CN108314665A - A kind of preparation method of 3- oxetanes formic acid - Google Patents
A kind of preparation method of 3- oxetanes formic acid Download PDFInfo
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- CN108314665A CN108314665A CN201810322077.9A CN201810322077A CN108314665A CN 108314665 A CN108314665 A CN 108314665A CN 201810322077 A CN201810322077 A CN 201810322077A CN 108314665 A CN108314665 A CN 108314665A
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- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D305/08—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring atoms
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Abstract
The present invention provides a kind of preparation methods of 3 oxetanes formic acid,The preparation method is using 3 hydroxypropionitriles as raw material,By hydrolyzing esterification,It pulls out hydrogen reaction and reduction reaction obtains 2 benzyloxymethyls 1,3 propylene glycol,Then by 2 benzyloxymethyls 1,3 propylene glycol pass through ring-closure reaction,Debenzylation and oxidation reaction obtain the 3 oxetanes formic acid,Preparation method provided by the present invention,Using 3 hydroxypropionitriles as raw material, it is only necessary to the reactions of 3 steps, and 2 benzyloxymethyl 1 of key intermediate can be prepared,3 propylene glycol,Only need the reaction of 6 steps that 3 oxetanes formic acid can be prepared on final entirety route,Substantially reduce reaction route,Reduce reaction step,Compared to the preparation method for needing 10 steps to react in existing method,Yield higher,And it is easily operated,It is advantageously implemented industrialized production.
Description
Technical field
The invention belongs to medicine intermediates to synthesize field, be related to a kind of preparation method of 3- oxetanes formic acid.
Background technology
3- oxetanes formic acid is a kind of important centre, can apply the side chain as spiro-compound, Jin Ergai
The structure for becoming spiro-compound expands the new property of compound, therefore has relatively broad application, but preparation method is several
Do not report.
US2008/0021032 A1 disclose pyrazoles glucokinase agonist, and wherein 3- oxetanes formic acid can be made
For a side chain of pyrazoles glucokinase agonist, the function and effect of agonist, disclosed 3- oxetanes can be improved
The synthetic method of formic acid is prepared, specific reaction equation is as follows mainly using diester malonate as raw material by the reaction of ten steps：
But reaction step is longer in this route, has reached the reaction of ten steps, has caused overall yield of reaction low, and key step
It is rapid to need to carry out column chromatography purifying, it is unfavorable for industrial amplification, therefore limit the application of this route.
Therefore, it need further to study about the synthetic method of 3- oxetanes formic acid at present, needs exploitation a kind of
Synthesis step is simple, easy to operate, high income, is conducive to method prepared by large-scale production, this is for 3- oxetanes first
The application of acid has important meaning.
Invention content
The purpose of the present invention is to provide a kind of preparation methods of 3- oxetanes formic acid.
For this purpose, the present invention uses following technical scheme：
The present invention provides a kind of preparation method of 3- oxetanes formic acid, the preparation method is with 3- hydroxypropionitriles
Raw material, through hydrolysis esterification, pull out hydrogen reaction and reduction reaction obtain 2- benzyloxymethyls -1,3-PD, then will
2- benzyloxymethyl -1,3- propylene glycol obtains the 3- oxetanes by ring-closure reaction, debenzylation and oxidation reaction
Formic acid.
3- oxetanes formic acid preparation method provided by the invention, using 3- hydroxypropionitriles as raw material, it is only necessary to 3 steps are anti-
Key intermediate 2- benzyloxymethyls -1,3-PD should can be prepared, only need 6 steps to react on final entirety route
3- oxetanes formic acid can be prepared, substantially reduce reaction route, reduce reaction step, compared to existing side
The preparation method for needing 10 steps to react in method, yield higher, and it is easily operated, it is advantageously implemented industrialized production.
Preferably, the hydrolysis esterification is 3- hydroxypropionitriles and ethyl alcohol, in acid condition, anti-under catalyst
It should obtain 3- hydroxypropionates.
Preferably, relative to the 3- hydroxypropionitriles of 1g, the dosage of the ethyl alcohol is 3.5-5mL, for example, can be 3.5mL,
3.6mL, 3.8mL, 4mL, 4.3mL, 4.5mL, 4.8mL or 5mL.
Preferably, the catalyst is thionyl chloride.
In the present invention, it is carried out by thionyl chloride catalysis esterification, it is better compared to other catalytic reagents,
Ultimate yield can reach 50%.
Preferably, relative to the 3- hydroxypropionitriles of 250g, the dosage of the thionyl chloride is 130-150mL, such as can be with
It is 130mL, 135mL, 138mL, 140mL, 142mL, 145mL, 148mL or 150mL.
Preferably, the acid condition is provided by hydrochloric acid or sulfuric acid.
In the present invention, acid condition so that the cyan-hydrolysis in 3- hydroxypropionitriles, specific dosage can be according to the realities of reaction
Border needs suitably to be adjusted.
