CN113461551A - 3-amino-1-adamantanol and preparation method and application thereof - Google Patents
3-amino-1-adamantanol and preparation method and application thereof Download PDFInfo
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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 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 59
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 229960001280 amantadine hydrochloride Drugs 0.000 claims abstract description 24
- WOLHOYHSEKDWQH-UHFFFAOYSA-N amantadine hydrochloride Chemical compound [Cl-].C1C(C2)CC3CC2CC1([NH3+])C3 WOLHOYHSEKDWQH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000010992 reflux Methods 0.000 claims abstract description 21
- 238000001035 drying Methods 0.000 claims abstract description 15
- 238000001914 filtration Methods 0.000 claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 64
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 57
- 239000000706 filtrate Substances 0.000 claims description 56
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 27
- 239000011259 mixed solution Substances 0.000 claims description 26
- 239000000843 powder Substances 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 23
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 229910017604 nitric acid Inorganic materials 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- 230000008569 process Effects 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 7
- 229960001254 vildagliptin Drugs 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- HIFJUMGIHIZEPX-UHFFFAOYSA-N sulfuric acid;sulfur trioxide Chemical compound O=S(=O)=O.OS(O)(=O)=O HIFJUMGIHIZEPX-UHFFFAOYSA-N 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 3
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 238000000967 suction filtration Methods 0.000 description 20
- 239000012065 filter cake Substances 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 15
- 206010012601 diabetes mellitus Diseases 0.000 description 8
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 4
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 3
- 229960003805 amantadine Drugs 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000002218 hypoglycaemic effect Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 238000006396 nitration reaction Methods 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DWPIPTNBOVJYAD-UHFFFAOYSA-N 3-aminoadamantan-1-ol Chemical compound C1C(C2)CC3CC1(N)CC2(O)C3 DWPIPTNBOVJYAD-UHFFFAOYSA-N 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- -1 Amino-adamantane Compounds Chemical class 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 102100024295 Maltase-glucoamylase Human genes 0.000 description 1
- ZOKXTWBITQBERF-UHFFFAOYSA-N Molybdenum Chemical compound [Mo] ZOKXTWBITQBERF-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 108010028144 alpha-Glucosidases Proteins 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 208000006443 lactic acidosis Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000011733 molybdenum Substances 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000001467 thiazolidinediones Chemical class 0.000 description 1
Images
Classifications
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of chemical synthesis preparation, in particular to 3-amino-1-adamantanol and a preparation method and application thereof. Comprises the following steps; firstly, preparing to obtain mixed acid, then adding amantadine hydrochloride into the mixed acid, reacting for a period of time, adding crushed ice until the reaction solution becomes clear dark green, then adjusting the pH value to obtain a product, refluxing the product with an organic solution A and an organic solution B respectively, filtering and drying to obtain the 3-amino-1-adamantanol. The method obtains the 3-amino-1-adamantanol with high yield by cheap and easily obtained raw materials and simple operation, has low cost and quick reaction, and is more suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of chemical synthesis preparation, and particularly relates to 3-amino-1-adamantanol and a preparation method and application thereof.
Background
Diabetes mellitus is a metabolic disease which is characterized by uncontrolled chronic hyperglycemia and is accompanied by various complications due to various causes, and the incidence rate of diabetes mellitus rises year by year in recent years and becomes one of three chronic diseases threatening the health of human beings in the 21 st century. By 2015, the number of diabetics has exceeded 4 billion worldwide, and by 2040 years, the number of diabetics worldwide will rise to 6.42 billion, and diabetes has become a global public health problem.
The pathogenesis of diabetes is mainly due to insufficient insulin secretion and/or function defect. Clinically, diabetes is mainly divided into type I diabetes and type ii diabetes, with type ii diabetes accounting for over 90%. At present, the treatment of type II diabetes mainly depends on oral medication except for insulin injection. The traditional oral medicines for treating diabetes mainly comprise: sulfonylureas, meglitinides, biguanides, thiazolidinediones, α -glucosidase preparations, and the like, however, these drugs are not suitable for long-term administration to diabetic patients because they cause obesity, lactic acidosis, hypoglycemia, and other adverse reactions. Dipeptidyl peptidase-IV (DPP-IV) inhibitors, which are diabetes treatment drugs on the market in recent years, are widely used due to the advantages of definite hypoglycemic treatment effect, low hypoglycemia risk, no obesity and the like.
