CN108069889A - A kind of synthetic method of azetidine -3- formic acid - Google Patents
A kind of synthetic method of azetidine -3- formic acid Download PDFInfo
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- CN108069889A CN108069889A CN201611010633.6A CN201611010633A CN108069889A CN 108069889 A CN108069889 A CN 108069889A CN 201611010633 A CN201611010633 A CN 201611010633A CN 108069889 A CN108069889 A CN 108069889A
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- azetidine
- formic acid
- synthetic method
- intermediate product
- acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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Abstract
The present invention relates to organic synthesis fields; more particularly to a kind of synthetic method of 3 formic acid of azetidine; it is with 2; 2 dihydroxymethyl malonic acid, 1,3 diethylester, after mesyl chloride is protected; it is reacted with benzhydrylamine; using decarboxylation, benzhydryl protection is taken off, obtains 3 formic acid of finished product azetidine.This synthetic method is with 2,2 dihydroxymethyl malonic acid 1,3 diethylester for raw material, and cheap and easily-available, entire synthetic line and does not use extremely toxic substance Cymag, have great industrial production prospect compared to the cost reduction more than 30% of original synthetic line.
Description
Technical field
The present invention relates to organic synthesis fields, and in particular to a kind of synthetic method of azetidine -3- formic acid.
Background technology
Azetidine -3- formic acid can be used for synthesis panimmunity suppression as a kind of important intermediate, downstream product
Preparation is used especially for treating or preventing the disease or illness mediated by lymphocytes interactions, such as China Patent No.
CN101679235A discloses a kind of azetidine derivatives and their purposes as prostaglandin E 2 antagonists.
At present, the following US20100249399 of the synthetic route of azetidine -3- formic acid：
It needs, using substantial amounts of extremely toxic substance Cymag, to cause operator the harmful effects such as poisoning in building-up process,
And the waste water generated has the potential risk of pollution environment.In addition the initial feed benzhydryl -3- hydroxyl nitrogen that the route uses
The azetidine market price is more expensive, and downstream product is caused to hold at high price.
The content of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of synthetic method of azetidine -3- formic acid, life is reduced
Cost is produced, and without using Cymag.
In order to achieve the above object, the present invention is achieved by the following technical programs：
A kind of synthetic method of azetidine -3- formic acid, synthetic route are as follows：
Comprise the following steps：
(1) reacted with 2,2- dihydroxymethyl malonic acid -1,3- diethylesters (A) for raw material and mesyl chloride, generate intermediate production
Object (B)；
(2) intermediate product (B) and benzhydrylamine are reacted, generation intermediate product (C)；
(3) intermediate product (C) is obtained into intermediate product (D) after decarboxylic reaction；
(4) by intermediate product (D) under catalyst action, de- benzhydryl protection is reacted with hydrogen, pH value is adjusted with alkali,
Obtain target product (E) azetidine -3- formic acid.
Preferably, step (1) reaction temperature is -15~10 DEG C, and the reaction time is 12~36h.
Preferably, step (2) reaction temperature is 100~120 DEG C, and the reaction time is 12~36h.
Preferably, step (3) reaction temperature is 70~100 DEG C, and the reaction time is 12~36h.
Preferably, step (4) reaction temperature is 10~60 DEG C, and the reaction time is 3~10h.
Preferably, catalyst is hydroxide palladium carbon in the step (4).
Preferably, pH value is adjusted with alkali in the step (4), the alkali is in potassium carbonate, sodium carbonate, sodium acid carbonate
One kind adjusts pH to 6-7.
Compared with prior art, the present invention it has the following advantages：Synthetic method of the present invention is not used with extremely toxic substance cyaniding
Sodium, life injury and environmental pollution caused by avoiding it, and with 2,2- dihydroxymethyl malonic acid -1,3- diethylester for raw material, just
Preferably be easy to get, entire synthetic line compared to original synthetic line cost reduction more than 30%, so as to being conducive to downstream raw material
The cost of medicine is adjusted, and has great industrial production prospect.
