CN117658830A - Preparation method of trans-2-aminocyclopentanol with high optical purity - Google Patents
Preparation method of trans-2-aminocyclopentanol with high optical purity Download PDFInfo
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- CN117658830A CN117658830A CN202311589335.7A CN202311589335A CN117658830A CN 117658830 A CN117658830 A CN 117658830A CN 202311589335 A CN202311589335 A CN 202311589335A CN 117658830 A CN117658830 A CN 117658830A
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- aminocyclopentanol
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- high optical
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- JFFOUICIRBXFRC-RFZPGFLSSA-N (1r,2r)-2-aminocyclopentan-1-ol Chemical compound N[C@@H]1CCC[C@H]1O JFFOUICIRBXFRC-RFZPGFLSSA-N 0.000 title claims abstract description 38
- 230000003287 optical effect Effects 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims abstract description 12
- -1 cyclopentane epoxide Chemical class 0.000 claims abstract description 11
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZQEBQGAAWMOMAI-ZETCQYMHSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@H]1C(O)=O ZQEBQGAAWMOMAI-ZETCQYMHSA-N 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 7
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000012044 organic layer Substances 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 10
- 235000019441 ethanol Nutrition 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical group CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- JFFOUICIRBXFRC-WHFBIAKZSA-N (1s,2s)-2-aminocyclopentan-1-ol Chemical compound N[C@H]1CCC[C@@H]1O JFFOUICIRBXFRC-WHFBIAKZSA-N 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 2
- 229940125904 compound 1 Drugs 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 238000006264 debenzylation reaction Methods 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BBIPVJCGIASXJB-PKTZIBPZSA-N (11R,15S)-5-anilino-4-[[4-(6-fluoropyridin-2-yl)phenyl]methyl]-8-methyl-1,3,4,8,10-pentazatetracyclo[7.6.0.02,6.011,15]pentadeca-2,5,9-trien-7-one Chemical compound N1([C@H]2CCC[C@H]2N=C1N(C(C1=C2NC=3C=CC=CC=3)=O)C)C1=NN2CC(C=C1)=CC=C1C1=CC=CC(F)=N1 BBIPVJCGIASXJB-PKTZIBPZSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000011914 asymmetric synthesis Methods 0.000 description 2
- 238000010009 beating Methods 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical group C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- FEGVMDAESGIXLU-VXGBXAGGSA-N (1r,2r)-2-(benzylamino)cyclopentan-1-ol Chemical compound O[C@@H]1CCC[C@H]1NCC1=CC=CC=C1 FEGVMDAESGIXLU-VXGBXAGGSA-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
- ZQEBQGAAWMOMAI-SSDOTTSWSA-N (2r)-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H]1C(O)=O ZQEBQGAAWMOMAI-SSDOTTSWSA-N 0.000 description 1
- 150000000179 1,2-aminoalcohols Chemical group 0.000 description 1
- VEUMANXWQDHAJV-UHFFFAOYSA-N 2-[2-[(2-hydroxyphenyl)methylideneamino]ethyliminomethyl]phenol Chemical compound OC1=CC=CC=C1C=NCCN=CC1=CC=CC=C1O VEUMANXWQDHAJV-UHFFFAOYSA-N 0.000 description 1
- 241000186063 Arthrobacter Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 239000004367 Lipase Substances 0.000 description 1
- 102000004882 Lipase Human genes 0.000 description 1
- 108090001060 Lipase Proteins 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 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
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 235000019421 lipase Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- PZBBESSUKAHBHD-UHFFFAOYSA-N methyl 2-oxocyclopentane-1-carboxylate Chemical compound COC(=O)C1CCCC1=O PZBBESSUKAHBHD-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
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical compound NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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
- 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
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/09—Geometrical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of trans-2-aminocyclopentanol with high optical purity. Mainly comprises the following steps: firstly, ring-opening the cyclopentane epoxide in ammonia water to obtain a trans-2-aminocyclopentanol raceme; and secondly, taking optical pure N-Boc-proline as a resolving agent, resolving racemic trans-2-aminocyclopentanol in an alcohol solvent to obtain (1R, 2R) -2-aminocyclopentanol resolved acid salt or (1S, 2S) -2-aminocyclopentanol resolved acid salt, and then carrying out alkaline hydrolysis to obtain the optical pure trans-2-aminocyclopentanol. The preparation method has the advantages of easily available raw materials, short steps, high yield and suitability for technological production.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of trans-2-aminocyclopentanol with high optical purity.
