CN106588568B - A kind of preparation method of 1,1- cyclopropyl dimethanol - Google Patents
A kind of preparation method of 1,1- cyclopropyl dimethanol Download PDFInfo
- Publication number
- CN106588568B CN106588568B CN201611076798.3A CN201611076798A CN106588568B CN 106588568 B CN106588568 B CN 106588568B CN 201611076798 A CN201611076798 A CN 201611076798A CN 106588568 B CN106588568 B CN 106588568B
- Authority
- CN
- China
- Prior art keywords
- cyclopropyl
- solvent
- preparation
- catalyst
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to technical field of medicine synthesis, are related to the preparation method of one kind 1,1- cyclopropyl dimethanol.Specifically, preparation method of the invention includes the following steps: 1) in the presence of catalyst A, solvent A and acid binding agent, using diethyl malonate and 1,2- dichloroethanes prepares 1,1- cyclopropyl dicarboxylate；2) in the presence of solvent B and catalyst B, 1,1- cyclopropyl dicarboxylate is restored using reducing agent, obtains target product 1,1- cyclopropyl dimethanol.Raw material used by preparation method of the invention is cheap, is easy to get, is nontoxic, and catalyst activity is higher, and solvent is recyclable, and cost significantly reduces；Reaction condition is mild, and product is easily isolated, and three industrial wastes are few, meets Green Chemistry requirement.In addition, preparation method of the invention can significantly improve the yield of target product, 2 step total recoverys may be up to 88%.
Description
Technical field
The invention belongs to technical field of medicine synthesis, are related to a kind of for synthesizing the key intermediate 1,1- of Montelukast Sodium
The preparation method of cyclopropyl dimethanol.
Background technique
Montelukast Sodium (carboxylic acid sodium salt of montelukast) be it is a kind of it is efficient, safe, less toxic relieving asthma, be anti-inflammatory, antiallergy
Medicine.By United States Merck company development & production, listed for the first time in Finland and Mexico within 1998.The drug is a kind of leukotriene receptor
Antagonist can selectively be combined with the leukotriene receptor in respiratory tract, play the effect for blocking Anaphylactic mediator, and then make to breathe
Road is unimpeded, effective Control of asthma symptom.Therefore, have the function of inhibiting this kind of drug of the anaphylactogen in conjunction with leukotriene receptor by
Gradually become the research and development focus of anti-asthmatic medicament.
1,1- cyclopropyl dimethanol (also known as 1,1- cyclopropyl dimethanol, 1,1- cyclopropane dimethanol, cyclopropane dimethanol etc.)
It is the precursor compound for synthesizing Montelukast side-chain structure, wherein containing cyclopropyl structure, synthesis difficulty is larger, because becoming
The hot spot and difficult point of such pharmaceutical synthesis research.
By literature search it is found that the synthetic method of the compound mainly include the following types:
(1) Zeng Xianwei reports a kind of synthesis technology of cyclopropane dimethanol (referring to Zeng Xianwei, the conjunction of cyclopropane dimethanol
At [J], animal and veterinary scientific and technological information, 2003,6:34).The technique uses ethylene-malonic acid for raw material, under concentrated sulfuric acid catalyst
With ethanol condensed at ethyl ester, then with lithium aluminium hydride reduction at cyclopropane dimethanol.The route raw material higher cost needs in reaction
Using hazardous chemicals such as the concentrated sulfuric acid, lithium aluminium hydride reductions, and severe reaction conditions, route of synthesis is cumbersome, industrialized production risk
Greatly, difficulty is big, should not use；
(2) Zhang Zhenming et al. reports preparation method (Zhang Zhenming, Li Runlai, the Japanese plum of one kind 1,1- cyclopropane dimethanol
Peace etc., a kind of antiasthmatic intermediate 1, the preparation [J] of 1- cyclopropane dimethanol, Speciality Petrochemicals, 2013,30 (5): 37-
40).This method is using pentaerythrite and hydrobromic acid as raw material, using dithyl sulfate-acetic acid as catalyst, is heated to reflux life under normal pressure
Dibromoneopentyl glycol is produced, reduction reaction then occurs with zinc powder in alcohol-water, generates 1,1- cyclopropane dimethanol, yield reaches
80% or so.But this method uses extremely toxic substance dithyl sulfate, and is restored using zinc powder, reduction efficiency it is low and
It is more to generate the three wastes, processing cost is high, unfriendly to environment；
(3) above-mentioned technique is optimized (referring to Zhang Li, Zhang Tongbin, Chen Hongbo etc., in Montelukast Sodium in Zhang Li et al.
