CN109096320B - Method for preparing benzoyl coriolide - Google Patents
Method for preparing benzoyl coriolide Download PDFInfo
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- CN109096320B CN109096320B CN201710476945.4A CN201710476945A CN109096320B CN 109096320 B CN109096320 B CN 109096320B CN 201710476945 A CN201710476945 A CN 201710476945A CN 109096320 B CN109096320 B CN 109096320B
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- coriolide
- triethylchlorosilane
- corey lactone
- primary alcohol
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- 238000000034 method Methods 0.000 title claims abstract description 29
- FTUAIEDAAMWBHD-UHFFFAOYSA-N Coriolide Natural products CCCCCC(O)C=CC=C/CCCCCCC=C=O FTUAIEDAAMWBHD-UHFFFAOYSA-N 0.000 title abstract description 7
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 title abstract description 5
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims abstract description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 65
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- 150000003138 primary alcohols Chemical class 0.000 claims abstract description 29
- -1 (-) -benzoyl Chemical group 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 239000005711 Benzoic acid Substances 0.000 claims description 7
- 235000010233 benzoic acid Nutrition 0.000 claims description 7
- 238000005886 esterification reaction Methods 0.000 claims description 3
- CZEBTZMIQZVUSE-UHFFFAOYSA-N [6-cyano-1-[(2-methylpropan-2-yl)oxycarbonyl]indol-2-yl]boronic acid Chemical compound C1=C(C#N)C=C2N(C(=O)OC(C)(C)C)C(B(O)O)=CC2=C1 CZEBTZMIQZVUSE-UHFFFAOYSA-N 0.000 description 38
- 239000012535 impurity Substances 0.000 description 27
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 24
- AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 23
- OBRRYUZUDKVCOO-RVMXOQNASA-N [(3aS,4R,5S,6aR)-4-(hydroxymethyl)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] benzoate Chemical compound O([C@@H]1[C@H]([C@@H]2CC(=O)O[C@@H]2C1)CO)C(=O)C1=CC=CC=C1 OBRRYUZUDKVCOO-RVMXOQNASA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 10
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 10
- 239000005051 trimethylchlorosilane Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 150000003333 secondary alcohols Chemical class 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 239000003223 protective agent Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 238000006480 benzoylation reaction Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- OBRRYUZUDKVCOO-FVCCEPFGSA-N [(3ar,4s,5r,6as)-4-(hydroxymethyl)-2-oxo-3,3a,4,5,6,6a-hexahydrocyclopenta[b]furan-5-yl] benzoate Chemical compound O([C@H]1[C@@H]([C@H]2CC(=O)O[C@H]2C1)CO)C(=O)C1=CC=CC=C1 OBRRYUZUDKVCOO-FVCCEPFGSA-N 0.000 description 2
- RHDGNLCLDBVESU-UHFFFAOYSA-N but-3-en-4-olide Chemical compound O=C1CC=CO1 RHDGNLCLDBVESU-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000010606 normalization Methods 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 230000009257 reactivity Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VYTZWRCSPHQSFX-GBNDHIKLSA-N (-)-corey lactone Chemical compound O1C(=O)C[C@@H]2[C@@H](CO)[C@H](O)C[C@@H]21 VYTZWRCSPHQSFX-GBNDHIKLSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000011020 pilot scale process Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a method for preparing a high-purity compound shown as a formula 3, which comprises the steps of protecting primary alcohol of (-) -coriolide shown as a formula 4 with triethylchlorosilane in dichloromethane in the presence of diisopropylethylamine to obtain the compound shown as the formula 3, wherein R is triethylchlorosilane; wherein the molar ratio of the (-) -coriolide shown in the formula 4 to the triethylchlorosilane is 1-1.5, and the molar ratio of the (-) -coriolide shown in the formula 4 to the diisopropylethylamine is 1.5-3; the volume/mass (ml/g) of the dichloromethane and the (-) -coriolide shown in the formula 4 is 3-10; the reaction temperature is 20-30 ℃. The invention also provides a method for preparing the benzoyl coriolide shown in the formula 1 by using the obtained high-purity compound shown in the formula 3. The method has good selectivity, convenient operation and easy industrialization, thereby being capable of preparing the (-) -benzoyl colactone with high yield.
