CN103992258A - Preparation method for - Google Patents
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- CN103992258A CN103992258A CN201410051948.XA CN201410051948A CN103992258A CN 103992258 A CN103992258 A CN 103992258A CN 201410051948 A CN201410051948 A CN 201410051948A CN 103992258 A CN103992258 A CN 103992258A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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 carbon atoms
- C07D207/24—Oxygen or sulfur atoms
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing N-Boc-pyrrolidone. Particularly, the invention relates to an effective method for preparing the compound 3 - oxygen generation of pyrrolidine - 1 - formic acid tert-butyl ester, wherein the existence of the specific organic solution has an important role in the yeild and the purity of the end product.
Description
Technical field
The object of the invention is a kind of method for the preparation of 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester, described 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester is the important structure unit for the preparation of active pharmaceutical ingredient.
Background technology
Several different methods for the preparation of the compound of the formula (I) of 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester by name is disclosed in document:
Described compound is also referred to as N-Boc-3-pyrrolidone, and this compound is for the preparation of the important intermediate of active pharmaceutical ingredient or structural unit.
Jihoon Lee etc., at Bioorganic & Medicinal Chemistry Letters, have described a kind of appreciable currently known methods, the compound of the formula that is wherein ethyl by R (II) in 13 (2003), 4399-4403:
At DMSO/H
2o(10:1) decarboxylation 4 hours at 120-130 DEG C in, to provide the compound of the formula (I) of unsegregated molar yield as 70%.Reaction product is in fact not separated, and undeclared its chemical purity.
Another example of identical decarboxylic reaction is disclosed in the paragraph [0033] of the Chinese patent application CN102241617A having announced, wherein at DMSO: heat at 120-130 DEG C and react for 4 hours in water (10:1), with AcOEt: sherwood oil (1:10) is processed product, and the product that molar yield is 70% is provided.But, repeat this program with small-scale in our laboratory time, only obtain 13.9% molar yield (referring to the first experiment in table 1 below).
Disclosure demonstration above, this reaction is carried out conventionally in the mixture of water or water and DMSO.
In fact must consider that compound 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester has by the amine functional group of tertbutyloxycarbonyl (Boc) protection; well-known tertbutyloxycarbonyl is group (it is easily cut open in aqueous hydrochloric acid) unstable under acidic condition; therefore can not under sour environment, carry out decarboxylic reaction; otherwise; on the compound being replaced by phenmethyl, ethyl or methyl at the tertiary butyl, can accomplish this point; as RufineAkue-Gedu at Synthesis; 2007; No.21, described in p.3319-3322.
Therefore, the main drawback of art methods is summarized as follows: the molar yield after molar yield, the especially separation of decarboxylic reaction is low, product purity is low, acquisition is extremely difficult as product 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester (in the situation that not using chromatogram purification or reducing molar yield) of solid, and such product obtains usually used as oily matter.Because product is not as solid, therefore not as the form acquisition that is adapted to pass through crystallization purifying, so the chemical purity of the product of the formula of preparing according to currently known methods (I) is normally low, therefore can not be used for carrying out the synthetic of active pharmaceutical ingredient in technical scale.
Summary of the invention
Therefore, the problem to be solved in the present invention is to provide the improved method for the preparation of 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester of formula (I).
This problem solves by the method for preparing 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester described in claims, and the content that these claims limit is integral part of the present disclosure.
Other feature and advantage of method of the present invention come from description related to the preferred embodiment below, and described preferred implementation provides in the mode of non-limiting example.
Brief description of the drawings
Fig. 1 shows the scheme of synthetic 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester according to a preferred aspect of the present invention.
Embodiment
The decarboxylation that the present invention relates to the compound that utilizes formula (II) carrys out the method for compound 3-oxo-pyrrolidine-1-formic acid tertiary butyl ester of preparation formula (I):
Wherein R is the C1-C5 alkyl of straight or branched.