Preferably, the temperature of the hydrolysis esterification is 60-80 DEG C, for example, can be 60 DEG C, 62 DEG C, 65 DEG C, 70 DEG C,
75 DEG C, 78 DEG C or 80 DEG C.
Preferably, the time of the hydrolysis esterification is 5-8h, such as can be 5h, 5.5h, 6h, 6.5h, 7h, 7.5h
Or 8h.
It is preferably, described that pull out hydrogen reaction be that 3- hydroxyl -2- benzyls are obtained by the reaction in 3- hydroxypropionates and chloromethyl benzyl ether
Oxygroup methylpropanoate.
Preferably, it is described pull out hydrogen reaction carried out in the presence of lithium diisopropylamine (LDA).
In the present invention, it refers to being sloughed hydrogen atom using organic alkali to pull out hydrogen reaction, is connect in the position reaction of hydrogen atom
Upper corresponding functional group, has connected functional group's benzyloxymethyl in reaction in the present invention.
Preferably, the molar ratio of the 3- hydroxypropionates and chloromethyl benzyl ether, lithium diisopropylamine is 1:(2-
3):(2-3), such as can be 1:2:2、1:2.2:2.3、1:2.5:2.4、1:2.6:2.7 or 1:3:3.
Preferably, the solvent for pulling out hydrogen reaction is tetrahydrofuran or ether.
Preferably, it is described pull out hydrogen reaction protective gas protection under carry out.
Preferably, the protective gas include in nitrogen, helium or argon gas any one or at least two combination,
Preferably nitrogen.
Preferably, the temperature for pulling out hydrogen reaction is -80 DEG C to -30 DEG C, for example, can be -80 DEG C, -78 DEG C, -75 DEG C, -
60 DEG C, -50 DEG C, -40 DEG C, -35 DEG C or -30 DEG C.
In the present invention, 3- hydroxypropionates are added drop-wise in the tetrahydrofuran solution of LDA at -78 DEG C or so first,
Reaction 1h or so is carried out, then chloromethyl benzyl ether is added dropwise, -40 DEG C or so is then warming up to and is reacted.
Preferably, the time for pulling out hydrogen reaction is 4-5h, such as can be 4h, 4.2h, 4.5h, 4.6h, 4.8h or 5h.
Preferably, the reduction reaction is obtained by the reaction for 3- hydroxyls -2- benzyloxymethyls ethyl propionate with reducing agent described
2- benzyloxymethyl -1,3- propylene glycol.
Preferably, the reducing agent is sodium borohydride or Lithium Aluminium Hydride.
Preferably, the molar ratio of the 3- hydroxyls -2- benzyloxymethyls ethyl propionate and reducing agent is 1:3-5, such as can
To be 1:3、1:3.2、1:3.5、1:3.8、1:4、1:4.5、1:4.8 or 1:5.
Preferably, the solvent of the reduction reaction is any one in methanol, ethyl alcohol or isopropanol or at least two
Combination.
Preferably, the temperature of the reduction reaction is 0-30 DEG C, for example, can be 0 DEG C, 10 DEG C, 12 DEG C, 15 DEG C, 20 DEG C,
25 DEG C, 28 DEG C, 29 DEG C or 30 DEG C.
Preferably, the time of the reduction reaction be 2-5h, such as can be 2h, 2.3h, 2.5h, 2.8h, 3h, 3.5h,
4h, 4.2h, 4.5h or 5h.
Preferably, the ring-closure reaction is that 2- benzyloxymethyls -1,3-PD is obtained by the reaction with methane sulfonyl chloride, sodium hydrogen
3- benzyloxymethyl oxetanes.
Preferably, the molar ratio that 2- benzyloxymethyls -1,3-PD is reacted with methane sulfonyl chloride, sodium hydrogen is 1:(0.95-
1.5):(2-2.5), such as can be 1:0.95:2、1:1:2.1、1:1.2:2.2、1:1.4:2.4 or 1:1.5:2.5.
In the present invention, in ring-closure reaction, paratoluensulfonyl chloride, benzene sulfonyl chloride, p-nitrophenyl sulphonyl can also be used
Chlorine, m-nitrobenzene sulfonyl chloride, ortho-nitrophenyl sulfonic acid chloride etc. substance substitute methane sulfonyl chloride；Use potassium hydrogen, butyl lithium, the tert-butyl alcohol
Potassium, sodium tert-butoxide etc. substitute sodium hydrogen.
Preferably, the solvent of the ring-closure reaction is n,N-Dimethylformamide.
Preferably, the temperature of the ring-closure reaction is 0-30 DEG C, for example, can be 0 DEG C, 10 DEG C, 12 DEG C, 15 DEG C, 20 DEG C,
25 DEG C, 28 DEG C, 29 DEG C or 30 DEG C.
Preferably, the time of the ring-closure reaction be 2-5h, such as can be 2h, 2.3h, 2.5h, 2.8h, 3h, 3.5h,
4h, 4.2h, 4.5h or 5h.
