit of diamond, and hydrocarbon molecules close to spherical shape, and has unique physical and chemical properties. The adamantane and the derivatives thereof have wide application, are widely applied to various fields such as biomedicine, functional polymer materials, lubricating oil, catalysts, surfactants, pesticides and the like, and are called as a new generation of fine chemical raw materials. Its special structure makes it possess excellent liposolubility and low toxicity, and possesses unique pharmacological action, and the adamantane and its derivative can be used in medicine for preparing various specific medicines. Such as adamantane derivatives, are useful for the synthesis of specific drugs. 3-amino-1-adamantanol is an important 1, 3-disubstituted diamondoid drug intermediate, such as LAF237(US20080167479A1) used for synthesizing oral anti-type 2 diabetes drugs.
The following methods are disclosed in the literature for the synthesis of 3-amino-1-adamantanol: the method comprises the following steps: deamination hydrolysis of 1, 3-diamantane under specific conditions gives 3-amino-1-adamantanol (i.k. moiseev, v.p. konovalova, s.s. novikov, khim.1973, 10, 2378-2349). The method firstly prepares the 1, 3-diamantane, and has the disadvantages of multiple reaction steps, low selectivity and low yield. The method 2 comprises the following steps: selective oxidation of amantadine with acetone trifluoroperoxide gave 3-amino-1-adamantanol (G.Asenslo, M.E.Gonzalez-Nunez, J.Am.chem.Soc.1993, 115, 7250-7253). The raw materials adopted by the method are difficult to obtain and unstable, and the reaction conditions are difficult to industrialize. The method 3 comprises the following steps: 3-bromo-1-adamantanecarboxylic acid was subjected to azide rearrangement with sodium azide and then hydrolyzed to give 3-amino-1-adamantanol (A. Donetti, E.Bellor, Synthetic communications.1943, 3, 165-166). The method has low reaction safety coefficient by using sodium azide and is not easy to industrialize.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides the synthesis method of the 3-amino-1-adamantanol, which has the characteristics of simple steps, easy operation, environmental friendliness, low cost, high yield and suitability for industrial production, and the dichloromethane, chloroform and other solutions after washing and using the product can be recycled, so that the production cost is reduced.
In order to achieve the aim of the invention, the invention adopts the specific scheme that:
a synthetic method of 3-amino-1-adamantanol takes adamantane formic acid as a substrate, and the formula is as follows:
the preparation method comprises the following steps:
(1) slowly adding adamantane formic acid into the liquid bromine, stirring and refluxing for reaction for 48-60 hours at the temperature of 20-10 ℃ under the action of an anhydrous aluminum trichloride catalyst, and reacting for 5 hours at the temperature of 20-30 ℃ to synthesize 3-bromine-1-adamantane formic acid;
(2) reacting the synthesized 3-bromo-1-adamantanecarboxylic acid with triethylamine, diphenyl phosphorazide and tert-butyl alcohol at 80-110 ℃ for 12-16 hours in an organic solvent to synthesize 3-bromo-1-tert-butoxycarbonylamamidated adamantane;
(3) carrying out reflux reaction on 3-bromo-1-tert-butoxycarbonylamantadine in a hydrobromic acid solution with the excessive molar concentration of 10% for 24-48 hours to synthesize bromate type 3-amino-1-adamantanol;
(4) and (2) adding the synthesized bromate type 3-amino-1-adamantanol into an equimolar sodium hydroxide solution, heating to 30 ℃ while stirring, cooling to separate out a solid, performing suction filtration, and performing vacuum drying to obtain the 3-amino-1-adamantanol.
The invention has the beneficial effects that:
the method has the characteristics of simple and easy operation, environmental friendliness, low cost, high yield and suitability for industrial production, and the dichloromethane, chloroform and other solutions after washing and using the product can be recycled, so that the production cost is reduced.
Detailed Description
The present invention is further described below by way of specific examples, but the present invention is not limited to only the following examples. Variations, combinations, or substitutions of the invention, which are within the scope of the invention or the spirit, scope of the invention, will be apparent to those of skill in the art and are within the scope of the invention.
