CN115028553A - Preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine - Google Patents
Preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine Download PDFInfo
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- CN115028553A CN115028553A CN202210694327.8A CN202210694327A CN115028553A CN 115028553 A CN115028553 A CN 115028553A CN 202210694327 A CN202210694327 A CN 202210694327A CN 115028553 A CN115028553 A CN 115028553A
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- boc
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- cyclohexanediamine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims abstract description 18
- PQMCFTMVQORYJC-PHDIDXHHSA-N (1r,2r)-2-aminocyclohexan-1-ol Chemical compound N[C@@H]1CCCC[C@H]1O PQMCFTMVQORYJC-PHDIDXHHSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- ZWAJLVLEBYIOTI-UHFFFAOYSA-N cyclohexene oxide Chemical compound C1CCCC2OC21 ZWAJLVLEBYIOTI-UHFFFAOYSA-N 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
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 7
- -1 azodicarboxylic diester Chemical class 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 6
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 claims description 5
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical group CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- FWFSEYBSWVRWGL-UHFFFAOYSA-N cyclohexene oxide Natural products O=C1CCCC=C1 FWFSEYBSWVRWGL-UHFFFAOYSA-N 0.000 claims description 3
- 238000006751 Mitsunobu reaction Methods 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 229910052799 carbon Inorganic materials 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 2
- 238000007142 ring opening reaction Methods 0.000 abstract description 2
- 229960002009 naproxen Drugs 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- AKVIZYGPJIWKOS-DTWKUNHWSA-N tert-butyl n-[(1r,2s)-2-aminocyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1N AKVIZYGPJIWKOS-DTWKUNHWSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAIYTHASVJZIGQ-QWHCGFSZSA-N benzyl n-[(1r,2s)-2-aminocyclohexyl]carbamate Chemical compound N[C@H]1CCCC[C@H]1NC(=O)OCC1=CC=CC=C1 FAIYTHASVJZIGQ-QWHCGFSZSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 238000007710 freezing Methods 0.000 description 2
- 230000008014 freezing Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XVROWZPERFUOCE-RKDXNWHRSA-N tert-butyl n-[(1r,2r)-2-hydroxycyclohexyl]carbamate Chemical compound CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1O XVROWZPERFUOCE-RKDXNWHRSA-N 0.000 description 2
- 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-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
- 239000000556 agonist Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- IDQLGJJPYSFXPM-CHWSQXEVSA-N benzyl n-[(1r,2r)-2-hydroxycyclohexyl]carbamate Chemical compound O[C@@H]1CCCC[C@H]1NC(=O)OCC1=CC=CC=C1 IDQLGJJPYSFXPM-CHWSQXEVSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000001415 gene therapy Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/04—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from amines with formation of carbamate groups
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/02—Ortho- or ortho- and peri-condensed systems
- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
- C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
- C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
- C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
- C07C2603/18—Fluorenes; Hydrogenated fluorenes
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- 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 Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine, belonging to the technical field of medical intermediates. The epoxy cyclohexane is taken as a raw material and is subjected to ring opening with ammonia water to obtain trans-2-aminocyclohexanol; then carrying out Boc or Cbz protection on the amino; then carrying out mitsunobu reaction with hexamethyldisilazane to obtain N-Boc/Cbz-cis-1, 2-cyclohexanediamine; finally, the chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine is obtained by salt-forming resolution of the chiral N-Boc/Cbz-cis- (1R,2S) -naproxen in an organic solvent. The preparation method has low cost, short steps and low requirements on equipment, and the configuration of the carbon atom connected with the hydroxyl is turned over through the mitsunobu reaction.
Description
Technical Field
The invention relates to a preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine, belonging to the technical field of medical intermediates.