Vildagliptin, chemical name: (S) -1- [2- (3-hydroxyadamantane-1-amino) ] acetyl ] pyrrolidine-2-carbonitrile (shown in figure); the DPP-IV inhibitor has high selectivity, competitiveness and reversibility, and can effectively control blood sugar when used alone or combined with other antidiabetic drugs clinically. In 2008, vildagliptin is marketed in europe, enters the Chinese market under the trade name 'jiaweile' in 2011, is marketed in many countries in the world at present, and has a good development prospect.
The 3-amino-1-adamantanol is an important intermediate for synthesizing vildagliptin, and the molecular formula of the intermediate is as follows: c10H17NO; molecular weight: 167.25, respectively; melting point: 265 ℃ of water; the characteristics are as follows: white crystals. The structural formula is as follows:
in the prior art, the research and report of the synthesis method of 3-amino-1-adamantanol mainly comprises the following methods, for example, Khusnutdinov RI et al, Selective hydration of Adamantane and Its Derivatives, CBr4As solvent, molybdenum hexacarbonyl as catalyst, refluxing at 140-180 deg.C to obtain 3-amino-1-adamantanol, with a yield of 80%. Villhauer, E et al in the literature "N- (sub-sized glycerol) -2-cyanopyrrodides, Pharmaceutical compositions combining the same and the same use in inhibiting Dipeptidyl Peptidase-IV" starting with amantadine hydrochloride by H2SO4/HON3Oxidizing a system, performing KOH alkaline hydrolysis, extracting by dichloromethane, drying by anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate to obtain the 3-amino-1-adamantanol, wherein the yield is not reported. Xie Bing Yu et al in the literature "Synthesis of Bridggel head Bis-substisted Amino-adamantane Compounds" using adamantanecarboxylic acid as a starting material, by bromination, azidation, Curtius rearrangement, alkaline hydrolysis, extraction with dichloromethane, drying over anhydrous sodium sulfate, suction filtration, and concentration of the filtrate to obtain 3-Amino-1-adamantanol with a yield of 34%. The peri-cyclone peak is prepared from amantadine as raw material through H2SO4/HON3The system is alkaline hydrolyzed, extracted by dichloromethane and concentrated by organic phase to prepare 3-amino-1-adamantanol, and the yield is 74.8 percent. During the synthesis of vildagliptin, songwatio et al use amantadine as raw material, after mixed acid and alkaline hydrolysis, extract with dichloromethane, wash with saturated sodium chloride solution, dry with anhydrous magnesium sulfate, suction filter, concentrate filtrate to obtain 3-amino-1-adamantanol, yield 78%. Penjun et al in the 'optimization of synthesis process of 3-aminoadamantanol' literature use amantadine hydrochloride as raw material and boric acid as catalyst, after mixed acid and alkaline hydrolysis, extract with dichloromethane, dry with anhydrous sodium sulfate, filter, concentrate filtrate to obtain 3-amino-1-adamantanol with a yield of 84%. In the improvement of the synthesis process of vildagliptin, Hanchuming et al uses amantadine as raw material, and after mixed acid nitration and alkaline hydrolysis, the raw material reacts for 3 hours at 50 ℃, dichloromethane extraction, anhydrous sodium sulfate drying, suction filtration and filtrate concentration are carried out to prepare 3-amino-1-adamantanol, and the yield is 73.8%. And patent No. CN201010114206.9 (of a 3-amino-1-adamantanol)Preparation method) uses amantadine hydrochloride as raw material, and the 3-amino-1-adamantanol is prepared by nitration with nitrating agent, alkaline hydrolysis, extraction with dichloromethane, drying with anhydrous sodium sulfate, suction filtration, concentration of filtrate, and recrystallization with ethyl acetate, with the yield of 75%.