Preferably, the debenzylation is to restore to obtain by 3- benzyloxymethyl oxetanes using palladium-carbon catalyst
3- oxetane methanols.
Preferably, relative to the 3- benzyloxymethyl oxetanes of 1mol, the dosage of palladium-carbon catalyst is 30-50g, example
Such as can be 30g, 40g, 42g, 44g, 45g, 46g, 47g, 48g, 49g or 50g.
Preferably, the solvent of the debenzylation is methanol and/or ethyl alcohol.
Preferably, the temperature of the debenzylation is 20-40 DEG C, for example, can be 20 DEG C, 22 DEG C, 25 DEG C, 26 DEG C, 28
DEG C, 30 DEG C, 35 DEG C, 38 DEG C or 40 DEG C.
Preferably, the time of the debenzylation be 10-20h, such as can be 10h, 11h, 12h, 13h, 14h,
15h, 16h, 17h, 18h, 19h or 20h.
Preferably, the oxidation reaction is 3- oxetane methanols and wears this Martin's oxidant reaction and obtain the 3- oxygen
Azetidine formic acid.
In the present invention, it wears this Martin's oxidant and carries out oxidation so that reacting milder, reaction speed is moderate, and dosage is few,
Post-processing is simple.
Preferably, the 3- oxetane methanols are 1 with the molar ratio for wearing this Martin's oxidant:1.5-3, such as can be with
It is 1:1.5、1:2、1:2.1、1:2.3、2:2.5、1:2.7、1:2.9 or 1:3.
Preferably, the solvent of the oxidation reaction includes any one in dichloromethane, chloroform or carbon tetrachloride
Or at least two combination.
Preferably, the temperature of the oxidation reaction is 20-40 DEG C, for example, can be 20 DEG C, 22 DEG C, 25 DEG C, 26 DEG C, 28
DEG C, 30 DEG C, 35 DEG C, 38 DEG C or 40 DEG C.
Preferably, the time of the oxidation reaction be 1-3h, such as can be 1h, 1.2h, 1.5h, 1.7h, 1.9h,
2.1h, 2.5h, 2.8h, 2.9h or 3h.
3- oxetanes formic acid preparation method provided by the invention specifically includes following steps：
(1) 3- hydroxypropionitriles and ethyl alcohol under acid condition, are hydrolyzed under thionyl chloride catalysis at 60-80 DEG C
Esterification 5-8h3- hydroxypropionates；
(2) it is 1 by molar ratio:(2-3):3- hydroxypropionates, chloromethyl benzyl ether and the diisopropylaminoethyl of (2-3)
Lithium pull out hydrogen reaction 4-5h and obtains 3- hydroxyl -2- benzyloxies under protective gas protection at being -80 DEG C to -30 DEG C in temperature
Ylmethyl ethyl propionate；
(3) it is 1 by molar ratio:3- hydroxyls -2- benzyloxymethyls the ethyl propionate of 3-5 is gone back with reducing agent at 0-30 DEG C
Original reaction 2-5h obtains 2- benzyloxymethyl -1,3- propylene glycol；
(4) it is 1 by molar ratio:(0.95-1.5):2- benzyloxymethyl -1,3- the propylene glycol of (2-2.5), methane sulfonyl chloride
Ring-closure reaction 2-5h, which is carried out, at being 0-30 DEG C in temperature with sodium hydrogen obtains 3- benzyloxymethyl oxetanes；
(5) 3- benzyloxymethyl oxetanes palladium-carbon catalysts are subjected to debenzylation 10-20h at 20-40 DEG C
Obtain 3- oxetane methanols；
(6) it is 1 by molar ratio:The 3- oxetane methanols of 1.5-3 are carried out with this Martin's oxidant is worn at 20-40 DEG C
Oxidation reaction 1-3h obtains 3- oxetanes formic acid.
3- oxetanes formic acid preparation method provided by the invention, specific reaction route are as follows：
Compared with the existing technology, the invention has the advantages that：
3- oxetanes formic acid preparation method provided by the invention, using 3- hydroxypropionitriles as raw material, it is only necessary to 3 steps are anti-
Key intermediate 2- benzyloxymethyls -1,3-PD should can be prepared, only need 6 steps to react on final entirety route
3- oxetanes formic acid can be prepared, substantially reduce reaction route, reduce reaction step, compared to existing side
The preparation method for needing 10 steps to react in method, yield higher, and easily operated are advantageously implemented industrialized production, have compared with
High market value.
Specific implementation mode
The technical solution further illustrated the present invention below by specific implementation mode.Those skilled in the art should be bright
, the embodiment, which is only to aid in, understands the present invention, should not be regarded as a specific limitation of the invention.