Background
The single protecting group-cis- (1R,2S) -cyclohexanediamine is a medical intermediate with important value due to the unique chemical structure and pharmacological activity of the single protecting group-cis- (1R,2S) -cyclohexanediamine. (1R,2S) -2-aminocyclohexylcarbamic acid tert-butyl ester, CAS: 364385-54-6, english name: (1R,2S) -1N-Boc-cyclohexane-1, 2-diamine; (1R,2S) -1N-benzyloxycarbonylcyclohexyl-1, 2-diamine, CAS: 1067631-22-4, english name: benzyl (1R,2S) -2-aminocyclohexylcarbamate. It can be used for synthesizing inhibitor or agonist with gene therapy effect with nucleoside/peptide nuclear compound, and has high exploratory property in the direction of synthesizing new medicine.
At present, the mono-protecting group-cis- (1R,2S) -cyclohexanediamine is not commercialized, the price of a customized product is expensive, and the document [ Journal of Organic Chemistry,2004, vol.69, #6, p.1858-1865] reports that epoxy cyclohexane is used as a starting material, and (1R,2S) -2-aminocyclohexyl carbamic acid tert-butyl ester is obtained through nearly 7 steps, the steps are too long, and explosive sodium azide is used, so that the use of a reagent has a safety hazard and is not suitable for preparing products in large quantity.
Therefore, it is necessary to carry out an in-depth research on the synthesis process of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine, and provide a better, mild, safe and stable reaction route to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine. The epoxy cyclohexane is taken as a raw material and is subjected to ring opening with ammonia water to obtain trans-2-aminocyclohexanol; then carrying out Boc or Cbz protection on the amino; then carrying out a mitsunobu reaction with hexamethyldisilazane to obtain N-Boc/Cbz-cis-1, 2-cyclohexanediamine; and finally carrying out salt resolution on the chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine and (S) -naproxen in an organic solvent. The preparation method has low cost, short steps and low requirements on equipment, and the configuration of the carbon atom connected with the hydroxyl is turned over through the mitsunobu reaction.
The invention relates to a preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine, which comprises the following steps:
the first step is as follows: mixing epoxy cyclohexane with ammonia water and methanol, heating to react and open ring to obtain trans-2-aminocyclohexanol;
the second step: dissolving trans-2-aminocyclohexanol in an organic solvent in the presence of a base with Boc 2 O or Cbz-Cl to obtain N-Boc/Cbz-trans-aminocyclohexanol;
the third step: mixing N-Boc/Cbz-trans-aminocyclohexanol, triphenylphosphine, hexamethyldisilazane and an organic solvent, and dropwise adding azodicarboxylic diester to react to obtain N-Boc/Cbz-cis-1, 2-cyclohexanediamine;
the fourth step: and (2) placing the N-Boc/Cbz-cis-1, 2-cyclohexanediamine and (S) -naproxen in a mixed organic solvent, heating and refluxing, cooling to separate out a complex intermediate, and dissociating to obtain the chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine.
Further, in the technical scheme, the molar ratio of the cyclohexene oxide, 25% ammonia water and methanol in the first step is 1:15-20: 5-8.
Further, in the above technical solution, in the second step, the organic solvent is selected from dichloromethane or toluene, and the base is selected from sodium hydroxide or triethylamine.
Further, in the above technical scheme, in the second step, the trans-2-aminocyclohexanol and Boc are reacted 2 The molar ratio of O/Cbz-Cl to the base is 1:1.05-1.15: 1.15-1.25.
Further, in the above-mentioned technical means, the azodicarboxylic diester in the third step is selected from diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).
Further, in the above technical scheme, the molar ratio of the N-Boc/Cbz-trans-aminocyclohexanol, triphenylphosphine, azodicarboxylic diester and hexamethyldisilazane in the third step is 1:1.2-2.2:1.2-2.2: 1.2-2.5.
Further, in the above technical solution, the organic solvent in the fourth step is selected from isopropanol, ethyl acetate or a mixture thereof.
Further, in the technical scheme, in the fourth step, the molar ratio of the N-Boc/Cbz-cis-1, 2-cyclohexanediamine to the (S) -naproxen is 1: 0.95-1.05.
Advantageous effects of the invention
Compared with the synthesis method reported in the literature, the method has the following beneficial effects:
1) the whole process has short synthetic route and cheap starting raw materials, and avoids hydrogenation of noble metals or use of explosive reagents; the yield of the optimized mitsunobu reaction condition is improved to 75-80 percent and is completely in a cis-structure. The post-treatment can remove the by-products such as triphenyl phosphine oxide and the like in a manner of forming hydrochloride.
