CN105085569B - A kind of preparation method of 1,2- dioxanes derivative - Google Patents
A kind of preparation method of 1,2- dioxanes derivative Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 150000000077 1,2-dioxanes Chemical class 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 72
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 24
- 150000002978 peroxides Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 17
- -1 III compound Chemical class 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 14
- 239000013078 crystal Substances 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- 239000000376 reactant Substances 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 239000012044 organic layer Substances 0.000 claims description 11
- LHJQIRIGXXHNLA-UHFFFAOYSA-N calcium peroxide Chemical compound [Ca+2].[O-][O-] LHJQIRIGXXHNLA-UHFFFAOYSA-N 0.000 claims description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical group OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000004343 Calcium peroxide Substances 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 235000019402 calcium peroxide Nutrition 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims 1
- AFCIMSXHQSIHQW-UHFFFAOYSA-N [O].[P] Chemical compound [O].[P] AFCIMSXHQSIHQW-UHFFFAOYSA-N 0.000 claims 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- 150000002012 dioxanes Chemical class 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- ORILYTVJVMAKLC-UHFFFAOYSA-N adamantane Chemical compound C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- XYIPYISRNJUPBA-UHFFFAOYSA-N [3-(3'-methoxyspiro[adamantane-2,4'-dioxetane]-3'-yl)phenyl] dihydrogen phosphate Chemical compound O1OC2(C3CC4CC(C3)CC2C4)C1(OC)C1=CC=CC(OP(O)(O)=O)=C1 XYIPYISRNJUPBA-UHFFFAOYSA-N 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 2
- 229910052753 mercury Inorganic materials 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- WOTBPOGYFGKWIB-UHFFFAOYSA-N C(=O)O.OC=1C=C(C(=O)O)C=CC1 Chemical compound C(=O)O.OC=1C=C(C(=O)O)C=CC1 WOTBPOGYFGKWIB-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- VGBBJZYOAOCLLS-UHFFFAOYSA-N adamantane-2-carbaldehyde Chemical compound C1C(C2)CC3CC1C(C=O)C2C3 VGBBJZYOAOCLLS-UHFFFAOYSA-N 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940078916 carbamide peroxide Drugs 0.000 description 1
- 239000012612 commercial material Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000000113 cyclohexyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- KAKKHKRHCKCAGH-UHFFFAOYSA-L disodium;(4-nitrophenyl) phosphate;hexahydrate Chemical compound O.O.O.O.O.O.[Na+].[Na+].[O-][N+](=O)C1=CC=C(OP([O-])([O-])=O)C=C1 KAKKHKRHCKCAGH-UHFFFAOYSA-L 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000005954 phosphonylation reaction Methods 0.000 description 1
- 238000007539 photo-oxidation reaction Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- AQLJVWUFPCUVLO-UHFFFAOYSA-N urea hydrogen peroxide Chemical compound OO.NC(N)=O AQLJVWUFPCUVLO-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of preparation method of 1,2 dioxane derivatives, described 1,2 dioxane derivatives are formula Ι compounds represented comprising following steps：II compound represented of modus ponens and Buddha's warrior attendant alkanone react III compound represented of synthesis formula by Wittig, then obtain IV compound represented of formula by phosphorylated, then obtain product by oxidation reaction.The preparation method of 1, the 2 dioxane derivative of one kind of the present invention, has many advantages, such as that safe, production cost is low, is easy to industrialized production.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to the preparation method of one kind 1,2- dioxane derivatives.
Background technology
AMPPD, No. CAS is：122341-56-4, general entitled 3- (2- spirals adamantane) -4- methoxyl groups -4- (3- phosphorus
Oxygen acyl)-phenyl -1,2- dioxane disodium salts（Molecular formula refers to formula Ι）, it is newest oversoul in a kind of biochemical field
Quick alkaline phosphatase substrate, has a wide range of applications in Measurement for Biotechnique.
（Ι）
Existing synthesis AMPPD is completed generally according to following process program：Substituted-phenyl methoxyl group is obtained by commercial materials
Methene base adamantane（Intermediate）, then AMPDD is prepared by phosphonylation and photooxidation.European patent (the patent No.
EP0518387), it is that raw material is reacted by McMurry among preparation key by 2- Buddha's warrior attendants alkanone and 3- hydroxybenzoic acid formic acid
Body, route are short, it is desirable that lower temperature（- 80 degree）Operation temperature and higher equipment requirement it is high, be unfavorable for industrialized production.In
State's patent（CN1020799）Then there is a problem of same.