A synthetic method of 3-amino-1-adamantanol takes adamantane formic acid as a substrate, and the formula is as follows:
the preparation method comprises the following steps:
(1) slowly adding adamantane formic acid into the liquid bromine, stirring and refluxing for reaction for 48-60 hours at the temperature of 20-10 ℃ under the action of an anhydrous aluminum trichloride catalyst, and reacting for 5 hours at the temperature of 20-30 ℃ to synthesize 3-bromine-1-adamantane formic acid;
(2) reacting the synthesized 3-bromo-1-adamantanecarboxylic acid with triethylamine, diphenyl phosphorazide and tert-butyl alcohol at 80-110 ℃ for 12-16 hours in an organic solvent to synthesize 3-bromo-1-tert-butoxycarbonylamamidated adamantane;
(3) carrying out reflux reaction on 3-bromo-1-tert-butoxycarbonylamantadine in a hydrobromic acid solution with the excessive molar concentration of 10% for 24-48 hours to synthesize bromate type 3-amino-1-adamantanol;
(4) and (2) adding the synthesized bromate type 3-amino-1-adamantanol into an equimolar sodium hydroxide solution, heating to 30 ℃ while stirring, cooling to separate out a solid, performing suction filtration, and performing vacuum drying to obtain the 3-amino-1-adamantanol.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the present invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (1)
1. A method for synthesizing 3-amino-1-adamantanol is characterized in that adamantane formic acid is used as a substrate, and the formula is as follows:
the preparation method comprises the following steps:
(1) slowly adding adamantane formic acid into the liquid bromine, stirring and refluxing for reaction for 48-60 hours at the temperature of 20-10 ℃ under the action of an anhydrous aluminum trichloride catalyst, and reacting for 5 hours at the temperature of 20-30 ℃ to synthesize 3-bromine-1-adamantane formic acid;
(2) reacting the synthesized 3-bromo-1-adamantanecarboxylic acid with triethylamine, diphenyl phosphorazide and tert-butyl alcohol at 80-110 ℃ for 12-16 hours in an organic solvent to synthesize 3-bromo-1-tert-butoxycarbonylamamidated adamantane;
(3) carrying out reflux reaction on 3-bromo-1-tert-butoxycarbonylamantadine in a hydrobromic acid solution with the excessive molar concentration of 10% for 24-48 hours to synthesize bromate type 3-amino-1-adamantanol;
(4) and (2) adding the synthesized bromate type 3-amino-1-adamantanol into an equimolar sodium hydroxide solution, heating to 30 ℃ while stirring, cooling to separate out a solid, performing suction filtration, and performing vacuum drying to obtain the 3-amino-1-adamantanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010028740.1A CN111170849A (en) | 2020-01-11 | 2020-01-11 | Synthesis method of 3-amino-1-adamantanol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010028740.1A CN111170849A (en) | 2020-01-11 | 2020-01-11 | Synthesis method of 3-amino-1-adamantanol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111170849A true CN111170849A (en) | 2020-05-19 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010028740.1A Pending CN111170849A (en) | 2020-01-11 | 2020-01-11 | Synthesis method of 3-amino-1-adamantanol |
Country Status (1)
| Country | Link |
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| CN (1) | CN111170849A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116924918A (en) * | 2023-07-20 | 2023-10-24 | 浙江荣耀生物科技股份有限公司 | Preparation method of 3-amino-1-adamantanol |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747212A (en) * | 2009-12-22 | 2010-06-23 | 广东工业大学 | Method for synthesizing 3-amino-1-adamantanol |
-
2020
- 2020-01-11 CN CN202010028740.1A patent/CN111170849A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747212A (en) * | 2009-12-22 | 2010-06-23 | 广东工业大学 | Method for synthesizing 3-amino-1-adamantanol |
Non-Patent Citations (2)
| Title |
|---|
| A. DONETTI等: "Synthesis of 1-amino-3-hydroxyadamantane" * |
| 谢炳玉等: "含氨基的金刚烷桥头二取代化合物合成研究" * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116924918A (en) * | 2023-07-20 | 2023-10-24 | 浙江荣耀生物科技股份有限公司 | Preparation method of 3-amino-1-adamantanol |
| CN116924918B (en) * | 2023-07-20 | 2024-02-09 | 浙江荣耀生物科技股份有限公司 | Preparation method of 3-amino-1-adamantanol |
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Application publication date: 20200519 |