2) When the racemate is resolved, tartaric acid series or mandelic acid is adopted, the salt-forming resolution efficiency is low, and when (S) -naproxen is used for crystallization resolution, the once salt-forming yield reaches more than 40 percent, and the free product is 99.5 percent ee.
Detailed Description
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
Adding 2.2Kg of 25% ammonia water and 197g of methanol into a reaction flask, cooling to 0-5 ℃, dropwise adding 98.2g (1mol,1.0eq) of cyclohexene oxide, subsequently heating to 35-40 ℃, reacting overnight, concentrating under reduced pressure, evaporating to remove a large amount of methanol and ammonia gas, cooling and filtering to obtain 106.3g of trans-2-aminocyclohexanol, the yield is 92.3%, and the HPLC is 95.4%. 1 HNMR(400MHz,CDCl3):δ3.20-3.07(m,1H),2.47-2.36(m,1H),2.12(s,3H),2.05-1.01(m,8H).
Example 2
Adding 103.7g (0.9mol,1.0eq) of trans-2-aminocyclohexanol and 600mL of dichloromethane into a reaction bottle, controlling the temperature to be 20-30 ℃, dropwise adding 350mL of a dichloromethane solution containing 2O 225.9g (1.035mol,1.15eq) of Boc2 and 94g of a 48% sodium hydroxide aqueous solution at the temperature, detecting the pH value to be more than or equal to 11 in the dropwise adding process, reacting for 6 hours after the dropwise adding is finished, separating a lower-layer alkali aqueous phase, washing an organic phase with water, concentrating the organic phase, adding N-heptane, cooling and pulping to obtain 178.5g of N-Boc-trans-2-aminocyclohexanol with the yield of 92.1 percent，HPLC 99.5％。 1 HNMR(400MHz,CDCl3):δ7.53(s,1H),4.59(s,1H),3.36-3.32(m,1H),3.15-3.01(m,1H),2.21-2.03(m,2H),1.80-1.65(m,2H),1.42(s,9H),1.40-1.15(m,4H).
Example 3
In a reaction flask, 103.7g (0.9mol,1.0eq) of trans-2-aminocyclohexanol, 105mL of dichloromethane and triethylamine (102g,1.0mol,1.10eq) were charged, a Cbz-Cl 161.2g (0.945mol,1.05eq) solution was added dropwise at 0 to 5 ℃ while controlling the temperature, reaction was carried out at 0 ℃ for 3 hours after completion of addition, salts formed during the reaction were filtered off, the organic phase was washed with water, saturated brine, the organic phase was concentrated, toluene and N-heptane were added and slurried to obtain 202.4g of N-Cbz-trans-2-aminocyclohexanol with a yield of 90.2%, HPLC: 99.8 percent. 1 HNMR(400MHz,CDCl3):δ7.39-7.28(m,5H),5.12(s,1H),5.08(s,1H),4.84(s,2H),3.41-3.35(m,1H),3.32-3.26(m,1H),2.06-1.97(m,2H),1.73-1.66(m,2H),1.36-1.09(m,4H).
Example 4
Under the protection of nitrogen, 17.2g (0.08mol,1.0eq) of N-Boc-trans-2-aminocyclohexanol, 31.5g (0.12mol,1.5eq) of triphenylphosphine, 20.7g (0.128mol,1.6eq) of hexamethyldisilazane and 120mL of dichloromethane are put into a reaction bottle, the mixture is stirred uniformly and controlled at 0 ℃, 24.3g (0.12mol,1.5eq) of DIAD/40 mL of dichloromethane are slowly dropped, then the temperature is raised to 40-45 ℃ for reaction for 6 hours, TLC detection reaction is finished, reaction liquid is cooled to-30 ℃ and stirred for 2 hours, a large amount of solid is deposited (PPh 3O and DIADH2 complex), more than 95% of by-products are filtered and removed (if necessary, the by-product can be frozen and deposited once again), filtrate is concentrated to dryness under reduced pressure, 200mL of methanol and 4.5g of p-toluenesulfonic acid are added, the reflux reaction is heated and the reflux reaction is carried out for 1 hour, and the mixture is concentrated to dryness under reduced pressure again, adding 150mL of dichloromethane, washing with sodium bicarbonate, washing with saturated salt water, concentrating an organic layer, and performing flash column chromatography to obtain 12.9g of N-Boc-cis-1, 2-cyclohexanediamine as an oily liquid with the yield of 75.1% and the GC content of 99.6%. 1 HNMR(400MHz,CDCl3):δ4.43(s,1H),3.13-3.09(m,1H),2.43-2.32(m,1H),1.98-1.94(m,2H),1.78-1.72(m,2H),1.45-1.40(m,11H),1.28-1.07(m,4H).
