CN117126101A - Efficient preparation method of hydrochloride intermediate with proline structure - Google Patents
Efficient preparation method of hydrochloride intermediate with proline structure Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title abstract description 11
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 11
- -1 formyl-azabicyclo hexane carboxylate compound Chemical class 0.000 claims abstract description 10
- 230000003647 oxidation Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 38
- 239000000243 solution Substances 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methyl-cyclopentane Natural products CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 14
- 229910052760 oxygen Inorganic materials 0.000 claims description 13
- 239000001301 oxygen Substances 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 12
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims description 11
- 239000007800 oxidant agent Substances 0.000 claims description 10
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 8
- 239000005708 Sodium hypochlorite Substances 0.000 claims description 7
- 230000001590 oxidative effect Effects 0.000 claims description 7
- 235000010265 sodium sulphite Nutrition 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 claims description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 claims description 4
- 239000011787 zinc oxide Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- YRIZYWQGELRKNT-UHFFFAOYSA-N 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione Chemical compound ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O YRIZYWQGELRKNT-UHFFFAOYSA-N 0.000 claims description 2
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910021389 graphene Inorganic materials 0.000 claims description 2
- MHCFAGZWMAWTNR-UHFFFAOYSA-M lithium perchlorate Chemical compound [Li+].[O-]Cl(=O)(=O)=O MHCFAGZWMAWTNR-UHFFFAOYSA-M 0.000 claims description 2
- 229910001486 lithium perchlorate Inorganic materials 0.000 claims description 2
- 239000011656 manganese carbonate Substances 0.000 claims description 2
- 235000006748 manganese carbonate Nutrition 0.000 claims description 2
- 229940093474 manganese carbonate Drugs 0.000 claims description 2
- 229910000016 manganese(II) carbonate Inorganic materials 0.000 claims description 2
- XMWCXZJXESXBBY-UHFFFAOYSA-L manganese(ii) carbonate Chemical compound [Mn+2].[O-]C([O-])=O XMWCXZJXESXBBY-UHFFFAOYSA-L 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 claims description 2
- UDYFLDICVHJSOY-UHFFFAOYSA-N sulfur trioxide-pyridine complex Substances O=S(=O)=O.C1=CC=NC=C1 UDYFLDICVHJSOY-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical group CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000012065 filter cake Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 101800000535 3C-like proteinase Proteins 0.000 description 2
- 101800002396 3C-like proteinase nsp5 Proteins 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000032798 delamination Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- FBPINGSGHKXIQA-UHFFFAOYSA-N 2-amino-3-(2-carboxyethylsulfanyl)propanoic acid Chemical compound OC(=O)C(N)CSCCC(O)=O FBPINGSGHKXIQA-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 235000021185 dessert Nutrition 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000003362 replicative effect Effects 0.000 description 1
- NCDNCNXCDXHOMX-XGKFQTDJSA-N ritonavir Chemical compound N([C@@H](C(C)C)C(=O)N[C@H](C[C@H](O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1SC=NC=1)CC=1C=CC=CC=1)C(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-XGKFQTDJSA-N 0.000 description 1
- 229960000311 ritonavir Drugs 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of preparation of key intermediates of nemaltevir, in particular to a synthetic route of a hydrochloride intermediate with a proline structure, wherein a more efficient oxidation process route for preparing a formyl-azabicyclo hexane carboxylate compound (a compound of formula 6) from a hydroxymethyl-azabicyclo hexane carboxylate compound (a compound of formula 7) is shown, and the whole preparation method is optimized to reduce the production cost and is suitable for large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical industry, and particularly relates to a high-efficiency preparation method of a hydrochloride intermediate with a proline structure.
Background
The invention is based on the synthetic route provided by literature Tetrahedron (2017), 73 (30), 4285-4294 and patent document CN 108314639B. Wherein the point of difference from this journal literature route is that the oxidizing agent used in the step of preparing the azabicyclohexane carboxylate compound by the oxidation reaction is different. Secondly, in the final hydrolysis step, the journal literature route requires the first dissolution with ethyl acetate. The above patent documents describe a synthetic route of Boc-prolyl, wherein a sodium bromide/sodium hypochlorite/TEMPO system is used in a similar oxidation reaction system, and the process flow of the system has strict requirements on pH, so that the reaction reproducibility is poor, and the situation that raw materials cannot react completely often occurs. Therefore, none of the above mentioned process routes is suitable for scale-up production.
