CN116925022A - Preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene - Google Patents
Preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene Download PDFInfo
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- CN116925022A CN116925022A CN202310823983.8A CN202310823983A CN116925022A CN 116925022 A CN116925022 A CN 116925022A CN 202310823983 A CN202310823983 A CN 202310823983A CN 116925022 A CN116925022 A CN 116925022A
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- Prior art keywords
- allyl
- oxabicyclo
- oct
- ene
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- WBRYUDKSKFXYOD-SNVBAGLBSA-N (3as)-3a-prop-2-enyl-2,3,4,5-tetrahydrocyclopenta[b]furan Chemical compound C1COC2=CCC[C@@]21CC=C WBRYUDKSKFXYOD-SNVBAGLBSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 15
- -1 2-oxoglutarate dicarbonyl methyl ester Chemical class 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 6
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 claims abstract description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012346 acetyl chloride Substances 0.000 claims abstract description 5
- 229940101545 mi-acid Drugs 0.000 claims abstract description 4
- 230000009471 action Effects 0.000 claims abstract description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 8
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 229940043279 diisopropylamine Drugs 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000003638 chemical reducing agent Substances 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 3
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 230000009467 reduction Effects 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 2
- 229910000497 Amalgam Inorganic materials 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- 239000012320 chlorinating reagent Substances 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 10
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000006227 byproduct Substances 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- PBZROIMXDZTJDF-UHFFFAOYSA-N hepta-1,6-dien-4-one Chemical compound C=CCC(=O)CC=C PBZROIMXDZTJDF-UHFFFAOYSA-N 0.000 description 3
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QSECPQCFCWVBKM-UHFFFAOYSA-N 2-iodoethanol Chemical compound OCCI QSECPQCFCWVBKM-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- AEBWATHAIVJLTA-ZKCHVHJHSA-N C1CC[C@@H]2CCC[C@H]21 Chemical group C1CC[C@@H]2CCC[C@H]21 AEBWATHAIVJLTA-ZKCHVHJHSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000013078 crystal Substances 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
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004134 energy conservation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
- C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene, which comprises the following steps: (1) 2-oxoglutarate dicarbonyl methyl ester (M8) and 2-iodine-1-ethanol acetate (M2) are alkylated in anhydrous acetone, and then are cyclized at p-TsOH to obtain M9; (2) The obtained M9 is subjected to alkaline hydrolysis, and is resolved in a solvent by using alpha-phenethylamine to obtain M10a; (3) condensing the obtained M10a with Mi's acid to obtain M11a; (4) reducing the obtained M11a to obtain M12a; (5) Dehydrating the obtained M12a under the action of acetyl chloride and triethylamine to obtain (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene. The method has the advantages of short reaction route, easily obtained raw materials, fewer byproducts, stable reaction conditions, simple and convenient operation and suitability for large-scale production.
Description
Technical Field
The invention belongs to the technical field of chemical drug intermediate preparation methods, and particularly relates to a preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene.
Background
(S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene (CAS number: 1052236-86-8), the structure of which is shown in formula (A), is an important chemical intermediate, and is commonly used as a resolving agent for chiral alcohol production. The (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene stereospecifically generates an asymmetric acetal B, and the trans-bicyclo [3.3.0] octane skeleton C is hardly formed, so that the asymmetric center of the bicyclo C1 is well controlled.
The preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene disclosed at home and abroad mainly comprises the following steps:
(1) The method reported by Tetrahedron Letters (1994) is:
alkenyl ether P1 was synthesized in 5 steps starting from 2-allyloxycarbonyl-cyclopentan-1-one (M1). Alkylation of M1 with M2 in dry acetone gives M3 in 89% yield. Allyl ketone ester M3 was reacted by Shimizu-Tsuji to give allyl ketone M4, which was then treated with catalytic amounts of p-TsOH in methanol to give cyclic acetal M5 in a total yield of 74%. M5 was treated with acetyl chloride in chloroform for 20 hours to give chloride M6, which upon refluxing, was immediately used with triethylamine in methylene chloride to give the racemate of the objective alkenyl ether P1 in a total yield of 95%. Alkenyl ether P1 may be decomposed in silica gel, but may be purified by alumina gel column chromatography.
(2) The method reported in EP1535917A1 is:
starting with M3, allyl ketone M4 is obtained by Shimizu-Tsuji reaction, then treated with catalytic amounts of P-TsOH in methanol to obtain cyclic acetal M5, and then P1 is resolved by L-lactic acid to finally obtain two enantiomers of P1.