Find surprisingly, under the condition that has hydrocarbon organic solvent or aromatic organic solvent, carry out decarboxylation, molar yield or the purity of product significantly improve.Type and the amount of the impurity forming between the reaction period in reaction mixture, on the existed facts of hydrocarbon organic solvent or aromatic organic solvent, are reduced.The product that this allows to improve molar yield or separates surprisingly the formula (I) as solid.Be separated to unexpectedly as solid instead of as the product of the formula (I) of oily matter and there is very high advantage, because can significantly improve the purity of product.Table has below shown the purity (higher than 96%) of the raising that the solid product prepared according to method of the present invention reaches.
In art methods, to be prepared to oily matter be the shortcoming that we need to solve to product, could in the situation that not using chromatographic column or sublimating technologe, improve its purity because only have by product being prepared into solid.In fact, in order to carry out synthesis step below, be, essential higher than 95% purity level.In addition, product being prepared into solid instead of oily matter has advantages of much better easy to use.
In addition, the existence of those solvents also allows to obtain much transparent reaction mixture in the time that reaction finishes, this may be to be caused by the minimizing of DeR, and therefore final separated product is also than not existing the product of preparing under the condition of hydrocarbon organic solvent or aromatic organic solvent much transparent.
Finally, the existence of such solvent allows to form the impurity of much less, thereby allows to prepare product with higher molar yield, and the molar yield after separating is higher than 40%, and is generally approximately 60%.
R substituting group is the C1-C5 alkyl substituent of straight or branched, therefore can be selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, n-pentyl, 2-methyl butyl, 3-methyl butyl, 2-ethyl propyl, sec-butyl, 2,2-dimethyl propyl and neo-pentyl.
According to a preferred aspect of the present invention, preferred alkyl is ethyl, because preparation 4-oxo-pyrrolidine-1,3-dioctyl phthalate 1-tertiary butyl ester 3-ethyl ester is more prone to and is more economical, and because this intermediate provides easier decarboxylic reaction, provide the impurity of less amount.
Decarboxylic reaction of the present invention can carry out in each hydrocarbon organic solvent or each aromatic organic solvent.
Hydrocarbon refers to the organic compound of a carbon containing and hydrogen atom.
Also can use the mixture of such organic solvent, because their existence in reaction mixture identical result while allowing obtain and only use a kind of hydrocarbon organic solvent or aromatic organic solvent.
The example of such hydrocarbon organic solvent can be alkane, naphthenic hydrocarbon, for example heptane, octane-iso.
The example of such aromatic organic solvent can be aromatic hydrocarbons, indenes, toluene, naphthalene, pyrene, dimethylbenzene, halogenated organic solvent, chlorobenzene.
According to a preferred aspect of the present invention, aromatic organic solvent is preferred.
More particularly, toluene is most preferred solvent.
According to a preferred aspect of the present invention, the solvent with higher is preferred, because they allow to realize higher temperature of reaction, thereby reduces the reaction times.
Obviously, this reaction also can be carried out under the condition that has other added solvent, and described other added solvent are not hydrocarbon organic solvent or aromatic organic solvent.
The preferred added solvent using is water and methyl-sulphoxide or its mixture.
Another preferred aspect of the present invention is optional one or more antioxidants that exist in reaction mixture.As shown in the table below, these additives have the effect that improves molar yield.Can add to reaction mixture the phenolic antioxidant of many typical alkyl or alkoxyl group replacement, for example BHT, 2,6-DTBP, particularly preferably is BHT.
For carrying out this decarboxylic reaction, the antioxidant of phosphine type is also preferred.
Permitted eurypalynous phosphine and be can be used for carrying out the present invention, for example Ph
3p, tBu
3p or (MeOPh)
3p, preferably triphenylphosphine (Ph
3p).
According to the preferred embodiment of the present invention, decarboxylic reaction can carry out under the condition that has BHT and triphenylphosphine.
The amount of the antioxidant adding can be 0.01% to 1% w/w of the compound of formula (II).Preferably, use approximately 0.1% anti-oxidant additives.
Table below provides Comparative Example, and it allows to recognize by feature of the present invention, be first the strong effect that solvent provides, and is the additional effect being provided by the existence of antioxidant subsequently.
Table 1
As already mentioned, reaction can be carried out under the condition that also has for example water of other solvents and/or DMSO.Water: the preferred volume ratio of toluene is 1:4.
