CN103992258B - The preparation method of N-Boc-ketopyrrolidine - Google Patents
The preparation method of N-Boc-ketopyrrolidine Download PDFInfo
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- CN103992258B CN103992258B CN201410051948.XA CN201410051948A CN103992258B CN 103992258 B CN103992258 B CN 103992258B CN 201410051948 A CN201410051948 A CN 201410051948A CN 103992258 B CN103992258 B CN 103992258B
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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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- Pyrrole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
The present invention relates to the preparation method of N Boc ketopyrrolidine.In particular it relates to utilize decarboxylic reaction to prepare the effective ways of compound 3 oxo-pyrrolidine 1 carboxylate of formula (I): the productivity of the existence end-product of the most specific organic solvent and purity aspect play vital effect.
Description
Technical field
It is an object of the invention to a kind of side for preparing 3-oxo-pyrrolidine-1-carboxylate
Method, described 3-oxo-pyrrolidine-1-carboxylate is the weight for preparing active pharmaceutical ingredient
Want construction unit.
Background technology
Document discloses the formula for preparing entitled 3-oxo-pyrrolidine-1-carboxylate
(I) the multiple method of compound:
Described compound is also referred to as N-Boc-3-ketopyrrolidine, and this compound is for preparing active drug
The important intermediate of thing composition or construction unit.
Jihoon Lee etc. at Bioorganic & Medicinal Chemistry Letters, 13
(2003), 4399-4403 describes a kind of appreciable known method, be wherein ethyl by R
The compound of formula (II):
At DMSO/H2O(10:1) at 120-130 DEG C decarboxylation 4 hours, to provide unsegregated
Molar yield is the compound of the formula (I) of 70%.Product is not separated, and
Its chemical purity undeclared.
Another example of identical decarboxylic reaction is disclosed in the Chinese patent application announced
In the paragraph [0033] of CN102241617A, wherein at DMSO: at 120-130 in water (10:1)
At DEG C, heating is reacted for 4 hours, processes product with AcOEt: petroleum ether (1:10), carries
The product having supplied molar yield to be 70%.But, with small-scale weight in our laboratory
During this program multiple, the molar yield only obtaining 13.9% (sees first reality in table 1 below
Test).
Disclosure above shows, this reaction is generally at the mixture of water or water with DMSO
In carry out.
In fact it must be considered that compound 3-oxo-pyrrolidine-1-carboxylate has by uncle
The amine functional group that butoxy carbonyl (Boc) is protected, it is commonly known that tertbutyloxycarbonyl is at acid condition
The group (it is easily cut open in aqueous hydrochloric acid solution) of lower instability, therefore can not be in acid
Decarboxylic reaction is carried out under property environment, otherwise, replaced by benzyl, ethyl or methyl at the tert-butyl group
Compound on can accomplish this point, as RufineAkue-Gedu is at Synthesis, 2007,
No.21, p.3319-3322 described in.
Therefore, the major defect of art methods is summarized as follows: the molar yield of decarboxylic reaction,
Molar yield after especially separating is low, and product purity is low, it is thus achieved that as the product 3-oxygen of solid
(do not using chromatogram purification for pyrrolidine-1-carboxylate or reducing the situation of molar yield
Under) extremely difficult, such product obtains usually used as grease.Owing to product is not as solid
Body, therefore obtain, so according to known methods not as the form being adapted to pass through crystallization purifying
The chemical purity of the product of the formula (I) of preparation is typically low, therefore cannot be used for advising in industry
The synthesis of active pharmaceutical ingredient is carried out on mould.
Summary of the invention
Therefore, the problem to be solved in the present invention is to provide the 3-oxo pyrroles for preparing formula (I)
The method of the improvement of alkane-1-carboxylate.
This problem passes through the preparation 3-oxo-pyrrolidine-1-formic acid uncle described in claims
The method of butyl ester solves, and the content that these claims limit is the ingredient of the disclosure.
