CN114315609B - Technological method for preparing cis-2-aminocyclohexanol - Google Patents
Technological method for preparing cis-2-aminocyclohexanol Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- PQMCFTMVQORYJC-NTSWFWBYSA-N (1r,2s)-2-aminocyclohexan-1-ol Chemical compound N[C@H]1CCCC[C@H]1O PQMCFTMVQORYJC-NTSWFWBYSA-N 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 39
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims abstract description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010992 reflux Methods 0.000 claims description 15
- 239000007787 solid Substances 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 7
- 238000002360 preparation method Methods 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 abstract description 2
- 239000010410 layer Substances 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- NJNCYFUGUYIMEQ-CHWSQXEVSA-N (1r,2r)-2-(benzylamino)cyclohexan-1-ol Chemical compound O[C@@H]1CCCC[C@H]1NCC1=CC=CC=C1 NJNCYFUGUYIMEQ-CHWSQXEVSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- -1 grinding aids Substances 0.000 description 2
- HSPSCWZIJWKZKD-UHFFFAOYSA-N n-chloroacetamide Chemical compound CC(=O)NCl HSPSCWZIJWKZKD-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PQMCFTMVQORYJC-PHDIDXHHSA-N (1r,2r)-2-aminocyclohexan-1-ol Chemical compound N[C@@H]1CCCC[C@H]1O PQMCFTMVQORYJC-PHDIDXHHSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 1
- NJNCYFUGUYIMEQ-UHFFFAOYSA-N 2-(benzylamino)cyclohexan-1-ol Chemical compound OC1CCCCC1NCC1=CC=CC=C1 NJNCYFUGUYIMEQ-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- PQMCFTMVQORYJC-UHFFFAOYSA-N 2-aminocyclohexan-1-ol Chemical compound NC1CCCCC1O PQMCFTMVQORYJC-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 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
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- ZWAJLVLEBYIOTI-UHFFFAOYSA-N cyclohexene oxide Chemical compound C1CCCC2OC21 ZWAJLVLEBYIOTI-UHFFFAOYSA-N 0.000 description 1
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohexene oxide Natural products O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000007730 finishing process Methods 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000011968 lewis acid catalyst Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a process method for preparing cis-2-aminocyclohexanol, and belongs to the technical field of organic synthesis. The method is based on cyclohexene, and comprises the steps of mixing with common raw materials NXS or CH 3 CONHX, in the presence of a catalyst, followed by DBU ring closure; then carrying out ring-opening reaction with alcohol in the presence of a catalyst; finally, the compound is resolved by salifying with resolving agent, and the corresponding enantiomerically pure cis-2-aminocyclohexanol or hydrochloride thereof is obtained after the compound is dissociated. The method has the advantages that the method is relatively short in reaction route, simple and smooth in technological process, byproducts are removed in a proper stage through technological adjustment, and the chiral compound can be efficiently prepared through three steps of cyclization reaction, ring-opening reaction, salifying resolution and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a process method for preparing cis-2-aminocyclohexanol.
Background
Beta-amino alcohol is an important basic chemical raw material, has important and wide application in the fields of organic synthetic chemistry, pharmaceutical chemistry, natural product synthetic chemistry, chemical production and the like, and is also widely applied to the fields of medicines, pesticides, grinding aids, plasticizers, surfactants and the like. The compound can be obtained by the synthesis of nucleophilic reagents such as ethylene oxide, propylene oxide, cyclohexene oxide, ammonia, amine, alcohol amine and the like.