Background
The 1, 2-amino alcohol skeleton structure is widely applied to various natural products and bioactive molecules, and particularly chiral cyclic 1, 2-amino alcohol compounds are important structural components of a large number of medicaments and polypeptide nucleic acids, and provide a large amount of research materials for medicine development. Meanwhile, it is also used as a potent chiral ligand and chiral auxiliary in asymmetric synthesis, such as (1R, 2R) -trans-2-aminocyclopentanol, which is an important intermediate for the synthesis of ITI-214 (lenrispinon), ITI-214 (lenrispinon) is a PDE inhibitor as a potential therapeutic approach for Parkinson's disease, and is being studied in clinical phase 2.
The literature reports that the preparation method of the trans-2-aminocyclopentanol with optical purity mainly comprises the following three steps:
first, the ring-opening reaction of the isolated cyclopentane epoxide with the chiral amine produces diastereomers. Document Journal ofOrganic Chemistry,1985, vol.50, #21, p.4154-4155 reports that cyclopentane epoxide and (R) -alpha-methylbenzylamine form diastereomers under the action of trimethylaluminum, and the optically pure trans-2-aminocyclopentanol is obtained by column chromatography separation and palladium on carbon debenzylation. The method uses trimethyl aluminum which is easy to spontaneously ignite, has high safety risk, and is not easy to carry out amplified production by utilizing column chromatography separation.
Second, asymmetric synthesis. The epoxide is enantioselectively opened by a suitable nucleophile. Patent EP1398310 discloses a method for preparing optically pure trans-2-aminocyclopentanol by using methyl 2-oxo-cyclopentylcarboxylate as a raw material, carrying out hydrogenation reduction in the presence of a chiral ruthenium catalyst to obtain chirality, and carrying out four steps of hydrazinolysis, rearrangement and hydrolysis; organic Letters,2013, vol.15, #12, p.2895-2897 report that cyclopentane and phenyl carbamate acquire chirality under the action of macromolecular chiral compound (salen) Co-OTf catalyst, and the target product is obtained through hydrolysis, and the method has low atom utilization rate and high production cost.
Third, resolution of racemates or related precursors. Document Bulletin de la Societe Chimique de France,1933, vol. <4>53, p.864 reported resolution of trans-2-aminocyclopentanol racemate using chiral tartaric acid, which method is not ideal in resolution effect, and the obtained salt is poor in optical purity, with an ee value of about 70%; the documents Journal ofOrganic Chemistry,2006, vol.71, #6 and p.2320-2331 report that chiral mandelic acid is used for resolution of racemic trans-N-benzyl-2-aminocyclopentanol, and then the resolution and palladium carbon debenzylation are carried out to obtain optically pure trans-2-aminocyclopentanol, and the salt obtained by the method has high optical purity but needs to undergo the palladium carbon hydrogenation debenzylation step; the literature Tetrahedron: asymmetry 22 (2011) 2134-2143 reports a method for resolving related precursors of trans-2-aminocyclopentanol by using arthrobacter lipase, and the method has the advantages that the obtained product has high optical purity, but the enzyme is difficult to obtain, the source is limited, the cost is high, the steps are more, and the industrial production is difficult to realize.
The existing synthesis method lacks a direct and effective technical means, so that a route with few steps, high yield and high optical purity is necessary to be developed.
Disclosure of Invention
In order to overcome the problems, the invention discloses a preparation method of trans-2-aminocyclopentanol with high optical purity. Mainly comprises the following steps: firstly, ring-opening the cyclopentane epoxide in ammonia water to obtain a trans-2-aminocyclopentanol raceme; and secondly, taking optical pure N-Boc-proline as a resolving agent, resolving the racemic trans-2-aminocyclopentanol in an alcohol solvent to obtain single enantiomer trans- (1R, 2R) -2-aminocyclopentanol resolved acid salt or trans- (1S, 2S) -2-aminocyclopentanol resolved acid salt, and then carrying out alkaline hydrolysis to obtain the optical pure trans-2-aminocyclopentanol. The preparation method has the advantages of easily available raw materials, short steps, high yield, high optical purity and suitability for technological production.