Mesosome 1, the synthesis [J] of 1- cyclopropyl dimethanol, fine-chemical intermediate, 2014,44 (4): 48-51), with dibromoneopentyl glycol
For starting material, esterification first occurs with acetic anhydride, obtains new penta diester of oxalic acid dibromo；It is anti-that reduction occurs with zinc powder again
It answers, obtains 1, l- cyclopropyl dimethyl esters, direct hydrolysis obtains 1,1- cyclopropyl dimethanol without isolation, and yield is on 78% left side
It is right.Although reducing process still uses zinc powder as reducing agent the method reduce the use of toxic raw materials, reduction efficiency is low
And the problem of pollution environment, is not avoided effectively；
(4) Qiu Fei reports a kind of method (Qiu Fei, synthesis of 1,1- cyclopropyl dimethanol for synthesizing 1,1- cyclopropyl dimethanol
[J], modern chemical industry, 2009,29 (10): 41-43).This method uses diethyl malonate for raw material, using PEG400 as phase transfer
Catalyst reacts with 1,2- dichloroethanes under potassium carbonate effect, obtains 1,1- ethylene-malonic acid diethylester；Again in tri-chlorination
Under aluminium catalysis, with potassium borohydride reduction, 1,1- cyclopropane dimethanol is obtained, 2 step total recoverys are 55% or so.This method is not only kept away
The use of severe poisonous chemicals is exempted from, raw material is cheap and easy to get, and cost is relatively low, and reaction condition is mild, environmentally friendly.But
Since the activity of catalyst system in reduction step is not high, causes the yield of the step relatively low, affect the total recovery of product.
Summary of the invention
For material toxicity existing for 1,1- cyclopropyl dimethanol preparation method in the prior art big, severe reaction conditions,
The technical problems such as high production cost, environmental friendliness are low, yield is low, the present invention is intended to provide a kind of raw material is cheap, is easy to get, nothing
Poison, reaction condition is mild, controllable, and environmental friendliness is high, 1, the 1- cyclopropyl dimethanol preparation method that product yield significantly improves.
Specifically, the present invention adopts the following technical scheme:
The preparation method of one kind 1,1- cyclopropyl dimethanol comprising following steps:
1) 1,1- cyclopropyl dicarboxylate is prepared using diethyl malonate and 1,2- dichloroethanes:
Diethyl malonate, 1,2- dichloroethanes, catalyst A, solvent A and acid binding agent are added into reaction vessel, is stirring
Reaction system is heated to reflux under the conditions of mixing, until diethyl malonate reacts completely；After reaction, reaction system is cooling
It to room temperature and filters, filter cake is washed with solvent A, after merging filtrate and washing lotion, by air-distillation recycling design A, obtains 1,1-
Cyclopropyl dicarboxylate crude product；Wherein: diethyl malonate: 1,2- dichloroethanes: catalyst A: the molar ratio of acid binding agent
For 1:1.1~1.5:0.05~0.5:2~2.5；Diethyl malonate: the amount ratio of solvent A is 1g:2~10mL；
2) 1,1- cyclopropyl dimethanol is prepared using 1,1- cyclopropyl dicarboxylate:
1,1- cyclopropyl dicarboxylate crude product obtained in step 1) is added into reaction vessel, through Non-aqueous processing
Solvent B and catalyst B is cooled to 0 DEG C under agitation and keeps temperature constant, reducing agent is added portionwise, after charging,
Reaction system is heated to reflux, until 1,1- cyclopropyl dicarboxylate reacts completely；After reaction, reaction system is cold
But to 0 DEG C, add water quenching reaction and continue stirring 2~3 hours, extraction is added and is extracted 2~5 times with organic solvent, merges organic
Phase, it is dry, extraction organic solvent is recycled by vacuum distillation, then by way of vacuum distillation, in the pressure condition of 4mmHg
The lower fraction collected boiling range and be 92~95 DEG C, as 1,1- cyclopropyl dimethanol；Wherein: 1,1- cyclopropyl dicarboxylate:
Catalyst B: the molar ratio of reducing agent is 1:2~6:3~8；1,1- cyclopropyl dicarboxylate: the amount ratio of solvent B is 1g:
2~10mL.