For the cyclohexane skeleton structure, 2-aminocyclohexanol is divided into two configurations of cis and trans, wherein the trans 2-aminocyclohexanol is relatively fully researched; whereas the cis 2-aminocyclohexanol product is not reported much, the prior art (J.org.chem., 2006,71,2320-2331) process is mainly:
firstly reacting trans-2-benzylamino cyclohexanol with benzoyl chloride in triethylamine to obtain a benzoyl protection product on nitrogen, then reacting with excessive thionyl chloride to generate oxazoline, then heating and refluxing in a 6M hydrochloric acid aqueous solution to generate cis/trans isomer with the ratio of 8/1, and obtaining a pure cis-product 2-benzylamino cyclohexanol after column chromatography; then, after salt formation and resolution with mandelic acid, the enantiomerically pure 1R, 2S-2-benzylaminocyclohexanol is obtained; finally, palladium-carbon catalytic hydrogenation debenzylation is carried out to obtain cis-1R, 2S-2-aminocyclohexanol. When the starting material is enantiomerically pure trans-2-benzylaminocyclohexanol, the product is also enantiomerically pure cis-2-aminocyclohexanol. The reaction route is longer, and column chromatography is needed to separate the cis-trans products in the reaction process, which is not beneficial to industrialized amplification.
Therefore, the adoption of common raw materials which are easy to obtain in the market and a shorter synthetic route, the process method for preparing the cis-2-aminocyclohexanol under the condition of column chromatography is avoided, and the improvement of the core competitiveness of the product is still necessary.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a process method for preparing cis-2-aminocyclohexanol. The synthesis method starts from cyclohexene and is combined with common raw materials of NXS or CH 3 CONHX, in the presence of a catalyst, followed by DBU ring closure; then carrying out ring-opening reaction with alcohol in the presence of a catalyst; finally, the compound is resolved by salifying with resolving agent, and the corresponding enantiomerically pure cis-2-aminocyclohexanol or hydrochloride thereof is obtained after the compound is dissociated. The method has the advantages that the method is relatively short in reaction route, simple and smooth in technological process, byproducts are removed in a proper stage through technological adjustment, and the chiral compound can be efficiently prepared through three steps of cyclization reaction, ring-opening reaction, salifying resolution and the like.
The invention relates to a process method for preparing cis-2-aminocyclohexanol, which comprises the following steps:
the first step: cyclization reaction
Cyclohexene is mixed with acetonitrile/water in NXS or CH 3 The CONHX reacts with the catalyst, then DBU is added to react at a raised temperature, and an intermediate 2 is obtained; x is chlorine or bromine;
and a second step of: ring opening reaction
Adding the intermediate 2 into a catalyst and an alcohol solvent, and heating for reaction; after the reaction is finished, obtaining an intermediate 3 after reduced pressure distillation;
and a third step of: salt formation resolution
Mixing the intermediate 3 with ethanol, adding a mixed solution of L-DBTA and ethanol, and heating and refluxing for reaction; cooling to separate out solid, and filtering to obtain diastereoisomeric salt; adding aqueous hydrochloric acid solution to acidity, layering ethyl acetate, regulating the aqueous layer to alkalinity again, and extracting and distilling dichloromethane to obtain (1R, 2S) -2-aminocyclohexanol.
Further, in the technical scheme, the reaction temperature of the first step is 0-90 ℃; the catalyst is B (C) 6 F 5 ) 3 Or Me 2 S。
Further, in the above technical scheme, the first-step catalyst is B (C 6 F 5 ) 3 When the molar ratio of the catalyst to cyclohexene is 0.01 to 0.05:1, a step of; the molar ratio of the two is preferably 0.02:1. when the catalyst is Me 2 In the S, the molar ratio of the catalyst to cyclohexene is 0.3-0.6:1, a step of; the molar ratio of the two is preferably 0.5:1.
further, in the above technical solution, in the first step, the NXS or CH 3 The molar ratio of CONHX to cyclohexene is 1:1-1.2.
Further, in the technical scheme, the reaction temperature of the second step is 40-100 ℃; the reaction time is 1-3 hours.
Further, in the above technical scheme, the catalyst in the second step is B (C 6 F 5 ) 3 Or BF 3 -Et 2 O。
Further, in the above technical scheme, in the second step, the alcohol is selected from methanol, ethanol or isopropanol; preferably from methanol.
Further, in the technical scheme, the molar ratio of the resolving agent L-DBTA to the intermediate 3 in the third step is 0.48-0.55:1, the preferred molar ratio of the two is 1:1.
further, in the above technical scheme, the third step of water layer is adjusted to ph=10-12 with sodium hydroxide or potassium hydroxide.
