CN105503927B - Method for synthesizing 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester - Google Patents
Method for synthesizing 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester Download PDFInfo
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- CN105503927B CN105503927B CN201610014647.9A CN201610014647A CN105503927B CN 105503927 B CN105503927 B CN 105503927B CN 201610014647 A CN201610014647 A CN 201610014647A CN 105503927 B CN105503927 B CN 105503927B
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- pyrroles
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- 238000000034 method Methods 0.000 title claims abstract description 19
- 239000004327 boric acid Substances 0.000 title abstract description 8
- SSUYQPXZLFAVGI-UHFFFAOYSA-N S1NC=CC=C1.N1CCN=CC1 Chemical compound S1NC=CC=C1.N1CCN=CC1 SSUYQPXZLFAVGI-UHFFFAOYSA-N 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 alkenyl bromide Chemical compound 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000012044 organic layer Substances 0.000 claims description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- SLCVBVWXLSEKPL-UHFFFAOYSA-N neopentyl glycol Chemical compound OCC(C)(C)CO SLCVBVWXLSEKPL-UHFFFAOYSA-N 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000005292 vacuum distillation Methods 0.000 claims description 3
- 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 claims description 2
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical class CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 2
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims description 2
- 238000001514 detection method Methods 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical class CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims 1
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical class CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims 1
- 238000001816 cooling Methods 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 8
- 229910052763 palladium Inorganic materials 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 239000003513 alkali Substances 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 150000007857 hydrazones Chemical class 0.000 abstract description 3
- 230000003321 amplification Effects 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- 239000007818 Grignard reagent Substances 0.000 abstract 2
- 150000004795 grignard reagents Chemical class 0.000 abstract 2
- ICGLPKIVTVWCFT-UHFFFAOYSA-N 4-methylbenzenesulfonohydrazide Chemical compound CC1=CC=C(S(=O)(=O)NN)C=C1 ICGLPKIVTVWCFT-UHFFFAOYSA-N 0.000 abstract 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 abstract 1
- NIOHTSPOVHTOTN-UHFFFAOYSA-N S1NC=CC=C1.N1NCCC1 Chemical compound S1NC=CC=C1.N1NCCC1 NIOHTSPOVHTOTN-UHFFFAOYSA-N 0.000 abstract 1
- 229910052796 boron Inorganic materials 0.000 abstract 1
- 230000008878 coupling Effects 0.000 abstract 1
- 238000010168 coupling process Methods 0.000 abstract 1
- 238000005859 coupling reaction Methods 0.000 abstract 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 229930192474 thiophene Natural products 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 238000002156 mixing Methods 0.000 description 5
- RABBMOYULJIAFU-UHFFFAOYSA-N 1h-pyrrole;thiophene Chemical compound C=1C=CNC=1.C=1C=CSC=1 RABBMOYULJIAFU-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- UNVYSECOIMWWKM-UHFFFAOYSA-N 3,6-dihydro-2h-thiopyran Chemical compound C1CC=CCS1 UNVYSECOIMWWKM-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- JMJRYTGVHCAYCT-UHFFFAOYSA-N oxan-4-one Chemical compound O=C1CCOCC1 JMJRYTGVHCAYCT-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
Classifications
-
- 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
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
Abstract
The invention discloses a method for synthesizing 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester. According to the method, tetrahydropyrazole (thiazine) furan-4-ketone serves as the raw material, generates hydrazone with p-toluenesulfonhydrazide, then reacts with NBS/organic alkali to generate alkenyl bromide and next forms Grignard reagent with magnesium metal, after the Grignard reagent is formed, boron reagent is added for a reaction, and the 3, 6-dihydro-2H-pyrazine (thiazine) furan-4-boric acid ester is obtained. By means of the method, ultralow temperature, column chromatography and palladium catalyzed coupling in a literature method are avoided, raw materials are easy to obtain, cost is low, conditions are mild, and the method has potential industrial application and amplification prospect.
Description
Technical field
A kind of method of -4- borates the present invention relates to synthesis 3,6- dihydros -2H- pyrroles (thiophene) is muttered, belongs to pharmaceutical intermediate
Synthesis field.
Background technology
Cyclenes based structures are widely present in new research and development or in marketed drug, for example：3,6- dihydros -2H- pyrroles (thiophene) mutters -4-
Borate can be used for natural products and anticancer, inverase as general synthetic intermediate after Suzuki is coupled
Synthesis.