In the above preparation method, catalyst A described in step 1) is metal iodide, and the metal iodide is selected from iodine
Change sodium (NaI), potassium iodide (KI), lithium iodide (LiI), magnesium iodide (MgI2), calcium iodide (CaI2) in any one, preferably NaI
And KI.
In the above preparation method, solvent A described in step 1) is dipolar aprotic solvent, the dipolar aprotic
Solvent is selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), tetrahydrofuran (THF), dimethyl sulfoxide
(DMSO), any one in acetone (Ac), preferably DMF and THF.
In the above preparation method, acid binding agent described in step 1) is selected from potassium carbonate (K2CO3), sodium carbonate (Na2CO3), carbon
Potassium hydrogen phthalate (KHCO3), sodium bicarbonate (NaHCO3), potassium hydroxide (KOH), any one in sodium hydroxide (NaOH), preferably
K2CO3And Na2CO3。
In the above preparation method, solvent B described in step 2) is ether solvent, and the ether solvent is selected from ether
(DEE), propyl ether (DPE), butyl ether (DBE), tetrahydrofuran (THF), oxinane (THP), appointing in 1,4- dioxane (DOA)
It anticipates one kind, preferably THF and THP.
In the above preparation method, catalyst B described in step 2) is lewis acid, and the lewis acid is selected from lithium chloride
(LiCl), zinc chloride (ZnCl2), copper chloride (CuCl2), aluminium chloride (AlCl3), iron chloride (FeCl3) in any one, it is excellent
Select LiCl and AlCl3。
In the above preparation method, reducing agent described in step 2) is metal hydride, and the metal hydride is selected from boron
Hydrofining (KBH4), sodium borohydride (NaBH4), Lithium Aluminium Hydride (LiAlH4) in any one, preferably KBH4And NaBH4。
In the above preparation method, extraction described in step 2) is selected from ethyl acetate (EA), methylene chloride with organic solvent
(DCM), any one in chloroform (TCM), preferably EA.
In a preferred embodiment, diethyl malonate in step 1): 1,2- dichloroethanes: catalyst A: acid is tied up
The molar ratio of agent is 1:1.3:0.1:2.2.
In a preferred embodiment, diethyl malonate in step 1): the amount ratio of solvent A is 1g:5mL.
In a preferred embodiment, 1,1- cyclopropyl dicarboxylate in step 2): catalyst B: reducing agent
Molar ratio be 1:4.4:4.4.
In a preferred embodiment, 1,1- cyclopropyl dicarboxylate in step 2): the amount ratio of solvent B is
1g:4.8mL。
In a preferred embodiment, the water of quenching reaction is used in step 2): the volume ratio of solvent B is 1:1.
Compared with prior art, by adopting the above technical scheme the invention has the following advantages that
(1) raw material used by preparation method of the invention is cheap and easy to get, and severe toxicity class and the dangerous original of tool is not used
Material；
(2) catalyst activity used by preparation method of the invention is high and cheap, and recycled solvent is at low cost；
(3) preparation method reaction condition of the invention is mild, and product is easily isolated, and three industrial wastes are few, environmentally friendly, symbol
Close Green Chemistry requirement；
(4) preparation method of the invention can significantly improve the yield of target product, and 2 step total recoverys may be up to 88%, far
Total recovery higher than in the prior art 55% or so.