Chinese patent CN103772433A and CN200510021054, the phosphoric acid protected using 2- Buddha's warrior attendants alkanone and substituent group
Diformazan/ethoxycarbonyl benzyl methyl ether is raw material, is reacted by Wittig, obtains intermediate, this route also requires that lower operation
Temperature（- 70 to -50 degree）, equally it is unfavorable for industrialized production.
Chinese patent (CN103951704A）The use of the phenyl grignard reagent of adamantane -2- aldehyde and 3 hydroxyl protections is original
Material synthesis key intermediate, synthetic route used is longer, is equally not easy industrial applications.United States Patent (USP) US4956477,
US6417380 and US6124478, the adamantane replaced using cyano are prepared key intermediate by grignard reaction, made in the process
With hypertoxic cyanide so that the process route is equally not suitable for industrialized production.
Invention content
The purpose of the present invention is to provide it is a kind of it is safe, production cost is low, is easy to the 1,2- dioxies of industrialized production
The preparation method of cyclohexane derivative.
To solve the above problems, the technical solution adopted in the present invention is as follows：
The preparation method of one kind 1,2- dioxane derivatives, 1, the 2- dioxanes derivative are shown in formula Ι
Compound, include the following steps：II compound represented of modus ponens and Buddha's warrior attendant alkanone are reacted by Wittig shown in synthesis formula III
Compound, IV compound represented of formula is then obtained by phosphorylated, product is then obtained by oxidation reaction；
（Ι）
（Ⅱ）,
Wherein, PG is ester group；
（Ⅲ）
（Ⅳ）.
In the present invention, preferred scheme is that the PG is benzoic acid ester group.
In the present invention, preferred scheme is that the PG is alkyl or the benzoic acid ester group of nitro substitution.
In the present invention, preferred scheme is that the PG is nitrobenzoyl perester radical.
In the present invention, preferred scheme is that the molar ratio of II compound represented of the formula and Buddha's warrior attendant alkanone is 1:1.
In the present invention, preferred scheme is that II compound represented of modus ponens is dissolved in organic solvent, obtains molal volume
The solution of II compound represented of formula of a concentration of 0.4-0.6mol/L；Then at a temperature of -40 DEG C ~ 20 DEG C, alkali gold is added
The mixture for belonging to salt and Buddha's warrior attendant alkanone then heats to room temperature, reacts 10-12 hours, II compound represented of the formula, alkali gold
Belong to salt, the molar ratio of Buddha's warrior attendant alkanone is 1:0.9-1.1: 0.9-1.1；Salt acid for adjusting pH value is added to 6.8-7.5, has isolated
Then machine layer removes organic solvent by revolving, obtains reactant；Reactant is dissolved with methanol, the first hydrogen-oxygen is then added
Change sodium solution, react 1.5-2.5 hours, the molar ratio of first sodium hydroxide and II compound represented of formula is 1:0.9-
1.1；Then salt acid for adjusting pH value is added to 3.8-4.2, filtering is washed with methanol, water, abandons filtrate, then dry, obtain
III compound represented of formula；III compound represented of formula is dissolved in tetrahydrofuran, a concentration of 0.4- of molal volume is obtained
The solution of III compound represented of formula of 0.6mol/L；Then it is added pyridine, the volume ratio of the pyridine and tetrahydrofuran is 1:
7-9；Then phosphorus oxychloride is added dropwise, reacts 1.5-2.5 hours, 3- hydroxypropionitriles are added, stirs 10-14 hours, III institute of the formula
Compound, phosphorus oxychloride, the molar ratio of 3- hydroxypropionitriles shown are 2:3-5:4-7；Saturated ammonium chloride solution is added, has isolated
Machine layer, dry, revolving removal solvent obtains IV compound represented of formula, is then dissolved with methanol, the second hydroxide is then added
Sodium solution is stirred to react 4-6 hours, and the molar ratio of III compound represented of the formula and the second sodium hydroxide is 1:4-6, revolving
It is recrystallized after removal solvent, obtains white crystals；White crystals are soluble in water, peroxide is added, shown in the formula III
The mass ratio of compound and peroxide is 9:8-11 is stirred to react 2-4h, then recrystallizes, obtain white solid to get.
