CN115433194A - Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative - Google Patents
Synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative Download PDFInfo
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- CN115433194A CN115433194A CN202211109518.XA CN202211109518A CN115433194A CN 115433194 A CN115433194 A CN 115433194A CN 202211109518 A CN202211109518 A CN 202211109518A CN 115433194 A CN115433194 A CN 115433194A
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- pyrrole
- furan
- trichloroacetylfuran
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- XJHUPUJCESXRQR-UHFFFAOYSA-N 2,2,2-trichloro-1-(2,3-dihydrofuran-4-yl)ethanone Chemical compound ClC(Cl)(Cl)C(=O)C1=COCC1 XJHUPUJCESXRQR-UHFFFAOYSA-N 0.000 claims abstract description 23
- RPZAAFUKDPKTKP-UHFFFAOYSA-N n-(methoxymethyl)-1-phenyl-n-(trimethylsilylmethyl)methanamine Chemical compound COCN(C[Si](C)(C)C)CC1=CC=CC=C1 RPZAAFUKDPKTKP-UHFFFAOYSA-N 0.000 claims abstract description 12
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims abstract description 11
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 5
- 238000002156 mixing Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- PQXKHYXIUOZZFA-UHFFFAOYSA-M lithium fluoride Chemical compound [Li+].[F-] PQXKHYXIUOZZFA-UHFFFAOYSA-M 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- 238000001308 synthesis method Methods 0.000 claims description 9
- 239000002585 base Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 229910003002 lithium salt Inorganic materials 0.000 claims description 6
- 159000000002 lithium salts Chemical class 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- 229940043279 diisopropylamine Drugs 0.000 claims description 4
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- 239000002994 raw material Substances 0.000 abstract description 8
- 230000000694 effects Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 description 14
- 229940125782 compound 2 Drugs 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 238000000926 separation method Methods 0.000 description 9
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229940126214 compound 3 Drugs 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- OCLXPRZQCIGHFQ-UHFFFAOYSA-N methyl 2,3-dihydrofuran-4-carboxylate Chemical compound COC(=O)C1=COCC1 OCLXPRZQCIGHFQ-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229940125904 compound 1 Drugs 0.000 description 5
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical compound O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 238000007363 ring formation reaction Methods 0.000 description 4
- 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 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical compound COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- -1 Pyridine compound Chemical class 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- LTVDTKRMOQDRCH-UHFFFAOYSA-N furan;1h-pyrrole Chemical compound C=1C=CNC=1.C=1C=COC=1 LTVDTKRMOQDRCH-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003233 pyrroles Chemical class 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- 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)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives, which comprises the following steps: (1) Mixing 2, 3-dihydrofuran with trichloroacetyl chloride and alkali, and reacting to obtain 2, 3-dihydro-4-trichloroacetylfuran; (2) Reacting 2, 3-dihydro-4-trichloroacetylfuran with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine and methanol to obtain the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative. The invention is an ideal synthetic route with simple and short reaction steps, easily available raw materials, high reaction activity and more general reaction conditions.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives.
Background
Pyrrole and furan are important compounds widely applied in the fields of medicine, pesticides, materials and the like, and are often introduced into pharmaceutical compounds as active molecular fragments in view of the structural characteristics of the pyrrole and furan, and at present, medicines only containing pyrrolidine fragments are more than 50. The hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative has pyrrole and furan fragments, has a plurality of potential active sites, has high activity for preventing and treating diseases such as inflammation and metabolic syndrome, and has great prospect for the biological activity of the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative and downstream products thereof. Based on this, it is necessary to explore an ideal synthetic route.
Few synthesis reports of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives exist, and the key step is the construction of a furopyrrole framework; in the prior art, the construction of a furopyrrole framework is mainly realized by the action of 2, 3-dihydro-4-furoic acid methyl ester and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, wherein the 2, 3-dihydro-4-furoic acid methyl ester is not mature and commercialized, gamma-butyrolactone is used as a raw material, and is etherified and esterified with methyl formate in the presence of methanol, and then the furopyrrole framework is obtained by self-preparation through strong acid dehydration.