Specific embodiment
To make the purpose, technical scheme and advantage of the embodiment of the present invention clearer, below in conjunction with the embodiment of the present invention,
Technical solution in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is the present invention one
Divide embodiment, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art are not making
All other embodiments obtained under the premise of creative work, belong to the scope of protection of the invention.
Embodiment 1：The synthesis of intermediate product (B)
110g 2,2- dihydroxymethyl malonic acid -1,3- diethylesters, 1.5L dichloromethanes are added in clean 3L there-necked flasks
Alkane, 150g triethylamines, mechanical agitation 10min are cooled to 0 DEG C, and 115g mesyl chlorides are slowly added dropwise thereto, and 0-5 DEG C of temperature control has
A large amount of solid salt generations, drip off room temperature reaction overnight, and next day adds in 1L water washings, and organic layer is dried in layering, is concentrated and dried,
Obtain intermediate product (B) 180g, yield 95.7%, without purification.
Embodiment 2：The synthesis of intermediate product (C)
1.5L toluene is added in clean 3L there-necked flasks, adds 180g intermediate products (B) made from embodiment 1, after
It is continuous to add in 87g benzhydrylamines and 150g triethylamines, 110 DEG C of back flow reactions are heated to, has solid generation, is refluxed overnight, are stopped anti-
Should, desalination is filtered, washes organic layer, dry concentration obtains intermediate product (C) 120g, without purification.
Embodiment 3：The synthesis of intermediate product (D)
120g intermediate products (C) made from embodiment 2 are added in the hydrochloric acid of 1L 6N, are heated to 80 degree, insulation reaction
Overnight, there is gas generation, pay attention to preventing slug, next day, evaporating water obtains brown oil object, adds in acetone 300mL heating
Recrystallization, obtains intermediate product (D) 78g, appearance is faint yellow solid.1H-NMR Spectrum (CDCl3), δ (ppm)：
3.00-3.90 (5H, m), 4.95 (1H, s), 7.25-7.28 (2H, m), 7.33 (4H, m), 7.53 (4H, m).
Embodiment 4：The synthesis of target product (E)
Intermediate product (D) 78g made from embodiment 3 is added in the mixture of 500mL methanol and 100mL water, is added in
Hydroxide palladium carbon (10%) 7g, is passed through hydrogen thereto, and the pressure of reaction vessel is made to reach 3 megapascal, reacts 6h, and the reaction was complete,
Filtration of catalyst adds in 500mL water, boils off methanol, diphenyl-methane is extracted with ethyl acetate twice, and water layer concentration is dry, obtains
To solid rejoin 300mL water, with potash solid adjust pH=6.7 have turbid phenomenon, be extracted with ethyl acetate, it is organic
Layer is dry, and concentration is dry can to obtain solid product azetidine -3- formic acid 25g, yield 85%.
To sum up, the embodiment of the present invention has the advantages that：Entire synthetic line is raw materials used cheap and easily-available, to compared with
The cost reduction of original synthetic line more than 30%.
It should be noted that herein, relational terms such as first and second and the like are used merely to a reality
Body or operation are distinguished with another entity or operation, are deposited without necessarily requiring or implying between these entities or operation
In any this actual relation or order.Moreover, term " comprising ", "comprising" or its any other variant are intended to
Non-exclusive inclusion, so that process, method, article or equipment including a series of elements not only will including those
Element, but also including other elements that are not explicitly listed or further include as this process, method, article or equipment
Intrinsic element.In the absence of more restrictions, the element limited by sentence "including a ...", it is not excluded that
Also there are other identical elements in process, method, article or equipment including the element.
The above embodiments are merely illustrative of the technical solutions of the present invention, rather than its limitations；Although with reference to the foregoing embodiments
The present invention is described in detail, it will be understood by those of ordinary skill in the art that：It still can be to foregoing each implementation
Technical solution recorded in example modifies or carries out equivalent substitution to which part technical characteristic；And these modification or
It replaces, the essence of appropriate technical solution is not made to depart from the spirit and scope of various embodiments of the present invention technical solution.