Other feature and advantage of the method for the present invention come from following retouches preferred implementation
Stating, described preferred implementation is given by way of non-limiting example.
Accompanying drawing explanation
Fig. 1 shows the synthesis 3-oxo-pyrrolidine tertiary fourth of-1-formic acid according to a preferred aspect of the present invention
The scheme of base ester.
Detailed description of the invention
The present invention relates to the use of the decarboxylation of compound of formula (II) to prepare the compound of formula (I)
The method of 3-oxo-pyrrolidine-1-carboxylate:
Wherein R is the C1-C5 alkyl of straight or branched.
It has been found, surprisingly, that at the bar that there is hydrocarbon organic solvent or aromatic organic solvent
Carrying out decarboxylation under part, molar yield or the purity of product significantly improve.In reactant mixture, hydrocarbon has
The impurity that formed during reaction is decreased on the existed facts of machine solvent or aromatic organic solvent
Type and amount.This allows improve molar yield or separate the formula (I) as solid surprisingly
Product.It is separated to unexpectedly as solid not as the product of the formula (I) of grease
Thing has the highest advantage, because the purity of product can be significantly improved.Table below shows
The purity of the raising that the solid product prepared according to the method for the present invention is reached (is higher than
96%).
In art methods, product is prepared to grease is the shortcoming that we need to solve, because of
For only by product is prepared as solid could be in the situation not using chromatographic column or sublimating technologe
Lower its purity of raising.It is true that in order to perform following synthesis step, the purity higher than 95%
Level is required.Additionally, product is prepared as solid rather than grease has much better
The advantage being easy to use.
Additionally, the existence of those solvents allows also to obtain transparent reaction much at the end of reaction
Mixture, this is probably and is caused by the minimizing of degradation reaction, and the most final separation product is also
More transparent than the product of preparation under conditions of there is not hydrocarbon organic solvent or aromatic organic solvent
Many.
Finally, the existence of such solvent allows to be formed the impurity of much less, hence allows to more
High molar yield prepares product, and the molar yield after i.e. separating is higher than 40%, and is usually
About 60%.
R substituent is the C1-C5 alkyl substituent of straight or branched, therefore can be selected from methyl,
Ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl,
2-methyl butyl, 3-methyl butyl, 2-ethyl propyl, sec-butyl, 2,2-dimethyl propyl and new
Amyl group.
According to a preferred aspect of the present invention, preferred alkyl is ethyl, because preparation 4-oxo pyrrole
Coughing up alkane-1,3-dioctyl phthalate 1-tertiary butyl ester 3-ethyl ester is more prone to and more economical, and because this
Plant intermediate and provide easier decarboxylic reaction, lesser amount of impurity is i.e. provided.
The decarboxylic reaction of the present invention can be organic at each hydrocarbon organic solvent or each aromatic series
Solvent is carried out.
Hydrocarbon refers to the organic compound containing only carbon and hydrogen atom.
The mixture of such organic solvent can also be used, because they are in the reactive mixture
Existence allow to obtain identical with when only using a kind of hydrocarbon organic solvent or aromatic organic solvent
Result.
The example of such hydrocarbon organic solvent can be alkane, cycloalkane, such as heptane, different pungent
Alkane.
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 be preferably as it
Allow for higher reaction temperature, thus reduce the response time.
Obviously, this reaction can also be carried out existing under conditions of other added solvent, described its
His added solvent is not hydrocarbon organic solvent or aromatic organic solvent.
The preferred added solvent used is water and dimethyl sulfoxide or its mixture.
Another preferred aspect of the present invention is to be optionally present one or more in the reactive mixture
Antioxidant.As shown in the table below, these additives have the effect improving molar yield.
Many typical alkyl or the substituted phenolic antioxidant of alkoxyl can be added to reactant mixture,
Such as BHT, 2,6-DTBP, particularly preferably BHT.