Description
Technical Field
The present invention relates to the field of chemical synthesis. In particular, the invention relates to a preparation method of benzoyl corilactone (Corey Lactone benzoate) and high-purity (-) -coriolide primary alcohol triethylsilane.
Background
The benzoylcoriolide comprises (-) -benzoylcoriolide or its enantiomer (+) -benzoylcoriolide or its racemate (+ -) -benzoylcoriolide.
Wherein the chemical name of (-) -Corey Lactone 3-benzoate is as follows: (3aR,4S,5R,6aS) - (-) -5- (benzoyloxy) -hexahydro-4- (hydroxymethyl) -2H-cyclopenta [ b ]]Furan-2-one, chemical name in english: (3aR,4S,5R,6aS) - (-) -5-benzodioxol-HEXAHYDRO-4-HYDROXYMETHYL-2H-CYCLOPENTA [ B ]]FURAN-2-ONE; the molecular formula is as follows: c15H16O5(ii) a Molecular weight: 276.28, respectively; CAS accession number: 39746-00-4; the structure is as follows:
(-)-Corey Lactone benzoate (+)-Corey Lactone benzoate
(-) -benzoyl coriolide (+) -benzoyl coriolide
(-) -Corey Lactone 3-benzoate is an important intermediate of Prostaglandin (PG) drugs, but the literature on their synthesis reports is very few.
Literature Nature Chemical Biolgy 2009,26-28 demethylates Corey Lactone benzoates from methylated derivatives; patents US6353000 and US6353014 obtain (-) -Corey Lactone benzoate from the reduction of the corresponding aldehyde. The raw materials used in the two methods are not easy to obtain, the cost is high, and the production is not facilitated.
In another method, (-) -Corey Lactone is used as a raw material, and benzoyl is selectively introduced to a secondary hydroxyl group to synthesize a target product.
(-)-Corey Lactone
(-) -coriolide
(-) -Corey Lactone (CAS registry number: 32233-40-2) is a common chemical intermediate, and the product of the company (Huanggang Luban pharmaceutical Co., Ltd.) has already been produced industrially on a large scale and is a product sold in the company. The preparation of (-) -Corey Lactone benzoate from (-) -Corey Lactone is a relatively practical route.
CN10532079A reports that the benzoylation of (-) -Corey Lactone gave disubstituted (-) -Corey Lactone dibenzoate compounds, which were then selectively debenzoylated under acidic conditions in a yield of only 32%. The process was repeated to find: 1. the selectivity is poor, and a large amount of secondary hydroxyl benzoyl is removed; 2. the raw material (-) -Corey Lactone needs to be repeatedly concentrated and recovered from water, the production period is long, the loss is large, and the industrialization is difficult.
Another method reported by Tetrahedron letters 2004, 1973-: the product is obtained by selective protection of the primary hydroxyl group with a bulky protecting group such as tert-butyldimethylphenyl or triphenylmethyl, followed by benzoylation of the secondary hydroxyl group and subsequent deprotection of the primary hydroxyl group. The synthetic method has the following defects: after the primary hydroxyl is protected by the protective group with large steric hindrance, the reaction activity is poor and impurities are more during the secondary hydroxyl benzoylation reaction; the intermediate is difficult to purify, impurities are brought to the next step, so that the final product is difficult to crystallize and purify, column chromatography purification is needed, the production period is long, and the cost is increased.
Therefore, a method for preparing (-) benzoyl colelactone with high yield, good selectivity, convenient operation and easy industrialization is urgently needed in the field.