Embodiment 1
The present embodiment prepares 3- oxetanes formic acid by following steps
(1) 3- hydroxypropionates are prepared by 3- hydroxypropionitriles, specific reaction equation is as follows：
Ethyl alcohol (1L) is put into three-necked bottle, and stirring is cooled to 0 DEG C, concentrated hydrochloric acid (80mL) is slowly added dropwise.Chlorination is slowly added dropwise again
Sulfoxide (132mL), system is slowly increased to room temperature.3- hydroxypropionitriles (250g) are slowly added dropwise, drips off system and flows back 6 hours, occur
A large amount of white powders.System is cooled to 0 DEG C, and it is 7 or so to adjust pH with solid sodium carbonate.Filtering, filtrate concentration, distillation obtain 3- hydroxyls
Base ethyl propionate 208g, yield 50%.
1H NMR(300MHz,CDCl3) δ 4.20 (dd, 2H) 3.84 (t, J=6.1Hz, 2H)；2.76(brs,1H,OH)；
2.55 (td, J=5.8,1.6Hz, 2H), 1.25 (t, 3H).
(2) 3- hydroxyl -2- benzyloxymethyl ethyl propionates are prepared by 3- hydroxypropionates, specific reaction equation is as follows：
The LDA tetrahydrofuran solutions (3mol, 1.5L) of 2M are put into 5L eggplant-shape bottles, and the protection of nitrogen part is cooled to -78 DEG C,
The product (150g, 1.44mol) that a dropping step (1) obtains.It drips off system continuation to be stirred to react at -78 DEG C 1 hour, continues to drip
Chlorination methylbenzyl ether (454g, 3mol), reaction mixture is warming up to -40 DEG C, and stirs 4 hours at this temperature.It submits
Saturated ammonium chloride (2L) is quenched.Ethyl acetate is extracted twice, and is merged, dry, and concentration obtains pale yellow oil 130g.It will production
Object direct plunges into reaction in next step.
(3) 2- benzyloxymethyls -1,3-PD is prepared by 3- hydroxyl -2- benzyloxymethyl ethyl propionates, it is specific to react
Formula is as follows：
The pale yellow oil (110g) that step (2) obtains is dissolved in methanol (600mL), is stirred, ice bath, it is a to add
Enter sodium borohydride (55g, 1.47mol), add, system is to slowly warm up to room temperature, and is stirred at room temperature 3 hours.Saturation is added dropwise
Sodium bicarbonate (400mL) is quenched, and continues stirring 1 hour, and system concentration, ethyl acetate extracts 3 times, merges organic phase, dry,
Concentration, with ethyl acetate and petroleum ether 1:1 recrystallization, obtains white crystalline body 82g, yield 85%.
1H NMR(CDCl3,400MHz):δ 7.38-7.26 (m, 5H), 4.50 (s, 2H), 3.97 (dd, 2H), 3.77 (d,
4H),3.60(d,2H),2.74(s,2H),2.05-2.00(m,1H)。
(4) 3- benzyloxymethyl oxetanes is prepared by 2- benzyloxymethyls -1,3-PD, specific reaction equation is such as
Under：
The white powder (75g, 0.38mol) that step (3) obtains is dissolved in n,N-Dimethylformamide (1L), ice bath, nitrogen
Gas part is protected, a that sodium hydrogen (in the mineral oil of 15.2g, 0.38mol, 60%) is added, and stirs 1 hour, methane sulphur is added dropwise
Acyl chlorides (43g, 0.375mol), system are warmed to room temperature and continue stirring 2 hours.Then system is cooled to 0 DEG C, and another part portion adds
Enter sodium hydrogen (15.2g, 0.38mol), system is to slowly warm up to room temperature again, and continues stirring 3 hours.The meaning of 1M is added dropwise in ice bath
Think to adjust pH to neutrality, 2L water is added, ethyl acetate 300mL is extracted 5 times, merges organic phase, is washed 3 times, dry concentration, remaining
Object is dissolved in methanol 500mL, and 100mL is added into methanol phase, stirs 20 minutes, and layering, then lower layer continuously adds 100mL oil
Ether is again stirring for 20min, layering, lower layer's concentration, ethyl acetate and petroleum ether 1:10 crystallizations.Obtain white solid 53g, yield
78%.
1H NMR(400MHz,CDCl3) δ 7.39-7.26 (m, 5H), 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-
4.41 (m, 2H), 3.72 (d, 2H), 3.33-3.20 (m, 1H).
(5) 3- oxetane methanols are prepared by 3- benzyloxymethyl oxetanes, specific reaction equation is as follows：
The white solid (50g, 0.28mol) that step (4) obtains is dissolved in methanol (300mL), is separately added into formic acid
(30mL), 10%Pd-C (10g), system are stirred at room temperature 15 hours, filter, and concentration obtains white solid 23.4g, yield 95%.