For performing this decarboxylic reaction, the antioxidant of phosphine type is also preferred.
Permitted eurypalynous phosphine to can be used for performing the present invention, such as Ph3P、tBu3P or (MeOPh)3P,
Preferably triphenylphosphine (Ph3P).
According to the preferred embodiment of the present invention, can there is BHT and triphenyl in decarboxylic reaction
Carry out under conditions of phosphine.
The amount of the antioxidant added can be 0.01% to 1% weight of the compound of formula (II)
/ weight.Preferably, the anti-oxidant additives of about 0.1% is used.
Table below provides Comparative Example, its allow to recognize by inventive feature,
First it is the powerful effect of solvent offer, the additional effect provided by the existence of antioxidant is provided
Really.
Table 1
As it has been mentioned, reaction can there is also other solvents such as water and/or DMSO
Under conditions of carry out.Water: the preferred volume ratio of toluene is 1:4.
The existence of a certain amount of water is also useful to reaction.
The reaction of the present invention generally uses compound 1 to 20 molecular equivalency relative to formula (II)
Water carry out.The water of 3 to 5 molecular equivalency is preferably used, because this brings more preferable result.
Decarboxylic reaction can be carried out, preferably within the temperature range of 80 DEG C to 130 DEG C
The scope of 110-115 DEG C.
Toluene is the preferred solvent for the inventive method, because embodiment 3 shows, with other
Solvent phase ratio, toluene provides more preferable result.
The method of the present invention can use any combination of above-mentioned parameter or condition to carry out.
Experimental section
Can according to Jihoon Lee etc. at Bioorganic & Medicinal Chemistry Letters,
13 (2003), initial product 4-oxo-pyrrolidine-1,3-diformazan is prepared in the teaching in 4399-4403
Acid 1-tertiary butyl ester 3-ethyl ester (the wherein compound of the formula (II) of R=Et).
Embodiment 1
Load to the 5L reactor being equipped with mechanical agitator and thermometer in a nitrogen atmosphere
1.33Kg4-oxo-pyrrolidine-1,3-dioctyl phthalate 1-tertiary butyl ester 3-ethyl ester (the wherein formula of R=Et
(II) compound), 1.3g PPh3, 1.3g2,6-DI-tert-butylphenol compounds (2,6-DTBP),
And this mixture is dissolved in the mixture of 2 liters of toluene and 1.33 liters of DMSO.By obtain
Mixture is heated to 115 DEG C (internal temperatures), is then added dropwise over 400mL in 5-6 hour
(using TLC monitoring reaction to convert, eluant is AcOEt: normal hexane to water until reacted
(1:3)), keep internal temperature to be 113-120 DEG C simultaneously.Reactant mixture is cooled down,
And dilute with 500mL cold water.Water layer 2x500mL toluene is extracted.By merge
Organic layer 800mL0.5%Na2CO3Solution washs, and then washs with 2x800mL saline,
Finally wash with 600mL water.Organic layer is transferred in 5 liters of reactors, and add 15g
Anhydrous magnesium sulfate and 30g activated carbon.The mixture obtained is stirred 1 hour, then filters.
Concentrate the filtrate to be dried (toluene should be removed as much as possible), it is thus achieved that reddish liquid.
It is slowly added to 700mL hexamethylene, to obtain product precipitation under 0-5 DEG C and stirring.By this slurry
Liquid filters, and is vacuum dried in 25-29 DEG C of baking oven by product.Owing to product easily distils, temperature
Degree should be maintained below 30 DEG C.This experiment provides 593g white solid, and it has
Molar yield after the m.p.(of 35.4-36.9 DEG C separates is 62%).Product have 98% pure
Degree (HPLC A/A%).