In the present invention, preferred scheme be the organic solvent be methyl tertiary butyl ether(MTBE) isopropyl ether, ether, tetrahydrofuran and
At least one of 1,4- dioxane.
In the present invention, preferred scheme be the alkali metal salt be LHMDS, LDA, n-BuLi, tert-butyl lithium, the tert-butyl alcohol
Potassium and at least one of sodium tert-butoxide and sodium hydride.
In the present invention, preferred scheme is that the peroxide is in calper calcium peroxide, hydrogen peroxide and carbamide peroxide
It is at least one.
In the present invention, preferred scheme is II compound represented of modus ponens, is dissolved in methyl tertiary butyl ether(MTBE), obtains a mole body
The solution of II compound represented of formula of a concentration of 0.5mol/L of product；Then at a temperature of -40 DEG C, sodium hydride and Buddha's warrior attendant is added
The mixture of alkanone, then heats to room temperature, react 10 hours, II compound represented of the formula, sodium hydride, Buddha's warrior attendant alkanone
Molar ratio is 1:1:1；Salt acid for adjusting pH value is added to 7.1, isolates organic layer, methyl tertbutyl is then removed by revolving
Ether obtains reactant；Reactant is dissolved with methanol, is then added the first sodium hydroxide solution, reacts 2 hours, described first
The molar ratio of sodium hydroxide and II compound represented of formula is 1: 1；Then salt acid for adjusting pH value is added to 4.0, first is used in filtering
Alcohol, water are washed, and are abandoned filtrate, are then dried, and III compound represented of formula is obtained；III compound represented of formula is dissolved in tetrahydrochysene
In furans, the solution of III compound represented of formula of a concentration of 0.5mol/L of molal volume is obtained；Then pyridine, the pyrrole is added
The volume ratio of pyridine and tetrahydrofuran is 1:8；Then phosphorus oxychloride is added dropwise, reacts 2 hours, 3- hydroxypropionitriles are added, stirring 12 is small
When, III compound represented of the formula, phosphorus oxychloride, the molar ratio of 3- hydroxypropionitriles are 2:3:6；It is molten that saturated ammonium chloride is added
Liquid isolates organic layer, dry, and revolving removal solvent obtains IV compound represented of formula, then dissolved with methanol, then added
Enter methanol dissolving, the second sodium hydroxide solution is then added and is stirred to react 5 hours, III compound represented of the formula and the second hydrogen
The molar ratio of sodium oxide molybdena is 1:5, revolving recrystallizes after removing solvent, obtains white crystals；White crystals are soluble in water, it is added
Peroxide, it according to weight ratio is 1 that the peroxide, which is calper calcium peroxide and hydrogen peroxide,:The mixture of 1 composition, the formula III
The mass ratio of compound represented and peroxide is 9:10, be stirred to react 3h, then recrystallize, obtain white solid to get.
Compared with prior art, the invention has the advantages that：Preparation method using the present invention, can be in higher temperature
Degree（-40℃~20℃）Under synthesized, reduce production cost, avoid conventional method medium temperature spend it is low and to equipment requirement
Problem that is excessively high and being difficult to realize industrialized production；In addition, carrying out annulation using peroxide, reaction can be made more equal
One, the uneven and sodium vapor lamp of reaction, mercury lamp existing for the sodium vapor lamp used in prior synthesizing method, mercury lamp can be avoided to be brought
Security risk；The preparation method of the present invention avoids the use of cyanide, and production is safer；In addition, the method for the present invention
Yield is high, is convenient for industrial production.
The present invention is described in detail With reference to embodiment.
Specific implementation mode
Embodiment 1
The preparation method of one kind 1,2- dioxane derivatives, 1, the 2- dioxanes derivative are shown in formula Ι
Compound, preparation method includes the following steps：II compound represented 198g of modus ponens（0.5mol）, it is dissolved in 1000mL methyl
In tertbutyl ether, the solution of II compound represented of formula of a concentration of 0.5mol/L of molal volume is obtained；Then in -40 DEG C of temperature
Under degree, the mixture of 0.5mol sodium hydrides and 0.5mol Buddha's warrior attendant alkanones is added, then heats to room temperature, reacts 10 hours；It is added
Salt acid for adjusting pH value isolates organic layer to 7.1, then removes methyl tertiary butyl ether(MTBE) by revolving, obtains reactant；It will reaction
Object is dissolved with methanol, and the first sodium hydroxide solution is then added, and is reacted 2 hours, shown in first sodium hydroxide and formula II
The molar ratio of compound is 1: 1；Then salt acid for adjusting pH value is added to 4.0, filtering is washed with methanol, water, abandons filtrate,
Then it dries, obtains III compound represented of formula.It weighs to obtained III compound represented of formula, quality 108g
（Yield is 79%）, it is detected using NMR, 1H NMR (400MHz, CDCl3)：δ 1.71-1.99 (m, 12H), 2.65
(m, 1H), 3.23 (m, 1H), 3.34 (s, 3H), 7.02-7.06 (m, 2H), 7.14-7.21 (m, 2H).