The main components of the Paxovid are Nemactetavir and ritonavir, and the Nemactetavir is a peptidomimetic inhibitor of the main protease Mpro of the new coronavirus, and the main protease Mpro of the new coronavirus is inhibited to prevent the virus from replicating by inhibiting the polyprotein precursor.
The hydrochloride of the proline structure is a key intermediate for synthesizing the nemaltevir, and the intermediate has three chiral centers and a three-membered ring structure, has certain synthesis difficulty and has high production cost. Whereas the hydrochloride salt of the proline structure is one of the key intermediates for the synthesis of the main component of nemortevir, the market demand of which increases with the increase of the demand of paxovid.
Disclosure of Invention
In view of the deficiencies in the prior art, the present invention provides a more efficient route to oxidation of formyl-azabicyclo hexane carboxylate compounds (compounds of formula 7) and optimizes the route to reduce production costs and to suit scale-up production.
In order to achieve the technical purpose of the invention, the technical scheme of the invention is as follows:
the invention firstly provides a hydroxymethyl-azabicyclo hexane carboxylate compound, which has the structural formula:
further provided is a formyl-azabicyclo hexane carboxylate compound having the structural formula:
further, the invention provides a preparation method of the formyl-azabicyclo hexane carboxylic ester compound, which comprises the following steps: the compound of formula 6 is oxidized in the presence of a catalyst to produce the compound of formula 7.
The oxidant or oxidant/catalyst combination capable of achieving the above reaction may be dessert oxidation agent, pyridinium chlorochromate, pyridine sulfur trioxide complex, sodium hypochlorite/TEMPO/KBr/NaHCO 3 2-iodoxybenzoic acid, oxygen/trifluoromethylsulfinic acid, bipyridinium dichromate, hydrogen peroxide/molybdenum trioxide, oxygen/manganese carbonate/zinc oxide, oxygen/TEMPO/nitrotetrafluoroborate, trichlorocyanuric acid/TEMPO, oxygen/zinc oxide/graphene, oxygen/ruthenium trichloride, pyridine/oxygen/palladium acetate, lithium perchlorate/N-hydroxyphthalimide.
Wherein the reactive oxidizing reagent is most preferably sodium hypochlorite (NaClO)
Most preferably, the reaction catalysts are TEMPO and potassium bromide (KBr).
The reactant is most preferably sodium bicarbonate.
The reaction solvent was DCM, aqueous sodium sulfite.
The most preferred molar ratio of the reactants is compound 6:naclo:tempo:kbr:nahco 3 ＝1:1.2:0.02:0.2:3.0
The reaction temperature may be 25-35 ℃.
The reaction time may be 7-8 hours.
A preferred embodiment of the invention is: after the reagent is added, naClO solution is added into a low-temperature cold bath, and after the reaction is finished, sodium sulfite aqueous solution is used for quenching reaction.
Further, the reaction also includes a purification step.
Further, the purification method is extraction with methylene chloride, drying, filtration, and then concentration under reduced pressure.
The compound of formula 9 is prepared from the compound of formula 8 by hydrolysis/hydrogenolysis reaction.
In the hydrolysis reaction, the reagent may be hydrochloric acid or ethyl acetate.
In the hydrolysis reaction, the solvent is isopropanol and MTBE.
Sodium hypochlorite (NaClO) is selected in the aspect of an oxidizing reagent, the oxidizing agent is low in price, and the efficiency and the selectivity are high under the condition that TEMPO is used as a catalyst. TEMPO can stabilize the presence of N-oxygen radicals. When KBr is used as a cocatalyst, TEMPO can rapidly catalyze the oxidation of hypochlorite to alcohol, aldehyde or ketone is generated in a high selectivity way, and chiral and N-protecting groups carried by a substrate are not influenced. And sodium hypochlorite is commonly used for disinfection of drinking water, so that the toxicity is low, and other low-cost oxidants have great toxicity. In addition, after the sodium bicarbonate is quantitatively added, the reaction reproducibility is better, and the phenomenon that the raw materials cannot be completely converted is basically avoided. Finally, the invention omits the step of adding ethyl acetate for dissolution during the hydrolysis reaction.
The method optimizes the dosage of the solvent, the raw materials and the auxiliary materials and other process parameters on the basis of the prior art, optimizes a more stable process, increases the yield compared with the prior art (the whole process yield in the literature is 12.3 percent, and the whole process yield after the optimization is 16.7 percent), and is more beneficial to production and amplification.
Detailed Description
In order to further understand the present invention, the following describes in detail a preparation method of a hydrochloride intermediate with a proline structure according to the present invention with reference to examples. It should be understood that these examples are presented merely to further illustrate the features of the present invention and are not intended to limit the scope of the invention or the scope of the claims.