Detailed description of the invention
Fig. 1 is target product 1,1- cyclopropyl dimethanol1H-NMR spectrum.
Specific embodiment
Technical solution of the present invention is made below in conjunction with specific embodiment further elucidated above.Unless otherwise saying
Bright, instrument used in the following example, material and reagent etc. can be obtained by routine business means.
The preparation of embodiment 1:1,1- cyclopropyl dimethanol.
Diethyl malonate 40g (249.73mmol), 1,2- bis- are added into the four-hole boiling flask equipped with mechanical stirring device
Chloroethanes 32.14g (324.65mmol), sodium iodide 3.75g (24.97mmol), DMF 200mL and Anhydrous potassium carbonate 75.93g
Reaction system, is heated to reflux by (549.41mmol) under agitation, and GC monitors extent of reaction, is disappeared with diethyl malonate
For reaction end.After reaction, reaction solution is cooled to room temperature and is filtered, filter cake is washed with DMF, after merging filtrate and washing lotion
DMF (recyclable to apply) is evaporated off in normal pressure, obtains 1,1- cyclopropyl dicarboxylate crude product 42g (yield 93%).Crude product without
Processing, which need to be further purified, can be directly used for reacting in next step.
It is thick that 1,1- cyclopropyl dicarboxylate obtained is walked on being added into the four-hole boiling flask equipped with mechanical stirring device
Product 42g (225.56mmol), anhydrous THF 200mL and lithium chloride 42.35g (998.92mmol), pass through ice under agitation
Mixture is cooled to 0 DEG C and keeps temperature constant by salt bath, and potassium borohydride 53.88g (998.92mmol) is added portionwise, has fed
Reaction system is heated to reflux by Bi Hou, and GC monitors extent of reaction, is disappeared with 1,1- cyclopropyl dicarboxylate for reaction eventually
Point.After reaction, reaction solution is cooled to 0 DEG C again by ice salt bath, adds water 200mL quenching reaction and continues to stir 2h,
Ethyl acetate is added to be extracted and (divided 3 times, each 100mL), organic phase is merged, anhydrous sodium sulfate is dry, passes through vacuum distillation
Ethyl acetate (recyclable to apply) is removed, then by way of vacuum distillation, it is 92 that boiling range is collected under the pressure condition of 4mmHg
~95 DEG C of fraction obtains colourless viscous liquid 22.45g, as 1,1- cyclopropyl dimethanol (two step total recoverys 88%).
Boiling point (b.p.): 235~236 DEG C；
Nuclear magnetic resonance spectroscopy (1H-NMR, CDCl3): δ 0.49 (s, 4H ,-CH2-CH2), 3.56 (s, 4H ,-CH2- O-),
4.06 (s, 2H ,-OH).
The preparation of embodiment 2:1,1- cyclopropyl dimethanol.
Diethyl malonate 40g (249.73mmol), 1,2- bis- are added into the four-hole boiling flask equipped with mechanical stirring device
Chloroethanes 27.20g (274.70mmol), potassium iodide 2.07g (12.49mmol), THF 240mL and natrium carbonicum calcinatum 52.94g
Reaction system, is heated to reflux by (499.46mmol) under agitation, and GC monitors extent of reaction, is disappeared with diethyl malonate
For reaction end.After reaction, reaction solution is cooled to room temperature and is filtered, filter cake is washed with THF, after merging filtrate and washing lotion
THF (recyclable to apply) is evaporated off in normal pressure, obtains 1,1- cyclopropyl dicarboxylate crude product 40g (yield 89%).Crude product without
Processing, which need to be further purified, can be directly used for reacting in next step.