Claims (7)
1. a kind of synthetic method of azetidine -3- formic acid, which is characterized in that synthetic route is as follows：
Comprise the following steps：
(1) reacted with 2,2- dihydroxymethyl malonic acid -1,3- diethylesters (A) for raw material and mesyl chloride, generate intermediate product
(B)；
(2) intermediate product (B) and benzhydrylamine are reacted, generation intermediate product (C)；
(3) intermediate product (C) is obtained into intermediate product (D) under hydrochloric acid effect after decarboxylic reaction；
(4) by intermediate product (D) under catalyst action, de- benzhydryl protection is reacted with hydrogen, pH value is adjusted with alkali, obtains mesh
Mark product (E) azetidine -3- formic acid.
2. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that step (1) reaction
Temperature is -15~10 DEG C, and the reaction time is 12~36h.
3. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that step (2) reaction
Temperature is 100~120 DEG C, and the reaction time is 12~36h.
4. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that step (3) reaction
Temperature is 70~100 DEG C, and the reaction time is 12~36h.
5. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that step (4) reaction
Temperature is 10~60 DEG C, and the reaction time is 3~10h.
6. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that urged in the step (4)
Agent is hydroxide palladium carbon.
7. the synthetic method of azetidine -3- formic acid as described in claim 1, which is characterized in that used in the step (4)
Alkali adjusts pH value, and the one kind of the alkali in potassium carbonate, sodium carbonate, sodium acid carbonate adjusts pH to 6-7.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4555260A (en) * | 1979-11-16 | 1985-11-26 | Shell Oil Company | Method for sterilizing male parts of plants |
| US6316638B1 (en) * | 1998-05-26 | 2001-11-13 | Warner-Lambert Company | Conformationally constrained amino acid compounds having affinity for the alpha2delta subunit of a calcium channel |
| WO2002005183A1 (en) * | 2000-07-06 | 2002-01-17 | Bill Good Marketing, Inc. | Systems and methods for contact management and campaign management |
| CN101600711A (en) * | 2006-12-22 | 2009-12-09 | 工业研究有限公司 | The azetidine analogues of nucleosidase and phosphorglase inhibitor |
| CN101646650A (en) * | 2007-03-30 | 2010-02-10 | 塔加西普特公司 | Sub-type selective azabicycloalkane derivatives |
| CN104292142A (en) * | 2013-07-17 | 2015-01-21 | 天津大地康和医药技术有限公司 | Aryl removing method of N-aryl heterocyclic butane |
| CN105237455A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Preparation method of 3-substituted azetidine |
-
2016
- 2016-11-10 CN CN201611010633.6A patent/CN108069889B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4555260A (en) * | 1979-11-16 | 1985-11-26 | Shell Oil Company | Method for sterilizing male parts of plants |
| US6316638B1 (en) * | 1998-05-26 | 2001-11-13 | Warner-Lambert Company | Conformationally constrained amino acid compounds having affinity for the alpha2delta subunit of a calcium channel |
| WO2002005183A1 (en) * | 2000-07-06 | 2002-01-17 | Bill Good Marketing, Inc. | Systems and methods for contact management and campaign management |
| CN101600711A (en) * | 2006-12-22 | 2009-12-09 | 工业研究有限公司 | The azetidine analogues of nucleosidase and phosphorglase inhibitor |
| CN101646650A (en) * | 2007-03-30 | 2010-02-10 | 塔加西普特公司 | Sub-type selective azabicycloalkane derivatives |
| CN104292142A (en) * | 2013-07-17 | 2015-01-21 | 天津大地康和医药技术有限公司 | Aryl removing method of N-aryl heterocyclic butane |
| CN105237455A (en) * | 2015-10-14 | 2016-01-13 | 湖南华腾制药有限公司 | Preparation method of 3-substituted azetidine |
Non-Patent Citations (2)
| Title |
|---|
| ROSS A. MILLER ET AL.: "A practical process for the preparation of azetidine-3-carboxylic acid", 《SYNTHETIC COMMUNICATIONS》 * |
| 道格拉斯.C.奈克等: "《有机化学》", 30 November 1985, 化学工业出版社 * |
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