Take 27g（0.1mol）III compound represented of formula is dissolved in 200mL tetrahydrofurans, and it is a concentration of to obtain molal volume
The solution of III compound represented of formula of 0.5mol/L；Then 25mL pyridines are added；Then 0.15mol phosphorus oxychloride is added dropwise, instead
It answers 2 hours, 0.3mol 3- hydroxypropionitriles is added, stir 12 hours；Saturated ammonium chloride solution is added, isolates organic layer, does
Dry, revolving removal solvent obtains IV compound represented of formula, is then dissolved with methanol, methanol dissolving is then added, is then added
Sodium hydroxide solution is stirred to react 5 hours, and the molar ratio of III compound represented of the formula and sodium hydroxide is 1:5, revolving is gone
Except being recrystallized after solvent, white crystals are obtained（It is weighed as 25g）；White crystals are soluble in water, 30g peroxide, institute is added
It according to weight ratio is 1 that state peroxide, which be calper calcium peroxide and hydrogen peroxide,:The mixture of 1 composition, is stirred to react 3h, then ties again
Crystalline substance, obtain white solid to get.It weighs to white solid, weight 32g（Yield is 76%）, it is detected using NMR,
1H NMR (300MHz, CDCl3), δ 1.75-1.98 (m, 12H), 2.63 (m, 1H), 3.26 (m, 1H), 3 32 (s,
3H) , 7.05-7.25 (m, 4H)。
（Ι）
（Ⅱ）,
（Ⅲ）
（Ⅳ）.
Embodiment 2
The preparation method of one kind 1,2- dioxane derivatives, the object of formula Ι, formula II, formula III, formula IV in the present embodiment
Matter is same as Example 1, and 1, the 2- dioxanes derivative is formula Ι compounds represented, and preparation method includes such as
Lower step：II compound represented of modus ponens, is dissolved in organic solvent, obtains shown in the formula II of a concentration of 0.4mol/L of molal volume
Compound solution；Then at a temperature of -20 DEG C, the mixture of alkali metal salt and Buddha's warrior attendant alkanone is added, then heats to
Room temperature, react 10 hours, II compound represented of the formula, alkali metal salt, Buddha's warrior attendant alkanone molar ratio be 1:0.9: 0.9；Add
Enter salt acid for adjusting pH value to 6.8, isolate organic layer, organic solvent is then removed by revolving, obtains reactant；By reactant
It is dissolved with methanol, the first sodium hydroxide solution is then added, reacted 1.5 hours, shown in first sodium hydroxide and formula II
The molar ratio of compound is 1:0.9；Then salt acid for adjusting pH value is added to 3.8, filtering is washed with methanol, water, abandons filter
Then liquid is dried, III compound represented of formula is obtained；III compound represented of formula is dissolved in tetrahydrofuran, a mole body is obtained
The solution of III compound represented of formula of a concentration of 0.4mol/L of product；Then pyridine, the body of the pyridine and tetrahydrofuran is added
Product is than being 1:7；Then phosphorus oxychloride is added dropwise, reacts 1.5 hours, 3- hydroxypropionitriles are added, stirs 10 hours, shown in the formula III
Compound, phosphorus oxychloride, the molar ratio of 3- hydroxypropionitriles be 2:3:4；Saturated ammonium chloride solution is added, isolates organic layer,
Drying, revolving removal solvent, obtains IV compound represented of formula, is then dissolved with methanol, and methanol dissolving is then added, then adds
Enter the second sodium hydroxide solution to be stirred to react 4 hours, III compound represented of the formula and the molar ratio of the second sodium hydroxide are
1:4, revolving recrystallizes after removing solvent, obtains white crystals；White crystals are soluble in water, peroxide, the formula is added
The mass ratio of III compound represented and peroxide is 9:8, it is stirred to react 2h, is then recrystallized, obtains white solid, i.e.,
.It weighs, product yield 72% is detected using NMR, 1H NMR (300MHz, CDCl3), δ 1.75-1.98 (m,
12H), 2.63 (m, 1H), 3.26 (m, 1H), 3 32 (s, 3H), 7.05-7.25 (m, 4H).