It is thick that 1,1- cyclopropyl dicarboxylate obtained is walked on being added into the four-hole boiling flask equipped with mechanical stirring device
Product 40g (214.82mmol), anhydrous THF 240mL and aluminium chloride 57.29g (429.64mmol), pass through ice under agitation
Mixture is cooled to 0 DEG C and keeps temperature constant by salt bath, and sodium borohydride 24.38g (644.46mmol) is added portionwise, has fed
Reaction system is heated to reflux by Bi Hou, and GC monitors extent of reaction, is disappeared with 1,1- cyclopropyl dicarboxylate for reaction eventually
Point.After reaction, reaction solution is cooled to 0 DEG C again by ice salt bath, adds water 240mL quenching reaction and continues to stir 3h,
Chloroform is added to be extracted and (divided 3 times, each 100mL), organic phase is merged, anhydrous sodium sulfate is dry, is removed by vacuum distillation
Chloroform (recyclable to apply), then by way of vacuum distillation, it is 92~95 DEG C that boiling range is collected under the pressure condition of 4mmHg
Fraction obtains colourless viscous liquid 19.85g, as 1,1- cyclopropyl dimethanol (two step total recoverys 77%).To products obtained therefrom into
Row nuclear-magnetism and boiling point test, result and the data in embodiment 1 are almost the same.
The preparation of embodiment 3:1,1- cyclopropyl dimethanol.
Diethyl malonate 40g (249.73mmol), 1,2- bis- are added into the four-hole boiling flask equipped with mechanical stirring device
Chloroethanes 37.08g (374.60mmol), sodium iodide 18.75g (124.87mmol), DMA 300mL and Carbon Dioxide hydrogen potassium
Reaction system, is heated to reflux by 62.50g (624.33mmol) under agitation, and GC monitors extent of reaction, with malonic acid diethyl
It is reaction end that ester, which disappears,.After reaction, reaction solution is cooled to room temperature and is filtered, filter cake is washed with DMA, merging filtrate and
DMA (recyclable apply) is evaporated off in normal pressure after washing lotion, and obtaining 1,1- cyclopropyl dicarboxylate crude product 39.5g, (yield is
87%).Crude product can be directly used for reacting in next step it is not necessary that processing is further purified.
It is thick that 1,1- cyclopropyl dicarboxylate obtained is walked on being added into the four-hole boiling flask equipped with mechanical stirring device
Product 39.5g (212.13mmol), anhydrous THP 300mL and zinc chloride 173.48g (1272.80mmol), lead under agitation
It crosses ice salt bath mixture is cooled to 0 DEG C and keeps temperature constant, potassium borohydride 91.53g (1697.04mmol) is added portionwise,
After charging, reaction system is heated to reflux, GC monitors extent of reaction, is anti-with the disappearance of 1,1- cyclopropyl dicarboxylate
Answer terminal.After reaction, reaction solution is cooled to 0 DEG C again by ice salt bath, adds water 300mL quenching reaction and continues to stir
3h is added methylene chloride and is extracted and (divided 3 times, each 100mL), merges organic phase, and anhydrous sodium sulfate is dry, is steamed by decompression
Methylene chloride (recyclable to apply) is gone in distillation, then by way of vacuum distillation, collects boiling range under the pressure condition of 4mmHg and is
92~95 DEG C of fraction obtains colourless viscous liquid 20.32g, as 1,1- cyclopropyl dimethanol (two step total recoverys 80%).It is right
Products obtained therefrom carries out nuclear-magnetism and boiling point test, and result and the data in embodiment 1 are almost the same.
The preparation of embodiment 4:1,1- cyclopropyl dimethanol.
Diethyl malonate 40g (249.73mmol), 1,2- bis- are added into the four-hole boiling flask equipped with mechanical stirring device
Chloroethanes 32.14g (324.65mmol), potassium iodide 4.14g (24.97mmol), DMF 200mL and Anhydrous potassium carbonate 75.93g
Reaction system, is heated to reflux by (549.41mmol) under agitation, and GC monitors extent of reaction, is disappeared with diethyl malonate
For reaction end.After reaction, reaction solution is cooled to room temperature and is filtered, filter cake is washed with DMF, after merging filtrate and washing lotion
DMF (recyclable to apply) is evaporated off in normal pressure, obtains 1,1- cyclopropyl dicarboxylate crude product 41g (yield 91%).Crude product without
Processing, which need to be further purified, can be directly used for reacting in next step.