The invention provides a preparation method of trans-2-aminocyclopentanol with high optical purity, which comprises the following operation steps: the equation is used as follows:
firstly, performing ring-opening reaction on cyclopentane epoxide in ammonia water, filtering insoluble substances after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain trans-2-aminocyclopentanol raceme 1;
secondly, resolving the trans-2-aminocyclopentanol raceme 1 and optical pure N-Boc-proline into salts in alcohol, and filtering to obtain a compound 2-L-N-Boc-proline or ent-2-D-N-Boc-proline;
and thirdly, adjusting the pH value of the compound 2-L-N-Boc-proline or ent-2-D-N-Boc-proline to be alkaline by an alkaline aqueous solution, extracting by an organic solvent, concentrating an organic layer, and pulping to obtain the trans-2-aminocyclopentanol with high optical purity.
Further, in the first step, the molar ratio of the cyclopentane epoxide to the ammonia water is 1.0:5.0-12.0.
Further, in the first step, the ring-opening reaction temperature is 20-60 ℃.
Further, in the second step, the reaction solvent alcohol is selected from absolute ethyl alcohol or isopropyl alcohol.
Further, in the second step, the molar ratio of trans-2-aminocyclopentanol racemate to optically pure N-Boc-proline is 1:0.5-1.0, preferably 1:0.5.
Further, in the second step, the reaction temperature is 0-90 ℃.
Further, in the third step, the base is selected from KOH or NaOH.
Further, in the third step, the organic solvent is selected from 2-methyltetrahydrofuran.
The invention has the following advantages:
1. the optical pure N-Boc-proline is used as a resolving agent to directly resolve the trans-2-aminocyclopentanol, and the enantiomer with single optical purity can be obtained through alkaline hydrolysis, and the ee value is more than 99%.
2. The method has the advantages of cheap and easily obtained raw materials, short steps, simple and convenient operation, high yield, good optical purity and suitability for technological production.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Example 1
Synthesis of Compound 1
To the reaction flask were added cyclopentane epoxide (84.1 g,1.0 mol), aqueous ammonia (concentration 25%,408.0g,6.0 mol), stirred at 20-30℃for 16 hours, cyclopentane epoxide as a starting material was controlled in GC < 1%, filtered, and the filtrate was concentrated under reduced pressure to give a pale yellow oil, left to stand overnight at low temperature, and solidified to give 97.1g of pale yellow solid compound 1, GC:95.7%, yield 96.2%.
Synthesis of Compound 2
Adding compound 1 (GC 95.7%,97.1g,0.96 mol) and 200mL of absolute ethyl alcohol into a reaction bottle, stirring until the compound is fully dissolved, heating to 60-70 ℃, dropwise adding 280mL of absolute ethyl alcohol solution of N-Boc-L-proline (103.3 g,0.48 mol), continuously heating and refluxing for 2 hours after the dropwise adding, fully dissolving the system, slowly reducing the temperature to 0-5 ℃, preserving the temperature for 3 hours, filtering, leaching a filter cake by 50mL of cold absolute ethyl alcohol, and obtaining 107.3g of white solid compound, 99.5% of HPLC, 99.2% of ee value and 35.3% of yield.
Synthesis of (1S, 2S) -2-aminocyclopentanol
100mL of water and Compound 2 (100.0 g,0.316 mol) were added to a reaction flask under nitrogen atmosphere, and stirred at 10-20deg.C55mL of 30% NaOH solution is added dropwise, 2-methyltetrahydrofuran is added for extraction (150 mL multiplied by 3), the organic layers are combined, saturated saline is used for washing, the organic layers are concentrated under reduced pressure, 30mL of n-heptane is added after the organic layers are concentrated under reduced pressure for pulping for 1 hour, and white solid (1S, 2S) -2-aminocyclopentanol is obtained by filtration, 28.0g, GC:99.8%,99.4% ee and yield are 87.7%; HNMR (CDCl) 3 400 MHz) is consistent with standard nuclear magnetism.
Example 2
This example operates with reference to the preparation of compound 1 of example 1.
Synthesis of 2-L-N-Boc-proline
Adding compound 1 (GC 95.0%,92.0g,0.80 mol) and 200mL of isopropyl into a reaction bottle, stirring until the mixture is fully dissolved, heating the mixture to 60-70 ℃, dropwise adding 720mL of isopropyl alcohol solution of N-Boc-L-proline (172.2 g,0.80 mol), continuously heating and refluxing for 2 hours after the dripping, fully dissolving the system, slowly reducing the temperature to 0-5 ℃, preserving the heat for 3 hours, filtering the mixture, leaching the filter cake by 100mL of cold isopropyl alcohol, and obtaining 186.7g of white solid compound, 99.3% of HPLC (high performance liquid chromatography), 98.2%ee and 73.8% of yield.