The synthesis method has certain defects in the aspects of universality and scale-up production; firstly, the synthetic raw material gamma-butyrolactone of the intermediate methyl 2, 3-dihydro-4-furoate belongs to a product of easy-to-prepare toxin tube and is not easy to obtain; secondly, when a furan pyrrole framework is built by 2, 3-dihydro-4-furoate methyl ester and N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, the yield of the product is only less than 10% under the conventional reaction condition, if a target product is to be obtained with high yield, the target product needs to be obtained at 140 ℃ without solvent reaction, the high temperature condition has certain potential safety hazard, and the solvent-free state is only suitable for preparation of a small amount of product, and is not suitable for generation of large-batch products.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives. The invention is an ideal synthetic route with simple and short reaction steps, easily available raw materials, high reaction activity and more general reaction conditions.
The technical scheme of the invention is as follows:
the first purpose of the invention is to provide a synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives, which is carried out according to the following route:
(1) Mixing 2, 3-dihydrofuran (compound 1) with trichloroacetyl chloride and alkali, and reacting to obtain 2, 3-dihydro-4-trichloroacetylfuran (compound 2);
(2) Reacting 2, 3-dihydro-4-trichloroacetylfuran (compound 2) with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine (compound 3) and methanol to obtain the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative (compound 4).
In one embodiment of the present invention, in step (1), the base is one or more of diisopropylamine, triethylamine and pyridine.
In one embodiment of the invention, in the step (1), the molar ratio of the 2, 3-dihydrofuran to the trichloroacetyl chloride is 1 (1-2); the molar ratio of 2, 3-dihydrofuran to base is 1 to 3.
In one embodiment of the present invention, step (1) further comprises an organic solvent, wherein the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide and acetonitrile.
In one embodiment of the invention, in the step (1), the reaction temperature is 20-30 ℃ and the reaction time is 2-6 h.
Preferably, in the step (1), the specific process of the reaction is as follows:
adding an organic solvent into a reaction device, firstly adding the organic solvent and 2, 3-dihydrofuran, then controlling the temperature to be-5-15 ℃, then adding trichloroacetyl chloride, then controlling the temperature to be-5 ℃, finally adding alkali, after the addition is finished, heating to 20-30 ℃, and reacting for 2-6 h;
after the reaction is finished, diluting the reaction solution with an organic solvent, washing twice with dilute hydrochloric acid, washing once with a saturated sodium bicarbonate solution, drying with anhydrous sodium sulfate, filtering, and desolventizing the filtrate to obtain a crude compound 2, namely a crude product 2, 3-dihydro-4-trichloroacetylfuran;
more preferably, the dilute hydrochloric acid has a concentration of 1 to 2M.
In one embodiment of the present invention, in the step (2), the specific reaction process is as follows:
adding 2, 3-dihydro-4-trichloroacetylfuran into an organic solvent, controlling the temperature to be 20-30 ℃, adding N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine and lithium salt, and replacing argon for protection reaction after the addition is finished;
then, heating to 60-100 ℃, reacting for 8-18h, cooling to room temperature after the reaction is finished, adding methanol, and reacting for 1-6 h at room temperature;
finally, pouring the reaction solution into ice water, adjusting the reaction solution to be alkaline by using saturated sodium bicarbonate solution, and adding ethyl acetate for extraction for three times; and (3) combining organic phases, washing with saturated saline solution, drying with anhydrous sodium sulfate, and purifying by column chromatography to obtain a compound 4, namely the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative.
In one embodiment of the present invention, in the step (2), the molar ratio of 2, 3-dihydro-4-trichloroacetylfuran to N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is 1 (1-3); the molar ratio of the 2, 3-dihydro-4-trichloroacetylfuran to the methanol is 1 (5-15).
In one embodiment of the invention, the lithium salt is one or more of lithium fluoride, lithium bromide, lithium chloride; the molar ratio of the 2, 3-dihydro-4-trichloroacetylfuran to the lithium salt is 1 (2-5).