Example 1:
isopropanol (5.0L) and 1 (200 g,1.0 eq.) were added to the reaction flask, then 2 (127.5 g,0.53 eq.) was added to the reaction flask, the temperature was raised to 60 ℃, stirring was maintained for 0.5-1 hour, then cooling to 43 ℃, seed crystals (ee > 99.0%) were added to the reaction flask, stirring was stopped, crystal precipitation was waited, after crystal precipitation, heat was continued for 1-2 hours, and filtration was continued to obtain a white filter cake. Adding the obtained white filter cake and isopropanol (2.5L) into a reaction bottle, starting stirring, heating to 60 ℃, stirring for 15-30 minutes, then cooling to 39 ℃, adding seed crystals (ee > 99.0%), stopping stirring, waiting for crystal precipitation, continuing to keep the temperature for 1-2 hours after crystal precipitation, filtering to obtain a white filter cake, adding the filter cake and water into the reaction bottle, starting stirring, dripping dilute hydrochloric acid solution, adjusting PH=2-3, stirring for 15-30 minutes, filtering, leaching the filter cake with water, collecting the filter cake, and drying under reduced pressure at 45-55 ℃ to obtain white powdery solid 3 (50 g, resolution yield 50%).
Example 2:
toluene (200 mL), DMF (0.5 mL) and 3 (100 g) were added to the reaction flask, stirring was started, then thionyl chloride (68.3 g,1.2 eq.) was added dropwise to the reaction flask, the temperature was controlled to be not more than 35℃during the dropwise addition, and after the dropwise addition, the mixture was stirred at room temperature for 2-3 hours. Subsequently, the reaction flask was placed in a-10 ℃ cold bath, 25% ammonia water (280 g) was added dropwise to the reaction flask, the temperature was controlled to be equal to or less than 20 ℃ during the addition, the mixture was warmed to room temperature, stirred for 2 to 3 hours, after the reaction was completed, saturated aqueous ammonium chloride solution (400 mL) was added to quench the mixture, the aqueous phase was extracted twice with toluene (500 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the obtained organic phase was concentrated to dryness under reduced pressure to give white solid 4 (90 g, yield 90%).
Example 3:
4 (50 g,1.0 eq.) and toluene (450 mL) were added to the reaction flask, nitrogen was replaced 3 times, then a solution of potassium tert-butoxide (56.8 g,2.1 eq.) in tetrahydrofuran (400 mL) was added dropwise to the flask, the temperature was controlled to be less than or equal to 35 ℃ during the addition, the reaction was completed for 1-2 hours at room temperature, after the reaction was completed by TLC detection, the flask was placed in a cold bath at less than or equal to-10 ℃ and quenched with saturated aqueous ammonium chloride solution, the reaction was allowed to stand for stratification, the aqueous phase was extracted with toluene (250 mL x 2) twice, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the obtained organic phase was concentrated to dryness under reduced pressure to give a white solid 5 (37.0 g, yield 90%).
Example 4:
tetrahydrofuran (700 mL) and NaBH were added to the reaction flask 4 (50 g,4.5 eq.) nitrogen was replaced 3 times, then the reaction flask was moved to a cryogenic cold bath, the internal temperature was controlled at less than or equal to 0 ℃, nitrogen was replaced 3 times, then 50% BF was slowly added dropwise 3 THF (235 g,6.0 eq.) is added to the reaction flask at a temperature of 10 ℃ or less, and then reacted for 2 hours at room temperature, then a tetrahydrofuran solution of 5 (50 g,1.0 eq.) is added dropwise to the reaction flask, the temperature is raised to 50-60 ℃ and the mixture is stirred for 2-3 hours, then a water quenching reaction is added dropwise to the system, and NaOH solution (80 g dissolved in 500mL water) and 30% H are added 2 O 2 Solution (750 g), followed by heating to 25℃to 35℃and adding Boc 2 O (76.5 g,1.2 eq.) and stirring for 1-2 hours at constant temperature, the reaction solution was filtered through celite, MTBE (500 mL) was added to the filtrate, after stirring for 0.5 hour, the aqueous phase was separated off, the organic phase was added to the aqueous sodium sulfite solution and stirred for 0.5 hour, the aqueous phase was separated off again, the organic phase was dried over anhydrous sodium sulfate, filtered, the filter cake was rinsed with MTBE (200 mL), the filtrates were combined, and the filtrate was concentrated to dryness under reduced pressure to give yellow oily liquid 6 (51 g, 73% yield).