However, the above scheme has the technical problems of high raw material cost, unstable reaction conditions, high operation difficulty and difficult realization of industrial production.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a preparation method of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene, which has the advantages of cheap and easily available raw materials, stable reaction conditions, simple operation and easy realization of industrial production.
A method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene, comprising the following steps:
the synthetic route adopted by the invention can be expressed as follows by chemical equations:
the invention is further provided as follows:
in step (1): adding potassium carbonate into the anhydrous acetone solution of M8 and M2, filtering, concentrating, adding methanol and p-TsOH, and cyclizing to obtain M9;
preferably, the alkylation reaction temperature of the step (1) is 30-70 ℃ and the reaction time is 10-30 h. The cyclization reaction temperature is 30-70 ℃ and the reaction time is 2-6 h.
In the step (2): carrying out alkaline hydrolysis on M9 obtained in the step (1), and carrying out resolution on the M9 in a solvent by using alpha-phenethylamine to obtain M10a;
the alkali is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and the dosage is 1-3 equivalents of M9;
the solvent is one or more of acetone, ethanol, toluene, ethyl acetate and water, and the dosage is 1mol of M10 to 100-500 mL;
in the step (3): condensing the M10a obtained in the step (2) with Mi's acid under the action of a condensing agent and a catalyst to obtain M11a;
the condensing agent is one or more of CDI (N' N-carbonyl diimidazole), EDCI (1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), oxalyl chloride and pivaloyl chloride, and the dosage is 1-3 equivalents of M10a;
the catalyst is one or more of triethylamine, diethylamine, diisopropylamine, pyridine and lutidine, and the dosage is 1-3 equivalents of M10a;
in the step (4): adding the M11a obtained in the step (3) into a solvent, and then adding a reducing agent for reduction to obtain M12a;
the reducing agent is one or more of potassium borohydride, lithium aluminum hydride, zinc amalgam and hydrazine hydrate, and the dosage is 1-3 equivalents of M11a;
the solvent is one or more of water, methanol, ethanol, tetrahydrofuran and dichloromethane, and the dosage is 1mol of M11a to 100-500 mL;
in the step (5): treating M12a and a chloro reagent obtained in the step (4) in chloroform, and then adding alkali to obtain a target product (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene (P1 a);
the chlorating agent is one or more of oxalyl chloride, special acyl chloride, acetyl chloride, thionyl chloride and phosphorus oxychloride, and the dosage is 1-3 equivalents of M12a;
the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine and diisopropylamine, and the dosage is 1mol of M11a to 100-500 mL;
compared with the prior art, the invention has the beneficial effects that:
(1) The alpha-phenethylamine is utilized to split the M10 carboxylic acid, so that the splitting effect is good, the generation of byproducts is reduced, and the energy conservation and the emission reduction are realized;
(2) The carbon chain is prolonged by using Mi's acid, so that the method is easier to operate compared with the format reaction, the yield is higher, and the cost is lower;
drawings
The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate the invention and together with the embodiments of the invention, serve to explain the invention. In the drawings:
FIG. 1 is a useful chemical equation for the synthetic route employed in the present invention;
Detailed Description
In order that the above-recited objects, features and advantages of the present invention will become more apparent, a more particular description of the invention will be rendered by reference to specific embodiments thereof which are illustrated in the appended drawings.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Further, reference herein to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic can be included in at least one implementation of the invention. The appearances of the phrase "in one embodiment" in various places in the specification are not necessarily all referring to the same embodiment, nor are separate or alternative embodiments mutually exclusive of other embodiments.
Example 1: preparation of M9
In a 1000mL four port flask, potassium carbonate (45 g,0.327 mol) was added to a mixture of 2-oxoglutarate methyl carbonyl (M8, 31g,0.218 mol) and 2-iodo-1-ethanolate (M2, 51.4g,0.240 mol) in dry acetone (500 mL), stirred at 60℃for 24 hours, cooled to room temperature, filtered, distilled off acetone under reduced pressure, methanol (300 mL) was added, stirred for dissolution, then p-toluenesulfonic acid (0.17 g,0.001 mol) was added, stirred at 70℃for 4 hours, concentrated, washed, and dried to give 37.9 g of colorless oil, yield 87.2%;
example 2: preparation of M10a
Adding 20 g of M9 prepared in example 1, 200 g of 10% sodium hydroxide aqueous solution into a 1000mL four-port reaction bottle, stirring for 6h at 30-40 ℃, cooling to room temperature, regulating the pH to 2-3, filtering, drying, then dissolving into 200 g of acetone, stirring to dissolve, adding 13 g of alpha-phenethylamine, heating to 50-60 ℃, dripping about 15-20 g of water to dissolve, slowly cooling to separate out crystals, filtering, and acidizing to obtain 8.0 g of white solid M10a, wherein the yield is 43.1%;
example 3: preparation of M11a
18.6 g of M11a prepared in example 2, 200mL of acetonitrile, 17.3 g of Mitsui acid, 1.0 g of lutidine and 30.9 g of diisopropylamine are added into a 1000mL four-port reaction bottle, the temperature is controlled to be 0-10 ℃, 15.1 g of pivaloyl chloride is added dropwise, the temperature is controlled to be 50-55 ℃ after the dropwise is finished, the temperature is kept for 3 hours, then the mixture is acidified, the temperature is reduced and the crystallization is carried out to obtain 19.1 g of M11a, and the yield is 83.8%;
example 4: preparation of M12a
Adding 22.8 g of M12a prepared in example 3 and 200mL of tetrahydrofuran into a 1000mL four-port reaction bottle, controlling the temperature to be 0-10 ℃, adding lithium aluminum hydride in batches, heating to 20-30 ℃ after the addition, preserving the heat for 3 hours, then slowly adding a small amount of water and a small amount of sodium hydroxide solution, adding a small amount of anhydrous sulfuric acid solid, filtering, concentrating under reduced pressure to obtain 15.9 g of M12a, and obtaining the yield of 79.5%;
example 5: preparation of P1a
In a 1000mL four-port reaction bottle, 20.0 g of M12a prepared in example 4, 300mL of chloroform and 92.4 g of acetyl chloride are added, the temperature is controlled to be 10-30 ℃, the mixture is stirred for 20 hours, volatile matters are removed under reduced pressure, 119.2 g of triethylamine, 0.5 g of butanol and 170 g of dichloromethane are added, the mixture is refluxed for 2 hours, the mixture is cooled and filtered, and the solvent is concentrated under reduced pressure to obtain 13.7 g of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene (P1 a), and the yield is 91.3%;
the content of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-alkene is more than 99.5% by gas phase detection, and the retention time is consistent with that of a standard substance.
The foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A process for the preparation of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene comprising the steps of:
in step (1): adding potassium carbonate into the anhydrous acetone solution of M8 and M2, filtering, concentrating, adding methanol and p-TsOH, and cyclizing to obtain M9;
in the step (2): carrying out alkaline hydrolysis on M9 obtained in the step (1), and carrying out resolution on the M9 in a solvent by using alpha-phenethylamine to obtain M10a;
in the step (3): condensing the M10a obtained in the step (2) with Mi's acid under the action of a condensing agent and a catalyst to obtain M11a;
in the step (4): adding the M11a obtained in the step (3) into a solvent, and then adding a reducing agent for reduction to obtain M12a;
in the step (5): treating M12a and a chloro reagent obtained in the step (4) in chloroform, and then adding alkali to obtain a target product P1a;
the synthetic route of the (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene can be represented by the chemical formula:
2. the process for the preparation of (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, characterized in that the alkylation reaction temperature of step (1) is 30-70 ℃ and the reaction time is 10-30 h; the cyclization reaction temperature is 30-70 ℃ and the reaction time is 2-6 h.
3. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein the base in the step (2) is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, and the amount is 1 to 3 equivalents of M9.
4. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein the solvent in the step (2) is one or more of acetone, ethanol, toluene, ethyl acetate and water, and the dosage is 1 mol:100-500 mL of M10.
5. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (3), the condensing agent is one or more of N' N-carbonyldiimidazole, 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide, oxalyl chloride and pivaloyl chloride in an amount of 1 to 3 equivalents of M10 a.
6. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (3), the catalyst is one or more of triethylamine, diethylamine, diisopropylamine, pyridine and lutidine, and the amount of the catalyst is 1 to 3 equivalents of M10 a.
7. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (4), the reducing agent is one or more of potassium borohydride, lithium aluminum hydride, zinc amalgam and hydrazine hydrate, and the dosage is 1-3 equivalents of M11 a.
8. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (4), the solvent is one or more of water, methanol, ethanol, tetrahydrofuran and dichloromethane, and the dosage is 1 mol:100-500 mL of M11 a.
9. The process for producing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in step (5), the chlorinating agent is one or more of oxalyl chloride, special acyl chloride, acetyl chloride, sulfoxide chloride and phosphorus oxychloride, and the amount is 1 to 3 equivalents of M12 a.
10. The method for preparing (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene according to claim 1, wherein in the step (5), the alkali is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine and diisopropylamine, and the dosage is 1mol of M11a to 100-500 mL.
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