Embodiment 3
The preparation method of one kind 1,2- dioxane derivatives, 1, the 2- dioxanes derivative are shown in formula Ι
Compound, formula Ι, formula II, formula III, the substance of formula IV in the present embodiment are same as Example 1, and preparation method includes such as
Lower step：II compound represented of modus ponens, is dissolved in organic solvent, obtains shown in the formula II of a concentration of 0.6mol/L of molal volume
Compound solution；Then at a temperature of 20 DEG C, the mixture of alkali metal salt and Buddha's warrior attendant alkanone is added, then heats to room
Temperature, react 12 hours, II compound represented of the formula, alkali metal salt, Buddha's warrior attendant alkanone molar ratio be 1: 1.1:1.1；It is added
Salt acid for adjusting pH value isolates organic layer to 7.5, then removes organic solvent by revolving, obtains reactant；Reactant is used
Methanol dissolves, and the first sodium hydroxide solution is then added, and reacts 2.5 hours, first sodium hydroxide is changed with shown in formula II
The molar ratio for closing object is 1:1.1；Then salt acid for adjusting pH value is added to 4.2, filtering is washed with methanol, water, abandons filtrate,
Then it dries, obtains III compound represented of formula；III compound represented of formula is dissolved in tetrahydrofuran, it is dense to obtain molal volume
Degree is the solution of III compound represented of formula of 0.6mol/L；Then pyridine, the volume ratio of the pyridine and tetrahydrofuran is added
It is 1: 9；Then phosphorus oxychloride is added dropwise, reacts 2.5 hours, 3- hydroxypropionitriles are added, stirs 14 hours, shown in the formula III
Compound, phosphorus oxychloride, the molar ratio of 3- hydroxypropionitriles are 2: 5: 7；Saturated ammonium chloride solution is added, isolates organic layer,
Drying, revolving removal solvent, obtains IV compound represented of formula, is then dissolved with methanol, and methanol dissolving is then added, then adds
Enter the second sodium hydroxide solution to be stirred to react 6 hours, III compound represented of the formula and the molar ratio of the second sodium hydroxide are
1:6, revolving recrystallizes after removing solvent, obtains white crystals；White crystals are soluble in water, peroxide, the formula is added
The mass ratio of III compound represented and peroxide is 9:11, it is stirred to react 4h, is then recrystallized, obtains white solid, i.e.,
.It weighs, product yield 73% is detected using NMR, 1H NMR (300MHz, CDCl3), δ 1.75-1.98 (m,
12H), 2.63 (m, 1H), 3.26 (m, 1H), 3 32 (s, 3H), 7.05-7.25 (m, 4H).
The above embodiment is only the preferred embodiment of the present invention, and the scope of protection of the present invention is not limited thereto,
The variation and replacement for any unsubstantiality that those skilled in the art is done on the basis of the present invention belong to institute of the present invention
Claimed range.