1H NMR(400MHz,CDCl3) δ 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-4.43 (m, 2H), 3.91
(d,2H),3.24-3.20(m,1H),1.56(brs,1H)。
(6) 3- oxetanes formic acid is prepared by 3- oxetane methanols, specific reaction equation is as follows：
The object (20g, 0.23mol) that step (5) obtains is dissolved in dichloromethane (2L), ice bath, is stirred, Yi Fenyi
Part is added and wears this Martin's oxidant (195g, 0.46mol).System warms naturally to room temperature, continues stirring 2 hours.It is added dropwise 10%
2L water, layering is added in sodium thiosulfate (200mL), and the extraction of water phase dichloromethane merges organic phase, washes three times, saturated common salt
Washing, dry, concentration, residue is dissolved in 50mL petroleum ethers, ice bath, and 1mL ethyl acetate, mistake after half an hour is added dropwise under stirring
Filter, obtains 19g white powders, yield 81%.
1H NMR(400MHz,CDCl3)δ10.82(s,1H),4.92(dd,2H),4.88(dd,2H),3.90(ddd,1H)。
Embodiment 2
The present embodiment prepares 3- oxetanes formic acid by following steps
(1) 3- hydroxypropionates are prepared by 3- hydroxypropionitriles, specific reaction equation is as follows：
Ethyl alcohol (875mL) is put into three-necked bottle, and stirring is cooled to 0 DEG C, concentrated hydrochloric acid (80mL) is slowly added dropwise.It is slowly added dropwise again
Thionyl chloride (130mL), system is slowly increased to room temperature.3- hydroxypropionitriles (250g) are slowly added dropwise, drips off system and flows back 5 hours,
There are a large amount of white powders.System is cooled to 0 DEG C, and it is 7 or so to adjust pH with solid sodium carbonate.Filtering, filtrate concentration, distillation obtain
3- hydroxypropionate 200g, yield 48.1%.
1H NMR(300MHz,CDCl3) δ 4.20 (dd, 2H) 3.84 (t, J=6.1Hz, 2H)；2.76(brs,1H,OH)；
2.55 (td, J=5.8,1.6Hz, 2H), 1.25 (t, 3H).
(2) 3- hydroxyl -2- benzyloxymethyl ethyl propionates are prepared by 3- hydroxypropionates, specific reaction equation is as follows：
The LDA tetrahydrofuran solutions (2.88mol, 1.5L) of 2M are put into 5L eggplant-shape bottles, and the protection of nitrogen part is cooled to -78
DEG C, the product (150g, 1.44mol) that a dropping step (1) obtains.System continuation is dripped off to be stirred to react at -78 DEG C 1 hour, after
Continuous that chloromethyl benzyl ether (2.88mol) is added dropwise, reaction mixture is warming up to -40 DEG C, and stirs 4 hours at this temperature.It passs
Saturated ammonium chloride (2L) is handed over to be quenched.Ethyl acetate is extracted twice, and is merged, dry, and concentration obtains pale yellow oil 130g.It will
Product direct plunges into reaction in next step.
(3) 2- benzyloxymethyls -1,3-PD is prepared by 3- hydroxyl -2- benzyloxymethyl ethyl propionates, it is specific to react
Formula is as follows：
The pale yellow oil (110g) that step (2) obtains is dissolved in methanol (600mL), is stirred, ice bath, it is a to add
Enter sodium borohydride (1.38mol), add, system is to slowly warm up to room temperature, and is stirred at room temperature 2 hours.Unsaturated carbonate is added dropwise
Hydrogen sodium (400mL) is quenched, and continues stirring 1 hour, and system concentration, ethyl acetate extracts 3 times, merges organic phase, dry, dense
Contracting, with ethyl acetate and petroleum ether 1:1 recrystallization, obtains white crystalline body 80g, yield 82.9%.
1H NMR(CDCl3,400MHz):δ 7.38-7.26 (m, 5H), 4.50 (s, 2H), 3.97 (dd, 2H), 3.77 (d,
4H),3.60(d,2H),2.74(s,2H),2.05-2.00(m,1H)。
(4) 3- benzyloxymethyl oxetanes is prepared by 2- benzyloxymethyls -1,3-PD, specific reaction equation is such as
Under：
The white powder (75g, 0.38mol) that step (3) obtains is dissolved in n,N-Dimethylformamide (1L), ice bath, nitrogen
Gas part is protected, a a that sodium hydrogen (0.475mol, 60% mineral oil in) is added, and stirs 1 hour, methane sulfonyl chloride is added dropwise
(0.361mol), system are warmed to room temperature and continue stirring 2 hours.Then system is cooled to 0 DEG C, and sodium hydrogen is added in another part portion
(0.475mol), system are to slowly warm up to room temperature again, and continue stirring 3 hours.Ice bath, the meaning that 1M is added dropwise adjust pH into
Property, 2L water is added, ethyl acetate 300mL is extracted 5 times, merges organic phase, is washed 3 times, dry concentration, and residue is dissolved in methanol
100mL is added into methanol phase by 500mL, stirs 20 minutes, and layering, then lower layer continuously adds 100mL petroleum ethers, stirs again
20min is mixed, is layered, lower layer concentrates, ethyl acetate and petroleum ether 1:10 crystallizations.Obtain white solid 51g, yield 75%.
1H NMR(400MHz,CDCl3) δ 7.39-7.26 (m, 5H), 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-
4.41 (m, 2H), 3.72 (d, 2H), 3.33-3.20 (m, 1H).
(5) 3- oxetane methanols are prepared by 3- benzyloxymethyl oxetanes, specific reaction equation is as follows：
The white solid (50g, 0.28mol) that step (4) obtains is dissolved in methanol (300mL), is separately added into formic acid
(30mL), 10%Pd-C (11.2g), system are stirred at room temperature 10 hours, filter, and concentration obtains white solid 22.1g, yield
89.6%.
1H NMR(400MHz,CDCl3) δ 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-4.43 (m, 2H), 3.91
(d,2H),3.24-3.20(m,1H),1.56(brs,1H)。
(6) 3- oxetanes formic acid is prepared by 3- oxetane methanols, specific reaction equation is as follows：
The object (20g, 0.23mol) that step (5) obtains is dissolved in dichloromethane (2L), ice bath, is stirred, Yi Fenyi
Part is added and wears this Martin's oxidant (0.345mol).System warms naturally to room temperature, continues stirring 1 hour.It is thio to be added dropwise 10%
2L water, layering is added in sodium sulphate (200mL), and the extraction of water phase dichloromethane merges organic phase, washes three times, saturated salt solution
It washes, dry, concentration, residue is dissolved in 50mL petroleum ethers, ice bath, is stirred lower dropwise addition 1mL ethyl acetate, is filtered after half an hour,
Obtain 18g white powders, yield 76.7%.
1H NMR(400MHz,CDCl3)δ10.82(s,1H),4.92(dd,2H),4.88(dd,2H),3.90(ddd,1H)。
Embodiment 3
The present embodiment prepares 3- oxetanes formic acid by following steps
(1) 3- hydroxypropionates are prepared by 3- hydroxypropionitriles, specific reaction equation is as follows：
Ethyl alcohol (1.25L) is put into three-necked bottle, and stirring is cooled to 0 DEG C, concentrated hydrochloric acid (80mL) is slowly added dropwise.It is slowly added dropwise again
Thionyl chloride (150mL), system is slowly increased to room temperature.3- hydroxypropionitriles (250g) are slowly added dropwise, drips off system and flows back 8 hours,
There are a large amount of white powders.System is cooled to 0 DEG C, and it is 7 or so to adjust pH with solid sodium carbonate.Filtering, filtrate concentration, distillation obtain
3- hydroxypropionate 205g, yield 49.3%.
1H NMR(300MHz,CDCl3) δ 4.20 (dd, 2H) 3.84 (t, J=6.1Hz, 2H)；2.76(brs,1H,OH)；
2.55 (td, J=5.8,1.6Hz, 2H), 1.25 (t, 3H).
(2) 3- hydroxyl -2- benzyloxymethyl ethyl propionates are prepared by 3- hydroxypropionates, specific reaction equation is as follows：
The LDA tetrahydrofuran solutions (4.32mol, 1.5L) of 2M are put into 5L eggplant-shape bottles, and the protection of nitrogen part is cooled to -78
DEG C, the product (150g, 1.44mol) that a dropping step (1) obtains.System continuation is dripped off to be stirred to react at -78 DEG C 1 hour, after
Continuous that chloromethyl benzyl ether (4.32mol) is added dropwise, reaction mixture is warming up to -40 DEG C, and stirs 4 hours at this temperature.It passs
Saturated ammonium chloride (2L) is handed over to be quenched.Ethyl acetate is extracted twice, and is merged, dry, and concentration obtains pale yellow oil 128g.It will
Product direct plunges into reaction in next step.
(3) 2- benzyloxymethyls -1,3-PD is prepared by 3- hydroxyl -2- benzyloxymethyl ethyl propionates, it is specific to react
Formula is as follows：
The pale yellow oil (110g) that step (2) obtains is dissolved in methanol (600mL), is stirred, ice bath, it is a to add
Enter sodium borohydride (2.3mol), add, system is to slowly warm up to room temperature, and is stirred at room temperature 5 hours.Unsaturated carbonate hydrogen is added dropwise
Sodium (400mL) is quenched, and continues stirring 1 hour, and system concentration, ethyl acetate extracts 3 times, merges organic phase, dry, concentration,
With ethyl acetate and petroleum ether 1:1 recrystallization, obtains white crystalline body 78g, yield 81%.
1H NMR(CDCl3,400MHz):δ 7.38-7.26 (m, 5H), 4.50 (s, 2H), 3.97 (dd, 2H), 3.77 (d,
4H),3.60(d,2H),2.74(s,2H),2.05-2.00(m,1H)。
(4) 3- benzyloxymethyl oxetanes is prepared by 2- benzyloxymethyls -1,3-PD, specific reaction equation is such as
Under：
The white powder (75g, 0.38mol) that step (3) obtains is dissolved in n,N-Dimethylformamide (1L), ice bath, nitrogen
Gas part is protected, a that sodium hydrogen (in the mineral oil of 15.2g, 0.38mol, 60%) is added, and stirs 1 hour, methane sulphur is added dropwise
Acyl chlorides (0.57mol), system are warmed to room temperature and continue stirring 2 hours.Then system is cooled to 0 DEG C, and sodium is added in another part portion
Hydrogen (15.2g, 0.38mol), system are to slowly warm up to room temperature again, and continue stirring 5 hours.The meaning tune of 1M is added dropwise in ice bath
PH is saved to neutrality, 2L water is added, ethyl acetate 300mL is extracted 5 times, merges organic phase, is washed 3 times, dry concentration, and residue is molten
In methanol 500mL, 100mL is added into methanol phase, stirs 20 minutes, layering, then lower layer continuously adds 100mL petroleum ethers,
It is again stirring for 20min, is layered, lower layer concentrates, ethyl acetate and petroleum ether 1:10 crystallizations.Obtain white solid 52g, yield
76.8%.
1H NMR(400MHz,CDCl3) δ 7.39-7.26 (m, 5H), 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-
4.41 (m, 2H), 3.72 (d, 2H), 3.33-3.20 (m, 1H).
(5) 3- oxetane methanols are prepared by 3- benzyloxymethyl oxetanes, specific reaction equation is as follows：
The white solid (50g, 0.28mol) that step (4) obtains is dissolved in methanol (300mL), is separately added into formic acid
(30mL), 10%Pd-C (14g), system are stirred at room temperature 20 hours, filter, and concentration obtains white solid 22.5g, yield
91.2%.
1H NMR(400MHz,CDCl3) δ 4.84-4.78 (m, 2H), 4.54 (s, 2H), 4.49-4.43 (m, 2H), 3.91
(d,2H),3.24-3.20(m,1H),1.56(brs,1H)。
(6) 3- oxetanes formic acid is prepared by 3- oxetane methanols, specific reaction equation is as follows：
The object (20g, 0.23mol) that step (5) obtains is dissolved in chloroform (2L), ice bath, is stirred, Yi Fenyi
Part is added and wears this Martin's oxidant (0.69mol).System warms naturally to room temperature, continues stirring 3 hours.10% thio sulphur is added dropwise
2L water, layering is added in sour sodium (200mL), and water phase chloroform extraction merges organic phase, and three times, saturated common salt is washed for washing,
Dry, concentration, residue is dissolved in 50mL petroleum ethers, ice bath, is stirred lower dropwise addition 1mL ethyl acetate, is filtered, obtain after half an hour
17.9g white powders, yield 76.2%.
1H NMR(400MHz,CDCl3)δ10.82(s,1H),4.92(dd,2H),4.88(dd,2H),3.90(ddd,1H)。
Applicant states that the present invention illustrates the method detailed of the present invention, but the present invention not office by above-described embodiment
It is limited to above-mentioned method detailed, that is, does not mean that the present invention has to rely on above-mentioned method detailed and could implement.Technical field
Technical staff it will be clearly understood that any improvement in the present invention, equivalence replacement and auxiliary element to each raw material of product of the present invention
Addition, the selection etc. of concrete mode, all fall within protection scope of the present invention and the open scope.
Claims (10)
1. a kind of preparation method of 3- oxetanes formic acid, which is characterized in that the preparation method is original with 3- hydroxypropionitriles
Material, through hydrolysis esterification, pull out hydrogen reaction and reduction reaction obtain 2- benzyloxymethyls -1,3-PD, then by 2-
Benzyloxymethyl -1,3- propylene glycol obtains the 3- oxetanes first by ring-closure reaction, debenzylation and oxidation reaction
Acid.
2. preparation method according to claim 1, which is characterized in that the hydrolysis esterification is 3- hydroxypropionitriles and second
In acid condition, 3- hydroxypropionates are obtained by the reaction in alcohol under catalyst.
3. preparation method according to claim 2, which is characterized in that relative to the 3- hydroxypropionitriles of 1g, the ethyl alcohol
Dosage is 3.5-5mL；
Preferably, the catalyst is thionyl chloride；
Preferably, relative to the 3- hydroxypropionitriles of 250g, the dosage of the thionyl chloride is 130-150mL；
Preferably, the acid condition is provided by hydrochloric acid or sulfuric acid.
4. preparation method according to claim 2 or 3, which is characterized in that the temperature of the hydrolysis esterification is 60-80
℃；
Preferably, the time of the hydrolysis esterification is 5-8h.
5. according to the preparation method described in any one of claim 1-4, which is characterized in that the hydrogen that pulls out reacts for 3- hydroxyls third
3- hydroxyl -2- benzyloxymethyl ethyl propionates are obtained by the reaction with chloromethyl benzyl ether in acetoacetic ester；
Preferably, it is described pull out hydrogen reaction carried out in the presence of lithium diisopropylamine；
Preferably, the molar ratio of the 3- hydroxypropionates and chloromethyl benzyl ether, lithium diisopropylamine is 1:(2-3):
(2-3)。
6. preparation method according to claim 5, which is characterized in that the solvent for pulling out hydrogen reaction is tetrahydrofuran or second
Ether；
Preferably, it is described pull out hydrogen reaction protective gas protection under carry out；
Preferably, the protective gas include in nitrogen, helium or argon gas any one or at least two combination, preferably
For nitrogen；
Preferably, the temperature for pulling out hydrogen reaction is -80 DEG C to -30 DEG C；
Preferably, the time for pulling out hydrogen reaction is 4-5h.
7. according to the preparation method described in any one of claim 1-6, which is characterized in that the reduction reaction is 3- hydroxyls-
2- benzyloxymethyls -1,3- the propylene glycol is obtained by the reaction with reducing agent in 2- benzyloxymethyls ethyl propionate；
Preferably, the reducing agent is sodium borohydride or Lithium Aluminium Hydride；
Preferably, the molar ratio of the 3- hydroxyls -2- benzyloxymethyls ethyl propionate and reducing agent is 1:3-5；
Preferably, the solvent of the reduction reaction be methanol, ethyl alcohol or isopropanol in any one or at least two combination；
Preferably, the temperature of the reduction reaction is 0-30 DEG C；
Preferably, the time of the reduction reaction is 2-5h.
8. according to the preparation method described in any one of claim 1-7, which is characterized in that the ring-closure reaction is 2- benzyloxies
3- benzyloxymethyl oxetanes is obtained by the reaction with methane sulfonyl chloride, sodium hydrogen in methyl-1,3-propanediol；
Preferably, the molar ratio that 2- benzyloxymethyls -1,3-PD is reacted with methane sulfonyl chloride, sodium hydrogen is 1:(0.95-
1.5):(2-2.5)；
Preferably, the solvent of the ring-closure reaction is n,N-Dimethylformamide；
Preferably, the temperature of the ring-closure reaction is 0-30 DEG C；
Preferably, the time of the ring-closure reaction is 2-5h.
9. according to the preparation method described in any one of claim 1-8, which is characterized in that the debenzylation is to use palladium
C catalyst restores 3- benzyloxymethyl oxetanes to obtain 3- oxetane methanols；
Preferably, relative to the 3- benzyloxymethyl oxetanes of 1mol, the dosage of palladium-carbon catalyst is 30-50g；
Preferably, the solvent of the debenzylation is methanol and/or ethyl alcohol；
Preferably, the temperature of the debenzylation is 20-40 DEG C；
Preferably, the time of the debenzylation is 10-20h；
Preferably, the oxidation reaction is 3- oxetane methanols and wears this Martin's oxidant reaction and obtain the 3- oxa-s ring
Butane formic acid；
Preferably, the 3- oxetane methanols are 1 with the molar ratio for wearing this Martin's oxidant:1.5-3；
Preferably, the solvent of the oxidation reaction include in dichloromethane, chloroform or carbon tetrachloride any one or extremely
Few two kinds of combination；
Preferably, the temperature of the oxidation reaction is 20-40 DEG C；
Preferably, the time of the oxidation reaction is 1-3h.
10. according to the preparation method described in any one of claim 1-9, which is characterized in that the preparation method specifically includes
Following steps：
(1) under acid condition, esterification is hydrolyzed at 60-80 DEG C under thionyl chloride catalysis for 3- hydroxypropionitriles and ethyl alcohol
React 5-8h3- hydroxypropionates；
(2) it is 1 by molar ratio:(2-3):3- hydroxypropionates, chloromethyl benzyl ether and the lithium diisopropylamine of (2-3) exist
Under protective gas protection, pull out hydrogen reaction 4-5h at being -80 DEG C to -30 DEG C in temperature and obtain 3- hydroxyl -2- benzyloxy first
Base ethyl propionate；
(3) it is 1 by molar ratio:3- hydroxyls -2- benzyloxymethyls the ethyl propionate of 3-5 carries out restoring at 0-30 DEG C anti-with reducing agent
2-5h is answered to obtain 2- benzyloxymethyl -1,3- propylene glycol；
(4) it is 1 by molar ratio:(0.95-1.5):2- benzyloxymethyl -1,3- propylene glycol, methane sulfonyl chloride and the sodium of (2-2.5)
Hydrogen carries out ring-closure reaction 2-5h at being 0-30 DEG C in temperature and obtains 3- benzyloxymethyl oxetanes；
(5) 3- benzyloxymethyls oxetanes and palladium-carbon catalyst debenzylation 10-20h is carried out at 20-40 DEG C to obtain
To 3- oxetane methanols；
(6) it is 1 by molar ratio:The 3- oxetane methanols of 1.5-3 are aoxidized with this Martin's oxidant is worn at 20-40 DEG C
Reaction 1-3h obtains 3- oxetanes formic acid.
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