Synthesis of (1S, 2S) -2-aminocyclopentanol
Under the protection of nitrogen, 100mL of water and a compound 2-L-N-Boc-proline (100.0 g,0.316 mol) are added into a reaction bottle, stirred, 10-20 ℃ and 75mL of 30% KOH solution are added dropwise, 2-methyltetrahydrofuran is added for extraction (150 mL multiplied by 3), the organic layers are combined, saturated saline is washed, the organic layers are concentrated under reduced pressure, 30mL of N-heptane is added after the organic layers are concentrated under reduced pressure for beating 1 hour, and the white solid (1S, 2S) -2-aminocyclopentanol 27.4g, GC:99.8%,98.5% ee and yield 85.8% are obtained after filtration; HNMR (CDCl) 3 400 MHz) is consistent with standard nuclear magnetism.
Example 3
This example operates with reference to the preparation of compound 1 of example 1.
Synthesis of Compound ent-2-D-N-Boc-proline
Adding compound 1 (GC 95.2%,101.0g,1.00 mol) and 200mL of absolute ethanol into a reaction bottle, stirring until the mixture is fully dissolved, heating the mixture to 60-70 ℃, dropwise adding 300mL of absolute ethanol solution of N-Boc-D-proline (107.6 g,0.50 mol), continuously heating and refluxing for 2 hours after the dropwise adding, fully dissolving the system, slowly cooling to 0-5 ℃, preserving the temperature for 3 hours, filtering, leaching a filter cake by 50mL of cold ethanol, and obtaining 114.2g of white solid compound, 99.6% of HPLC (high performance liquid chromatography), 99.3% ee and 36.1% of yield. Synthesis of (1R, 2R) -2-aminocyclopentanol
Under the protection of nitrogen, 100mL of water and a compound ent-2-D-N-Boc-proline (100.0 g,0.316 mol) are added into a reaction bottle, stirring is carried out, 55mL of 30% NaOH solution is added dropwise at the temperature of 10-20 ℃, 2-methyltetrahydrofuran is added for extraction (150 mL multiplied by 3), the organic layers are combined, saturated saline is washed, the organic layers are concentrated under reduced pressure, 30mL of N-heptane is added after the organic layers are concentrated under reduced pressure for beating for 1 hour, and the white solid (1R, 2R) -2-aminocyclopentanol 28.2g, GC:99.9%,99.5% ee and the yield is 88.3% are obtained through filtering; HNMR (CDCl) 3 400 MHz) is consistent with standard nuclear magnetism.
This example was carried out with reference to the preparation of compound 1 of example 1, 23g of compound 1 (0.2 mol,1.0 eq), using different resolution conditions, with the following results:
the foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above 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 spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (8)
1. The preparation method of the trans-2-aminocyclopentanol with high optical purity is characterized by comprising the following steps of:
firstly, performing ring-opening reaction on cyclopentane epoxide in ammonia water, filtering insoluble substances after the reaction is finished, and concentrating the filtrate under reduced pressure to obtain trans-2-aminocyclopentanol raceme 1;
secondly, resolving the trans-2-aminocyclopentanol raceme 1 and optical pure N-Boc-proline into salts in alcohol, and filtering to obtain a compound 2-L-N-Boc-proline or ent-2-D-N-Boc-proline;
and thirdly, adjusting the pH value of the compound 2-L-N-Boc-proline or ent-2-D-N-Boc-proline to be alkaline by an alkaline aqueous solution, extracting by an organic solvent, concentrating an organic layer, and pulping to obtain the trans-2-aminocyclopentanol with high optical purity.
2. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the first step, the molar ratio of the cyclopentane epoxide to the ammonia water is 1.0:5.0-12.0.
3. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the first step, the ring-opening reaction temperature is 20-60 ℃.
4. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the second step, the reaction solvent alcohol is selected from absolute ethyl alcohol or isopropanol.
5. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the second step, the mol ratio of the trans-2-aminocyclopentanol racemate to the optical pure N-Boc-proline is 1:0.5-1.0.
6. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the second step, the reaction temperature is 0-90 ℃.
7. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the third step, the base is selected from KOH or NaOH.
8. The method for preparing the trans-2-aminocyclopentanol with high optical purity according to claim 1, wherein the method is characterized in that: in the third step, the organic solvent is selected from 2-methyltetrahydrofuran.
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