The existence of a certain amount of water is also useful to reaction.
Reaction of the present invention is used conventionally with respect to the water of compound 1 to the 20 molecule equivalent of formula (II) to be carried out.Preferably use the water of 3 to 5 molecule equivalents, because this brings better result.
Decarboxylic reaction can carry out in the temperature range of 80 DEG C to 130 DEG C, preferably the scope of 110-115 DEG C.
Toluene is the preferred solvent for the inventive method, because embodiment 3 shows, with other solvent phase ratios, toluene provides better result.
Method of the present invention can be carried out with any combination of above-mentioned parameter or condition.
experimental section
Can be according to Jihoon Lee etc. at Bioorganic & Medicinal Chemistry Letters, 13 (2003), initial product 4-oxo-pyrrolidine-1 is prepared in instruction in 4399-4403,3-dioctyl phthalate 1-tertiary butyl ester 3-ethyl ester (the wherein compound of the formula of R=Et (II)).
embodiment 1
Under nitrogen atmosphere, pack 1.33Kg4-oxo-pyrrolidine-1 into the 5L reactor that is equipped with mechanical stirrer and thermometer, 3-dioctyl phthalate 1-tertiary butyl ester 3-ethyl ester (the wherein compound of the formula of R=Et (II)), 1.3g PPh
3, 1.3g2,6-DI-tert-butylphenol compounds (2,6-DTBP), and this mixture being dissolved in the mixture of 2 liters of toluene and 1.33 liters of DMSO.The mixture obtaining is heated to 115 DEG C (internal temperatures), then in 5-6 hour, dropwise add 400mL water until reacted (use TLC monitoring reaction conversion, eluent is AcOEt: normal hexane (1:3)), keep internal temperature is 113-120 DEG C simultaneously.Reaction mixture is cooled down, and dilute with 500mL cold water.Water layer is extracted with 2x500mL toluene.By the organic layer 800mL0.5%Na of merging
2cO
3solution washing, then uses the water washing of 2x800mL salt, finally uses 600mL water washing.Organic layer is transferred in 5 liters of reactors, and added 15g anhydrous magnesium sulfate and 30g gac.The mixture obtaining is stirred 1 hour, then filter.Filtrate is concentrated into dry (toluene should be removed as much as possible), obtains blush liquid.0-5 DEG C and stir under slowly add 700mL hexanaphthene, to obtain product precipitation.These slurries are filtered, and by product vacuum-drying in 25-29 DEG C of baking oven.Because product easily distils, temperature should be maintained at lower than 30 DEG C.This experiment provides 593g white solid, and the molar yield after its m.p.(with 35.4-36.9 DEG C separates is 62%).Product has 98% purity (HPLC A/A%).
embodiment 2
In 250mL4 neck RBF, at 20 DEG C, N-Boc pyrrolidone ethyl formate (20.0g) (compound of the formula (II) that wherein R is Et) is dissolved in the mixture of toluene (30ml) and methyl-sulphoxide (20ml), and add 20mg3,5-di-t-butyl-4-hydroxytoluene (BHT).The mixture obtaining is heated to 115 DEG C (internal temperatures), and in 5h, dropwise adds water (4.2ml, 3.0 equivalents), maintenance internal temperature is 110-115 DEG C.Within 1 hour after water interpolation finishes, obtain the transformation efficiency of wishing.
Reaction mixture is cooled to 20 DEG C and water (10ml) dilution.Layer is separated, toluene for water layer (20ml) is extracted again.By 20ml5%w/w NaCl solution washing for the organic layer merging, then use 10%w/w NaCl(40ml) washing, finally use 20ml water washing.
The toluene solution obtaining is processed with gac.After filtration, filtrate is concentrated into dry, obtain orange (14g).
At-5/-10 DEG C, add hexanaphthene (12ml), the suspension obtaining is filtered, by 3.5ml hexanaphthene washed twice.By solid vacuum-drying in 25 DEG C of baking ovens, obtain 10.8g white solid.Molar yield after separation is 75%.