Further, in the above technical scheme, in the third step, after the aqueous layer is adjusted to be strong acid, the aqueous layer is directly distilled to be dry, ethanol is added for recrystallization, and the (1R, 2S) -2-aminocyclohexylhydrochloride is obtained.
Advantageous effects of the invention
1. The process comprises three steps of cyclization reaction, ring-opening reaction, salification resolution and the like, and has relatively short reaction route and smooth process.
2. Starting material NXS or CH 3 CONHX and catalyst B (C) 6 F 5 ) 3 Or Me 2 S and the like are cheap and easy to obtain in the market; when Me 2 When S is catalyzed, hydrogen peroxide is added after the reaction is finished, and is oxidized into DMSO which is easily removed by washing; the salt-forming resolution efficiency is higher, and the resolving agent can be effectively recycled.
3. In the second step of ring opening reaction, a Lewis acid catalyst is adopted to open the ring under the condition of alcohol, so that the repeatability is good; in the literature, under the condition of strong acid reflux (6M hydrochloric acid aqueous solution), hydrogen chloride continuously overflows, and hydrochloric acid needs to be repeatedly added in the reaction process.
Detailed Description
The above-described matters of the present invention will be described in further detail by way of examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and all techniques realized based on the above-described matters of the present invention are within the scope of the present invention.
Example 1
Cyclohexene (8.6 g,0.105 mol) was mixed with 90mL of acetonitrile and 10mL of water in a reaction flask, and stirred well. Then, the temperature was lowered to 0℃and NBS (17.8 g,0.1 mol) was added thereto, followed by stirring for 10 minutes. Subsequently B (C) 6 F 5 ) 3 (1 mmol) in acetonitrile (10 mL); after the dripping is finished, the mixture is stirred for 30 minutes under heat preservation, and then naturallyThe reaction was allowed to warm to room temperature for 2 hours. TLC checked for completion of the reaction, followed by DBU (0.25 mol)/50 mL of acetonitrile was warmed to reflux for 6 hours. After the reaction, the temperature was lowered to room temperature, the reaction solution was evaporated to dryness, ethyl acetate and 1N hydrochloric acid were added to the mixture to layer the mixture (water layer was used to adjust ph=4-5), and the organic layer was washed twice with water and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated by rotary evaporation to yield 13.3g of pale yellow oily liquid 2. Yield 95.2%, HNMR (400 MHz, CDCl) 3 ):4.40(dt,1H),3.83(dt,1H),1.65-1.78(m,4H),1.29-1.55(m,4H),1.16(3H,s).
Under the same conditions, NBS was replaced with NCS, and the reflux reaction time was 10 hours, with a yield of 91.1%.
Example 2
Cyclohexene (8.6 g,0.105 mol) was mixed with 90mL of acetonitrile and 10mL of water in a reaction flask, and stirred well. Then, the temperature was lowered to 0℃and acetyl bromide (13.8 g,0.1 mol) was added thereto, followed by stirring and reaction for 10 minutes. Subsequently B (C) 6 F 5 ) 3 (1 mmol) in acetonitrile (10 mL); after the completion of the dropwise addition, stirring was carried out for 30 minutes at a constant temperature, and then the reaction was carried out for 2 hours by naturally warming to room temperature. TLC checked for completion of the reaction, followed by DBU (0.25 mol) and 50mL of acetonitrile were added and the temperature was raised to reflux for 6 hours. After the reaction, the temperature was lowered to room temperature, the reaction solution was evaporated to dryness, ethyl acetate and 1N hydrochloric acid were added to the mixture to layer the mixture (aqueous layer was adjusted to ph=4-5), and the organic layer was washed once with water and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated in vacuo to give 13.1g of pale yellow oily liquid 2 in 93.9% yield.
Under the same conditions, acetyl bromide is replaced by acetyl chloramine, the reflux reaction time is 10 hours, and the yield is 90.8%.