In one embodiment of the invention, the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide, acetonitrile.
The beneficial technical effects of the invention are as follows:
the invention is based on the synthesis of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives in the prior art, and has the problems of difficult obtainment of reaction raw materials, low reaction yield, weak universality of closed-loop conditions, long reaction steps and the like.
The invention adopts 4-trichloroacetyl-2, 3-dihydrofuran as a cyclization raw material, improves the reaction activity, reduces the operation difficulty of the prior art, ensures that a reaction material obtains a target compound at a proper reaction temperature under good fluidity, has short steps (only 2 steps) in the whole route, simple and convenient operation, ideal product yield and stronger controllability, is a candidate route for amplifying and producing hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-methyl carboxylate derivatives, not only provides a reliable reference for the synthesis of similar compounds of furan and pyrrole, but also provides a more convenient way for exploring the biological activity of the furan and pyrrole compounds.
The application adopts 4-trichloroacetyl-2, 3-dihydrofuran as a cyclization raw material, is low in price and easy to obtain, and improves the industrial generation feasibility of the target compound to a great extent.
Drawings
FIG. 1 is a schematic diagram of the synthetic reaction of the present invention;
FIG. 2 is a schematic diagram of a synthesis reaction in the prior art;
FIG. 3 is a nuclear magnetic hydrogen spectrum of Compound 4 obtained in example 1.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives comprises the following steps:
(1) Synthesis of Compound 2
Adding 200ml of dichloromethane and 20g of compound 1 (2, 3-dihydrofuran, 285.34mmol and 1eq) into a reaction bottle, controlling the temperature to be 0 ℃, then adding 77.82g of trichloroacetyl chloride (428mmol and 1.5eq), controlling the temperature to be 0 ℃, then adding 45.14g of pyridine (570.69mmol and 2eq), raising the temperature to 25 ℃ after the addition is finished, and reacting for 3 hours;
after the reaction, the reaction mixture was poured into 500ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (200ml × 2), the organic phase obtained by liquid separation was washed once with 200ml of saturated sodium bicarbonate solution, and finally the organic phase obtained by liquid separation was washed once with 200ml of saturated common salt solution, and the organic phase obtained by liquid separation was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 54g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran) with a yield of 86.08% and a purity of 98%.
(2) Synthesis of Compound 4
Adding 54g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran, 250.63mmol and 1eq) into 540ml of acetonitrile, controlling the temperature at 25 ℃, adding 89.26g of compound 3 (N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, 375.95mmol and 1.5eq) and 19.5g of lithium fluoride (751.90mmol and 3eq), and replacing argon for protection after the addition is finished;
then heating to 82 ℃, stirring at a controlled temperature for reaction for 12h, cooling to room temperature after the reaction is finished, adding 80.31g of methanol (2510mmol, 10eq) and reacting at room temperature for 3h;
finally, the reaction was poured into 1.5L of ice water with stirring, adjusted to pH =8 with saturated sodium bicarbonate solution, extracted three times with ethyl acetate (500ml × 3); all organic phases are combined, washed by 500ml of saturated saline solution, dried by anhydrous sodium sulfate, filtered, desolventized by filtrate, and purified by column chromatography to obtain 41.84g of the compound 4 (hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative), the yield is 62.6%, and the purity is 98%.
Examples 2 to 7, comparative example 1
A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives is carried out under the same conditions as in example 1, wherein the types and the amounts of the bases are adjusted, and the specific types, the amounts and the first-step yield are detailed in Table 1.