Embodiment above shows during the decarboxylic reaction of the compound of formula (II), and how the existence of for example aromatics of specific organic solvent or hydrocarbon is bringing into play vital effect aspect the productive rate of end product and purity.
embodiment 3
Under identical condition, repeat the experiment of embodiment 2, but also add PPh
30.1%wt/wt, and use respectively methyl-phenoxide, chlorobenzene (being abbreviated as Cl-Bz) and methylcyclohexane (being abbreviated as Me-Cy) to replace toluene.
Table has below been summarized the result obtaining:
Table 2
All products according to this experiment preparation are all crystalline solid.In addition, the product of preparation demonstrates very high-caliber chemical purity thus.
Claims (10)
1. utilize the decarboxylation of the compound of formula (II) to carry out the method for the compound of preparation formula (I):
Wherein R is the C1-C5 alkyl of straight or branched, and described method is characterised in that, described decarboxylation is carried out under the condition that has hydrocarbon organic solvent or aromatic organic solvent.
2. the process of claim 1 wherein that R is ethyl.
3. the method for claim 1 to 2 any one, wherein solvent is aromatic organic solvent.
4. the method for claim 3, wherein said aromatic organic solvent is toluene.
5. the method for claim 1 to 4 any one, wherein said decarboxylation is carried out under the condition that also has one or more antioxidants.
6. the method for claim 5, wherein said antioxidant is BHT.
7. the method for claim 5, wherein said antioxidant is phosphine.
8. the method for claim 7, wherein said phosphine is triphenylphosphine.
9. the method for claim 5 to 8 any one, wherein said decarboxylation is carried out under the condition that has BHT and triphenylphosphine.
10. the method for claim 1 to 9 any one, is wherein used the water of 3 to 5 molecule equivalents.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT000032A ITVI20130032A1 (en) | 2013-02-14 | 2013-02-14 | PROCEDURE FOR THE PREPARATION OF N-BOC-PYRROLIDINONE |
| ITVI2013A000032 | 2013-02-14 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103992258A true CN103992258A (en) | 2014-08-20 |
| CN103992258B CN103992258B (en) | 2017-01-04 |
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ID=47953665
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410051948.XA Active CN103992258B (en) | 2013-02-14 | 2014-02-14 | The preparation method of N-Boc-ketopyrrolidine |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN103992258B (en) |
| IT (1) | ITVI20130032A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006070284A1 (en) * | 2004-12-31 | 2006-07-06 | Pfizer Products Inc. | Pyrrolidyl derivatives of heteroaromatic compounds as phosphodiesterase inhibitors |
| CN102060743A (en) * | 2010-12-17 | 2011-05-18 | 张家港瀚康化工有限公司 | Method for preparing N-benzyl-3-pyrrolidone |
| CN102241617A (en) * | 2011-05-25 | 2011-11-16 | 兰州景瑞生物科技有限公司 | Synthesis method of 1-tert-butoxycarbonyl-3-pyrrolidone |
-
2013
- 2013-02-14 IT IT000032A patent/ITVI20130032A1/en unknown
-
2014
- 2014-02-14 CN CN201410051948.XA patent/CN103992258B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006070284A1 (en) * | 2004-12-31 | 2006-07-06 | Pfizer Products Inc. | Pyrrolidyl derivatives of heteroaromatic compounds as phosphodiesterase inhibitors |
| CN102060743A (en) * | 2010-12-17 | 2011-05-18 | 张家港瀚康化工有限公司 | Method for preparing N-benzyl-3-pyrrolidone |
| CN102241617A (en) * | 2011-05-25 | 2011-11-16 | 兰州景瑞生物科技有限公司 | Synthesis method of 1-tert-butoxycarbonyl-3-pyrrolidone |
Non-Patent Citations (1)
| Title |
|---|
| JI HOON LEE等: "Synthesis and Biological Activity of Novel 1_-Methylcarbapenems with Oxyiminopyrrolidinyl amide Moiety", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 13, 31 December 2003 (2003-12-31), pages 4400 - 1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103992258B (en) | 2017-01-04 |
| ITVI20130032A1 (en) | 2014-08-15 |
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