Example 5
Under the protection of nitrogen, 17.2g (0.08mol,1.0eq) of N-Boc-trans-aminocyclohexanol, 31.5g (0.12mol,1.5eq) of triphenylphosphine, 20.7g (0.128mol,1.6eq) of hexamethyldisilazane and 120mL of dichloromethane were put into a reaction flask, the mixture was stirred uniformly at 0 ℃ and 40mL of DEAD (0.12mol,1.5eq) solution was slowly added dropwise, the mixture was heated to 40-45 ℃ to react for 5 hours, TLC detection was completed, the reaction solution was cooled to-30 ℃ and stirred for 2 hours, at which time a large amount of solid precipitated (PPh 3O and DEADDH 2 complex), more than 92% of by-product was removed by filtration (if necessary, freezing once again to precipitate and filter again), the filtrate was concentrated to dryness under reduced pressure, 200mL of methanol and 4.5g of p-toluenesulfonic acid were added, the mixture was heated to reflux for 1 hour, concentrated to dryness under reduced pressure, 150mL of dichloromethane was added, washing with sodium bicarbonate, washing with saturated salt water, concentrating the organic layer, and performing flash column chromatography to obtain 13.3g of N-Boc-cis-1, 2-cyclohexanediamine, wherein the yield is 77.3%, and the GC content is 99.2%.
Example 6
Under the protection of nitrogen, 24.9g (0.1mol,1.0eq) of N-Cbz-trans-aminocyclohexanol, 31.5g (0.12mol,1.5eq) of triphenylphosphine, 20.7g (0.128mol,1.6eq) of hexamethyldisilazane and 120mL of dichloromethane are added into a reaction bottle, the mixture is stirred uniformly and the temperature is controlled at 0 ℃, 40mL of DIAD solution 24.3g (0.12mol,1.5eq) of dichloromethane is slowly added dropwise, then the temperature is raised to 40-45 ℃ for reaction for 6 hours, and the TLC detection reaction is finished. The reaction solution was cooled to about-30 ℃ and stirred for 2 hours, at which time a large amount of solid precipitated (PPh 3O and DIADH2 complex), more than 95% of the by-product was removed by filtration (again, freezing and precipitating once more if necessary), the filtrate was concentrated to dryness under reduced pressure, 200mL of methanol and 4.5g of p-toluenesulfonic acid were added, the reaction was refluxed for 1 hour, again concentrated to dryness under reduced pressure, 150mL of dichloromethane was added, sodium bicarbonate was added, the mixture was washed with saturated brine, the organic layer was concentrated, flash column chromatography was performed to obtain 19.0g of N-Cbz-cis-1, 2-cyclohexanediamine, yield 76.7%, HPLC 99.8%. 1 HNMR(400MHz,CDCl3):δ7.26-7.18(m,5H),5.02(s,2H),4.99(s,1H),3.11-3.01(m,1H),2.32-2.28(m,1H),1.91-1.78(m,2H),1.60-1.57(m,2H),1.26-0.95(m,6H).