Disclosure of Invention
The invention aims to provide a method for preparing high-purity (-) -coriolide primary alcohol triethylsilane and preparing (-) benzoyl coriolide from the (-) -coriolide primary alcohol triethylsilane with high selectivity, convenient operation and easy industrialization and high yield.
In a first aspect, the present invention provides a method for preparing a compound of formula 3 in high purity, the method comprising performing the method shown in the following scheme:
in the formula, R is triethylchlorosilane;
the method comprises the following steps: protecting primary alcohol of (-) -coriolide shown in a formula 4 with triethylchlorosilane in dichloromethane in the presence of diisopropylethylamine to obtain a compound shown in a formula 3;
wherein the mol ratio of (-) -coriolide shown in the formula 4 to triethylchlorosilane is 1-1.5,
the mol ratio of the (-) -coriolide shown in the formula 4 to the diisopropylethylamine is 1.5-3;
the volume/mass (ml/g) of the dichloromethane and the (-) -coriolide shown in the formula 4 is 3-10;
the reaction temperature is 20-30 ℃.
In a specific embodiment, the ratio of (-) -coriolide of formula 4 to triethylchlorosilane is 1.1.
The formula 5 is (-) -Corey Lactone primary alcohol and secondary alcohol double-protected disubstituted impurity.
In a second aspect, the present invention provides a method for preparing a high purity benzoylcoriolide of formula 1, comprising performing the method as shown in the following scheme:
in the formula, R is triethylchlorosilane;
wherein the method comprises the steps of:
a. protecting primary alcohol of (-) -coriolide shown in a formula 4 by using triethylchlorosilane in dichloromethane in the presence of diisopropylethylamine in a solvent to obtain a compound shown in a formula 3;
b. carrying out esterification reaction on the compound shown in the formula 3 and benzoic acid to obtain (-) -benzoyl colactone shown in a formula 2 with protected primary alcohol; and
c. removing the primary alcohol protecting group of the (-) -benzoyl colactone shown in the formula 2 to obtain the (-) -benzoyl colactone shown in the formula 1;
in the step a, the first step is carried out,
the mol ratio of the (-) -coriolide shown in the formula 4 to the triethylchlorosilane is 1 to 1.5,
the mol ratio of the (-) -coriolide shown in the formula 4 to the diisopropylethylamine is 1.5-3;
the volume/mass (ml/g) of the dichloromethane and the (-) -coriolide shown in the formula 4 is 3-10;
the reaction temperature is 20-30 ℃.
In a specific embodiment, in step a, the ratio of (-) -coriolide of formula 4 to triethylchlorosilane is 1.1.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 shows the HNMR spectra for the primary alcohol triethylsilane protection of (-) -Corey Lactone;
FIG. 2 shows the MS spectrum of (-) -Corey Lactone primary alcohol triethylsilane protection;
FIG. 3 shows the HNMR spectra of the impurity (-) -Corey Lactone primary alcohol and secondary alcohol triethylsilane double protection;
FIG. 4 shows the MS spectra of the impurity (-) -Corey Lactone primary alcohol and secondary alcohol triethylsilane double protection;
FIG. 5 shows a (-) -Corey Lactone primary alcohol triethylsilane single-protection GC mapping spectrum;
FIG. 6 shows the double-protection GC location spectrum of the impurity (-) -Corey Lactone primary and secondary alcohol bis-triethylsilane;
FIG. 7 shows mixed isolated GC spectra of (-) -Corey Lactone primary alcohol triethylsilane protection and impurities (-) -Corey Lactone primary and secondary alcohol bistriethylsilane protection;
FIG. 8 shows a purity HPLC chromatogram of (-) -Corey Lactone benzoate;
FIG. 9 shows an optical content spectrum of (-) -Corey Lactone benzoate;
FIG. 10 shows an optical content spectrum of (. + -.) -Corey Lactone benzoate.
Detailed Description
The inventor has conducted extensive and intensive studies and unexpectedly found that a specific protecting group can be used for protecting the primary alcohol of (-) -Corey Lactone with high selectivity, then the primary alcohol is reacted with benzoic acid to obtain the (-) -Corey Lactone benzoate protected by the primary alcohol, and finally the primary alcohol protecting group is selectively removed to obtain the (-) -Corey Lactone benzoate. The invention has good reaction selectivity, easy crystallization and purification of the product and high purity; the reaction yield is high, and the cost is greatly reduced; convenient operation and easy industrialization. The present invention has been completed based on this finding.
Method of the invention
The invention provides a method for preparing (-) -Corey Lactone benzoate with high purity and high yield. From (-) -Corey Lactone, the (-) -Corey Lactone benzoate protected by primary alcohol is obtained by high-selectivity single protection of the primary alcohol, then the esterification reaction of the secondary alcohol and benzoic acid, and then the silicon-based protection of the primary alcohol is selectively removed, thus obtaining the (-) -Corey Lactone benzoate. The invention has good reaction selectivity, easy crystallization and purification of the product and high purity; the reaction yield is high, and the cost is greatly reduced; can adopt a one-pot method, is convenient to operate and is easy to industrialize.
Wherein the structure of (-) -Corey Lactone is shown as follows;
(-)-Corey Lactone
the technical scheme for preparing the high-purity primary alcohol protected (-) -Corey Lactone provided by the invention is as follows:
reacting (-) -Corey Lactone in a solvent S1, a base B1 and a protective agent C1 at a certain reaction temperature T1 to obtain high-purity primary alcohol protected (-) -Corey Lactone;
wherein the temperature T1 is 0-50 ℃, most preferably 20-30 ℃;
wherein the solvent S1 is one of dichloromethane, trichloromethane, 1, 2-dichloroethane, acetonitrile, DMF or THF; most preferably dichloromethane;
the volume/mass (ml/g) of the solvent S1 and (-) -Corey Lactone is 1:1-50ml/g, preferably 3-10 ml/g;
the alkali B1 is one of triethylamine, diisopropylethylamine, pyridine, imidazole or N-methylmorpholine; wherein the reaction yield of the diisopropylethylamine is highest, the disubstituted impurity is minimum, and the most preferable is diisopropylethylamine;
the molar ratio of (-) -Corey Lactone to the alkali B1 is 1-5, preferably 1: 1.5-3;
the protective agent C1 is one of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane and tert-butyldiphenylchlorosilane; the reaction effect of the triethylchlorosilane is best, the disubstituted impurity is minimum, the yield is highest, and the triethylchlorosilane is most preferred;
according to the charging proportion of the (-) -Corey Lactone and the protective agent, the double-substituted impurities are increased when the dosage of the protective agent is increased, the amount is small, the reaction is incomplete, the yield is low, and the optimal dosage is 1-1.5 eq.
The invention has the advantages that:
the method of the invention has the following advantages:
1. good selectivity, convenient operation and easy industrialization;
2. can prepare high-purity primary alcohol protected (-) -Corey Lactone; and
3. the yield of the prepared (-) benzoyl coriolide is high.
The technical solution of the present invention will be further described with reference to the following specific embodiments, but the following embodiments are not intended to limit the present invention, and all of the various application methods adopted according to the principles and technical means of the present invention belong to the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Example 1
Based on the reaction scheme shown above, the inventors examined the preparation of primary alcohol-protected (-) -Corey Lactone using trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane or t-butyldiphenylchlorosilane.
Table 1.
| Serial number | Protecting group | Yield of |
| 1 | Trimethylchlorosilane | 96％ |
| 2 | Triethylchlorosilane | 89％ |
| 3 | Tert-butyldimethylsilyl chloride | 87％ |
| 4 | Tert-butyldiphenylchlorosilane | 82％ |
As a result, it was found that trimethylchlorosilane yield was the highest and activity was the best.
Example 2
In this example, the inventors further examined possible impurities (i.e., primary alcohol, secondary alcohol disubstituted impurities) resulting from protection of the primary hydroxyl group by trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane, or t-butyldiphenylchlorosilane.