TABLE 1
| Serial number | Alkali | Equivalent (eq) | Yield (%) |
| Example 1 | |
2 | 86.08 |
| Example 2 | |
2 | 62.4 |
| Example 3 | |
2 | 58.3 |
| Example 4 | |
1 | 70.8 |
| Example 5 | Pyridine compound | 1.5 | 76.4 |
| Example 6 | Pyridine compound | 2.5 | 82.3 |
| Example 7 | |
3 | 78.8 |
| Comparative example 1 | |
2 | 43.8 |
As can be seen from the table, in examples 2 to 4 and comparative example 1, the reaction was carried out using different bases in step (1) as compared with example 1, and the reaction results showed that pyridine was superior in promoting the reaction as compared with triethylamine, diisopropylamine, and DBU (1, 8-diazohetero-bis-spiro [5.4.0] undec-7-ene). Examples 5 to 7, in comparison with example 1, the amount of pyridine used in step 1 was changed, and the reaction results showed that increasing or decreasing the amount of pyridine used in addition to example 1 caused a decrease in the yield of the reaction compound 2.
Examples 8 to 14, comparative example 2
A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives is carried out under the same conditions as in example 1, except that the amounts of compound 2, compound 3 and lithium fluoride are adjusted, and the details are shown in Table 2.
TABLE 2
In addition, 2, 3-dihydro-4-furoic acid methyl ester is used for replacing compound 2 for cyclization.
As can be seen from the table, in examples 8 to 9, the amount of the compound 3 used in the step (2) was increased, the number of by-products was increased, and the reaction yield was slightly decreased, as compared with example 1; compared with the example 1, the example 10 reduces the dosage of the compound 3, reduces the reaction rate, and slightly reduces the reaction yield under the same reaction time; in examples 11 to 14, the reaction yield was also reduced by changing the amount of lithium fluoride used as compared with example 1.
It is to be noted that, in comparative example 2, methyl 2, 3-dihydro-4-furoate was used
The reaction yield was only 4.9% under the same conditions as in example 1 as the cyclization raw material; therefore, the yield of the target product of the invention application is better than that of the comparative example.
Example 15
A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives comprises the following steps:
(1) Synthesis of Compound 2
Adding 100ml of dichloromethane and 10g of compound 1 (2, 3-dihydrofuran, 142.67mmol and 1eq) into a reaction bottle, controlling the temperature to be 0 ℃, then adding 38.90g of trichloroacetyl chloride (214mmol and 1.5 eq), controlling the temperature to be 0 ℃, then adding 22.60g of pyridine (285.35mmol and 2eq), raising the temperature to 20 ℃ after the addition is finished, and reacting for 3 hours;
after the reaction was completed, the reaction mixture was poured into 250ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (100ml × 2), the organic phase obtained by the liquid separation was washed once with 100ml of saturated sodium bicarbonate solution, and finally the organic phase obtained by the liquid separation was washed once with 100ml of saturated common salt solution, and the organic phase obtained by the liquid separation was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 25.79g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran) in a yield of 82.30% and a purity of 98.1%.
(2) Synthesis of Compound 4
27g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran, 125.32mmol, 1eq) was added to 270ml of acetonitrile, the temperature was controlled at 25 ℃, 44.61g of compound 3 (N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, 187.98mmol, 1.5eq) and 9.73g of lithium fluoride (375.1mmol, 3eq) were added, and the argon gas was replaced for protection after the addition;
then heating to 82 ℃, stirring at a controlled temperature for reaction for 8h, cooling to room temperature after the reaction is finished, adding 40.16g of methanol (1255mmol, 10eq) and reacting for 3h at room temperature;
finally, the reaction was poured into 750mL of ice water with stirring, adjusted to pH =8 with saturated sodium bicarbonate solution, basic and extracted three times with ethyl acetate (250ml × 3); all organic phases are combined, washed by 250ml of saturated saline solution, dried by anhydrous sodium sulfate, filtered, desolventized by filtrate, and purified by column chromatography to obtain 18.90g of the compound 4 (hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative), the yield is 56.31 percent, and the purity is 97.6 percent.