Claims (4)
1. one kind 1, the preparation method of 2- dioxane derivatives, 1, the 2- dioxanes derivative are shown in formula Ι
The disodium salt of compound, it is characterised in that include the following steps：II compound represented of modus ponens, is dissolved in organic solvent, obtains
The solution of II compound represented of formula of a concentration of 0.4-0.6mol/L of molal volume；Then at a temperature of -40 DEG C ~ 20 DEG C,
The mixture of alkali and Buddha's warrior attendant alkanone is added, then heats to room temperature, reacts 10-12 hours, II compound represented of the formula,
Alkali, Buddha's warrior attendant alkanone molar ratio be 1:0.9-1.1: 0.9-1.1；Salt acid for adjusting pH value is added to 6.8-7.5, isolates organic
Then layer removes organic solvent by revolving, obtains reactant；Reactant is dissolved with methanol, the first hydroxide is then added
Sodium solution reacts 1.5-2.5 hours, and the molar ratio of first sodium hydroxide and II compound represented of formula is 1:0.9-1.1；
Then salt acid for adjusting pH value is added to 3.8-4.2, filtering is washed with methanol, water, abandons filtrate, then dry, obtains formula III
Compound represented；III compound represented of formula is dissolved in tetrahydrofuran, a concentration of 0.4-0.6mol/L of molal volume is obtained
III compound represented of formula solution；Then it is added pyridine, the volume ratio of the pyridine and tetrahydrofuran is 1:7-9；Then
Phosphorus oxychloride is added dropwise, reacts 1.5-2.5 hours, 3- hydroxypropionitriles are added, stirs 10-14 hours, chemical combination shown in the formula III
Object, phosphorus oxychloride, the molar ratio of 3- hydroxypropionitriles are 2:3-5:4-7；Saturated ammonium chloride solution is added, isolates organic layer, does
Dry, revolving removal solvent obtains IV compound represented of formula, is then dissolved with methanol, the second sodium hydroxide solution is then added
It is stirred to react 4-6 hours, the molar ratio of III compound represented of the formula and the second sodium hydroxide is 1:4-6, revolving removal are molten
It is recrystallized after agent, obtains white crystals；White crystals are soluble in water, peroxide, III compound represented of the formula is added
Mass ratio with peroxide is 9:8-11 is stirred to react 2-4h, then recrystallizes, obtain white solid to get；
The alkali is at least one in LHMDS, LDA, n-BuLi, tert-butyl lithium, potassium tert-butoxide and sodium tert-butoxide and sodium hydride
Kind；
The peroxide is the mixture that calper calcium peroxide and hydrogen peroxide form；
（Ι）
（Ⅱ）,
Wherein ,-O-PG is nitrobenzoyl perester radical；
（Ⅲ）
（Ⅳ）.
2. the preparation method of 1,2- dioxanes derivative according to claim 1, it is characterised in that：II institute of the formula
The molar ratio of the compound and Buddha's warrior attendant alkanone shown is 1:1.
3. the preparation method of 1,2- dioxanes derivative according to claim 1, it is characterised in that：It is described organic molten
Agent is at least one of methyl tertiary butyl ether(MTBE), isopropyl ether, ether, tetrahydrofuran and 1,4- dioxane.
4. the preparation method of 1,2- dioxanes derivative according to claim 1, it is characterised in that：Shown in modus ponens II
Compound, be dissolved in methyl tertiary butyl ether(MTBE), obtain the molten of II compound represented of formula of a concentration of 0.5mol/L of molal volume
Liquid；Then at a temperature of -40 DEG C, the mixture of sodium hydride and Buddha's warrior attendant alkanone is added, then heats to room temperature, reaction 10 is small
When, II compound represented of the formula, sodium hydride, Buddha's warrior attendant alkanone molar ratio be 1:1:1；Salt acid for adjusting pH value is added to 7.1,
Organic layer is isolated, methyl tertiary butyl ether(MTBE) is then removed by revolving, obtains reactant；Reactant is dissolved with methanol, then
The first sodium hydroxide solution is added, reacts 2 hours, the molar ratio of first sodium hydroxide and II compound represented of formula is 1:
1；Then salt acid for adjusting pH value is added to 4.0, filtering is washed with methanol, water, abandons filtrate, then dry, obtains III institute of formula
The compound shown；III compound represented of formula is dissolved in tetrahydrofuran, the formula III of a concentration of 0.5mol/L of molal volume is obtained
The solution of compound represented；Then it is added pyridine, the volume ratio of the pyridine and tetrahydrofuran is 1:8；Then trichlorine is added dropwise
Oxygen phosphorus reacts 2 hours, and 3- hydroxypropionitriles are added, and stirs 12 hours, III compound represented of the formula, phosphorus oxychloride, 3- hydroxyls
The molar ratio of propionitrile is 2:3:6；Saturated ammonium chloride solution is added, isolates organic layer, dry, revolving removal solvent obtains formula
IV compound represented, is then dissolved with methanol, and the second sodium hydroxide solution is then added and is stirred to react 5 hours, the formula III
Compound represented and the molar ratio of the second sodium hydroxide are 1:5, revolving recrystallizes after removing solvent, obtains white crystals；It will
White crystals are soluble in water, peroxide are added, it according to weight ratio is 1 that the peroxide, which is calper calcium peroxide and hydrogen peroxide,:1
The mass ratio of the mixture of composition, III compound represented of the formula and peroxide is 9:10, it is stirred to react 3h, is then tied again
Crystalline substance, obtain white solid to get.
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