Table 2.
| Serial number | Protecting group | Yield of(％) | Disubstituted impurity (%) |
| 1 | Trimethylchlorosilane | 96％ | 7.5％ |
| 2 | Triethylchlorosilane | 89％ | 6.0％ |
| 3 | Tert-butyldimethylsilyl chloride | 87％ | 6.5％ |
| 4 | Tert-butyldiphenylchlorosilane | 82％ | 7.0％ |
The inventors have found that although the protection of the primary hydroxyl groups with triethylchlorosilane, t-butyldimethylchlorosilane or t-butyldiphenylchlorosilane yields slightly lower impurities than trimethylchlorosilane, there is no substantial difference. The use of chlorotrimethylsilane seems to be the best choice, considering that the yield and activity of chlorotrimethylsilane are far superior to those of chlorotriethylsilane, tert-butyldimethylchlorosilane or tert-butyldiphenylchlorosilane.
Example 3
In this example, the inventors have also investigated specific process conditions for preparing primary alcohol-protected (-) -Corey Lactone from trimethylchlorosilane, triethylchlorosilane, t-butyldimethylchlorosilane or t-butyldiphenylchlorosilane.
As a result, the inventors have unexpectedly found that the yields and the impurity cases at specific molar ratios in the presence of each base in each solvent at each reaction temperature examined using trimethylchlorosilane, t-butyldimethylchlorosilane or t-butyldiphenylchlorosilane are similar to those of examples 1 and 2.
If the preparation of primary alcohol-protected (-) -Corey Lactone with triethylchlorosilane in the presence of a specific base, diisopropylethylamine, in a specific solvent, at a specific reaction temperature and a specific molar ratio, the secondary alcohol disubstituted impurities generated by the preparation of the primary alcohol-protected (-) -Corey Lactone with triethylchlorosilane are far lower than those generated by the preparation of trimethylchlorosilane, t-butyldimethylchlorosilane or t-butyldiphenylchlorosilane, high purity of the primary alcohol-protected (-) -Corey Lactone can be prepared. The specific data are shown in the following table:
TABLE 3 reaction of triethylchlorosilane in different bases (triethylamine, diisopropylethylamine, pyridine, DBU, imidazole or N-methylmorpholine).
| Serial number | Alkali | Yield (%) | Disubstituted impurity (%) |
| 1 | Triethylamine | 91％ | 2.2％ |
| 2 | Diisopropylethylamine | 92％ | 0.8％ |
| 3 | Pyridine compound | 81％ | 1.5％ |
| 4 | DBU | 88％ | 1.3％ |
| 5 | Imidazole | 85％ | 2.0％ |
| 6 | N- |
70％ | 2.2％ |
According to the results in table 3, the specific base used was not regularly reproducible for the formation of disubstituted impurities, of which diisopropylethylamine works best.
Table 4 reactivity of triethylchlorosilane with diisopropylethylamine in different solvents.
| Serial number | Solvent(s) | Yield (%) | Disubstituted impurity (%) |
| 1 | Methylene dichloride | 92％ | 0.8 |
| 2 | Acetonitrile | 75％ | 2.5 |
| 3 | DMF | 85％ | 1.5 |
| 4 | |
80％ | 2.9 |
According to the results in Table 4, the effect of the specific solvent used on the yield and the formation of disubstituted impurities is not regularly reproducible, with the best results being obtained when dichloromethane is used as solvent.
TABLE 5 reactivity of triethylchlorosilane with diisopropylethylamine at different temperatures.
| Serial number | Solvent(s) | Yield (%) | Disubstituted impurity (%) |
| 1 | 0℃～10℃ | 82％ | 0.5％ |
| 2 | 10℃-20℃ | 86％ | 0.8％ |
| 3 | 20℃～30℃ | 92％ | 0.6％ |
| 4 | 40℃-50℃ | 80％ | 3.5％ |
According to the results in table 5, the specific reaction temperature of triethylchlorosilane and diisopropylethylamine has no regular and recyclable effect on yield and generation of disubstituted impurities, wherein the comprehensive effect of the reaction of triethylchlorosilane and diisopropylethylamine at 20-30 ℃ is the best.
TABLE 6 reaction of (-) -coriolide with triethylchlorosilane in different molar ratios
| Serial number | Molar ratio of (-) -coriolide to triethylchlorosilane | Yield (%) | Disubstituted impurity (%) |
| 1 | 0.8 | 78％ | 0.9％ |
| 2 | 1.1 | 92％ | 0.3％ |
| 3 | 1.3 | 86％ | 0.7％ |
| 4 | 1.8 | 83％ | 3.3％ |
TABLE 7 reaction of (-) -Coriolis lactone with diisopropylethylamine in different molar ratios
| Serial number | Molar ratio of (-) -coriolide to diisopropylethylamine | Yield (%) | Disubstituted impurity (%) |
| 1 | 1.2 | 82％ | 0.7％ |
| 2 | 1.6 | 87％ | 0.5％ |
| 3 | 2.5 | 91％ | 0.4％ |
| 4 | 3.4 | 80％ | 1.1％ |
TABLE 8 reaction of methylene chloride with (-) -coriolide at different volume/mass ratios (ml/g)
Based on the above examples, the present inventors have unexpectedly discovered that primary alcohol protected (-) -Corey Lactone can be prepared in high yields with minimal secondary impurities by reacting triethylchlorosilane in combination with diisopropylethylamine in a specific solvent, dichloromethane, at 20 ℃ to 30 ℃.
Example 6: laboratory-Scale preparation of benzoylcorinolide
17.2g (1eq) of (-) -Corey Lactone is put into a 500ml three-mouth bottle, 100ml of dichloromethane is added, stirring and mixing are carried out, 34.1ml (2.5eq) of diisopropylethylamine is added at room temperature, stirring is carried out, the temperature is reduced to 20 ℃, 16.6g (1.1eq) of triethylchlorosilane is slowly added dropwise, the temperature is kept for 20-30 ℃ for reaction for 2 hours, 18.3g (1.5eq) of benzoic acid is added, 26.9g (1.5eq) of EDCI and 0.7g of DMAP (0.1eq) are added, the mixture is kept for reaction for 20 hours at room temperature, 150ml (4.1eq) of 10% hydrochloric acid is added, the mixture is kept for reaction for 6-12 hours under stirring, layering is carried out, anhydrous sodium sulfate is added into a dichloromethane layer for drying, filtering is carried out, filtrate is evaporated to dryness, 50ml of petroleum ether is added for crystallization, 23.8g of (-) -Corey Lactone tonoate is obtained, the yield is 86%, the purity is 99.5.
Purity detection HPLC method: a chromatographic column: ZORBAX SB-C184.6mm 150mm,5 um; mobile phase A: 0.1% phosphoric acid water, mobile phase B: acetonitrile, gradient elution as follows; column temperature: 25 ℃; detection wavelength: 230 nm; flow rate: 1.0 ml/min; sample introduction amount: 5 μ l.
ee detection HPLC method: a chromatographic column: CHIRALPAK AD-H, 250 x 4.6mm, 5 um; mobile phase: n-hexane: ethanol 70: 30; flow rate: 0.5 ml/min; column temperature: 25 ℃; detection wavelength: 230 nm; sample introduction amount: 5 mu l of the solution; operating time: and (4) 40 min.
Example 7: pilot scale production of benzoylcorinolide
172g (1eq) of (-) -Corey Lactone is put into a 5000ml three-mouth bottle, 1000ml of dichloromethane is added, the mixture is stirred and mixed, 341ml (2.5eq) of diisopropylethylamine is added at room temperature, the temperature is reduced to 20 ℃ under stirring, 165.8g (1.1eq) of triethylchlorosilane is slowly added dropwise, the temperature is kept at 20-30 ℃ for reaction for 2 hours, 183g (1.5eq) of benzoic acid is added, 269g (1.5eq) of EDCI and 7g of DMAP (0.1eq) are added, the reaction is carried out at room temperature for 20 hours, 10% of 1500ml (4.1eq) of hydrochloric acid is added, the reaction is carried out for 6-12 hours under heat preservation and stirring, layers are separated, the dichloromethane layer is added with anhydrous sodium sulfate for drying, the filtration is carried out, the filtrate is evaporated to dryness, 500ml of petroleum ether is added for crystallization, 242.3g of (-) -Corey Lacey Lactone benzoate is obtained, the yield is 87.7%, the purity is 99..
Example 8: production scale preparation of benzoylcorinolide
17.2kg of (-) -Corey Lactone is put into a 500L reaction kettle, 130kg of dichloromethane is added, stirring and mixing are carried out, 25.3kg of diisopropylethylamine is added at room temperature, the temperature is reduced to 20 ℃ under stirring, 16.6kg (1.1eq) of triethylchlorosilane is slowly dripped, the temperature is kept for 20-30 ℃ for reaction for 2 hours, 18.3kg of benzoic acid is added, 26.9kg of EDCI and 0.7kg of DMAP are added, the reaction is carried out at room temperature for 20 hours, the cooling is carried out for 10 ℃, 150kg of 10% hydrochloric acid is added, the reaction is carried out for 6-12 hours under heat preservation and stirring, layering is carried out, anhydrous sodium sulfate is added into a dichloromethane layer for drying, filtering is carried out, filtrate is evaporated to dryness, 50L of petroleum ether is added for crystallization, and 24kg of (-) -Corey Lactone benzoate is obtained, the yield is 86.9%, the.
Example 9: preparation and structure confirmation of (-) -Corey Lactone primary alcohol triethylsilane
Putting 1.72g (1eq) (-) -Corey Lactone into a 50ml three-necked bottle, adding 20ml dichloromethane, stirring and mixing, adding 3.4ml (2.5eq) of diisopropylethylamine at room temperature, cooling to 20 ℃, slowly adding 1.66g (1.1eq) of triethylchlorosilane dropwise, keeping the temperature at 20-30 ℃ for reaction for 2 hours, pouring the reaction liquid into 20ml of ice water, separating an aqueous layer, drying with anhydrous sodium sulfate, filtering, evaporating the filtrate to dryness, and performing column chromatography separation and purification (petroleum ether elution) to obtain 2.63g of (-) -Corey Lactone primary alcohol triethylsilane, wherein the yield is 92% and the GC is 98.7%.
GC/MS(EI)：257(M-CH2CH3)。
1H-NMR(CDCl3,400MHZ):δ0.50-0.65[m,6H,Si(CH2CH3)3]；0,90-1.01[m,9H,Si(CH2CH3)3)；1.9-2.85(m,6H)；3.5-3.8(m,2H,CH2OSi)；4.12(dd,1H)；4.89(ddd,1H)。
GC (area normalization): a chromatographic column: DB-1; 60m 0.25mm 1.0 μm; nitrogen flow rate: 30.0 cm/sec; column temperature: maintaining at 290 deg.C for 40 min; sample inlet temperature: 250 ℃; FID detector temperature: 300 ℃; hydrogen flow rate: 40 ml/min; air flow rate: 400 ml/min; the split ratio is as follows: 50: 1; sample introduction amount: 1.0. mu.l.
Example 10: preparation and structure confirmation of disubstituted impurity ((-) -Corey Lactone primary alcohol and secondary alcohol double protection)
(-) -Corey Lactone (2.0g,11.62mmol) and dried pyridine (20.0ml) are put into a 50ml three-necked bottle, triethylchlorosilane (4.0g,26.72mmol) is added at room temperature, the temperature is raised to 60 ℃, stirring is carried out for one hour, 40ml of water is added into reaction liquid for dilution, 50ml of dichloromethane is extracted, anhydrous sodium sulfate is added into extract liquid for drying, filtering is carried out, filtrate is evaporated to dryness, and the obtained oily substance is purified by column chromatography (eluent: n-hexane, ethyl acetate, 7:3) to obtain 4.3g of colorless oily product (disubstituted impurity), the yield is 93%, and GC is 99.45%.