Example 7
Adding 21.4g (0.1mol,1.0eq) of N-Boc-cis-1, 2-cyclohexanediamine and 120mL of ethyl acetate into a reaction bottle, heating to 50 ℃, dropwise adding 23.0g (0.1mol,1.0 eq)/100 mL of isopropanol solution of (S) -naproxen, then heating to reflux reaction for 6 hours, slowly reducing the temperature in a gradient manner to 10 ℃, filtering to obtain a complex salt of the N-Boc-cis- (1R,2S) -cyclohexanediamine and the (S) -naproxen, then adding dichloromethane and 10% sodium hydroxide aqueous solution to adjust the pH value to 11-12, extracting with dichloromethane, concentrating an organic phase, cooling N-heptane, and pulping to obtain 8.0g of the N-Boc-cis- (1R,2S) -cyclohexanediamine, wherein the yield is 37.3%, GC 99.7% and 99.8% ee.
Example 8
N-Cbz-cis-1, 2-cyclohexanediamine 24.8(0.1mol,1.0eq) and ethyl acetate 120mL are charged into a reaction flask, and after heating to 50 ℃, 23.0g (0.1mol,1.0 eq)/100 mL of isopropanol solution is added dropwise, then heating to reflux reaction is carried out for 6 hours, the temperature is slowly reduced in a gradient manner to 10 ℃, and filtration is carried out to obtain a complex salt of N-Cbz-cis- (1R,2S) -cyclohexanediamine and (S) -naproxen, then MTBE and 1M hydrochloric acid are added to adjust the pH to 1.0-1.5, MTBE is used for extracting (S) -naproxen, the aqueous phase is adjusted to 10-11, dichloromethane is used for extracting, and N-heptane is reduced in temperature to obtain 10.1g of N-Cbz-cis- (1R,2S) -cyclohexanediamine, the yield is 40.5%, GC 99.8%, and 99.7% ee are obtained.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered as the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. A preparation method of chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine is characterized by comprising the following steps:
the first step is as follows: mixing epoxy cyclohexane with ammonia water and methanol, heating to react and open ring to obtain trans-2-aminocyclohexanol;
the second step is that: dissolving trans-2-aminocyclohexanol in an organic solventIn the presence of a base with Boc 2 O or Cbz-Cl to obtain N-Boc/Cbz-trans-aminocyclohexanol;
the third step: mixing N-Boc/Cbz-trans-aminocyclohexanol, triphenylphosphine, hexamethyldisilazane and an organic solvent, and dropwise adding azodicarboxylic diester for reaction to obtain N-Boc/Cbz-cis-1, 2-cyclohexanediamine;
the fourth step: and (2) placing the N-Boc/Cbz-cis-1, 2-cyclohexanediamine and (S) -naproxen in a mixed organic solvent, heating and refluxing, cooling to separate out a complex intermediate, and dissociating to obtain the chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine.
2. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the first step, the molar ratio of the cyclohexene oxide, 25% ammonia water and methanol is 1:15-20: 5-8.
3. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the second step, the organic solvent is selected from dichloromethane or toluene, and the base is selected from sodium hydroxide or triethylamine.
4. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the second step, the trans-2-aminocyclohexanol, Boc 2 The molar ratio of O/Cbz-Cl to the base is 1:1.05-1.15: 1.15-1.25.
5. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the third step, the azodicarboxylic acid diester is selected from diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD).
6. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the third step, the molar ratio of N-Boc/Cbz-trans-aminocyclohexanol, triphenylphosphine, azodicarboxylic diester and hexamethyldisilazane is 1:1.2-2.2:1.2-2.2: 1.2-2.5.
7. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the fourth step, the organic solvent is selected from isopropanol, ethyl acetate or a mixture thereof.
8. The method of preparing chiral N-Boc/Cbz-cis- (1R,2S) -cyclohexanediamine of claim 1, wherein: in the fourth step, the molar ratio of the N-Boc/Cbz-cis-1, 2-cyclohexanediamine to the (S) -naproxen is 1: 0.95-1.05.
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Denomination of invention: A Preparation Method for Chiral N-Boc/Cbz cis - (1R, 2S) - Cyclohexanediamine Granted publication date: 20240326 Pledgee: The Bank of Shanghai branch Caohejing Limited by Share Ltd. Pledgor: SHANGHAI HANHONG TECHNOLOGY CO.,LTD. Registration number: Y2024980024446 |
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