It is thick that 1,1- cyclopropyl dicarboxylate obtained is walked on being added into the four-hole boiling flask equipped with mechanical stirring device
Product 41g (220.19mmol), anhydrous THF 200mL and lithium chloride 42.35g (998.92mmol), pass through ice under agitation
Mixture is cooled to 0 DEG C and keeps temperature constant by salt bath, and potassium borohydride 53.88g (998.92mmol) is added portionwise, has fed
Reaction system is heated to reflux by Bi Hou, and GC monitors extent of reaction, is disappeared with 1,1- cyclopropyl dicarboxylate for reaction eventually
Point.After reaction, reaction solution is cooled to 0 DEG C again by ice salt bath, adds water 200mL quenching reaction and continues to stir 3h,
Ethyl acetate is added to be extracted and (divided 3 times, each 100mL), organic phase is merged, anhydrous sodium sulfate is dry, passes through vacuum distillation
Ethyl acetate (recyclable to apply) is removed, then by way of vacuum distillation, it is 92 that boiling range is collected under the pressure condition of 4mmHg
~95 DEG C of fraction obtains colourless viscous liquid 21.87g, as 1,1- cyclopropyl dimethanol (two step total recoverys 86%).To institute
It obtains product and carries out nuclear-magnetism and boiling point test, result and the data in embodiment 1 are almost the same.
The preparation of embodiment 5:1,1- cyclopropyl dimethanol.
Diethyl malonate 40g (249.73mmol), 1,2- bis- are added into the four-hole boiling flask equipped with mechanical stirring device
Chloroethanes 32.14g (324.65mmol), sodium iodide 3.75g (24.97mmol), THF 200mL and natrium carbonicum calcinatum 58.23g
Reaction system, is heated to reflux by (549.41mmol) under agitation, and GC monitors extent of reaction, is disappeared with diethyl malonate
For reaction end.After reaction, reaction solution is cooled to room temperature and is filtered, filter cake is washed with THF, after merging filtrate and washing lotion
THF (recyclable to apply) is evaporated off in normal pressure, obtains 1,1- cyclopropyl dicarboxylate crude product 40.5g (yield 90%).Crude product
It can be directly used for reacting in next step it is not necessary that processing is further purified.
It is thick that 1,1- cyclopropyl dicarboxylate obtained is walked on being added into the four-hole boiling flask equipped with mechanical stirring device
Product 42g (225.56mmol), anhydrous THF 200mL and aluminium chloride 133.20g (998.92mmol), pass through ice under agitation
Mixture is cooled to 0 DEG C and keeps temperature constant by salt bath, and sodium borohydride 37.79g (998.92mmol) is added portionwise, has fed
Reaction system is heated to reflux by Bi Hou, and GC monitors extent of reaction, is disappeared with 1,1- cyclopropyl dicarboxylate for reaction eventually
Point.After reaction, reaction solution is cooled to 0 DEG C again by ice salt bath, adds water 200mL quenching reaction and continues to stir 2h,
Ethyl acetate is added to be extracted and (divided 3 times, each 100mL), organic phase is merged, anhydrous sodium sulfate is dry, passes through vacuum distillation
Ethyl acetate (recyclable to apply) is removed again by way of vacuum distillation, it is 92 that boiling range is collected under the pressure condition of 4mmHg
~95 DEG C of fraction obtains colourless viscous liquid 21.07g, as 1,1- cyclopropyl dimethanol (two step total recoverys 83%).To institute
It obtains product and carries out nuclear-magnetism and boiling point test, result and the data in embodiment 1 are almost the same.
Above-described embodiment is only used for explanation and illustration specific embodiments of the present invention, and is not intended to limit of the invention
Protection scope.It should be understood that anyone skilled in the art presently disclosed technical scope it
The modifications or substitutions inside made should be covered by the protection scope of the present invention.