The mutter synthesis of -4- borates of 3,6- dihydros -2H- pyrroles (thiophene) is mainly at present：From tetrahydrochysene pyrrole (thiophene) -4- ketone is muttered strong
Under the conditions of alkali, ultralow temperature and PhNTf2Reaction generates thiazolinyl trifluoro sulphonic acid ester, or then exists into hydrazone with hydration hydrazine reaction
CuBr2/Et3N/MeOH system bromos, DBU obtains thiazolinyl bromine after eliminating, after subsequently Suzuki is coupled under the conditions of Metal Palladium
To product.
In the above-mentioned methods, reaction needs ultralow temperature, and using big excess copper salt, the of a relatively high precious metal palladium of cost is urged
Change and be coupled, the unfavorable factor such as column chromatography purifying, these directly affects amplification production efficiency.
The content of the invention
In order to overcome drawbacks described above, -4- the borates the invention discloses a kind of synthesis 3,6- dihydros -2H- pyrroles (thiophene) is muttered
Method.- 4- ketone is muttered as raw material with tetrahydrochysene pyrrole (thiophene), with unifor hydrazone is generated, then alkene is generated with the reaction of NBS/ organic bases
Bromide, then forms after RMgBr with magnesium metal, adds borane reagent reaction to obtain 3,6- dihydros -2H- pyrroles (thiophene) and mutters -4- boric acid
Ester.
One kind synthesis 3,6- dihydros -2H- pyrroles (thiophene) is muttered the method for -4- borates, it is characterised in that comprised the following steps：
The first step：By tetrahydrochysene pyrrole (thiophene) mutter -4- ketone, unifor and ethanol mixing after, heating reflux reaction, reaction
Solvent evaporated is finished, organic base and dichloromethane is added, NBS solution is added dropwise, after detection reaction completely, add aqueous hydrochloric acid solution to quench
Go out, separate organic layer, normal pressure solvent evaporated adds sulfolane, vacuum distillation obtains thiazolinyl bromine intermediate, G/C content more than 98%,
Yield 73-78%；
Second step：Magnesium metal and anhydrous ether solvent are added, is instilled and is started that thiazolinyl bromine is added dropwise after iodomethane causes, finish backflow
Reaction obtains RMgBr, is then added dropwise in trimethylborate, after reaction completely, adds aqueous hydrochloric acid solution to be quenched, organic layer
Ethyl acetate and glycol are added, are stirred at room temperature to reaction completely, organic layer saturated common salt washing, solvent evaporated adds normal heptane,
- 10 DEG C are cooled to, solid 3 is obtained after filtration, 6- dihydros -2H- pyrroles (thiophene) mutter -4- borates, GC and HNMR contents more than 98%,
Yield 62-66%.
Further, in above-mentioned technical proposal, in the first step, organic base is selected from diisopropyl ethyl amine, pyridine, 4- first
Yl pyridines, 3- picolines, DBU or TMG.
Further, in above-mentioned technical proposal, in the first step, tetrahydrochysene pyrrole (thiophene) mutter -4- ketone, unifor, have
The equivalent proportion of machine alkali and NBS is：1: 1-1.2: 1-3: 1-3.
Further, in above-mentioned technical proposal, in second step, anhydrous ether solvent is selected from tetrahydrofuran or 2- methyl tetrahydrochysenes
Furans.
Further, in above-mentioned technical proposal, in second step, thiazolinyl bromine, magnesium metal, trimethylborate and glycol rub
You are at ratio：1: 1-1.2: 1.2-1.5: 1.0-2.0.
Further, in above-mentioned technical proposal, in second step, glycol is selected from pinacol or neopentyl glycol.
The beneficial effect of the invention
Inventive process avoids the ultralow temperature, column chromatography and palladium chtalyst in literature method is coupled, raw material is easy to get, low cost
Honest and clean, mild condition amplifies application prospect with potential industry.
Specific embodiment
Embodiment 1
The synthesis of 3,6- dihydro -2H- pyrans -4- pinacol borates：
Step one：By Tetrahydro-pyran-4-one (10.0 grams, 0.1mol), unifor (18.6 grams, 0.1mol) and second
After 120 milliliters of mixing of alcohol, heating reflux reaction, after completion of the reaction solvent evaporated, is directly added into pyridine (11.9 grams, 0.15mol)
In 150 milliliters of dichloromethane, the solution that NBS (26.7 grams, 0.15mol) is dissolved in 40 milliliters of dichloromethane is subsequently added dropwise,
After reaction completely, add 10% hydrochloric acid to adjust PH=2-3, separate organic layer, after normal pressure solvent evaporated, add 20 milliliters of sulfolane, subtract
Pressure distillation obtains 11.9 grams of light yellow liquids：3,6- dihydro -2H- pyrans -4- bromines, GC：98.2%, yield 73%；
Step 2：Magnesium metal (1.9 grams, 78mmol) and 10 milliliters of tetrahydrofurans are added, after adding 2-3 drops iodomethane to cause
Start that the solution that 11.9 grams of 3,6- dihydro -2H- pyrans -4- bromines are dissolved in 60 milliliters of tetrahydrofurans is added dropwise, finish back flow reaction system
For into RMgBr, in being then added dropwise to trimethylborate (9.1 grams, 87mmol), after reaction completely, 15% hydrochloric acid solution is added
Adjust PH=3-4, organic layer to add 90 milliliters of ethyl acetate and pinacol (10.3 grams, 87mmol), be stirred at room temperature complete to reaction.