Example 3
In a reaction flask, cyclohexene (9.8 g,0.12 mol) and 90mL of acetonitrile and 10mL of water were mixed and stirred well. Then, the temperature was lowered to 0℃and NBS (17.8 g,0.1 mol) was added thereto, followed by stirring for 10 minutes. Then raising the temperature to 40-45 ℃ and dropwise adding Me 2 S (0.06 mol)/acetonitrile (10 mL); after the dripping is finished, the mixture is stirred for 8 hours under heat preservation. TLC checked for completion of the reaction, followed by DBU (0.25 mol)/50 mL of acetonitrile was warmed to reflux for 6 hours. After the reaction is finished, cooling to room temperature, adding 25% hydrogen peroxide until the system has no obvious smell, evaporating the reaction solution to dryness, adding ethyl acetate and 1N hydrochloric acid was separated (aqueous layer ph=4-5), the organic layer was washed twice with water and dried over anhydrous sodium sulfate. The organic layer was filtered and evaporated in vacuo to give 11.0g of pale yellow oily liquid 2 in 79.4% yield.
Under the same conditions, NBS was replaced with NCS, and the reflux reaction time was 10 hours, with a yield of 85.8%.
Example 4
In a reaction flask, cyclohexene (9.8 g,0.12 mol) and 90mL of acetonitrile and 10mL of water were mixed and stirred well. Then, the temperature was lowered to 0℃and acetyl bromide (13.8 g,0.1 mol) was added thereto, followed by stirring and reaction for 10 minutes. Then raising the temperature to 40-45 ℃ and dropwise adding Me 2 S (0.06 mol)/acetonitrile (10 mL); after the dripping is finished, the mixture is stirred for 8 hours under heat preservation. TLC checked for completion of the reaction, followed by DBU (0.25 mol)/50 mL of acetonitrile was warmed to reflux for 6 hours. After the reaction, cooling to room temperature, adding 25% hydrogen peroxide until the system has no obvious smell, evaporating the reaction solution, adding ethyl acetate and 1N hydrochloric acid for layering (the pH value of the water layer is regulated to be 4-5), washing the organic layer twice, and drying by anhydrous sodium sulfate. The organic layer was filtered and evaporated in vacuo to give 10.5g of pale yellow oily liquid 2 in 75.5% yield.
Under the same conditions, acetyl bromide is replaced by acetyl chloramine, the reflux reaction time is 10 hours, and the yield is 77.7%.
Example 5
In a reaction flask, intermediate 2 (27.8 g,0.2 mol) was mixed with anhydrous methanol and completely dissolved under stirring, followed by addition of 2mmol of catalyst B (C) 6 F 5 ) 3 The temperature was raised to reflux with stirring for 3 hours. After the reaction was completed, the reaction mixture was evaporated to dryness under reduced pressure to give a crude solid, and was slurried with methyl t-butyl ether/n-heptane/triethylamine (volume ratio: 1:8:0.1) to give 20.3g of an off-white solid intermediate 3 in 88.1% yield. HNMR data are consistent with literature [ j.org.chem.2006,71,2320-2331 ].
Example 6
In a reaction flask, intermediate 2 (27.8 g,0.2 mol) was mixed with anhydrous methanol and completely dissolved under stirring, followed by the addition of 4mmol of catalyst BF 3 -Et 2 O, heating to reflux reaction for 3 hours under stirring. After the reaction is finished, the reaction solution is decompressed and evaporated to dryness,the crude solid product is obtained, methyl tertiary butyl ether/n-heptane/triethylamine (volume ratio is 1:8:0.1) is added for beating, and 20.9g of off-white solid 3 is obtained, and the yield is 90.9%.