Example 5:
6 (50 g,1.0 eq.), methylene chloride (1.0L), potassium bromide (5.0 g,0.2 eq.), TEMPO (0.65 g,0.02 eq.), sodium bicarbonate (52.2 g,3.0 eq.) and water were added to a reaction flask, the flask was then cooled in a low temperature cold bath, 9% naclo solution (4.12 kg,1.2 eq.) was added dropwise to the flask, the reaction was quenched by adding aqueous sodium sulfite solution after the TLC detection at a temperature of 10 ℃ or less during the dropwise addition, stirred at room temperature for 0.5 hours, allowed to stand for delamination, the aqueous phase was extracted twice with methylene chloride (200 ml of 2), the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to give yellow oily liquid 7 (41.1 g, yield 82%).
Example 6:
7 (40.0 g,1.0 eq.), methanol (400 mL), potassium carbonate (57.6 g,2.5 eq.) are added to the flask, stirred at room temperature for 2-4 hours, followed by iodine (42.8 g,1.0 eq.) and stirred at room temperature for 2-3 hours, after TLC determination the reaction is completed, aqueous sodium thiosulfate solution is added to quench the reaction, followed by ethyl acetate (100 mL), stirred for 0.5 hours, and allowed to stand for delamination, the aqueous phase is extracted twice with ethyl acetate (100 mL x 2), the organic phases are combined, dried over anhydrous sodium sulfate, filtered, the filter cake is washed with ethyl acetate (100 mL), the filtrates are combined, concentrated to dryness under reduced pressure to give yellow oily liquid 8 (38.3 g, 85%).
Example 7:
hydrochloric acid/ethyl acetate (1M, 90 mL) and 8 (30 g,1.0 eq.) were added to the reaction flask, warmed to 25-35 ℃, stirred at a constant temperature for 2-3 hours, the reaction solution concentrated to dryness under reduced pressure, then isopropanol (60 mL) was added, warmed to 50-60 ℃, MTBE (240 mL) was added dropwise to the reaction solution, the dropping was completed, cooled to 10-20 ℃, stirred at a constant temperature for 2 hours, filtered, and the filter cake was rinsed with a mixed solution of MTBE (15 mL) and isopropanol (5 mL) to give a white solid 9 (15.4 g, 81%).
Claims (10)
1. A process for the preparation of formyl-azabicyclo hexane carboxylic acid ester compounds, characterized in that a compound of formula 6 is prepared by oxidation of a compound of formula 7 in an oxidizing agent or an oxidizing agent/catalyst combination,
2. the process of claim 1 wherein the oxidant or oxidant/catalyst combination is dessert-martin oxidant, pyridinium chlorochromate, sulfur trioxide pyridine complex, sodium hypochlorite/TEMPO/KBr/NaHCO 3 2-iodoxybenzoic acid, oxygen/trifluoromethylsulfinic acid, bipyridinium dichromate, hydrogen peroxide/molybdenum trioxide, oxygen/manganese carbonate/zinc oxide, oxygen/TEMPO/nitrotetrafluoroborate, trichlorocyanuric acid/TEMPO, oxygen/zinc oxide/graphene, oxygen/ruthenium trichloride, pyridine/oxygen/palladium acetate, lithium perchlorate/N-hydroxyphthalimide.
3. A preparation method of formyl-azabicyclo hexane carboxylic ester compound is characterized in that a compound of formula 6 is subjected to an oxidation reaction to prepare a compound of formula 7, wherein the oxidation reaction is carried out in a sodium hypochlorite/TEMPO/KBr/NaHCO reaction 3 And (3) carrying out oxidation reaction in the system.
4. The method according to claim 1, wherein the oxidation reaction solvent is DCM and sodium sulfite aqueous solution.
5. The preparation method according to claim 1, wherein a NaClO solution is added in a low-temperature cold bath, and then a quenching reaction is performed by using a sodium sulfite aqueous solution.
6. The method according to claim 5, wherein the concentration of the NaClO solution is 9%.
7. The process according to claim 3, wherein the molar ratio of the reaction is that of the compound of formula 6: naClO: TEMPO: KBr: naHCO3 = 1:1.2:0.02:0.2:3.0.
8. The preparation method according to claim 1, comprising the steps of extraction with methylene chloride in the post-treatment step, drying, filtration, and then concentration under reduced pressure.
9. The method of claim 1, wherein the reaction time is 7 to 8 hours.
10. The process of claim 1, wherein the reaction temperature is 25-35 ℃.
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