Claims (10)
1. one kind 1, the preparation method of 1- cyclopropyl dimethanol comprising following steps:
1) 1,1- cyclopropyl dicarboxylate is prepared using diethyl malonate and 1,2- dichloroethanes:
Diethyl malonate, 1,2- dichloroethanes, catalyst A, solvent A and acid binding agent are added into reaction vessel, in stirring bar
Reaction system is heated to reflux under part, until diethyl malonate reacts completely；After reaction, reaction system is cooled to room
Temperature simultaneously filters, and filter cake is washed with solvent A, after merging filtrate and washing lotion, by air-distillation recycling design A, obtains 1,1- cyclopropyl
Base dicarboxylate crude product；
Wherein:
Diethyl malonate: 1,2- dichloroethanes: catalyst A: the molar ratio of acid binding agent is 1:1.1~1.5:0.05~0.5:2
~2.5；
Diethyl malonate: the amount ratio of solvent A is 1g:2~10mL；
Any one of catalyst A in sodium iodide, potassium iodide, lithium iodide, magnesium iodide, calcium iodide；
Solvent A appointing in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, tetrahydrofuran, dimethyl sulfoxide, acetone
It anticipates one kind；
Any one of acid binding agent in potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, sodium hydroxide；
2) 1,1- cyclopropyl dimethanol is prepared using 1,1- cyclopropyl dicarboxylate:
1,1- cyclopropyl dicarboxylate crude product, the solvent through Non-aqueous processing obtained in step 1) are added into reaction vessel
B and catalyst B is cooled to 0 DEG C under agitation and keeps temperature constant, reducing agent is added portionwise, will be anti-after charging
System is answered to be heated to reflux, until 1,1- cyclopropyl dicarboxylate reacts completely；After reaction, reaction system is cooled to
0 DEG C, add water quenching reaction and continue stirring 2~3 hours, extraction is added and is extracted 2~5 times with organic solvent, merges organic phase, does
It is dry, extraction organic solvent is recycled by vacuum distillation, then by way of vacuum distillation, receive under the pressure condition of 4mmHg
Collect the fraction that boiling range is 92~95 DEG C, as 1,1- cyclopropyl dimethanol；
Wherein:
1,1- cyclopropyl dicarboxylate: catalyst B: the molar ratio of reducing agent is 1:2~6:3~8；
1,1- cyclopropyl dicarboxylate: the amount ratio of solvent B is 1g:2~10mL；
Any one of solvent B in ether, propyl ether, butyl ether, tetrahydrofuran, oxinane, 1,4- dioxane；
Any one of catalyst B in lithium chloride, zinc chloride, copper chloride, aluminium chloride, iron chloride；
Any one of reducing agent in potassium borohydride, sodium borohydride, Lithium Aluminium Hydride.
2. preparation method according to claim 1, it is characterised in that:
Catalyst A described in step 1) is sodium iodide or potassium iodide.
3. preparation method according to claim 1, it is characterised in that:
Solvent A described in step 1) is N,N-dimethylformamide or tetrahydrofuran.
4. preparation method according to claim 1, it is characterised in that:
Acid binding agent described in step 1) is potassium carbonate or sodium carbonate.
5. preparation method according to claim 1, it is characterised in that:
Solvent B described in step 2) is tetrahydrofuran or oxinane.
6. preparation method according to claim 1, it is characterised in that:
Catalyst B described in step 2) is lithium chloride or aluminium chloride.
7. preparation method according to claim 1, it is characterised in that:
Reducing agent described in step 2) is potassium borohydride or sodium borohydride.
8. preparation method according to claim 1, it is characterised in that:
Any one of extraction organic solvent described in step 2) in ethyl acetate, methylene chloride, chloroform.
9. preparation method according to claim 1, it is characterised in that:
Diethyl malonate in step 1): 1,2- dichloroethanes: catalyst A: the molar ratio of acid binding agent is 1:1.3:0.1:2.2；
Diethyl malonate in step 1): the amount ratio of solvent A is 1g:5mL.