Example 7
In a reaction flask, intermediate 3 (115 g,1.0 mol) and 450mL of ethanol were mixed and completely dissolved with stirring. The L-DBTA-H is added dropwise at the temperature of 20-25 DEG C 2 O (188 g,0.5 mol) and 900mL of ethanol, and then heating and refluxing for 2 hours after the completion of the dropwise addition; and (3) cooling the reaction system to 0 ℃ in a gradient cooling mode, precipitating solids in the process, filtering to obtain diastereoisomeric salt, recrystallizing again by 880mL of ethanol, and filtering to obtain white solid salt. Adding 3N hydrochloric acid aqueous solution into the white solid salt to reach pH value of 2-3, extracting and layering by ethyl acetate twice (for L-DBTA recovery), adding sodium hydroxide solid into a water layer to adjust the pH value to 10-12, extracting by methylene dichloride for 3 times, drying by anhydrous magnesium sulfate, and evaporating the solvent to obtain 48.3g of white solid (1R, 2S) -2-aminocyclohexanol; melting point 88-89 deg.C, 98.3% ee.
Example 8
In a reaction flask, intermediate 3 (11.5 g,0.1 mol) and 45mL of ethanol were mixed and completely dissolved with stirring. The L-DBTA-H is added dropwise at the temperature of 20-25 DEG C 2 O (18.8 g,0.05 mol) and 90mL ethanol, and heating and refluxing for 2 hours after the completion of the dropwise addition of the ethanol for 40 minutes; and (3) cooling the reaction system to 0 ℃ in a gradient cooling mode, precipitating solids in the process, filtering to obtain diastereoisomeric salt, recrystallizing again by using 90mL of ethanol, and filtering to obtain white solid salt. The white solid salt was added with 3N aqueous hydrochloric acid to ph=2-3, the ethyl acetate was extracted and layered twice (for L-DBTA recovery), the aqueous layer was distilled under reduced pressure, toluene was added with water during the finishing process until a solid crude product was obtained, and after slurried with ethanol, dried to obtain 5.8g of an off-white solid, (1 r,2 s) -2-aminocyclohexylhydrochloride. HNMR (400 MHz, D) 2 O):4.06(t,1H),3.34(t,1H),1.45-1.78(m,8H).
The above embodiments illustrate the basic principles, main features and advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (8)
1. A process for preparing cis-2-aminocyclohexanol, comprising the steps of:
the first step: cyclization reaction
Cyclohexene is mixed with acetonitrile/water in NXS or CH 3 The CONHX reacts with the catalyst, then DBU is added to react at a raised temperature, and an intermediate 2 is obtained; x is chlorine or bromine; the catalyst of this step is B (C) 6 F 5 ) 3 Or Me 2 S；
And a second step of: ring opening reaction
Adding the intermediate 2 into a catalyst and an alcohol solvent, and heating for reaction; after the reaction is finished, obtaining an intermediate 3 after reduced pressure distillation; the catalyst of this step is B (C) 6 F 5 ) 3 Or BF 3 -Et 2 O；
And a third step of: salt formation resolution
Mixing the intermediate 3 with ethanol, adding a mixed solution of L-DBTA and ethanol, and heating and refluxing for reaction; cooling to separate out solid, and filtering to obtain diastereoisomeric salt; adding aqueous hydrochloric acid solution to acidity, layering ethyl acetate, regulating the aqueous layer to alkalinity again, and extracting and distilling dichloromethane to obtain (1R, 2S) -2-aminocyclohexanol.
2. The process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the reaction temperature of the first step is 0-90 ℃.
3. A process for the preparation of cis-2-aminocyclohexanol as claimed in claim 2, wherein: the first catalyst is B (C) 6 F 5 ) 3 When the molar ratio of the catalyst to cyclohexene is 0.01 to 0.05:1, a step of; when catalyzingMe as the agent 2 In the S, the molar ratio of the catalyst to cyclohexene is 0.3-0.6:1.
4. the process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the first step is that NXS or CH 3 The molar ratio of CONHX to cyclohexene is 1:1-1.2.
5. The process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the reaction temperature of the second step is 40-100 ℃; the reaction time is 1-3 hours.
6. The process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the alcohol in the second step is selected from methanol, ethanol or isopropanol.
7. The process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the molar ratio of the resolving agent L-DBTA to the intermediate 3 in the third step is 0.48-0.55:1.
8. the process for preparing cis-2-aminocyclohexanol as claimed in claim 1, wherein: the third step of water layer is adjusted to pH=10-12 by sodium hydroxide or potassium hydroxide.
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