Embodiment 2
In 250mL4 neck RBF, by N-Boc ketopyrrolidine Ethyl formate (20.0 at 20 DEG C
G) (wherein R is the compound of formula (II) of Et) is dissolved in toluene (30ml) and diformazan
In the mixture of sulfoxide (20ml), and add 20mg3,5-di-t-butyl-4-hydroxy-methylbenzene
(BHT).The mixture obtained is heated to 115 DEG C (internal temperatures), and in 5h by
It is added dropwise to water (4.2ml, 3.0 equivalents), keeps internal temperature to be 110-115 DEG C.Add at water
Terminate to obtain desired conversion ratio in latter 1 hour.
Reactant mixture is cooled to 20 DEG C and dilutes with water (10ml).Layer is separated, will
Water layer toluene (20ml) extracts again.The organic layer 20ml5%w/w NaCl that will merge
Solution washing, then uses 10%w/w NaCl(40ml) washing, finally wash with 20ml
Wash.
The toluene solution activated carbon obtained is processed.After filtration, concentrate the filtrate to
It is dried, obtains orange (14g).
At-5/-10 DEG C, add hexamethylene (12ml), the suspension obtained is filtered, uses 3.5ml
Hexamethylene washes twice.Solid is vacuum dried in 25 DEG C of baking ovens, obtains 10.8g white solid
Body.Molar yield after separation is 75%.
Above embodiment shows that, during the decarboxylic reaction of the compound of formula (II), specific have
The existence of machine solvent such as aromatic compound or hydrocarbon is how in terms of the productivity and purity of end-product
Play vital effect.
Embodiment 3
Under conditions of identical, repeat the experiment of embodiment 2, but be also added with PPh30.1%
Wt/wt, and by toluene respectively with methyl phenyl ethers anisole, chlorobenzene (being abbreviated as Cl-Bz) and hexahydrotoluene
(being abbreviated as Me-Cy) replaces.
Table below outlines the result obtained:
Table 2
It is all crystalline solid according to all products of this experiment preparation.Additionally, the product thus prepared
Thing demonstrates the most high-caliber chemical purity.
Claims (10)
1. utilize the decarboxylation of compound of formula (II) to the method preparing the compound of formula (I):
Wherein R is the C1-C5 alkyl of straight or branched, and described method is characterised by, described decarboxylation
Carry out under conditions of there is DMSO, water and cycloalkane or aromatic organic solvent, Qi Zhongsuo
Stating cycloalkane is hexahydrotoluene, and described aromatic organic solvent is toluene, dimethylbenzene, chlorobenzene
Or methyl phenyl ethers anisole.
2. the process of claim 1 wherein that R is ethyl.
3. the method for claim 1 or 2, 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 or 2, wherein said decarboxylation there is also one or more resist
Carry out under conditions of oxidant.
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 5, wherein said antioxidant is triphenylphosphine.
9. the method for claim 1 or 2, there is BHT and triphenyl in wherein said decarboxylation
Carry out under conditions of phosphine.
10. the method for claim 1 or 2, wherein uses the water of 3 to 5 molecular equivalency.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITVI2013A000032 | 2013-02-14 | ||
| IT000032A ITVI20130032A1 (en) | 2013-02-14 | 2013-02-14 | PROCEDURE FOR THE PREPARATION OF N-BOC-PYRROLIDINONE |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103992258A CN103992258A (en) | 2014-08-20 |
| CN103992258B true CN103992258B (en) | 2017-01-04 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201410051948.XA Active CN103992258B (en) | 2013-02-14 | 2014-02-14 | The preparation method of N-Boc-ketopyrrolidine |
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| 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 |
|---|
| Synthesis and Biological Activity of Novel 1_-Methylcarbapenems with Oxyiminopyrrolidinyl amide Moiety;Ji Hoon Lee等;《Bioorganic & Medicinal Chemistry Letters》;20031231;第13卷;第4400页流程图1第iv步 * |
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| Publication number | Publication date |
|---|---|
| ITVI20130032A1 (en) | 2014-08-15 |
| CN103992258A (en) | 2014-08-20 |
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