After layering, the washing of organic layer saturated common salt after solvent evaporated, adds normal heptane, is cooled to -10 DEG C, and 9.7 grams are obtained after filtration in vain
Color solid：3,6- dihydro -2H- pyrans -4- pinacol borates, GC：99.2%, HNMR>98%, yield 63%.
Embodiment 2
The synthesis of 3,6- dihydro -2H- pyrans -4- boric acid DOPCPs：
Step one：By Tetrahydro-pyran-4-one (10.0 grams, 0.1mol), unifor (18.6 grams, 0.1mol) and second
After the mixing of 120 milliliters of alcohol, heating reflux reaction, solvent evaporated after completion of the reaction, be directly added into DBU (22.8 grams, 0.15mol) and
In 150 milliliters of dichloromethane, the solution that NBS (26.7 grams, 0.15mol) is dissolved in 40 milliliters of dichloromethane is subsequently added dropwise, instead
After answering completely, add 10% hydrochloric acid to adjust PH=4-5, separate organic layer, after normal pressure solvent evaporated, add 20 milliliters of sulfolane, reduce pressure
Distillation obtains 12.2 grams of light yellow liquids：3,6- dihydro -2H- pyrans -4- bromines, GC：98.4%, yield 75%；
Step 2：Magnesium metal (1.9 grams, 78mmol) and 10 milliliters of tetrahydrofurans are added, after adding 2-3 drops iodomethane to cause
Start that the solution that 12.2 grams of 3,6- dihydro -2H- pyrans -4- bromines are dissolved in 60 milliliters of tetrahydrofurans is added dropwise, finish back flow reaction system
For into RMgBr, in being then added dropwise to trimethylborate (9.1 grams, 87mmol), after reaction completely, 15% hydrochloric acid solution is added
Adjust PH=3-4, organic layer to add 90 milliliters of ethyl acetate and neopentyl glycol (9.0 grams, 87mmol), be stirred at room temperature complete to reaction.
After layering, the washing of organic layer saturated common salt after solvent evaporated, adds normal heptane, is cooled to -10 DEG C, and 9.4 grams are obtained after filtration in vain
Color solid：3,6- dihydro -2H- pyrans -4- boric acid DOPCPs, GC：99.0%, HNMR>98%, yield 64%.
Embodiment 3
The synthesis of 3,6- dihydro -2H- thiapyran -4- pinacol borates：
Step one：By tetrahydric thiapyran-4-ketone (10.0 grams, 0.1mol), unifor (18.6 grams, 0.1mol) and second
After 120 milliliters of mixing of alcohol, heating reflux reaction, after completion of the reaction solvent evaporated, is directly added into pyridine (17.2 grams, 0.22mol)
In 150 milliliters of dichloromethane, the solution that NBS (35.6 grams, 0.20mol) is dissolved in 40 milliliters of dichloromethane is subsequently added dropwise,
After reaction completely, add 10% hydrochloric acid to adjust PH=2-3, separate organic layer, after normal pressure solvent evaporated, add 20 milliliters of sulfolane, subtract
Pressure distillation obtains 13.8 grams of light yellow liquids：3,6- dihydro -2H- thiapyran -4- bromines, GC：98.7%, yield 77%；
Step 2：Magnesium metal (2.2 grams, 92mmol) and 10 milliliters of tetrahydrofurans are added, after adding 2-3 drops iodomethane to cause
Start that the solution that 13.8 grams of 3,6- dihydro -2H- pyrans -4- bromines are dissolved in 60 milliliters of tetrahydrofurans is added dropwise, finish back flow reaction system
For into RMgBr, in being then added dropwise to trimethylborate (11.4 grams, 0.11mol), after reaction completely, add 10% hydrochloric acid molten
Liquid adjusts PH=3-4, organic layer to add 110 milliliters of ethyl acetate and pinacol (9.4 grams, 80mmol), is stirred at room temperature to having reacted
Entirely.After layering, the washing of organic layer saturated common salt after solvent evaporated, adds normal heptane, is cooled to -10 DEG C, and 10.8 are obtained after filtration
Gram off-white powder：3,6- dihydro -2H- thiapyran -4- pinacol borates, GC：99.0%, HNMR>98%, yield 62%.
Embodiment 4
The synthesis of 3,6- dihydro -2H- thiapyran -4- boric acid DOPCPs：
Step one：By tetrahydric thiapyran-4-ketone (10.0 grams, 0.1mol), unifor (18.6 grams, 0.1mol) and second
After the mixing of 120 milliliters of alcohol, heating reflux reaction, solvent evaporated after completion of the reaction, be directly added into triethylamine (25.2 grams,
0.25mol) and in 150 milliliters of dichloromethane, NBS (35.6 grams, 0.20mol) is subsequently added dropwise and is dissolved in 40 milliliters of dichloromethane
Solution, after reaction completely, add 10% hydrochloric acid to adjust PH=4-5, separate organic layer, after normal pressure solvent evaporated, add 20 milliliters of rings
Fourth sulfone, vacuum distillation obtains 13.2 grams of light yellow liquids：3,6- dihydro -2H- thiapyran -4- bromines, GC：98.7%, yield 74%；
Step 2：Magnesium metal (2.2 grams, 92mmol) and 10 milliliters of tetrahydrofurans are added, after adding 2-3 drops iodomethane to cause
Start that the solution that 13.2 grams of 3,6- dihydro -2H- pyrans -4- bromines are dissolved in 60 milliliters of tetrahydrofurans is added dropwise, finish back flow reaction system
For into RMgBr, in being then added dropwise to trimethylborate (11.4 grams, 0.11mol), after reaction completely, add 10% hydrochloric acid molten
Liquid adjusts PH=3-4, organic layer to add 110 milliliters of ethyl acetate and neopentyl glycol (10.0 grams, 96mmol), be stirred at room temperature to reaction
Completely.After layering, the washing of organic layer saturated common salt after solvent evaporated, adds normal heptane, is cooled to -10 DEG C, obtains after filtration
10.0 gram off-white powder：3,6- dihydro -2H- thiapyran -4- boric acid DOPCPs, GC：99.7%, HNMR>98%, yield 64%.
Claims (6)
1. the method that one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that comprise the following steps：
The first step：After tetrahydrochysene pyrrole/thiapyran -4- ketone, unifor and ethanol are mixed, heating reflux reaction, reaction is finished
Solvent evaporated, adds organic base and dichloromethane, and NBS solution is added dropwise, and after detection reaction completely, adds aqueous hydrochloric acid solution to be quenched,
Organic layer is separated, normal pressure solvent evaporated adds sulfolane, vacuum distillation to obtain thiazolinyl bromine intermediate, and G/C content more than 98% is received
Rate 73-78%；
Second step：Magnesium metal and anhydrous ether solvent are added, is instilled and is started that thiazolinyl bromine is added dropwise after iodomethane causes, finish back flow reaction
RMgBr is obtained, is then added dropwise in trimethylborate, after reaction completely, add aqueous hydrochloric acid solution to be quenched, organic layer is added
Ethyl acetate and glycol, are stirred at room temperature, organic layer saturated common salt washing complete to reaction, and solvent evaporated adds normal heptane, cooling
To -10 DEG C, solid 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, GC and HNMR contents more than 98%, yield are obtained after filtration
62-66%。
2. the method that according to claim 1 one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that：
In the first step, organic base is selected from diisopropyl ethyl amine, pyridine, 4- picolines, 3- picolines, DBU or TMG.
3. the method that according to claim 1 one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that：
In the first step, the equivalent proportion of tetrahydrochysene pyrrole/thiapyran -4- ketone, unifor, organic base and NBS is 1: 1-1.2: 1-3: 1-
3。
4. the method that according to claim 1 one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that：
In second step, anhydrous ether solvent is selected from tetrahydrofuran or 2- methyltetrahydrofurans.
5. the method that according to claim 1 one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that：
In second step, the mol ratio of thiazolinyl bromine, magnesium metal, trimethylborate and glycol is 1: 1-1.2: 1.2-1.5: 1.0-2.0.
6. the method that according to claim 1 one kind synthesizes 3,6- dihydros -2H- pyrroles/thiapyran -4- borates, it is characterised in that：
In second step, glycol is selected from pinacol or neopentyl glycol.
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