Example 16
A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives comprises the following steps:
(1) Synthesis of Compound 2
Adding 100ml of dichloromethane and 10g of compound 1 (2, 3-dihydrofuran, 142.67mmol and 1eq) into a reaction bottle, controlling the temperature to be 0 ℃, then adding 38.90g of trichloroacetyl chloride (214mmol and 1.5 eq), controlling the temperature to be 0 ℃, then adding 22.60g of pyridine (285.35mmol and 2eq), raising the temperature to 30 ℃ after the addition is finished, and reacting for 3 hours;
after the reaction, the reaction mixture was poured into 250ml of dichloromethane, washed twice with 1M diluted hydrochloric acid (100ml × 2), the organic phase obtained by separation was washed once with 100ml of saturated sodium bicarbonate solution, and finally the organic phase obtained by separation was washed once with 100ml of saturated common salt, and the organic phase obtained by separation was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain 25.20g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran) with a yield of 80.00% and a purity of 97.6%.
(2) Synthesis of Compound 4
Adding 27g of compound 2 (2, 3-dihydro-4-trichloroacetylfuran, 125.32mmol and 1eq) into 270ml of acetonitrile, controlling the temperature at 25 ℃, adding 44.58g of compound 3 (N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine, 187.98mmol and 1.5eq) and 9.72g of lithium fluoride (374.7mmol and 3eq), and replacing argon for protection reaction after the addition is finished;
then heating to 60 ℃, stirring at a controlled temperature for reacting for 18h, cooling to room temperature after the reaction is finished, adding 40.20g of methanol (1255mmol, 10eq) and reacting for 3h at room temperature;
finally, the reaction was poured into 750mL of ice water with stirring, adjusted to pH =8 with saturated sodium bicarbonate solution, basic and extracted three times with ethyl acetate (250ml × 3); all organic phases were combined, washed with 250ml of saturated brine, dried over anhydrous sodium sulfate, filtered, desolventized, and purified by column chromatography to obtain 17.27g of compound 4 (methyl hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylate derivative) in 51.3% yield and 97.3% purity.
Claims (9)
1. A synthetic method of hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivatives is characterized by comprising the following steps:
(1) Mixing 2, 3-dihydrofuran with trichloroacetyl chloride and alkali, and reacting to obtain 2, 3-dihydro-4-trichloroacetylfuran;
(2) Reacting 2, 3-dihydro-4-trichloroacetylfuran with N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine and methanol to obtain the hexahydro-3 aH-furan [2,3-c ] pyrrole-3 a-carboxylic acid methyl ester derivative.
2. The synthesis method according to claim 1, wherein in the step (1), the base is one or more of diisopropylamine, triethylamine and pyridine.
3. The synthesis method according to claim 1, wherein in the step (1), the molar ratio of the 2, 3-dihydrofuran to the trichloroacetyl chloride is 1 (1-2); the molar ratio of 2, 3-dihydrofuran to base is 1.
4. The synthesis method according to claim 1, wherein the step (1) further comprises an organic solvent, and the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide and acetonitrile.
5. The synthesis method according to claim 1, wherein in the step (1), the reaction temperature is 20-30 ℃ and the reaction time is 2-6 h.
6. The synthesis method according to claim 1, wherein in the step (2), the specific reaction process is as follows:
adding 2, 3-dihydro-4-trichloroacetylfuran into an organic solvent, controlling the temperature to be 20-30 ℃, adding N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine and lithium salt, and replacing argon for protection reaction after the addition is finished;
then heating to 60-100 ℃, reacting for 8-18h, cooling to room temperature after the reaction is finished, adding methanol, and reacting for 1-6 h at room temperature.
7. The synthesis method according to claim 1 or 6, wherein in the step (2), the molar ratio of the 2, 3-dihydro-4-trichloroacetylfuran to the N- (methoxymethyl) -N- (trimethylsilylmethyl) benzylamine is 1 (1-3); the molar ratio of the 2, 3-dihydro-4-trichloroacetylfuran to the methanol is 1 (5-15).
8. The synthesis method of claim 6, wherein the lithium salt is one or more of lithium fluoride, lithium bromide and lithium chloride; the molar ratio of the 2, 3-dihydro-4-trichloroacetylfuran to the lithium salt is 1 (2-5).
9. The synthesis method according to claim 6, wherein the organic solvent is one or more of dichloromethane, dichloroethane, N-dimethylformamide, and acetonitrile.
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