MS(Q-TOF micro ESI+):423(M+Na),823(2M+Na)
1H-NMR(CDCl3,400MHZ):δ0.50-0.65[m,12H,2Si(CH2CH3)3]；0,90-1.01[m,18H,2Si(CH2CH3)3)；1.86-2.81(m,6H)；3.48(m,2H,CH2OSi)；4.10(dd,1H)；4.90(ddd,1H)。
GC (area normalization): a chromatographic column: DB-1 column (60m 0.25mm 1.0 m); nitrogen flow rate: 30.0 cm/sec; column temperature: maintaining at 290 deg.C for 40 min; sample inlet temperature: 250 ℃; FID detector temperature: 300 ℃; hydrogen flow rate: 40 ml/min; air flow rate: 400 ml/min; air flow rate: 400 ml/min; the split ratio is as follows: 50: 1; sample introduction amount: 1.0. mu.l.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (1)
1. A method of preparing benzoylcoriolide of formula 1, comprising performing the method of the following scheme:
wherein R is triethylsilyl;
wherein the method comprises the steps of:
a. protecting primary alcohol of (-) -coriolide shown in a formula 4 by using triethylchlorosilane in dichloromethane in the presence of diisopropylethylamine in a solvent to obtain a compound shown in a formula 3;
b. carrying out esterification reaction on the compound shown in the formula 3 and benzoic acid to obtain (-) -benzoyl colactone shown in a formula 2 with protected primary alcohol; and
c. removing a primary alcohol protecting group of the (-) -benzoyl colactone shown in the formula 2 to obtain the (-) -benzoyl colactone shown in the formula 1;
in the step a, the first step is carried out,
the mol ratio of the (-) -coriolide shown in the formula 4 to the triethylchlorosilane is 1:1.1,
the mol ratio of (-) -coriolide shown in the formula 4 to diisopropylethylamine is 1: 1.5-3;
the volume/mass ratio of the dichloromethane to the (-) -coriolide shown in the formula 4 is 3-10 ml/g;
the reaction temperature is 20-30 ℃.
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| CA1131238A (en) * | 1977-05-26 | 1982-09-07 | Csaba Szantay | Process for the preparation of bicyclic lactone diol derivatives |
| CN103570757A (en) * | 2013-10-11 | 2014-02-12 | 天泽恩源（天津）医药技术有限公司 | Novel method for synthesizing Corey Lactone3-TBS (tert-Butyldimethylsilane) |
| US8785663B2 (en) * | 2010-01-28 | 2014-07-22 | Alfredo Paul Ceccarelli | Polymorphic forms of Lubiprostone |
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| CA1131238A (en) * | 1977-05-26 | 1982-09-07 | Csaba Szantay | Process for the preparation of bicyclic lactone diol derivatives |
| US8785663B2 (en) * | 2010-01-28 | 2014-07-22 | Alfredo Paul Ceccarelli | Polymorphic forms of Lubiprostone |
| CN103570757A (en) * | 2013-10-11 | 2014-02-12 | 天泽恩源（天津）医药技术有限公司 | Novel method for synthesizing Corey Lactone3-TBS (tert-Butyldimethylsilane) |
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Denomination of invention: Preparation of benzoyl corilactone Effective date of registration: 20220113 Granted publication date: 20210416 Pledgee: Bank of China Limited Huanggang branch Pledgor: HUANGGANG LUBAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2022420000007 |
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Denomination of invention: Preparation method of benzoyl coriolide Granted publication date: 20210416 Pledgee: Bank of China Limited Huanggang branch Pledgor: HUANGGANG LUBAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2024980002216 |