10. preparation method according to claim 1, it is characterised in that:
1,1- cyclopropyl dicarboxylate in step 2): catalyst B: the molar ratio of reducing agent is 1:4.4:4.4；
1,1- cyclopropyl dicarboxylate in step 2): the amount ratio of solvent B is 1g:4.8mL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611076798.3A CN106588568B (en) | 2016-11-30 | 2016-11-30 | A kind of preparation method of 1,1- cyclopropyl dimethanol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611076798.3A CN106588568B (en) | 2016-11-30 | 2016-11-30 | A kind of preparation method of 1,1- cyclopropyl dimethanol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106588568A CN106588568A (en) | 2017-04-26 |
| CN106588568B true CN106588568B (en) | 2019-04-26 |
Family
ID=58594297
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611076798.3A Active CN106588568B (en) | 2016-11-30 | 2016-11-30 | A kind of preparation method of 1,1- cyclopropyl dimethanol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106588568B (en) |
-
2016
- 2016-11-30 CN CN201611076798.3A patent/CN106588568B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| 1,1-环丙二甲醇的合成;邱飞;《现代化工》;20091031;第29卷(第10期);第41-43页 |
| 芳香醚合成中碘化钾催化剂的应用;缪程平等;《嘉兴学院学报》;20060530;第18卷(第3期);第36-39页 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106588568A (en) | 2017-04-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106242971B (en) | A kind of chloracetate synthesis in water technology and its new method for preparing 2,4-D ester | |
| CN107522743A (en) | A kind of half fumaric acid tenofovir Chinese mugwort draws phenol amine industrial continuous producing method | |
| CN103254201B (en) | A kind of preparation method of asenapine | |
| CN109293488A (en) | A kind of preparation method of 5-chloro-1-indanone | |
| JP2004123687A (en) | Perfluoroadamantyl acrylic acid ester and its intermediate | |
| CN102952039A (en) | Synthesis method of 4-chloro-2-trifluoromethylbenzonitrile | |
| CN101671242B (en) | Method for synthesizing trans-4-(trans-4'-alkyl cyclohexyl) cyclohexanal | |
| CN106588568B (en) | A kind of preparation method of 1,1- cyclopropyl dimethanol | |
| EP2471766B1 (en) | Process for producing 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol | |
| CN102249921A (en) | 2-(2,3-dimethyl phenyl) diester malonate, preparation method thereof, and application thereof | |
| CN102408317B (en) | Preparation method of hexafluoroisopropyl methyl ether | |
| CN110234622A (en) | For synthesizing the novel method of 1- aryl -1- trifluoromethyl cyclopropane | |
| CN107641067B (en) | Alpha-bromination method of o-diketone | |
| CN101851225A (en) | Method for synthesizing fludioxonil intermediate 4-aldehyde-2,2-difluorobenzodioxole | |
| CN103073391A (en) | Novel synthesis process for 4-phenyl-1-butanol | |
| CN106831863B (en) | Montelukast sodium intermediate and its preparation method and application | |
| CN109053679A (en) | Wear the preparation method of this Martin's oxidant | |
| CN101935326B (en) | Alkoxy aluminum preparation method | |
| CN102964233A (en) | Synthetic method of 3,5-2-fluoro-(trifluoromethyl)benzophenone | |
| CN105753765A (en) | Preparation method of ziprasidone intermediate | |
| CN111454315A (en) | Synthesis method of androst-16-ene-3 β -ol | |
| CN107721954A (en) | The novel preparation method of the benzofuranacetic acid of 2,3 dihydro of darifenacin intermediate 5 | |
| CN111393287A (en) | Novel process for synthesizing hexafluoroacetone | |
| JP7439604B2 (en) | Method for purifying lactone compounds | |
| CN113980686B (en) | Preparation method of lateral o-difluorobenzene liquid crystal compound containing cyclohexyl |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |