CN106565637A - Synthesis method of 3-oxetane acetic acid - Google Patents
Synthesis method of 3-oxetane acetic acid Download PDFInfo
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- CN106565637A CN106565637A CN201610961453.XA CN201610961453A CN106565637A CN 106565637 A CN106565637 A CN 106565637A CN 201610961453 A CN201610961453 A CN 201610961453A CN 106565637 A CN106565637 A CN 106565637A
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- oxetanes
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D305/06—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
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Abstract
The invention belongs to the fields of organic synthesis and medicine synthesis, and especially relates to a synthesis method of 3-oxetane acetic acid. The synthesis method includes the following steps: (1) performing a reaction to 3-oxetanone and benzyloxycarbonylmethylene triphenylphosphine to obtain an intermediate product 2-(oxetane-3-yl-methylene)benzyl acetate; (2) performing hydrogenation debenzylation to the 2-(oxetane-3-yl-methylene)benzyl acetate to obtain the final product 3-oxetane acetic acid. The reactions in the method can be carried out just at room temperature and reaction conditions are easy to control. The final product can be obtained through re-crystallization and purification, so that the product is high in purity, and deterioration of the product during purification is avoided. The method has reasonable route design, simple process, high yield and short synthesis period, and can provide a high-purity raw material for a subsequent synthesis reaction sufficiently and timely.
Description
Technical field
The invention belongs to organic synthesiss and pharmaceutical synthesis field, more particularly to a kind of synthesis side of 3- oxetanes acetic acid
Method.
Background technology
3- oxetanes acetic acid is a kind of important medicine intermediate, be can be widely applied in the design of drug molecule,
Its molecular weight is little, unique structure, can derive various downstream product, and tool has been widely used.
However, as ambient air temperature is higher or preserves the reasons such as sealing difference, all easily cause the compound to go bad, so
Cause the compound preserve steadily in the long term.Therefore, when needing to use the intermediate during organic synthesiss, it is difficult to directly
The chemical reagent is bought, voluntarily can only be synthesized, and be dosed in time in the reaction of next step in post synthesis.However,
Still there is no the synthetic method of the document report compound at present.
It would therefore be desirable to design one, raw material is cheap and easy to get, reaction condition is easily-controllable, reaction time is short, and product purity is high
Synthetic route, can provide purity higher raw material for follow-up reaction in time.
The content of the invention
The present invention provides to solve technical problem present in known technology that a kind of raw material is cheap and easy to get, reaction condition temperature
With synthesis side that is easily-controllable, being easy to the 3- oxetanes acetic acid that purifies and separates, synthetic route are reasonable in design, synthesis cycle is shorter
Method.
The present invention is adopted the technical scheme that by solving technical problem present in known technology：A kind of 3- oxa-s ring fourth
The synthetic method of alkane acetic acid, the synthetic method are comprised the following steps,
Step one, 3- oxetanones obtain intermediate product 2- (oxa-s with the reaction of (Bian oxygen carbonyl methylene) triphenylphosphine
Tetramethylene. -3- methylenes) benzyl acetate, its chemical equation is as follows：
Step 2, the hydrogenation of intermediate product 2- (oxetanes -3- methylenes) benzyl acetate de- Bian is finally produced
Thing 3- oxetanes acetic acid, its chemical equation are as follows：
Preferably：The concrete operation method of step one is：3- oxetanones are dissolved in solvents tetrahydrofurane, are cooled to
0-5℃；The tetrahydrofuran solution of (Bian oxygen carbonyl methylene) triphenylphosphine is added dropwise in above-mentioned system, room temperature after rising again naturally
Stirring 5-10 hours；TLC monitoring reactions are finished, and above-mentioned system is spin-dried for, and column chromatography purification obtains intermediate product 2- (oxa- ring fourths
Alkane -3- methylenes) benzyl acetate.
Preferably：The concrete operation method of step 2 is：Intermediate product 2- (oxetanes -3- methylenes) acetic acid benzyl
During ester and Pd/C catalyst add solvents tetrahydrofurane, with hydrogen exchange 3 times, above-mentioned closed system is stirred at room temperature into 4-12
Hour；TLC monitoring reactions are finished, and above-mentioned system is filtered.Filtrate is spin-dried for, and obtains final product 3- oxa-s by recrystallization purification
Tetramethylene. acetic acid.
Preferably：In step 2, reaction temperature and post-processing temperature are less than 40 DEG C.
Preferably：0.1%- of the consumption of Pd/C catalyst for reaction substrate mass percent in the second step reaction
1%, reaction pressure is 40-50psi.
Advantages of the present invention and good effect are：All reactions in technique of the present invention can occur anti-at room temperature
Should, reaction condition is simple and easy to control；Final products can be obtained by recrystallization purifying, and the purity for obtaining product is higher, and avoids
In purge process, product goes bad；Rationally, process is simple, yield are higher, and synthesis cycle is short, can in time, sufficiently for highway route design
Highly purified raw material is provided for follow-up synthetic reaction.
Description of the drawings
Fig. 1 is compound 3 in the present invention1HNMR spectrograms；
Fig. 2 is compound 4 in the present invention1HNMR spectrograms.
Specific embodiment
For the content of the invention, feature and effect of the present invention can be further appreciated that, hereby enumerate following examples and describe in detail such as
Under：
The synthetic route of the present invention is as follows：
Wherein, the compound 1 being related in the present invention is 3- oxetanones；Compound 2 is (Bian oxygen carbonyl methylene)
Triphenylphosphine；Compound 3 is 2- (oxetanes -3- methylenes) benzyl acetate；Compound 4 is 3- oxetanes second
Acid；THF is tetrahydrofuran；PE is petroleum ether；EA is ethyl acetate；DCM is dichloromethane；MeOH is methanol；MTBE is methyl
Tertbutyl ether.
Embodiment 1：Pilot plant test
The first step：
1 step one pilot plant test of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 1 | 72 | 4g | 0.056mol | 1.1eq |
| 2 | 410 | 20.7g | 0.051mol | 1.0eq |
| THF | - | 80mL | - | - |
In this reaction, the inventory of various compounds is as shown in table 1.
Operating procedure：Compound 2 (20.7g), THF (50mL) are added sequentially in 250m L there-necked flasks, by compound 1
(4g) and in 0-5 DEG C of instillation system of THF (30mL) mixed liquor, stirring 5 hours of rising again naturally, TLC (PE:EA=10:1) show former
Material (Rf=0.1) reaction is finished, and has product (Rf=0.3) to generate.
Post processing：Above-mentioned system is spin-dried for, column chromatography (PE:EA=20:1) purification obtains product point, is spin-dried for obtaining chemical combination
Thing 3 (white solid 8g), yield 65%.
Compound 31HNMR spectrograms are shown in Fig. 1, H-NMR (CDCl3, 400MHz)：δ 7.25 (m, 5H), δ 5.58 (m, 1H), δ
5.39 (m, 2H), δ 5.18 (m, 2H), δ 5.05 (s, 2H).
Second step：
2 step 2 pilot plant test of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 3 | 219 | 4.2g | 0.02mol | 1eq |
| Pd/C | - | 0.4g | - | 10w% |
| THF | - | 100mL | - | - |
In this reaction, the inventory of various compounds is as shown in table 2.
Operating procedure：Compound 3 (4.2g), THF (100mL), Pd/C 0.4g are added sequentially in 500ml single port bottles,
H2Displacement 3 times, is stirred at room temperature 8 hours.TLC(PE:EA=5:1) show that raw material (Rf=0.5) reaction is finished, (DCM:MeOH=
20:1) product (Rf=0.3) generates.
Post processing：Above-mentioned system is filtered, filtrate is spin-dried for, add MTBE 1g/5mL to dissolve which, will wherein insoluble part
Divide liquid to separate, soluble fraction is spin-dried for, add PE 1g/2mL recrystallization, obtain compound 4 (white solid 2.1g), yield
91.3%.
Note：Above-mentioned last handling process, cannot heat when being spin-dried for, and heating product can go bad.
Compound 41HNMR spectrograms are shown in Fig. 2, H-NMR (DMSO, 400MHz)：δ 4.65 (m, 2H), δ 4.28 (m, 2H), δ
3.21(m,1H),δ2.65(d,2H)。
Embodiment 2：Pilot experiment
The first step：
3 step one pilot experiment of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 1 | 72 | 40g | 0.56mol | 1.1eq |
| 2 | 410 | 207g | 0.51mol | 1.0eq |
| THF | - | 800mL | - | - |
In this reaction, the inventory of various compounds is as shown in table 3.
Operating procedure：Compound 2 (207g), THF (500mL) are added sequentially in 2L there-necked flasks, by compound 1
(40g) and in 0-5 DEG C of instillation system of THF (300mL) mixed liquor, stirring 7 hours of rising again naturally, TLC (PE:EA=10:1) show
Raw material (Rf=0.1) reaction is finished, and has product (Rf=0.3) to generate.
Post processing：Above-mentioned system is spin-dried for, column chromatography (PE:EA=20:1) purification obtains product point, is spin-dried for obtaining chemical combination
Thing 3 (white solid 75g), yield 61%.
Second step：
4 step 2 pilot experiment of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 3 | 219 | 50g | 0.23mol | 1eq |
| Pd/C | - | 5g | - | 10w% |
| THF | - | 500mL | - | - |
In this reaction, the inventory of various compounds is as shown in table 4.
Operating procedure：Compound 3 (50g), THF (500mL), Pd/C 5g are added sequentially in lL single port bottles, H2Displacement
3 times, it is stirred at room temperature 10 hours.TLC(PE:EA=5:1) show that raw material (Rf=0.5) reaction is finished, (DCM:MeOH=20:1)
There is product (Rf=0.3) to generate.
Post processing：Above-mentioned system is filtered, filtrate is spin-dried for, add MTBE 1g/5mL to dissolve which, will wherein insoluble part
Divide liquid to separate, soluble fraction is spin-dried for, add PE 1g/2mL recrystallization, obtain compound 4 (white solid 25g), yield
90.3%.
Note：Above-mentioned last handling process and cannot heat when being spin-dried for, heating product can go bad.
Embodiment 3：Amplification test
The first step：
5 step one amplification test of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 1 | 72 | 200g | 2.7mol | 1.2eq |
| 2 | 410 | 1.04kg | 2.4mol | 1.0eq |
| THF | - | 3mL | - | - |
In this reaction, the inventory of various compounds is as shown in table 5.
Operating procedure：Compound 2 (1.04kg), THF (2mL) are added sequentially in 5L there-necked flasks, by compound 1
(200g) and in 0-5 DEG C of instillation system of THF (1L) mixed liquor, stirring 10 hours of rising again naturally, TLC (PE:EA=10:1) show
Raw material (Rf=0.1) reaction is finished, and has product (Rf=0.3) to generate.
Post processing：Above-mentioned system is spin-dried for, column chromatography (PE:EA=20:1) purification obtains product point, is spin-dried for obtaining chemical combination
Thing 3 (white solid 420g), yield 68.5%.
Second step：
6 step 2 amplification test of table feeds intake table
| Compound | Molecular weight | Inventory | Relative molecular weight | Equivalents |
| 3 | 219 | 400g | 1.84mol | 1eq |
| Pd/C | - | 40g | - | 10w% |
| THF | - | 4L | - | - |
In this reaction, the inventory of various compounds is as shown in table 6.
Operating procedure：Compound 3 (400g), THF (4L), Pd/C 40g are added sequentially in 5L single port bottles, H2Displacement 3
It is secondary, it is stirred at room temperature 10 hours.TLC(PE:EA=5:1) show that raw material (Rf=0.5) reaction is finished, (DCM:MeOH=20:1) have
Product (Rf=0.3) is generated.
Post processing：Above-mentioned system is filtered, filtrate is spin-dried for, add MTBE 1g/5mL to dissolve which, will wherein insoluble part
Divide liquid to separate, soluble fraction is spin-dried for, add PE 1g/2mL recrystallization, obtain compound 4 (white solid 200g), yield
93.6%.
Note：Above-mentioned last handling process, cannot heat when being spin-dried for, and heating product can go bad.
Claims (5)
1. a kind of synthetic method of 3- oxetanes acetic acid, it is characterised in that：The synthetic method is comprised the following steps,
Step one, 3- oxetanones obtain intermediate product 2- (oxa- ring fourths with the reaction of (Bian oxygen carbonyl methylene) triphenylphosphine
Alkane -3- methylenes) benzyl acetate, its chemical equation is as follows：
The hydrogenation of intermediate product 2- (oxetanes -3- methylenes) benzyl acetate de- Bian is obtained final product 3- by step 2
Oxetanes acetic acid, its chemical equation are as follows：
2. the synthetic method of 3- oxetanes acetic acid as claimed in claim 1, it is characterised in that：The concrete operations of step one
Method is：3- oxetanones are dissolved in solvents tetrahydrofurane, 0-5 DEG C is cooled to；By (Bian oxygen carbonyl methylene) triphenyl
The tetrahydrofuran solution of phosphine is added dropwise in above-mentioned system, and 5-10 hours are stirred at room temperature after rising again naturally；TLC monitoring reactions are finished,
Above-mentioned system is spin-dried for, column chromatography purification obtains intermediate product 2- (oxetanes -3- methylenes) benzyl acetate.
3. the synthetic method of 3- oxetanes acetic acid as claimed in claim 2, it is characterised in that：The concrete operations of step 2
Method is：Intermediate product 2- (oxetanes -3- methylenes) benzyl acetates and Pd/C catalyst add solvents tetrahydrofurane
In, with hydrogen exchange 3 times, above-mentioned closed system is stirred at room temperature into 4-12 hours；TLC monitoring reactions are finished, by above-mentioned body
System filters.Filtrate is spin-dried for, and obtains final product 3- oxetanes acetic acid by recrystallization purification.
4. the synthetic method of 3- oxetanes acetic acid as claimed in claim 3, it is characterised in that：Reaction temperature in step 2
40 DEG C are less than with post-processing temperature.
5. the synthetic method of 3- oxetanes acetic acid as claimed in claim 3, it is characterised in that：In the second step reaction
0.1%-1% of the consumption of Pd/C catalyst for reaction substrate mass percent, reaction pressure is 40-50psi.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201610961453.XA CN106565637A (en) | 2016-11-04 | 2016-11-04 | Synthesis method of 3-oxetane acetic acid |
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| CN201610961453.XA CN106565637A (en) | 2016-11-04 | 2016-11-04 | Synthesis method of 3-oxetane acetic acid |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100255A1 (en) * | 2009-03-06 | 2010-09-10 | Lipideon Biotechnology Ag | Pharmaceutical hypocholesterolemic compositions |
| CN102712577A (en) * | 2009-10-28 | 2012-10-03 | 拜耳制药股份公司 | Substituted 3-phenylpropionic acids and the use thereof |
| CN103764658A (en) * | 2011-06-17 | 2014-04-30 | 安吉奥斯医药品有限公司 | Compounds, their pharmaceutical compositions and their uses as IDH1 mutants inhibitors for treating cancers |
| JP2016056133A (en) * | 2014-09-10 | 2016-04-21 | 第一三共株式会社 | Pyrazolone derivative having cyclic side chain |
-
2016
- 2016-11-04 CN CN201610961453.XA patent/CN106565637A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010100255A1 (en) * | 2009-03-06 | 2010-09-10 | Lipideon Biotechnology Ag | Pharmaceutical hypocholesterolemic compositions |
| CN102712577A (en) * | 2009-10-28 | 2012-10-03 | 拜耳制药股份公司 | Substituted 3-phenylpropionic acids and the use thereof |
| CN103764658A (en) * | 2011-06-17 | 2014-04-30 | 安吉奥斯医药品有限公司 | Compounds, their pharmaceutical compositions and their uses as IDH1 mutants inhibitors for treating cancers |
| JP2016056133A (en) * | 2014-09-10 | 2016-04-21 | 第一三共株式会社 | Pyrazolone derivative having cyclic side chain |
Non-Patent Citations (1)
| Title |
|---|
| C.D.NENITZESCU ET AL: "SYNTHESES OF α-SUBSTITUTED β-KETO ESTERS", 《RUSS CHEM BULL》 * |
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Application publication date: 20170419 |