Therefore, the preparation yield of the 3-amino-1-adamantanol is generally low at present, and although some methods can improve the yield, the required catalyst or raw materials are not easy to obtain, the price and the cost are high, the operation is complex, and the industrial production is difficult to realize. Through research on literature, most researchers at home and abroad mainly adopt a dichloromethane extraction process to extract products in the preparation of the 3-amino-1-adamantanol, and further research shows that the 3-amino-1-adamantanol has certain solubility in an aqueous solution, dichloromethane is difficult to completely extract, the extraction efficiency is low, so that the yield is generally low, and the post-treatment process of the 3-amino-1-adamantanol is a main bottleneck for limiting the improvement of the yield. Therefore, a new process for preparing 3-amino-1-adamantanol is needed to solve the above technical problems.
Disclosure of Invention
Aiming at the problems, the invention aims to provide 3-amino-1-adamantanol, a preparation method and application thereof, wherein the method is low in cost, quick in reaction and more suitable for industrial production.
The first purpose of the invention is to provide a preparation method of 3-amino-1-adamantanol, which comprises the following steps:
step 1, adding a strong acid B into a strong acid A in the process of continuously stirring under an ice bath condition to obtain mixed acid; the volume ratio of the strong acid A to the strong acid B is 5-10: 1;
step 2, keeping the temperature at 0-10 ℃, adding amantadine hydrochloride into the mixed acid in several times, continuing to react for 2-3 hours after the addition is finished, removing the ice bath, and reacting for 2-3 hours at room temperature to obtain a mixed solution A; wherein the proportion of amantadine hydrochloride to strong acid B is 1 g: 1 ml;
step 3, adding crushed ice into the mixed solution A during stirring, transferring to an ice bath when the reaction solution becomes clear greenish black, adding a proper amount of alkali, adjusting the pH value of the solution to be 12-14, and continuously reacting for 1-2 hours to obtain a product;
step 4, collecting the filtrate of the product in the step 3, adjusting the pH of the filtrate to 5-10 by using an acid regulator, concentrating the filtrate to be powder, refluxing for 1-2h by using an organic solvent A, and then standing for 0.5-1h under ice bath;
and 5, collecting the filtrate obtained in the step 4, concentrating the filtrate into powder, adding an organic solvent B, refluxing for 1-2h, standing for 0.5-1h under ice bath, filtering, and drying to obtain the 3-amino-1-adamantanol.
Preferably, in step 1, the strong acid a is fuming sulfuric acid or concentrated sulfuric acid, the strong acid B is concentrated nitric acid or fuming nitric acid, and the obtained mixed acid is one of fuming sulfuric acid and concentrated nitric acid, concentrated sulfuric acid and fuming nitric acid, concentrated sulfuric acid and concentrated nitric acid, fuming sulfuric acid and fuming nitric acid.
Preferably, in step 1, the strong acid a is concentrated sulfuric acid, the strong acid B is concentrated nitric acid, and the mixed acid is concentrated sulfuric acid and concentrated nitric acid.
Preferably, the base in step 3 is sodium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate.
Preferably, the acid regulator in step 4 is hydrochloric acid, glacial acetic acid or sulfuric acid.
Preferably, the acid regulator in the step 4 is hydrochloric acid, and the pH is adjusted to 7-8.
Preferably, the organic solvent A in the step 4 is one of methanol, 95% ethanol, 75% ethanol, isopropanol, ethyl acetate and toluene.
Preferably, the organic solution B in step 5 is one of a mixed solution of acetone and ethyl acetate, acetone and tetrahydrofuran, acetone and dichloromethane, ethyl acetate and tetrahydrofuran, ethyl acetate and dichloromethane, ethyl acetate and petroleum ether, and tetrahydrofuran and dichloromethane.
It is a second object of the present invention to provide 3-amino-1-adamantanol according to the above method.
The third purpose of the invention is to provide the application of the 3-amino-1-adamantanol in preparing vildagliptin.
Compared with the prior art, the invention has the following beneficial effects:
the invention obtains the 3-amino-1-adamantanol with high yield by cheap and easily obtained raw materials and a simple operation method, and the method has low cost and quick reaction and is more suitable for industrial production.
Drawings
FIG. 1 is a schematic diagram of a synthetic route provided in example 1 of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Under the ice-bath condition, 37.5ml of 98% concentrated sulfuric acid is added into a 100ml three-neck flask with a thermometer, 3.75ml of 65% concentrated nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. Keeping the temperature of the reaction liquid at 0 ℃, adding 3.75g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in equal amount within 2 hours, continuing to react for 2 hours in ice bath after the addition is finished, then removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed liquid A. Transferring the mixed solution A to a 250ml three-neck bottle, adding 60g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of potassium hydroxide solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (3) carrying out suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to 7 by using concentrated hydrochloric acid, then carrying out rotary evaporation and concentration on the filtrate to obtain a powder, refluxing the powder for 1h by using 60ml of 95% ethanol, and then placing the powder for 30min under ice bath. Filtering, removing filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 8ml mixed solution of acetone and ethyl acetate (v)Acetone (II)：vEthyl acetate3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 3-amino-1-adamantanol 3.20g, wherein the yield is as follows: 95 percent. Melting Point (m).p.)：260.5～263.5℃。
Example 2
Under the ice bath condition, 75ml of 98% concentrated sulfuric acid is added into a 250ml three-neck flask with a thermometer, 7.5ml of 65% concentrated nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. Keeping the temperature of the reaction liquid at 10 ℃, adding 7.5g of amantadine hydrochloride into the mixed acid in several times, specifically, adding amantadine hydrochloride into the mixed acid in ten times in equal amount within 2 hours, continuing to react for 2 hours in ice bath after the addition is finished, then removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed liquid A. Transferring the mixed solution A into a 500ml three-neck bottle, adding 120g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of potassium hydroxide solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (3) carrying out suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to be 8 by using concentrated hydrochloric acid, then carrying out rotary evaporation and concentration on the filtrate to obtain a powder, refluxing the powder for 1h by using 120ml of 95% ethanol, and then placing the powder for 30min under ice bath. Filtering, removing filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 16ml mixed solution of acetone and ethyl acetate (v)Acetone (II)：vEthyl acetate3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 6.15g of 3-amino-1-adamantanol, wherein the yield is as follows: 91.5 percent. m.p.261-263 ℃.
Example 3
Under the ice bath condition, 75ml fuming sulfuric acid is added into a 250ml three-neck flask with a thermometer, 7.5ml 65% concentrated nitric acid is added under stirring, and the stirring is continued for 10min, so that mixed acid is obtained. And (3) keeping the temperature of the reaction liquid at 5 ℃, adding 7.5g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in 2 hours, continuing to react for 3 hours in an ice bath after the addition is finished, removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed liquid A. Transferring the mixed solution A into a 500ml three-neck bottle, adding 120g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of sodium hydroxide solid under the condition of ice bath, and adjusting the pH value of the solution>12, adding the water and keepingThe reaction was continued for 2h with ice bath to yield a large amount of white thick solid. And (4) performing suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to be 5 by using glacial acetic acid, then performing rotary evaporation on the concentrated filtrate to obtain a powder, refluxing the powder for 2h by using 120ml of methanol, and then placing the powder for 30min under ice bath. Filtering, discarding filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 16ml mixed solution of acetone and tetrahydrofuran (v)Acetone (II)：vTetrahydrofuran (THF)3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 6.10g of 3-amino-1-adamantanol, wherein the yield is as follows: 90.7 percent. m.p.260.5-262.5 ℃.
Example 4
Under the ice-bath condition, 37.5ml of 98% concentrated sulfuric acid is added into a 100ml three-neck flask with a thermometer, 3.75ml of fuming nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. And (3) keeping the temperature of the reaction solution at 0 ℃, adding 3.75g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in an equal amount within 2 hours, continuing to react for 2 hours in an ice bath after the addition is finished, removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed solution A. Transferring the mixed solution A to a 250ml three-neck bottle, adding 60g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of potassium carbonate solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. The filtrate was collected by suction filtration, the pH of the filtrate was adjusted to 10 with sulfuric acid, and the filtrate was concentrated to a powder by rotary evaporation, refluxed with 60ml of 75% ethanol for 1 hour, and then left to stand on ice for 1 hour. Filtering, discarding filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 8ml mixed solution of acetone and dichloromethane (v)Acetone (II)：vMethylene dichloride3: 1) after refluxing for 1h, standing for 1h in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 3-amino-1-adamantanol 3.15g, wherein the yield is as follows: 93.5 percent. m.p.261-263 ℃.
Example 5
Under the ice-bath condition, 37.5ml fuming sulfuric acid is added into a 250ml three-neck flask with a thermometer, 7.5ml fuming nitric acid is added under stirring, and the process is continuedStirring for 10min to obtain mixed acid. And when the temperature of the reaction liquid is reduced to 0 ℃, adding 7.5g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in an equal amount within 3 hours, continuing to react for 3 hours under an ice bath, removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed liquid A. Transferring the mixed solution A to a 500ml three-neck bottle, adding 120g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of sodium carbonate solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 2h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (4) performing suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to be 7 by using sulfuric acid, then performing rotary evaporation and concentration on the filtrate to form powder, refluxing the powder for 2 hours by using 120ml of isopropanol, and then placing the powder for 30min under an ice bath. Filtering, discarding filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 16ml mixed solution of ethyl acetate and tetrahydrofuran (v)Ethyl acetate：vTetrahydrofuran (THF)3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 6.25g of 3-amino-1-adamantanol, wherein the yield is as follows: 93.0 percent. m.p.261.5-262.5 ℃.
Example 6
Under the ice bath condition, 30ml of 98% concentrated sulfuric acid is added into a 100ml three-neck flask with a thermometer, 3.75ml of 65% concentrated nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. And (3) keeping the temperature of the reaction solution at 0 ℃, adding 3.75g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in an equal amount within 2.5 hours, continuing to react for 2 hours under an ice bath, removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed solution A. Transferring the mixed solution A to a 250ml three-neck bottle, adding 60g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of potassium hydroxide solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (3) carrying out suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to be 8 by using concentrated hydrochloric acid, then carrying out rotary evaporation and concentration on the filtrate to be powdery, refluxing for 1h by using 60ml of ethyl acetate, and then placing for 30min under ice bath.Filtering, removing filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 8ml mixed solution of ethyl acetate and dichloromethane (v)Ethyl acetate：vMethylene dichloride3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 3-amino-1-adamantanol 3.08g, wherein the yield is as follows: 91.4 percent. m.p.260.5-261.5 ℃.
Example 7
Under the ice bath condition, 75ml of 98% concentrated sulfuric acid is added into a 250ml three-neck flask with a thermometer, 7.5ml of 65% concentrated nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. And (3) keeping the temperature of the reaction solution at 10 ℃, adding 7.5g of amantadine hydrochloride into the mixed acid in several times, specifically, adding the amantadine hydrochloride into the mixed acid in ten times in an equal amount within 2 hours, continuing to react for 2 hours in an ice bath after the addition is finished, then removing the ice bath, and continuing to react for 2 hours at room temperature to obtain a mixed solution A. Transferring the mixed solution A to a 500ml three-neck bottle, adding 120g of crushed ice under stirring, keeping the temperature of the reaction solution at 0-5 ℃ until the reaction solution becomes clear dark green, adding a proper amount of sodium bicarbonate solid under the condition of ice bath, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (3) carrying out suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to be 8 by using concentrated hydrochloric acid, then carrying out rotary evaporation and concentration on the filtrate to be powdery, refluxing for 1h by using 120ml of toluene, and then placing for 30min under ice bath. Filtering, discarding filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 16ml mixed solution of ethyl acetate and petroleum ether (v)Ethyl acetate：vPetroleum ether3: 1) after refluxing for 1h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 6.18g of 3-amino-1-adamantanol, wherein the yield is as follows: 91.9 percent. m.p.261-263 ℃.
Example 8
Under the ice-bath condition, 37.5ml of 98% concentrated sulfuric acid is added into a 100ml three-neck flask with a thermometer, 3.75ml of 65% concentrated nitric acid is added under stirring, and stirring is continued for 10min to obtain mixed acid. Keeping the temperature of the reaction solution at 0 ℃, adding 3.75g of amantadine hydrochloride into the mixed acid in portions, specifically, adding amantadine hydrochloride into the mixed acid in ten times and equal amount within 2 hours, and addingAfter the reaction is finished, the mixture is continuously reacted for 2 hours in an ice bath, then the ice bath is removed, and the reaction is continuously performed for 2 hours at room temperature to obtain a mixed solution A. Transferring the mixed solution A to a 250ml three-neck bottle, adding 60g of crushed ice while stirring, keeping the temperature of the reaction solution at 0-5 ℃, adding a proper amount of potassium hydroxide solid under the condition of transferring to an ice bath until the reaction solution becomes clear dark green, and adjusting the pH value of the solution>12, after the addition, the reaction was continued for 1h while maintaining ice bath conditions, yielding a large amount of white thick solid. And (3) carrying out suction filtration, collecting the filtrate, adjusting the pH value of the filtrate to 7 by using concentrated hydrochloric acid, then carrying out rotary evaporation and concentration on the filtrate to obtain a powder, refluxing for 2h by using 60ml of 95% ethanol, and then placing for 30min under ice bath. Suction filtering, discarding filter cake, collecting filtrate, concentrating filtrate to powder by rotary evaporation, adding 8ml of mixed solution of tetrahydrofuran and dichloromethane (v)Tetrahydrofuran (THF)：vMethylene dichloride3: 1) after refluxing for 2h, standing for 30min in ice bath, performing suction filtration, slightly rinsing with mixed liquor, and drying a filter cake to obtain 3-amino-1-adamantanol 3.02g, wherein the yield is as follows: 89.7 percent. m.p.260-262 ℃.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention.
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (10)
1. A preparation method of 3-amino-1-adamantanol is characterized by comprising the following steps:
step 1, adding a strong acid B into a strong acid A in the process of continuously stirring under an ice bath condition to obtain mixed acid; the volume ratio of the strong acid A to the strong acid B is 5-10: 1;
step 2, keeping the temperature at 0-10 ℃, adding amantadine hydrochloride into the mixed acid in several times, continuing to react for 2-3 hours after the addition is finished, removing the ice bath, and reacting for 2-3 hours at room temperature to obtain a mixed solution A; wherein the proportion of amantadine hydrochloride to strong acid B is 1 g: 1 ml;
step 3, adding crushed ice into the mixed solution A during stirring, transferring to an ice bath when the reaction solution becomes clear greenish black, adding a proper amount of alkali, adjusting the pH value of the solution to be 12-14, and continuously reacting for 1-2 hours to obtain a product;
step 4, collecting the filtrate of the product in the step 3, adjusting the pH of the filtrate to 5-10 by using an acid regulator, concentrating the filtrate to be powder, refluxing for 1-2h by using an organic solvent A, and then standing for 0.5-1h under ice bath;
and 5, collecting the filtrate obtained in the step 4, concentrating the filtrate into powder, adding an organic solvent B, refluxing for 1-2h, standing for 0.5-1h under ice bath, filtering, and drying to obtain the 3-amino-1-adamantanol.
2. The method according to claim 1, wherein in step 1, the strong acid A is fuming sulfuric acid or concentrated sulfuric acid, and the strong acid B is concentrated nitric acid or fuming nitric acid.
3. The method according to claim 2, wherein in step 1, the strong acid A is concentrated sulfuric acid, and the strong acid B is concentrated nitric acid.
4. The process according to claim 1, wherein the base in step 3 is sodium hydroxide, potassium carbonate, sodium carbonate or sodium hydrogen carbonate.
5. The process according to claim 1, wherein the acid regulator in the step 4 is hydrochloric acid, glacial acetic acid or sulfuric acid.
6. The process according to claim 5, wherein the acid regulator used in the step 4 is hydrochloric acid, and the pH is adjusted to 7 to 8.
7. The method according to claim 1, wherein the organic solvent A in step 4 is one of methanol, 95% ethanol, 75% ethanol, isopropanol, ethyl acetate, and toluene.
8. The method according to claim 1, wherein the organic solution B in the step 5 is one of a mixed solution of acetone and ethyl acetate, acetone and tetrahydrofuran, acetone and dichloromethane, ethyl acetate and tetrahydrofuran, ethyl acetate and dichloromethane, ethyl acetate and petroleum ether, and tetrahydrofuran and dichloromethane.
9. A process according to any one of claims 1 to 8 for the preparation of 3-amino-1-adamantanol.
10. Use of 3-amino-1-adamantanol prepared according to claim 9 in the preparation of vildagliptin.
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